WO2017170845A1 - Drug-conjugated block copolymer, block copolymer, and method for producing drug-conjugated block copolymer - Google Patents

Drug-conjugated block copolymer, block copolymer, and method for producing drug-conjugated block copolymer Download PDF

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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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drug
block copolymer
integer
conjugated block
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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

The present invention provides a polymer DDS which enables the controlled release of a drug having a carboxyl group. A drug-conjugated block copolymer according to the present invention is represented by the general formula: A-B. In the general formula, A represents a polyethylene glycol chain segment; and B represents a copolyamino acid chain segment containing a repeating unit represented by general formula (i) and/or (ii), wherein X in each of formulae (i) and (ii) represents a residue of the drug and the residue may have a linking group.

Description

薬物複合化ブロック共重合体、ブロック共重合体、および薬物複合化ブロック共重合体の製造方法Drug-conjugated block copolymer, block copolymer, and method for producing drug-conjugated block copolymer
　本発明は、薬物複合化ブロック共重合体、ブロック共重合体、および薬物複合化ブロック共重合体の製造方法に関する。 The present invention relates to a drug-conjugated block copolymer, a block copolymer, and a method for producing a drug-conjugated block copolymer.
　ポリエチレングリコール鎖セグメントと、酸性アミノ酸残基を含むコ－ポリアミノ酸鎖セグメントとを有するブロック共重合体を利用したドラッグデリバリーシステム（ＤＤＳ）に関する技術として、次のような文献がある。 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.
国際公開第２００９／１４２３２６号パンフレットInternational Publication No. 2009/142326 Pamphlet
　特許文献１に記載されるような従来型のポリマーＤＤＳは、水酸基を有する薬物を、当該水酸基を利用したエステル結合を介してポリアミノ酸セグメントの酸性アミノ酸残基に結合させた状態で搭載しており、当該酸性アミノ酸残基の構造変化を伴った加水分解反応によって薬物を放出するメカニズムを有している。従来型のポリマーＤＤＳの技術分野では、こうした薬物放出メカニズムの利用は、酸性アミノ酸残基と水酸基を有する薬物との組合せに制限されるとの既成概念があった。 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. In the technical field of the conventional polymer DDS, there was an established concept that the use of such a drug release mechanism is limited to a combination of an acidic amino acid residue and a drug having a hydroxyl group.
　本発明の主目的は、カルボキシル基を有する薬物の放出制御を可能にするポリマーＤＤＳの提供にある。 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.
　本発明によれば、一般式：Ａ－Ｂで表される薬物複合化ブロック共重合体が提供される。Ａは、ポリエチレングリコール鎖セグメントを表し、Ｂは、下記一般式（ｉ）で表される繰り返し単位、および／または、下記一般式（ｉｉ）で表される繰り返し単位を含むコ－ポリアミノ酸鎖セグメントを表し、下記一般式（ｉ）および下記一般式（ｉｉ）中、Ｘは、連結基を有していてもよい薬物の残基を表す。
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000008
 According to the present invention, there is provided 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) In the following general formula (i) and the following general formula (ii), X represents a drug residue optionally having a linking group.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000008
　本発明の別の局面によれば、下記一般式（ＩＩ）で表される、ブロック共重合体が提供される。
Figure JPOXMLDOC01-appb-C000009
 　上記式中、
　Ｒ１は、水素原子、非置換もしくは置換された炭素数１～１２の直鎖または分枝状のアルキル基、あるいは標的結合部位を有する基を表し、
　Ｒ２は、疎水性基を表し、
　Ｒ３は、水素原子、飽和もしくは不飽和の非置換もしくは置換された炭素数１～３０の直鎖または分枝状の脂肪族カルボニル基またはアリールカルボニル基、あるいは炭素数１～１２の非置換もしくは置換された直鎖または分枝状のアルキル基を表し、
　Ｌは、リンカーを表し、
　ｍは、３０～２０，０００の整数であり、
　ｘは、５～１００の整数であり、
　ａは、０～１００の整数であり、
　ｂは、０～１００の整数であり、
　ｃは、０～１００の整数であり、
　ｄは、０～１００の整数であり、
　ａとｃとの和は、１～２００であり、
　前記コ－ポリアミノ酸鎖セグメントにおける各反復単位の結合順は任意である。 According to another aspect of the present invention, a block copolymer represented by the following general formula (II) is provided.
Figure JPOXMLDOC01-appb-C000009
 In the above formula,
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. Represents a substituted linear or branched alkyl group,
L represents a linker;
m is an integer from 30 to 20,000,
x is an integer of 5 to 100,
a is an integer of 0 to 100;
b is an integer from 0 to 100;
c is an integer from 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.
