WO2017170845A1 - Copolymère séquencé conjugué à un médicament, copolymère séquencé et procédé de production de copolymère séquencé conjugué à un médicament - Google Patents

Copolymère séquencé conjugué à un médicament, copolymère séquencé et procédé de production de copolymère séquencé conjugué à un médicament Download PDF

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Publication number
WO2017170845A1
WO2017170845A1 PCT/JP2017/013201 JP2017013201W WO2017170845A1 WO 2017170845 A1 WO2017170845 A1 WO 2017170845A1 JP 2017013201 W JP2017013201 W JP 2017013201W WO 2017170845 A1 WO2017170845 A1 WO 2017170845A1
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group
drug
block copolymer
integer
conjugated block
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PCT/JP2017/013201
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English (en)
Japanese (ja)
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宏之 齋藤
義 井上
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ナノキャリア株式会社
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    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • A61K47/56—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • C08G69/40—Polyamides containing oxygen in the form of ether groups
    • 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 drug-conjugated block copolymer, a block copolymer, and a method for producing a drug-conjugated block copolymer.
  • the following documents are related to a drug delivery system (DDS) using a block copolymer having a polyethylene glycol chain segment and a copolyamino acid chain segment containing an acidic amino acid residue.
  • DDS drug delivery system
  • a conventional polymer DDS as described in Patent Document 1 is loaded with a drug having a hydroxyl group bonded to an acidic amino acid residue of a polyamino acid segment via an ester bond utilizing the hydroxyl group. And a mechanism for releasing a drug by a hydrolysis reaction accompanied by a structural change of the acidic amino acid residue.
  • a drug release mechanism is limited to a combination of an acidic amino acid residue and a drug having a hydroxyl group.
  • the main object of the present invention is to provide a polymer DDS capable of controlling the release of a drug having a carboxyl group.
  • a drug-conjugated block copolymer represented by the general formula: AB A represents a polyethylene glycol chain segment, B represents a repeating unit represented by the following general formula (i) and / or a co-polyamino acid chain segment comprising a repeating unit represented by the following general formula (ii)
  • X represents a drug residue optionally having a linking group.
  • a block copolymer represented by the following general formula (II) is provided.
  • R 1 represents a hydrogen atom, an unsubstituted or substituted linear or branched alkyl group having 1 to 12 carbon atoms, or a group having a target binding site
  • R 2 represents a hydrophobic group
  • R 3 represents a hydrogen atom, a saturated or unsaturated unsubstituted or substituted linear or branched aliphatic carbonyl group or arylcarbonyl group having 1 to 30 carbon atoms, or an unsubstituted or substituted group having 1 to 12 carbon atoms.
  • a method for producing a drug-conjugated block copolymer represented by the following general formula (I) comprises all or part of the side chain hydroxyl groups of the copolyamino acid chain segment of the block copolymer represented by the above general formula (II), a carboxyl group, and a linking group. Reacting with the carboxyl group of the optional drug to form an ester bond.
  • a drug-conjugated block copolymer that enables controlled release of a drug having a carboxyl group is provided.
  • a drug-conjugated block copolymer according to one embodiment of the present invention is described below.
  • the drug-conjugated block copolymer is represented by the general formula: AB.
  • A represents a polyethylene glycol chain segment.
  • B represents a repeating unit represented by the following general formula (i) and / or a co-polyamino acid chain segment containing a repeating unit represented by the following general formula (ii).
  • X represents a drug residue which may have a linking group.
  • the molecular weight of the polyethylene glycol chain segment may be, for example, 500 or more, further 2,000 or more, and for example, 50,000 or less, or 20,000 or less.
  • the co-polyamino acid chain segment typically further includes an amino acid residue having a hydrophobic group in the side chain. Any appropriate amino acid residue can be adopted as the amino acid residue.
  • the amino acid residue is preferably a glutamic acid residue having a hydrophobic group introduced in the side chain. Any appropriate hydrophobic group can be adopted as the hydrophobic group.
  • Examples of the hydrophobic group include a hydrophobic organic group. Examples of the hydrophobic organic group include C 4 to C 16 linear, branched or cyclic alkyl groups, C 6 to C 20 aryl groups, and C 7 to C 20 aralkyl groups or sterol residues. Groups.
