[go: up one dir, main page]

WO2019163942A1 - Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle - Google Patents

Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle Download PDF

Info

Publication number
WO2019163942A1
WO2019163942A1 PCT/JP2019/006774 JP2019006774W WO2019163942A1 WO 2019163942 A1 WO2019163942 A1 WO 2019163942A1 JP 2019006774 W JP2019006774 W JP 2019006774W WO 2019163942 A1 WO2019163942 A1 WO 2019163942A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrocarbon group
polymer
repeating unit
general formula
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2019/006774
Other languages
English (en)
Japanese (ja)
Inventor
片岡　一則
サビーナ カダール
オラシオ カブラル
宏昭 喜納
学瑩 劉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kawasaki Institute of Industrial Promotion
Original Assignee
Kawasaki Institute of Industrial Promotion
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 Kawasaki Institute of Industrial Promotion filed Critical Kawasaki Institute of Industrial Promotion
Publication of WO2019163942A1 publication Critical patent/WO2019163942A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • 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
    • C08G69/48—Polymers modified by chemical after-treatment
    • 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
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers

Definitions

  • the present invention relates to a polymer, a method for producing the polymer, a drug complex, and a micelle.
  • a polymer containing an aldehyde group or a ketone group (hereinafter sometimes referred to as “aldehyde / ketone-containing polymer”) is a physiologically active molecule having a functional group such as an amino group, an imino group, or a hydrazide group. Can be used to bond by formation.
  • the aldehyde group-containing polymer can also be used for core crosslinking of cationic polypeptides. For this reason, aldehyde / ketone-containing polymers have attracted attention, particularly in the pharmaceutical field, as carriers for drug delivery.
  • Non-Patent Documents 1 to 4 As a method of introducing an aldehyde into a polymer, a method of obtaining an aldehyde-introduced polymer by RAFT polymerization of 4-vinylbenzaldehyde is known (see, for example, Non-Patent Documents 1 to 4).
  • Non-Patent Documents 1 to 4 can introduce only aromatic aldehydes, so that aliphatic aldehydes, aromatic aldehydes, aliphatic ketones and aromatic ketones cannot be selectively introduced. It was.
  • the methods of Non-Patent Documents 1 to 4 have only a homopolymer because of RAFT polymerization, and there is a problem that the reaction process becomes complicated when other functional groups are introduced.
  • acetal group-introduced methacrylate is used.
  • it since it is bonded to the base polymer via an ester bond, it is dissociated at physiological pH (pH 7.4), which is inappropriate for drug delivery.
  • the present invention has been made in view of the above circumstances, and an object thereof is to provide a novel polymer, a method for producing the same, and a drug complex containing the polymer.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R 2 represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • Ra 11 and Ra 12 each independently represent a methyl group or an ethyl group, or Ra 11 and Ra 12 are bonded to each other to represent an ethylene group or a propylene group.
  • Ra 13 and Ra 14 each independently represent a methyl group or an ethyl group, or Ra 13 and Ra 14 are bonded to each other to represent an ethylene group or a propylene group.
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • the repeating unit (I′-1) represented by the following general formula (I′-1), the following general formula (I′-1) -2) By reacting with the compound (1a-2) represented by the formula (1a-2), the repeating unit (I′-1) represented by the following general formula (I′-1), the following general formula (I′-1) -2) to obtain a polymer (P2) having the repeating unit (I'-2) represented by formula (II) and the repeating unit (II ');
  • the polymer (P2) is subjected to at least one treatment selected from the group consisting of hydrolysis under alkaline conditions, transesterification, aminolysis, and hydrolysis under alkaline conditions and amide coupling.
  • the polymer (P3) is hydrolyzed under neutral or weakly acidic conditions, and the repeating unit (I-1) represented by the following general formula (I-1) or the following general formula (I-2)
  • a process for producing a polymer comprising
  • R 2 represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • Ra 11 and Ra 12 each independently represent a methyl group or an ethyl group, or Ra 11 and Ra 12 are bonded to each other to represent an ethylene group or a propylene group.
  • Ra 13 and Ra 14 each independently represent a methyl group or an ethyl group, or Ra 13 and Ra 14 are bonded to each other to represent an ethylene group or a propylene group.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • a drug complex comprising the polymer according to (1) and at least one drug bonded to the polymer.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • BM represents an active molecule.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • a micelle containing the drug complex of (5) A pharmaceutical composition comprising the drug complex according to (4) or (5) or the micelle according to (6).
  • the pharmaceutical composition according to (7) which is a pharmaceutical composition for treating or preventing cancer.
  • a novel polymer in which an aliphatic aldehyde and / or an aliphatic ketone and an aromatic aldehyde and / or an aromatic ketone are selectively introduced, a production method thereof, and a drug is bonded to the polymer.
  • Drug conjugates can be provided.
  • FIG. 1 is a synthesis scheme of an aromatic aldehyde group-containing polymer and an aliphatic aldehyde group-containing polymer according to an embodiment of the present invention.
  • FIG. 2 is a 1 H-NMR spectrum of a polymer according to one embodiment of the present invention.
  • FIG. 3 is a 1 H-NMR spectrum of a polymer according to one embodiment of the present invention.
  • FIG. 4 is a 1 H-NMR spectrum of a polymer according to one embodiment of the present invention.
  • FIG. 5 is a 1 H-NMR spectrum of a polymer according to one embodiment of the present invention.
  • FIG. 6 is an analysis result of the micelle size and polydispersion index (PDI) of the drug conjugate according to one embodiment of the present invention.