　本発明のさらに別の局面によれば、下記一般式（Ｉ）で表される薬物複合化ブロック共重合体の製造方法が提供される。
Figure JPOXMLDOC01-appb-C000010
 　上記製造方法は、上記一般式（ＩＩ）で表されるブロック共重合体のコ－ポリアミノ酸鎖セグメントの側鎖の水酸基の全部または一部と、カルボキシル基を有し、連結基を有していてもよい薬物の該カルボキシル基とを反応させてエステル結合を形成させる工程、を含む。 According to still another aspect of the present invention, a method for producing a drug-conjugated block copolymer represented by the following general formula (I) is provided.
Figure JPOXMLDOC01-appb-C000010
 The above production method 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.
　本発明によれば、カルボキシル基を有する薬物の放出制御を可能にする薬物複合化ブロック共重合体が提供される。 According to the present invention, a drug-conjugated block copolymer that enables controlled release of a drug having a carboxyl group is provided.
［１．薬物複合化ブロック共重合体］
　本発明の１つの実施形態による薬物複合化ブロック共重合体について以下に述べる。上記薬物複合化ブロック共重合体は一般式：Ａ－Ｂで表される。Ａは、ポリエチレングリコール鎖セグメントを表す。Ｂは、下記一般式（ｉ）で表される繰り返し単位、および／または、下記一般式（ｉｉ）で表される繰り返し単位を含むコ－ポリアミノ酸鎖セグメントを表す。下記一般式（ｉ）および下記一般式（ｉｉ）中、Ｘは、連結基を有していてもよい薬物の残基を表す。
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
 [1. Drug-conjugated block copolymer]
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). In the following general formula (i) and the following general formula (ii), X represents a drug residue which may have a linking group.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
　上記ポリエチレングリコール鎖セグメントの分子量は、例えば５００以上、さらには２，０００以上であってよく、また例えば５０，０００以下、さらには２０，０００以下であってよい。 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.
　上記コ－ポリアミノ酸鎖セグメントは、代表的には、側鎖に疎水性基を有するアミノ酸残基をさらに含む。上記アミノ酸残基としては、任意の適切なアミノ酸残基を採用し得る。上記アミノ酸残基は、好ましくは側鎖に疎水性基が導入されたグルタミン酸残基である。上記疎水性基としては、任意の適切な疎水性基を採用し得る。上記疎水性基としては、例えば、疎水性有機基が挙げられる。上記疎水性有機基としては、例えば、Ｃ４～Ｃ１６の直鎖、分岐鎖または環状構造を有するアルキル基、Ｃ６～Ｃ２０のアリール基、およびＣ７～Ｃ２０のアラルキル基またはステロール残基が挙げられる。上記Ｃ６～Ｃ２０のアリール基およびＣ７～Ｃ２０のアラルキル基としては、好ましくはフェニル基、ナフチル基、トリル基、キシリル基、ベンジル基、およびフェネチル基、さらに好ましくはベンジル基が挙げられる。また、上記ステロール残基が由来するステロールは、好ましくはコレステロール、コレスタノール、およびジヒドロキシコレステロールであり、より好ましくはコレステロールである。 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.
　上記コ－ポリアミノ酸鎖セグメントは、代表的には、側鎖に親水性基を有するアミノ酸残基をさらに含む。上記アミノ酸残基としては、任意の適切なアミノ酸残基を採用し得る。上記アミノ酸残基は、好ましくは任意に側鎖のカルボキシル基が他の親水性基に変換されたアスパラギン酸残基である。上記親水性基としては、任意の適切な親水性基を採用し得る。上記親水性基としては、例えば、水酸基が挙げられる。 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.