  • the C 6 -C 20 aryl group and the C 7 -C 20 aralkyl group are preferably phenyl, naphthyl, tolyl, xylyl, benzyl, and phenethyl, and more preferably benzyl.
  • the sterol from which the sterol residue is derived is preferably cholesterol, cholestanol, and dihydroxycholesterol, and more preferably cholesterol.
  • the co-polyamino acid chain segment typically further includes an amino acid residue having a hydrophilic group in the side chain. Any appropriate amino acid residue can be adopted as the amino acid residue.
  • the amino acid residue is preferably an aspartic acid residue in which a side-chain carboxyl group is optionally converted to another hydrophilic group. Any appropriate hydrophilic group can be adopted as the hydrophilic group. Examples of the hydrophilic group include a hydroxyl group.
  • the above drug is a compound having a carboxyl group.
  • the drug having a carboxyl group may be in a state where a linking group is disposed between the active domain portion and the carboxyl group.
  • a compound in which a linking group is disposed between an active domain portion of a drug and the carboxyl group is also treated as the drug having the carboxyl group.
  • the linking group include a divalent linking group having 0 to 5 carbon atoms which may contain an amide bond, an ester bond, an ether bond, and / or a hydrazide bond.
  • the drug-conjugated block copolymer is preferably represented by the following general formula (I).
  • R 1 represents a hydrogen atom, an unsubstituted or substituted linear or branched alkyl group having 1 to 12 carbon atoms, or a group having a target binding site.
  • R 2 represents a hydrophobic group.
  • R 3 represents a hydrogen atom, a saturated or unsaturated unsubstituted or substituted linear or branched aliphatic carbonyl group or arylcarbonyl group having 1 to 30 carbon atoms, or an unsubstituted or substituted group having 1 to 12 carbon atoms.
  • L represents a linker.
  • m is an integer of 30 to 20,000.
  • x is an integer of 5 to 100.
  • a is an integer of 0 to 100.
  • b is an integer of 0 to 100.
  • c is an integer of 0 to 100.
  • d is an integer of 0 to 100.
  • the sum of a and c is 1 to 200.
  • the order of binding of each repeating unit in the co-polyamino acid chain segment is arbitrary.
  • the target binding site refers to a site having a biological recognition function that can specifically bind to a substance derived from a living body and a virus to form a biological binding pair with the substance.
  • the group having a target binding site is, for example, a low molecular weight compound, a sugar chain, a peptide, an antibody and a fragment thereof, and the like, which can form a biological binding pair with a substance derived from a living body or a virus. You may comprise in the state contained as at least one part of a structure.
  • linker any appropriate linker can be adopted as the linker.
  • the linker include —NH—, —O—, —O—Z—NH—, —CO—, —CH 2 —, —O—Z—S—Z— and —OCO—Z—NH— (
  • Z is a C 1 -C 6 alkylene group independently), and a linker selected from the group consisting of:
  • m is an integer of 30 to 20,000 as described above.
  • m may be an integer of 50 or more, an integer of 100 or more, or an integer of 200 or more, and may be an integer of 5,000 or less, an integer of 500 or less, or an integer of 300 or less.
  • x is an integer of 5 to 100 as described above.
  • x may be, for example, an integer of 10 or more, further 15 or more, and may be an integer of 60 or less, an integer of 40 or less, or an integer of 25 or less.
  • a is an integer of 0 to 100 as described above. a may be an integer of 1 or more, further 5 or more, and may be an integer of 60 or less, or 40 or less, for example.
  • b is an integer of 0 to 100 as described above.
  • b may be an integer of 1 or more, further 5 or more, and may be an integer of 60 or less, or 40 or less.
  • c is an integer of 0 to 100 as described above. c may be, for example, an integer of 1 or more, further an integer of 5 or more, and may be an integer of 60 or less, further 40 or less.
  • d is an integer of 0 to 100 as described above.
  • d may be an integer of 1 or more, further 5 or more, and may be an integer of 60 or less, or 40 or less.
  • the sum of a and c is an integer of 1 to 200 as described above.
  • the sum of a and c may be, for example, an integer greater than or equal to 2, an integer greater than or equal to 3, an integer greater than or equal to 4, an integer greater than or equal to 5, an integer greater than or equal to 6, and an integer greater than or equal to 40. It may be an integer, an integer of 10 or less, or an integer of 8 or less.