  • FIG. PDI polydispersion index
  • FIG. 7 shows the analysis results of the micelle size and the degree of dispersion (PDI) of the drug conjugate according to one embodiment of the present invention.
  • FIG. 8 is an analysis result of the micelle size and the degree of dispersion (PDI) of the drug conjugate according to one embodiment of the present invention.
  • FIG. 9 shows the analysis results of the micelle size and the degree of dispersion (PDI) of the drug conjugate according to one embodiment of the present invention.
  • FIG. 10 is a graph showing a pH sensitive drug release profile of a drug conjugate according to a reference example.
  • FIG. 11 is a graph showing a pH-sensitive drug release profile of a drug complex according to a reference example.
  • FIG. 12 is a graph showing a pH sensitive drug release profile of a drug conjugate according to one embodiment of the present invention.
  • FIG. 13 is a graph showing changes in body weight of a mouse over time when a drug conjugate according to one embodiment of the present invention is administered to the mouse.
  • FIG. 14 shows the results of an in vivo antitumor test of a drug conjugate according to one embodiment of the present invention.
  • FIG. 15 shows the results of an in vivo antitumor test of a drug conjugate according to one embodiment of the present invention.
  • FIG. 16 is a graph showing the time course of survival rate when a drug conjugate according to one embodiment of the present invention is administered to mice.
  • FIG. 17 is an MRI image of the mouse brain when the drug conjugate according to one embodiment of the present invention is administered to the mouse.
  • FIG. 18 is an MRI image of the mouse brain when the drug conjugate according to one embodiment of the present invention is administered to the mouse.
  • the polymer of the present embodiment includes a repeating unit (I-1) represented by the following general formula (I-1), a repeating unit (I-2) represented by the following general formula (I-2), and the following general formula: It has a repeating unit (II) represented by (II).
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • the divalent aromatic hydrocarbon group for L 11 include a phenylene group and a benzylene group.
  • the divalent aromatic hydrocarbon group for L 11 may have a substituent. Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a nitro group, and a halide.
  • L 11 a benzylene group is preferable.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • the divalent aliphatic hydrocarbon group for L 12 include an ethylene group, a propylene group, a butylene group, and a pentylene group.
  • the divalent aliphatic hydrocarbon group for L may have a substituent.
  • the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and a halide.
  • a methylene group, an ethylene group or a propylene group is preferable, and a methylene group or an ethylene group is more preferable.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • examples of the aliphatic hydrocarbon group for R 11 and R 12 include an ethyl group, a propyl group, a butyl group, and a pentyl group.
  • the aliphatic hydrocarbon group for R 11 and R 12 may have a substituent.
  • substituents examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a tert-pentyl group, a cyclohexyl group, and a trihalomethyl group.
  • Examples of the aromatic hydrocarbon group of R 11 and R 12 include phenyl group, benzyl group, pyridyl group, naphthyl group, hydroxyphenyl group, methoxyphenyl group, ethoxyphenyl group, xylyl group, methylphenyl group, nitrophenyl group, chlorophenyl Group, fluorophenyl group, iodophenyl group, bromophenyl group and the like.
  • R 11 preferably a hydrogen atom or an aliphatic hydrocarbon group, more preferably a hydrogen atom or a methyl group, a hydrogen atom more preferred.
  • R 12 is preferably a hydrogen atom or an aliphatic hydrocarbon group, more preferably an aliphatic hydrocarbon group, and still more preferably a methyl group.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • the aliphatic hydrocarbon group for R x include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, cyclohexyl group, and trifluoro group.
  • a methyl group etc. are mentioned.
  • the aromatic hydrocarbon group for R x includes phenyl, benzyl, pyridyl, naphthyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, xylyl, methylphenyl, nitrophenyl, chlorophenyl, fluoro, Examples include an orophenyl group, an iodophenyl group, and a bromophenyl group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • Examples of the aliphatic hydrocarbon group represented by R x1 and R x2 include methyl group, ethyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, cyclohexyl group, and trihalomethyl. Group.
  • Examples of the aromatic hydrocarbon group represented by R x1 and R x2 include phenyl group, benzyl group, pyridyl group, naphthyl group, hydroxyphenyl group, methoxyphenyl group, ethoxyphenyl group, xylyl group, methylphenyl group, nitrophenyl group, chlorophenyl Group, fluorophenyl group, iodophenyl group, bromophenyl group and the like.
  • X is preferably OR x and more preferably OH (hydroxy group).
  • the polymer of the present embodiment has a repeating unit other than the repeating units (I-1), (I-2) and (II) (hereinafter sometimes referred to as “repeating unit (III)”). May be.
  • the repeating unit (III) is preferably a hydrophilic repeating unit.
  • a repeating unit derived from polyethylene glycol a repeating unit derived from poly (ethylethylene phosphate), a repeating unit derived from polyvinyl alcohol, polyvinyl Examples thereof include a repeating unit derived from pyrrolidone, a repeating unit derived from poly (oxazoline), and a repeating unit derived from poly (N- (2-hydroxypropyl) methacrylamide) (PHPMA).
  • the repeating unit (III) is preferably a repeating unit derived from polyethylene glycol.
  • the content of the repeating units (I-1), (I-2), (II) and (III) is not particularly limited.
  • the total content of the repeating unit (I-1) and the repeating unit (I-2) is preferably 5 to 100 mol%, preferably 10 to 80 mol based on the total (100 mol%) of all repeating units constituting the polymer. % Is more preferable, and 20 to 50 mol% is still more preferable.
  • the content of the repeating unit (II) is preferably from 0 to 80 mol%, more preferably from 10 to 60 mol%, more preferably from 20 to 40 mol%, based on the total (100 mol%) of all repeating units constituting the polymer. Further preferred.