　上記薬物は、カルボキシル基を有する化合物である。例えば、シプロフロキサシン、セフェピム、NMK-36、アルプロスタジル、ドリペネム、レボフロキサシン、パズフロキサシン、BILN-2061、セフォチアム、タラポルフィン、セフトリアキソン、トスフロキサシン、フロモキセフ、プルリフロキサシン、ML-04、イミペネム、エノキサシン、PD-123177、Fenofibric Acid、エプリステリド、オフロキサシン、エナラプリル、YY-984、コール酸、バルサルタン、オザグレル、パズフロキサシン、セフタジジム、エルドステイン 、チロキシン、VX-809、ベザフィブラート、タゾバクタム、チロフィバン、ルビプロストン、フェブキソスタット、アルガトロバン、エプロサルタン、ロメフロキサシン、ペラミビル、ラミプリル、リオチロニン、メトトレキサート、エノキサシン、フルルビプロフェン、ガチフロキサシン、エプリステリド、カンデサルタン、フェノフィブリン酸、Alvogen 、エトドラク、ベナゼプリル、CV11974、CV2961、CV2973、アジルサルタン、アセチルサリチル酸、アンピシリン、イブプロフェン、インドメタシン、カプトプリル、ジクロフェナク、ベンラファキシン、ナテグリニド、ニューロタン、ブラバスタチン、ペニシリン、ミチグリニド、メチシリン、リピトール、レパグリニド、レボセチリジン、レボフロキサシン、ロキソプロフェン、オキサシリン、Ro64-0802、Trifarotene、ベンダムスチン、バルプロ酸、メトトレキサート 、GSK-2636771、(R)-folitixorin、メルファラン、アミノレブリン酸、リゴサチブ、technetium Tc 99m trofolastat、MLN9708、GPC-3298306、S-588410、Minerval、CPI-613、CMS-024-02、angiotensin-(1-7)、177Lu-DOTATATE、MLN8237、CMS024、DCDS4501A、indoximod、NMK-36、18F-ML-10、mipsagargin、MK-8109、エルパモチド、ネリペピムト-S、CBP-501、タミバロテン、レボチロキシン、ベキサロテン、afamelanotide、GlutaDON、テクネチウム (99mTc) エタルフォラチド、Luminespib、salirasib、A-6、vosaroxin、TSU-68、ペレチノイン、プララトレキサート、フォリン酸、PCI-27483、エメペピムト-S、イトリグルミド、ML-04、エルトロンボパグ、フェブキソスタット、ウベニメクス、トレチノイン、インジウム111ペンテトレオチド、TLK286、SPI-1620、ペメトレキセド、ラルチトレキセド、E7974（ヘミアステリン誘導体）、およびRQ-00000008が挙げられる。 The above drug is a compound having a carboxyl group. For example, ciprofloxacin, cefepime, NMK-36, alprostadil, doripenem, levofloxacin, pazufloxacin, BILN-2061, cefotiam, talaporfin, ceftriaxone, tosufloxacin, flomoxef, pullrifloxacin, ML-04, imipenem , Enoxacin, PD-123177, Fenofibric® Acid, Epristeride, Ofloxacin, Enalapril, YY-984, Cholic acid, Valsartan, Ozagrel, Pazufloxacin, Ceftazidime, Erdosteine®, Tyroxine, VX-809, Bezafibrate, Tazobactam, Tirobium Stat, argatroban, eprosartan, lomefloxacin, peramivir, ramipril, liothyronine, methotrexate, enoxacin, flurbiprofen, gatifloxacin Epristeride, candesartan, fenofibric acid, Alvogen, etodolac, benazepril, CV11974, CV2961, CV2973, azilsartan, acetylsalicylic acid, ampicillin, ibuprofen, indomethacin, captopril, diclofenac, venlafaxine, nateglinidovaline, nateglinidova , Methicillin, lipitol, repaglinide, levocetirizine, levofloxacin, loxoprofen, oxacillin, Ro64-0802, Trifarotene, bendamustine, valproic acid, methotrexate, GSK-2636771, (R) -folitixorin, melphalan, aminolevulinic acid, tech s , MLN9708, GPC-3298306, S-588410, Minerval, CPI-613, CMS-024-02, angiotensin- (1-7), 177Lu-DOTATATE, MLN8237, CMS024, DCDS4501A, indoximod, NMK-36 18F-ML-10, mipsagargin, MK-8109, elpamotide, neripepimuto-S, CBP-501, tamibarotene, levothyroxine, bexarotene, afamelanotide, GlutaDON, technetium (99mTc) etafolatide, Luminespib, salirasib, A-6, -68, peretinoin, plalatrexate, folinic acid, PCI-27483, emepepimuto-S, itriglumide, ML-04, eltrombopag, febuxostat, ubenimex, tretinoin, indium 111 pentetreotide, TLK286, SPI-1620, pemetrexed, Raltitrexed, E7974 (hemiasterin derivative), and RQ-00000008.
　上記カルボキシル基を有する薬物は、その活性ドメイン部分とカルボキシル基との間に連結基が配置された状態にあってもよい。このように本明細書では、薬物の活性ドメイン部分と当該カルボキシル基との間に連結基が配置された状態にある化合物についても、上記カルボキシル基を有する薬物として取り扱う。上記連結基としては、例えば、アミド結合、エステル結合、エーテル結合、および／またはヒドラジド結合を含んでいても良い炭素数０～５の２価の連結基が挙げられる。 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. Thus, in this specification, 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. Examples of 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.