  • the sum of x, a, b, c and d may be, for example, 10 or more, 20 or more, further 30 or more, and for example, 200 or less, 100 or less, and further 50 or less. It may be.
  • x: (a + b + c + d) is, for example, 90:10 to 10:90, and for example, 80:20 to 20:80.
  • x: (b + d) is, for example, 20:80 to 80:20, for example, 25:75 to 75:25, and for example, 30:70 to 70:30.
  • the ratio (%) of (a + c) to (x + a + b + c + d) may be, for example, 2% or more, further 7% or more, and for example, 50% or less, further 35% or less. Good.
  • (a + c) :( b + d) is, for example, 90:10 to 30:70, and for example, 80:20 to 30:70.
  • x / (a + c) may be 0.5 or more, further 1 or more, for example, 15 or less, or 10 or less.
  • Block copolymer A block copolymer according to one embodiment of the present invention is described below.
  • the block copolymer is represented by the following general formula (II).
  • R 1 , R 2 , R 3 , L, m, x, a, b, c, and d are as described in the above formula (I).
  • the order of binding of each repeating unit in the co-polyamino acid chain segment is arbitrary.
  • the block copolymer represented by the formula (II) is a block copolymer represented by the formula (III).
  • R 1 , R 2 , R 3 , L, m and x are as described in the above formula (I), and e and f are each independently an integer of 0 to 200 And e + f is an integer from 1 to 200. Further, the order of binding of each repeating unit in the co-polyamino acid chain segment is arbitrary.
  • e and f are each independently an integer of 0 or more, further an integer of 2 or more, or even an integer of 10 or more, and for example an integer of 200 or less, It may be an integer of 120 or less, or even an integer of 80 or less.
  • e + f may be an integer of 5 or more, further an integer of 10 or more, for example, an integer of 100 or less, or an integer of 60 or less.
  • (x + e + f) may be, for example, 10 or more, further 20 or more, for example, 200 or less, or 100 or less.
  • x: (e + f) may be 90:10 to 10:90, for example, and may be 80:20 to 20:80, for example.
  • a method for producing a drug-conjugated block copolymer according to one embodiment of the present invention is described below.
  • the production method is a method for producing a drug-conjugated block copolymer represented by the general formula (I).
  • the production method includes all or part of the hydroxyl groups in the side chain of the copolyamino acid chain segment of the block copolymer represented by the general formula (II) and a carboxyl group, A step of reacting the carboxyl group of the drug optionally having a group to form an ester bond.
  • the above production method may further comprise a step of preparing polyethylene glycol-co-polyglutamic acid R 2 ester-polyaspartic acid (PEG-PR 2 LG-pAsp).
  • PEG-PR 2 LG-pAsp polyethylene glycol-co-polyglutamic acid
  • a glutamic acid residue and an aspartic acid residue in which R 2 is ester-bonded to the side chain are arbitrarily arranged.
  • the production method may further include a step of reducing the carboxyl group of the aspartic acid side chain of PEG-PR 2 LG-pAsp to a hydroxyl group.
  • a copolymer in polyethylene glycol-co-polyamino acid, a copolymer (PEG-PR 2 LG-pAsp (red)) in which a glutamic acid residue in which R 2 is ester-linked to a side chain and a reduced aspartic acid residue are arbitrarily arranged ) (That is, a block copolymer represented by the general formula (II)) can be obtained.
  • PEG-PR 2 LG-pAsp preparation step As an example of a method for preparing PEG-PR 2 LG-pAsp, a polymer having a polyethylene glycol (PEG) chain and a polymer having co-polyglutamic acid R 2 ester-polyaspartic acid (PR 2 LG-pAsp) And a method of coupling by an appropriate method.
  • PEG polyethylene glycol
  • aspartic anhydride (Asp-NCA) and N are used with polyethylene glycol having one end protected and the other end being an amino group as an initiator.
  • An example is a method in which -carboxy- ⁇ -R 2 -L-glutamic anhydride (R 2 LG-NCA) is added so as to have a desired degree of polymerization (number of amino acid units) and reacted.
  • Any appropriate initiator can be adopted as the initiator.