  • the content of the repeating unit (III) is preferably from 0 to 95 mol%, more preferably from 20 to 90 mol%, more preferably from 50 to 80 mol%, based on the total (100 mol%) of all repeating units constituting the polymer. Further preferred.
  • the ratio of the repeating unit (I-1) to the repeating unit (I-2) is within the above range, the toxicity can be alleviated when the drug conjugate is obtained by binding the drug to the polymer according to this embodiment. As well as adequate control of the maximum tolerated dose (MTD).
  • the repeating unit (I-1) and the repeating unit (I-2) By adjusting the ratio with I-2) within the above range, a synergistic therapeutic effect can be obtained.
  • the molecular weight of the polymer of this embodiment is preferably from 2,000 to 1,000,000 D, more preferably from 5,000 to 100,000 D, and even more preferably from 10,000 to 40,000 D.
  • the polymer production method of the present embodiment includes a polymer (P1) having a repeating unit (II ′) represented by the following general formula (II ′):
  • a compound (1a-1) represented by the following general formula (1a-1) is reacted with a compound (1a-2) represented by the following general formula (1a-2) to give the following general formula (I ′ -1) a repeating unit (I′-1), a repeating unit (I′-2) represented by the following general formula (I′-2), and a polymer (P2 And the polymer (P2) is hydrolyzed under neutral or weakly acidic conditions to give a repeating unit (I-1) represented by the following general formula (I-1):
  • R 2 represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • Ra 11 and Ra 12 each independently represent a methyl group or an ethyl group, or Ra 11 and Ra 12 are bonded to each other to represent an ethylene group or a propylene group.
  • Ra 13 and Ra 14 each independently represent a methyl group or an ethyl group, or Ra 13 and Ra 14 are bonded to each other to represent an ethylene group or a propylene group.
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • m, L 11 , L 12 , R 11 , R 12 and R x are the same as m, L 11 , L 12 , R 11 , R 12 and R x in the general formulas (I-1), (I-2) and (II).
  • Ra 11 and Ra 12 each independently represent a methyl group or an ethyl group, or Ra 11 and Ra 12 are bonded to each other to form an ethylene group or propylene. Represents a group.
  • Ra 11 and Ra 12 are bonded to each other to represent an ethylene group or a propylene group
  • the compound (1a-1) becomes a cyclic acetal or a cyclic ketal.
  • Ra 13 and Ra 14 each independently represent a methyl group or an ethyl group, or Ra 13 and Ra 14 are bonded to each other to form an ethylene group or a propylene group. Represents a group.
  • the compound (1a-2) becomes a cyclic acetal or a cyclic ketal.
  • Step (1) of production method (1) is an aminolysis reaction of polymer (P1), compound (1a-1) and compound (1a-2).
  • step (1) the acetal structure or ketal structure of compound (1a-1) and compound (1a-2) is introduced into the side chain of polymer (P1).
  • the amount of compound (1a-1) and compound (1a-2) in step (1) is not particularly limited, but compound (1a-1) is a volume ratio of compound (1a-1) and compound (1a-2).
  • / Compound (1a-2) 10/90 to 90/10 is preferable, 15/85 to 80/20 is more preferable, and 20/80 to 60/40 is still more preferable.
  • the reaction temperature in the step (1) is not particularly limited as long as the acetal structure or ketal structure of the compound (1a-1) and the compound (1a-2) is introduced into the side chain of the polymer (P1). It is 4 ° C to 100 ° C, preferably room temperature to 45 ° C.
  • the reaction time in the step (1) is not particularly limited as long as the acetal structure or ketal structure of the compound (1a-1) and the compound (1a-2) is introduced into the side chain of the polymer (P1). The time can be selected depending on the type and amount of the compound (1a), but is usually 4 hours to 5 days.
  • the reaction polymer (P1) and the compound (1a-1) are reacted, and then the compound (1a-2) can be reacted.
  • the reaction temperature is usually 4 ° C. to 100 ° C., preferably room temperature to 45 ° C.
  • the reaction time is preferably in the range of 4 hours to 5 days in total for all reactions.
  • the polymer (P2) is hydrolyzed under neutral or weakly acidic conditions, and the repeating units (I′-1) and (I′-2) of the polymer (P2) are obtained. ) Or a ketal structure is converted to a ketone.
  • the hydrolysis is not particularly limited as long as the acetal structure of the repeating units (I′-1) and (I′-2) of the polymer (P2) can be converted into an aldehyde or a ketal structure into a ketone.
  • a method of treating with 0.1N hydrochloric acid for 30 to 90 minutes (ii) a method of treating in the presence of acetone and indium (III) trifluoromethanesulfonate (catalyst), and (iii) in water at 30 ° C.
  • a method using a catalytic amount of sodium tetrakis (3,5-trifluoromethylphenyl) borate (iv) a method using 1-5 mol% Er (OTf) 3 in wet nitromethane at room temperature, (v) almost Known methods such as a method using a catalytic amount of cerium (III) triflate in wet nitromethane at room temperature under neutral pH conditions.
  • the polymer production method of the present embodiment includes a polymer (P1) having a repeating unit (II ′) represented by the following general formula (II ′): A compound (1a-1) represented by the following general formula (1a-1) is reacted with a compound (1a-2) represented by the following general formula (1a-2) to give the following general formula (I ′ -1) a repeating unit (I′-1), a repeating unit (I′-2) represented by the following general formula (I′-2), and a polymer (P2 And at least one treatment selected from the group consisting of hydrolysis under alkaline conditions, transesterification, aminolysis, hydrolysis under alkaline conditions, and amide coupling.
  • production method (2) includes a polymer (P1) having a repeating unit (II ′) represented by the following general formula (II ′): A compound (1a-1) represented by the following general formula (1a-1) is reacted with a compound (1a-2) represented by the following general formula (1a-2) to give the following
  • R 2 represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • Ra 11 and Ra 12 each independently represent a methyl group or an ethyl group, or Ra 11 and Ra 12 are bonded to each other to represent an ethylene group or a propylene group.
  • Ra 13 and Ra 14 each independently represent a methyl group or an ethyl group, or Ra 13 and Ra 14 are bonded to each other to represent an ethylene group or a propylene group.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • Step (1) of production method (2) is the same as step (1) of production method (1).
  • step (2a) of production method (2) polymer (P2) is subjected to a predetermined treatment, so that repeating units (I′-1) and (I′-2) are protected with an acetal structure, A desired functional group can be introduced into the side chain of the repeating unit (II ′).
  • Hydrolysis under alkaline conditions is, for example, a method of treating in a mixture of 0.5N NaOH solution and DMSO (volume ratio: 50/50) at room temperature for 30 minutes, or treating with triethylamine in DMSO at room temperature for 1 hour. And a method of treating with diisopropylethylamine in DMSO for 1 hour at room temperature.
  • Aminolysis can introduce an amino functional group by cleaving the ester with, for example, ethylenediamine or diaminopropane. By introducing an amino group, it can be combined with a fluorescent dye. Moreover, it can also attach
  • the resulting carboxylic acid is subjected to transesterification or amide coupling using a known coupling agent.
  • a known coupling agent for hydrolysis and amide coupling under alkaline conditions, for example, after the ester residue is treated by hydrolysis under alkaline conditions, the resulting carboxylic acid is subjected to transesterification or amide coupling using a known coupling agent. be able to.
  • the hydrophilic / hydrophobic balance of the polymer can be made desirable, contributing to self-assembly in polar or non-polar solvents.
  • step (2b) of production method (2) polymer (P3) is hydrolyzed under weakly acidic conditions, and the acetal structures of repeating units (I′-1) and (I′-2) of polymer (P3) are converted. Convert to aldehyde. Hydrolysis conditions are the same as in step (2) of production method (1).
  • the drug complex of the present embodiment contains the polymer and at least one drug bonded to the polymer.
  • the drug is not particularly limited, and a drug having a desired activity can be bound.
  • the drug may be referred to as an “active molecule”.
  • the active molecule refers to a molecule having some physiological or chemical activity.
  • the type of physiological activity or chemical activity possessed by the active molecule is not particularly limited, and the physiological activity possessed by a compound known as an active ingredient of a pharmaceutical or the chemical or physiological possessed by a diagnostic agent administered and used in the body May include activity.
  • Examples of the drug (active molecule) include, but are not limited to, an anticancer agent, a signal transduction inhibitor, an antimetabolite, an analgesic, an anti-inflammatory agent, a contrast agent, and the like.
  • Anticancer agents include, for example, vinca alkaloids such as vinblastine, COX-2 selective non-steroidal anti-inflammatory agents such as OSU-03012, BET bromodomain inhibitors such as (+)-JQ1, and staurosporine analogues such as K252A
  • demethylating agents such as hydralazine, alkylating agents such as bendamustine and chlorambucil, farnesyltransferase inhibitors such as AZD39, non-steroidal anti-inflammatory agents such as flurbiprofen, and the like.
  • a drug complex with the polymer By using a drug complex with the polymer, side effects can be expected to be reduced even with drugs such as anticancer drugs whose dose is limited by side effects. Therefore, such a drug is a preferred example of a drug that is conjugated to the polymer.
  • examples of such drugs include vinca alkaloid compounds such as vinblastine.
  • vinca alkaloids such as vinblastine, staurosporine analogs such as K252A, and BET bromodomain inhibitors such as (+)-JQ1 are preferable as the drug.
  • the drug and the drug are bonded. It can be carried out by reacting a group with an aldehyde group contained in the repeating unit (I) of the polymer.
  • a Schiff base include an amino group, an imino group, and a hydrazide group.
  • the Schiff base forming group may be introduced into the drug. The introduction of the Schiff base forming group can be performed by a known method.
  • vinblastine since vinblastine has no Schiff base-forming group, it can be bound to the polymer by introducing a hydrazide group to form desacetylvinblastine hydrazide (DAVBNH).
  • a Schiff base-forming group can also be introduced by a similar method for staurosporine analogs such as K252A and BET bromodomain inhibitor (+)-JQ1.
  • the drug conjugate of the present embodiment includes a repeating unit (IA-1) represented by the following general formula (IA-1), a repeating unit (IA-2) represented by the following general formula (IA-2), and the following A polymer having the repeating unit (II) represented by the general formula (II) is preferable.
  • L 11 represents a divalent aromatic hydrocarbon group.
  • L 12 represents a divalent aliphatic hydrocarbon group.
  • R 11 and R 12 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • BM represents an active molecule.
  • X represents OR x , SR x or NR x1 R x2 .
  • R x represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • R x1 and R x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
  • m, L 11 , L 12 , R 11 , R 12 , X, R x , R x1 and R x2 are represented by the general formula ( The same as m, L 11 , L 12 , R 11 , R 12 , X, R x , R x1, and R x2 in I-1), (I-2), and (II).
  • BM represents an active molecule. Examples of the active molecule include the compounds exemplified in the drug.
  • various drugs can be carried on a polymer by being carried on a polymer.
  • the amount of aldehyde group or ketone group to be introduced can be controlled, and the amount of drug bonded to the aldehyde group or ketone group can also be controlled. Therefore, the drug dosage can be controlled appropriately.
  • the aldehyde group or ketone group to be introduced can be selected from an aromatic aldehyde group, an aliphatic aldehyde group, an aromatic ketone group, and an aliphatic ketone group.