  • the initiator include MeO-PEG-CH 2 CH 2 CH 2 —NH 2 .
  • the above reaction is preferably carried out in a dehydrated organic solvent.
  • PEG-PR 2 LG-pAsp reduction step Any appropriate method can be adopted as a method of reducing the carboxyl group of the aspartic acid side chain to form a hydroxyl group.
  • a polymer micelle pharmaceutical composition comprising a drug-conjugated block copolymer (hereinafter sometimes referred to as block copolymer unit ⁇ ) according to one embodiment of the present invention is described below.
  • the polymer micelle pharmaceutical composition may further include a block copolymer unit ⁇ having a polyethylene glycol chain segment and a polyamino acid chain segment to which a target binding site is bound, and not the block copolymer unit ⁇ .
  • the polymer micelle pharmaceutical composition contains neither a target binding site nor a drug, and may further include a block copolymer unit ⁇ having a polyethylene glycol chain segment and a polyamino acid chain segment.
  • the block copolymer unit ⁇ and, if present, ⁇ and ⁇ are arranged radially with the polyethylene glycol chain segment facing outward.
  • the block copolymer is radially arranged when the polyethylene glycol chain segment is directed outward and the segment opposite to the polyethylene glycol chain segment (copolyamino acid chain segment) is aggregated inward. If it is in a state.
  • the polydispersity index (PDI) of the polymer micelle pharmaceutical composition can take any appropriate value.
  • the polydispersity index may be, for example, 0.01 or more, further 0.02 or more, for example, 0.8 or less, and further 0.5 or less.
  • the content of the block copolymer unit ⁇ in the polymer micelle pharmaceutical composition can take any appropriate value. As said content, it is 20 weight% or more, for example, and is 30 weight% or more, for example. When the content is not less than the predetermined value, it becomes easier to mount a sufficient amount of drug on the polymer micelle pharmaceutical composition. On the other hand, as said content, it is 90 weight% or less, for example, is 80 weight% or less, for example, is 70 weight% or less.
  • the block copolymer may contain two or more kinds of the above-mentioned block copolymer unit ⁇ and, if present, ⁇ and ⁇ .
  • the polyamino acid chain segments of the block copolymer units ⁇ and ⁇ preferably each contain an amino acid residue having a hydrophobic group in the side chain. Any appropriate amino acid residue can be adopted as the amino acid residue. Examples of the amino acid residue include a glutamic acid residue having a hydrophobic group introduced in the side chain, and an aspartic acid residue. Any appropriate hydrophobic group can be adopted as the hydrophobic group. Examples of the hydrophobic group include the hydrophobic groups described for the drug-conjugated block copolymer.
  • the polyamino acid chain segment of the block copolymer unit ⁇ preferably contains an amino acid residue having a hydrophilic group in the side chain. Any appropriate amino acid residue can be adopted as the amino acid residue. Examples of the amino acid residue include a glutamic acid residue and an aspartic acid residue. Any appropriate hydrophilic group can be adopted as the hydrophilic group. Examples of the hydrophilic group include a carboxyl group.
  • a drug-conjugated block copolymer represented by the above general formula (I) was prepared as follows. The hydroxyl group of the side chain of the reduced aspartic acid residue of polyethylene glycol-co-polyglutamic acid benzyl ester-polyreduced aspartic acid (PEG-PBLG-pAsp (red)) acetylated at one end of the co-polyamino acid The ester bond was formed by reacting with the carboxyl group of ibuprofen. As a result, a drug-conjugated block copolymer represented by the above general formula (I) was obtained.
  • Table 1 shows the results of measuring the number of ibuprofen residues by NMR for the obtained drug-conjugated block copolymer (shown as “PEG-PBLG-pAsp (red) -IB” in Table 1).
  • AA represents the average value of the number of amino acid residues of the drug-conjugated block copolymer
  • PEG MW represents the average molecular weight (Mw) of PEG (average molecular weight (Mw) is The degree of polymerization of PEG of 10,000 is calculated to be about 226 to 227).
  • OH ratio is (average value of the number of glutamic acid residues whose side chains are benzyl esterified) in the block copolymer before drug conjugation: (average value of the number of hydroxyl groups of the reduced aspartic acid residue) Represents.