  • a Schiff base of an aromatic aldehyde group or an aromatic ketone group is more stable than a Schiff base of an aliphatic aldehyde group or an aliphatic ketone group, so that when an aromatic aldehyde group is introduced, the drug is held more stably. Is done. Therefore, the sustained release of the drug can be controlled by selecting the type of aldehyde group or ketone group to be introduced according to the disease state or the type of drug. Furthermore, in the drug conjugate of the present embodiment, since the drug is stably maintained and the toxicity is alleviated while the drug is held in the polymer, side effects can be reduced and the therapeutic effect can be enhanced.
  • the drug complex can be administered to a living body as it is, but may be formulated by appropriately mixing with other components by a known technique. Accordingly, the present invention also provides a pharmaceutical composition comprising the drug conjugate.
  • the dosage form is not particularly limited, and emulsions, emulsions, solutions, gels, capsules, ointments, patches, patches, granules, tablets, contrast agents, etc. It can be.
  • the drug complex may be in the form of a micelle.
  • the micelle containing the drug complex can be prepared by a known method.
  • the drug conjugate is dissolved or suspended in a lipophilic or hydrophilic solvent, and the solution or suspension is dropped into a hydrophilic or lipophilic solvent and stirred to contain the drug conjugate.
  • Micelles can be prepared.
  • the pharmaceutical composition containing the drug conjugate may optionally contain other components of the drug conjugate.
  • components generally used in the pharmaceutical field can be used without particular limitation.
  • the pharmaceutical composition may be obtained by dissolving or suspending the drug complex in a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier those commonly used in the pharmaceutical field can be used without particular limitation. For example, water, physiological saline, phosphate buffer, DMSO, dimethylacetamide, ethanol, glycerol, mineral An oil etc. can be mentioned.
  • compositions include, in addition, solvents, solubilizers, suspending agents, tonicity agents, buffers, pH adjusting agents, excipients, stabilizers, antioxidants, osmotic pressure adjusting agents, Preservatives, colorants, fragrances and the like can be mentioned.
  • the administration route of the pharmaceutical composition is not particularly limited, and can be administered by an oral or parenteral route.
  • the parenteral route includes all routes other than oral administration such as intravenous, intramuscular, subcutaneous, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, etc. To do. Administration may be local administration or systemic administration.
  • the pharmaceutical composition can be administered in a single dose or in multiple doses, and the administration period and interval are the type of drug, the type and condition of the disease, the administration route, the age, weight and sex of the administration subject. It can be appropriately selected depending on the above.
  • the dosage of the pharmaceutical composition can be appropriately selected depending on the type of drug, the type and condition of the disease, the administration route, the age, weight and sex of the administration subject.
  • the dosage of the pharmaceutical composition can be a therapeutically effective amount, for example, about 0.01 to 1000 mg per kg body weight at a time.
  • the drug conjugate of this embodiment exhibits pH sensitive drug release characteristics, particularly when in the form of micelles.
  • drug release in the surrounding environment of acidified cancer (pH 6.6) and endosome (pH 5) after being taken into the cytoplasm is an aliphatic aldehyde group or an aliphatic ketone.
  • Drug conjugates with introduced groups are excellent. Therefore, when a highly toxic drug such as vinblastine is used, a drug complex into which an aromatic aldehyde group or an aromatic ketone group with a slow drug release at pH 5 to 6.6 is introduced is preferable.
  • a drug complex into which an aliphatic aldehyde group or aliphatic ketone group that releases drug quickly at pH 5 to 6.6 is introduced is preferable.
  • an aromatic aldehyde group or an aromatic ketone group is introduced into the repeating unit (IA-1), and an aliphatic aldehyde group or an aliphatic ketone group is introduced into the repeating unit (IA-2).
  • MTD maximum tolerated dose
  • the drug conjugate of the present embodiment can control the therapeutic efficacy by designing a drug release profile with high accuracy by using the repeating unit (IA-1) and the repeating unit (IA-2) in combination.
  • the drug conjugate of the present embodiment is in the form of micelles, side effects can be reduced because the drug is stably maintained and toxicity is alleviated while the drug is held in the polymer. Therefore, the micelle of the drug complex of this embodiment has a maximum tolerated dose (MTD) that is longer than that of the drug alone.
  • MTD maximum tolerated dose
  • Example 1 Synthesis of polymer 1 PEG-PBLA polymer (300 mg) was dissolved in DMF (3 mL), and 3,3-dimethoxybutan-1-amine (120 ⁇ L) and ⁇ [4- (dimethoxymethyl) phenyl] methanamine were dissolved. ⁇ (60 ⁇ L) was added. The reaction was stirred at 40 ° C. for 48 hours, HCl solution (300 ⁇ L, 0.1N) was added and stirred for 1 hour. Polymer 1 was recovered by dialyzing against water and freeze-drying the polymer. The reaction scheme is shown in FIG. The results of 1 H-NMR analysis of the obtained polymer 1 are shown in FIG. It was confirmed that 31 aliphatic ketone units and 4 aromatic aldehyde units were introduced into polymer 1.
  • Example 2 Synthesis of polymer 2 PEG-PBLA polymer (100 mg) was dissolved in DMF (1 mL), and 3,3-dimethoxybutan-1-amine (75 ⁇ L) and ⁇ [4- (dimethoxymethyl) phenyl] methanamine were dissolved. ⁇ (25 ⁇ L) was added. The reaction was stirred at 40 ° C. for 48 hours, HCl solution (100 ⁇ L, 0.1N) was added and stirred for 1 hour. Polymer 1 was recovered by dialyzing against water and freeze-drying the polymer. The reaction scheme is shown in FIG. The results of 1 H-NMR analysis of the obtained polymer 1 are shown in FIG. It was confirmed that 31 aliphatic ketone units and 6 aromatic aldehyde units were introduced into polymer 1.
  • Example 3 Synthesis of polymer 3 PEG-PBLA polymer (100 mg) was dissolved in DMF (1 mL), and 3,3-dimethoxybutan-1-amine (50 ⁇ L) and ⁇ [4- (dimethoxymethyl) phenyl] methanamine were dissolved. ⁇ (50 ⁇ L) was added. The reaction was stirred at 40 ° C. for 40 hours, HCl solution (100 ⁇ L, 0.1 N) was added and stirred for 1 hour. Polymer 1 was recovered by dialyzing against water and freeze-drying the polymer. The reaction scheme is shown in FIG. Further, FIG. 4 shows the 1 H-NMR analysis result of the obtained polymer 1. It was confirmed that 21 aliphatic ketone units and 9 aromatic aldehyde units were introduced into polymer 1.
  • Example 4 Synthesis of Polymer 4 PEG-PBLA polymer (100 mg) was dissolved in DMF (3 mL), and 3,3-dimethoxybutan-1-amine (50 ⁇ L) was added. The reaction was stirred at 40 ° C. for 16 hours and ⁇ [4- (dimethoxymethyl) phenyl] methanamine ⁇ (50 ⁇ L) was added. The reaction was stirred at 40 ° C. for 24 hours, HCl solution (100 ⁇ L, 0.1 N) was added and stirred for 1 hour. Polymer 1 was recovered by dialyzing against water and freeze-drying the polymer. The reaction scheme is shown in FIG. Further, FIG. 5 shows the result of 1 H-NMR analysis of the obtained polymer 1. It was confirmed that 9 aliphatic ketone units and 19 aromatic aldehyde units were introduced into polymer 1.
  • Example 5 Preparation of drug complex 1 15 mg of a polymer mixture obtained by mixing a compound having a hydrazide group introduced into vinblastine (DAVBNH: manufactured by DSK BioPharmacia, the same shall apply hereinafter) and polymer 1 in a ratio of 2: 1.
  • DMSO dimethylacetamide
  • DMAc dimethylacetamide
  • This solvent exchange produced a clear DMAc solution.
  • the obtained DMAc solution was added dropwise to water with stirring at a ratio of 1 to 10 water by volume to prepare micelles. This solution was dialyzed against water to remove the organic solvent. The resulting solution was concentrated by ultrafiltration using a 100 kDa MWCO filter membrane to obtain Drug Complex 1.
  • Example 7 Preparation of drug conjugate 3
  • Drug conjugate 3 was obtained in the same manner as in Example 5 except that polymer 3 was used instead of polymer 1.
  • Example 8 Preparation of drug conjugate 4
  • Drug conjugate 4 was obtained in the same manner as in Example 5 except that polymer 4 was used instead of polymer 1.
  • Reference Drug Complex 1 was obtained in the same manner as in Example 5 except that Reference Polymer 1 was used instead of Polymer 1.
  • Reference Drug Complex 2 was obtained in the same manner as in Example 5 except that Reference Polymer 2 was used instead of Polymer 1.
  • ⁇ Measurement of micelle size and PDI> For drug conjugates 1-4, the micelle size and polydispersity index (PDI) were determined by dynamic light scattering (DLS) techniques. The measurement was performed using a green laser (532 nm) as an incident beam and a Zetasizer nano ZS (Malvern instruments, UK) at a detection angle of 173 ° and a temperature condition of 25 ° C. The micelle size results of drug conjugates 1 to 4 are shown in FIGS. 6 to 9, respectively. The explanation of each index in FIGS. 6 to 9 is shown in Table 1.
  • DLS dynamic light scattering
  • the repeating unit (I-1) aromatic aldehyde group / aromatic ketone group introduction unit
  • the repeating unit (I-2) aliphatic aldehyde group / aliphatic ketone group. It was confirmed that the micelle size can be adjusted by adjusting the content ratio with the introduction unit).
  • FIG. 10 is a graph showing the pH sensitive drug release profile of Reference Drug Complex 1.
  • FIG. 11 is a graph showing the pH sensitive drug release profile of Reference Drug Complex 2.
  • FIG. 12 is a graph showing the pH sensitive drug release profile of Drug Complex 1. From the results shown in FIG. 10, it can be confirmed that the reference drug complex 1 into which only the aromatic aldehyde group is introduced has a slow drug release at pH 5 or higher. From the results shown in FIG. 11, it is confirmed that the reference drug complex 2 into which only the aliphatic ketone group is introduced is excellent in drug release at pH 5 or higher.
  • repeating unit (I-1) aromatic aldehyde group / aromatic ketone group introduction unit
  • repeating unit (I-2) aliphatic aldehyde group / aliphatic ketone group introduction unit
  • Administration group 1 PBS as control
  • Administration group 2 DAVBNH 2 mg / kg (MTD)
  • Administration group 3 Reference drug complex 1 (Reference example 3) 16 mg / kg (safety tolerance dose)
  • administration group 4 Reference drug complex 2 (Reference example 4) 2 mg / kg administration group 5: Drug complex 1 (Example) 5) 4mg / kg
  • the treatment schedule was as follows. First phase: set to 4 injections at 2 day intervals (0, 3, 6, and 9 days). Second phase: injection once a week until the mouse dies. In vivo imaging was performed using IVIS spectra (Xenogen Corporation), and D-luciferin potassium salt solution was used as a substrate for luciferase.
  • MRI was taken on the 28th day after the start of treatment.
  • MRI was taken on the 50th day after the start of treatment was also taken.
  • BioSpec1T manufactured by Bruker was used for MRI imaging.
  • FIGS. 14 and 15 are graphs showing tumor growth curves in each administration group in the evaluation of the brain tumor orthotopic model.
  • FIG. 16 is a graph showing the time course of survival rate in the evaluation of the brain tumor orthotopic model. From the results shown in FIGS. 14 to 16, it was confirmed that the drug complex 1 of Example 5 significantly reduced the brain tumor by tail vein injection and significantly prolonged the survival in the brain tumor orthotopic transplantation model. In particular, in the administration group 5 using the drug complex 1, it was confirmed that about 80% of the mice survived even after 70 days from the start of treatment.
  • FIG. 17 is an MRI image of the brain of a mouse on the 28th day after the start of treatment in each administration group for evaluation of a brain tumor orthotopic model.
  • the administration group 1 PBS as a control
  • DAVBNH administration group 2
  • administration group 3 reference drug complex 1, reference example 3
  • administration group 5 drug conjugate 1, example 5
  • FIG. 18 is an MRI image of the brain of a mouse 50 days after the start of treatment in administration groups 4 and 5 for evaluation of an orthotopic brain tumor model.
  • administration group 1 PBS as a control
  • most mice died 50 days after the start of treatment.
  • administration group 2 DAVBNH
  • administration group 3 reference drug complex 1, reference example 3
  • administration group 4 reference drug complex 2, reference example 4
  • administration group 5 drug complex 1, Example 5