  • IB number represents an average value of the number of ibuprofen residues measured by NMR in the drug-conjugated block copolymer.
  • Table 2 shows the results of measuring the ibuprofen content of the obtained polymer micelle (shown as “pAsp (red) micelle” in Table 2) and the drug-conjugated block copolymer.
  • IB NMR represents the ibuprofen content (%) in the drug-conjugated block copolymer measured by NMR.
  • IB HPLC represents the ibuprofen content (%) in polymer micelles measured by HPLC.
  • polymer micelles were obtained by the same method as in Test Example 1 using the drug-conjugated block copolymer.
  • Table 2 shows the results of measuring the ibuprofen content of the obtained polymer micelle (shown as “pGlu (red) micelle” in Table 2) and the drug-conjugated block copolymer.
  • a drug-conjugated block copolymer was prepared in the same manner as in Test Example 1 except that E7974 was used as the drug.
  • Table 3 shows the results of measuring the number of E7974 residues for the obtained drug-conjugated block copolymer (indicated as “PEG-PBLG-pAsp (red) -E7974” in Table 3).
  • “AA”, “PEG MW”, and “Bn: OH ratio” have the same meanings as in Table 1.
  • “E7974 number” represents the average number of E7974 residues in the drug-conjugated block copolymer as measured by HPLC after hydrolysis.
  • polymer micelles were obtained by the same method as in Test Example 1 using the drug-conjugated block copolymer.
  • Table 4 shows the result of measuring the E7974 content of the obtained polymer micelle (shown as “pGlu (red) micelle” in Table 4).
  • E7974 release test The micelle formulations of Test Examples 3 and 4 were added to PBS bathed in water at 37 ° C. so that the concentration of E7974 was 1 ⁇ g / mL, and gently shaken. A portion of PBS was collected after 24 hours and the concentration of E7974 released from micelles into PBS was measured. The ratio (%) of the amount of released E7974 to the total amount of E7974 was calculated. The results are shown in Table 4 as “drug release rate”.
  • the reduced aspartic acid side of the co-polyamino acid chain segment is used.
  • release of a drug having a carboxyl group can be controlled.
  • the present invention can be suitably used in the field of pharmaceutical preparations such as anticancer agents.

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Abstract

L'invention concerne un système d'administration de médicaments (DDS) polymère permettant la libération contrôlée d'un médicament contenant un groupe carboxyle. Le copolymère séquencé conjugué à un médicament selon l'invention est représenté par la formule générale : A-B. Dans la formule générale, A représente un segment de chaîne de polyéthylène glycol ; et B représente un segment de chaîne de copolyamino acide contenant une unité récurrente représentée par la formule générale (i) et/ou (ii), dans lesquelles X représente un résidu du médicament, ce résidu pouvant contenir un groupe de liaison.
PCT/JP2017/013201 2016-03-30 2017-03-30 Copolymère séquencé conjugué à un médicament, copolymère séquencé et procédé de production de copolymère séquencé conjugué à un médicament WO2017170845A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2020218390A1 (fr) * 2019-04-24 2020-10-29 国立大学法人東京工業大学 Conjugué et agent thérapeutique contre le cancer
JPWO2019151320A1 (ja) * 2018-01-30 2021-01-14 国立大学法人大阪大学 抗がん剤

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JP2008522624A (ja) * 2004-12-09 2008-07-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 ヘミアスタリン（ｈｅｍｉａｓｔｅｒｌｉｎ）アナログを使用する癌治療におけるチューブリンのアイソタイプのスクリーニング
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WO2010131675A1 (fr) * 2009-05-15 2010-11-18 日本化薬株式会社 Conjugue polymere de substance bioactive comprenant un groupe hydroxy

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JPWO2019151320A1 (ja) * 2018-01-30 2021-01-14 国立大学法人大阪大学 抗がん剤
EP3747909A4 (fr) * 2018-01-30 2021-09-15 Osaka University Agent anticancéreux
JP7267609B2 (ja) 2018-01-30 2023-05-02 国立大学法人大阪大学 抗がん剤
WO2020218390A1 (fr) * 2019-04-24 2020-10-29 国立大学法人東京工業大学 Conjugué et agent thérapeutique contre le cancer

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