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Polyamides (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)

Abstract

L'invention concerne un polymère ayant un motif répétitif (I-1) représenté par la formule générale (I-1), un motif répétitif (I-2) représenté par la formule générale (I-2), et un motif répétitif (II) représenté par la formule générale (II) (dans les formules, m représente 1 ou 2). L11 représente un groupe hydrocarboné aromatique divalent. L12 représente un groupe hydrocarboné aliphatique divalent. R11 et R12 représentent chacun d'une manière indépendante un atome d'hydrogène, un groupe hydrocarboné aliphatique ou un groupe hydrocarboné aromatique. X représente ORx, SRx, ou NRx1Rx2. Rx représente un atome d'hydrogène, un groupe hydrocarboné aliphatique ou un groupe hydrocarboné aromatique. Rx1 et Rx2 représentent chacun d'une manière indépendante un atome d'hydrogène, un groupe hydrocarboné aliphatique, ou un groupe hydrocarboné aromatique).
PCT/JP2019/006774 2018-02-22 2019-02-22 Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle Ceased WO2019163942A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018030209A JP7004590B2 (ja) 2018-02-22 2018-02-22 ポリマー、ポリマーの製造方法、薬物複合体及びミセル
JP2018-030209 2018-02-22

Publications (1)

Publication Number Publication Date
WO2019163942A1 true WO2019163942A1 (fr) 2019-08-29

Family

ID=67688386

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/006774 Ceased WO2019163942A1 (fr) 2018-02-22 2019-02-22 Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle

Country Status (2)

Country Link
JP (1) JP7004590B2 (fr)
WO (1) WO2019163942A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58192829A (ja) * 1982-05-07 1983-11-10 Seikagaku Kogyo Co Ltd 固定化生理活性物質の製造法
JPH01256530A (ja) * 1988-04-06 1989-10-13 Earth Chem Corp Ltd ポリアミノ酸誘導体およびそれを有効成分とする紫外線吸収剤
JPH02229804A (ja) * 1987-05-18 1990-09-12 Bachem Feinchemikalien Ag ペプチド合成用担体
JPH08259600A (ja) * 1986-04-30 1996-10-08 F Hoffmann La Roche Ag ポリペプチドおよび蛋白質の誘導体類
WO2006090924A1 (fr) * 2005-02-28 2006-08-31 The University Of Tokyo Copolymere bloc ayant un ligand peptidique
JP2010539312A (ja) * 2007-09-18 2010-12-16 ニルヴァーナス ツリー ハウス ベーフェー 両親媒性コポリマー及びこのようなポリマーを含む組成物
JP2011173802A (ja) * 2010-02-23 2011-09-08 Nano Career Kk 短鎖のカチオン性ポリアミノ酸およびその使用
WO2018038166A1 (fr) * 2016-08-23 2018-03-01 公益財団法人川崎市産業振興財団 Polymère, procédé de production de polymère, et complexe médicamenteux
WO2018038165A1 (fr) * 2016-08-23 2018-03-01 公益財団法人川崎市産業振興財団 Polymère, procédé de production de polymère et conjugué de médicament
WO2018151258A1 (fr) * 2017-02-20 2018-08-23 国立大学法人東京工業大学 Support d'administration de médicament et système d'administration de médicament

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58192829A (ja) * 1982-05-07 1983-11-10 Seikagaku Kogyo Co Ltd 固定化生理活性物質の製造法
JPH08259600A (ja) * 1986-04-30 1996-10-08 F Hoffmann La Roche Ag ポリペプチドおよび蛋白質の誘導体類
JPH02229804A (ja) * 1987-05-18 1990-09-12 Bachem Feinchemikalien Ag ペプチド合成用担体
JPH01256530A (ja) * 1988-04-06 1989-10-13 Earth Chem Corp Ltd ポリアミノ酸誘導体およびそれを有効成分とする紫外線吸収剤
WO2006090924A1 (fr) * 2005-02-28 2006-08-31 The University Of Tokyo Copolymere bloc ayant un ligand peptidique
JP2010539312A (ja) * 2007-09-18 2010-12-16 ニルヴァーナス ツリー ハウス ベーフェー 両親媒性コポリマー及びこのようなポリマーを含む組成物
JP2011173802A (ja) * 2010-02-23 2011-09-08 Nano Career Kk 短鎖のカチオン性ポリアミノ酸およびその使用
WO2018038166A1 (fr) * 2016-08-23 2018-03-01 公益財団法人川崎市産業振興財団 Polymère, procédé de production de polymère, et complexe médicamenteux
WO2018038165A1 (fr) * 2016-08-23 2018-03-01 公益財団法人川崎市産業振興財団 Polymère, procédé de production de polymère et conjugué de médicament
WO2018151258A1 (fr) * 2017-02-20 2018-08-23 国立大学法人東京工業大学 Support d'administration de médicament et système d'administration de médicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
W. NEUSE EBERHARD ET AL.: "Water-soluble polyamides as potential drug carriers", ANGEWANDTE MAKROMOLEKULARE CHEMIE, vol. 192, no. 3300, 1991, pages 35 - 50, XP002045582 *

Also Published As

Publication number Publication date
JP2019143083A (ja) 2019-08-29
JP7004590B2 (ja) 2022-02-04

Similar Documents

Publication Publication Date Title
JP5037684B2 (ja) ドセタキセル高分子誘導体、並びにその製造方法及びその用途
EP2258397B1 (fr) Conjugué de polymère et de substance physiologiquement active
KR101444274B1 (ko) 약제복합체용 블록 공중합체 및 의약조성물
WO2019204799A1 (fr) Polymères amphiphiles cationiques pour co-administration d'agents hydrophobes et d'acides nucléiques
WO2011058776A1 (fr) Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci
US20250009895A1 (en) Drug loading monomolecular nano polymer, prodrug, micelle, drug delivery system, preparation method, and use
WO2022052413A1 (fr) Vésicule polymère chargée de médicament à structure membranaire asymétrique, son procédé de préparation et son application dans la préparation de médicaments pour le traitement de la leucémie myéloïde aiguë
JPWO2006115293A1 (ja) ｐＨ応答性高分子ミセルの調製に用いる新規ブロック共重合体及びその製造法
US10441662B2 (en) Polymer, method for producing polymer, and drug conjugate
Japir et al. Tumor-dilated polymersome nanofactories for enhanced enzyme prodrug chemo-immunotherapy
CN109762099B (zh) 一种聚合物-抗肿瘤药物偶联物及其制备方法和用途
WO2014084378A1 (fr) Médicament anticancéreux comprenant un peptide contenant la séquence rgd cyclique
WO2018038166A1 (fr) Polymère, procédé de production de polymère, et complexe médicamenteux
JP7575731B2 (ja) 結合体、及び癌治療剤
US11007148B2 (en) Amphiphilic block copolymers for delivery of active agents
WO2019163942A1 (fr) Polymère, procédé de production d'un polymère, complexe médicamenteux, et micelle
CN113244175A (zh) 一种免疫囊泡美登素偶联物及其制备方法与应用
JP7084740B2 (ja) 薬物複合体、ミセル、及び医薬組成物
JP6872216B2 (ja) イミノ二酢酸を側鎖に有する親水性高分子及びその使用
US20240099977A1 (en) Small molecular drug-loaded polymer vesicle, preparation method therefor and use thereof
JP7100457B2 (ja) ブロックコポリマー、ミセル組成物、及び医薬組成物
CN120242043A (zh) 一种纳米药物组合物及其制备方法和应用
WO2017170846A1 (fr) Composition de micelle polymère pharmaceutique
WO2015002078A1 (fr) Nouvelle préparation à base d'un composé d'acide boronique
CA3015459A1 (fr) Preparation pharmaceutique contenant un derive polymere a base de camptothecine

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: 19756476

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: 19756476

Country of ref document: EP

Kind code of ref document: A1