　上記薬物複合化ブロック共重合体は、好ましくは下記一般式（Ｉ）で表される。
Figure JPOXMLDOC01-appb-C000013
 　上記式中、Ｒ１は、水素原子、非置換もしくは置換された炭素数１～１２の直鎖または分枝状のアルキル基、あるいは標的結合部位を有する基を表す。Ｒ２は、疎水性基を表す。Ｒ３は、水素原子、飽和もしくは不飽和の非置換もしくは置換された炭素数１～３０の直鎖または分枝状の脂肪族カルボニル基またはアリールカルボニル基、あるいは炭素数１～１２の非置換もしくは置換された直鎖または分枝状のアルキル基を表す。Ｌは、リンカーを表す。ｍは、３０～２０，０００の整数である。ｘは、５～１００の整数である。ａは、０～１００の整数である。ｂは、０～１００の整数である。ｃは、０～１００の整数である。ｄは、０～１００の整数である。ａとｃとの和は、１～２００である。前記コ－ポリアミノ酸鎖セグメントにおける各反復単位の結合順は任意である。 The drug-conjugated block copolymer is preferably represented by the following general formula (I).
Figure JPOXMLDOC01-appb-C000013
 In the above formula, 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. Represents a substituted straight or branched alkyl group. 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.
　本明細書において、標的結合部位とは、生体およびウイルスに由来する物質に対し特異的に結合して当該物質と生物学的な結合対を形成し得る、生物学的な認識機能を有する部位を意味する。標的結合部位を有する基は、例えば、低分子化合物、糖鎖、ペプチド、抗体およびその断片等であって、生体およびウイルスに由来する物質と生物学的な結合対を形成し得る化合物を、その構造の少なくとも一部として含有した状態で構成されていてもよい。 In this specification, 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. means. 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.
　上記リンカーとしては、任意の適切なリンカーを採用し得る。上記リンカーとしては、例えば、－ＮＨ－、－Ｏ－、－Ｏ－Ｚ－ＮＨ－、－ＣＯ－、－ＣＨ２－、－Ｏ－Ｚ－Ｓ－Ｚ－および－ＯＣＯ－Ｚ－ＮＨ－（ここで、Ｚは独立してＣ１～Ｃ６アルキレン基である。）からなる群より選ばれるリンカーが挙げられる。 Any appropriate linker can be adopted as the linker. Examples of the linker include —NH—, —O—, —O—Z—NH—, —CO—, —CH 2 —, —O—Z—S—Z— and —OCO—Z—NH— ( Here, Z is a C 1 -C 6 alkylene group independently), and a linker selected from the group consisting of:
　上記式（Ｉ）中、ｍは、上述の通り３０～２０，０００の整数である。ｍは、例えば５０以上の整数、１００以上の整数、さらには２００以上の整数であってよく、また例えば５，０００以下の整数、５００以下の整数、さらには３００以下の整数であってよい。 In the above formula (I), m is an integer of 30 to 20,000 as described above. For example, 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.
　上記式（Ｉ）中、ｘは、上述の通り５～１００の整数である。ｘは、例えば１０以上の整数、さらには１５以上の整数であってよく、また例えば６０以下の整数、４０以下の整数、さらには２５以下の整数であってよい。 In the above formula (I), 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.
　上記式（Ｉ）中、ａは、上述の通り０～１００の整数である。ａは、例えば１以上の整数、さらには５以上の整数であってよく、また例えば６０以下の整数、さらには４０以下の整数であってよい。 In the above formula (I), 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.
　上記式（Ｉ）中、ｂは、上述の通り０～１００の整数である。ｂは、例えば１以上の整数、さらには５以上の整数であってよく、また例えば６０以下の整数、さらには４０以下の整数であってよい。 In the above formula (I), b is an integer of 0 to 100 as described above. For example, 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.
　上記式（Ｉ）中、ｃは、上述の通り０～１００の整数である。ｃは、例えば１以上の整数、さらには５以上の整数であってよく、また例えば６０以下の整数、さらには４０以下の整数であってよい。 In the above formula (I), 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.
　上記式（Ｉ）中、ｄは、上述の通り０～１００の整数である。ｄは、例えば１以上の整数、さらには５以上の整数であってよく、また例えば６０以下の整数、さらには４０以下の整数であってよい。 In the above formula (I), d is an integer of 0 to 100 as described above. For example, 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.
　上記式（Ｉ）中、ａとｃとの和は、上述の通り１～２００の整数である。ａとｃとの和は、例えば２以上の整数、３以上の整数、４以上の整数、５以上の整数、さらには６以上の整数であってよく、また例えば４０以下の整数、２０以下の整数、１０以下の整数、さらには８以下の整数であってよい。 In the above formula (I), 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.
　上記式（Ｉ）中、ｘとａとｂとｃとｄとの和は、例えば１０以上、２０以上、さらには３０以上であってよく、また例えば２００以下、１００以下、さらには５０以下であってよい。 In the above formula (I), 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.
　上記式（Ｉ）中、ｘ：（ａ＋ｂ＋ｃ＋ｄ）は、例えば９０：１０～１０：９０であり、また例えば８０：２０～２０：８０である。 In the above formula (I), x: (a + b + c + d) is, for example, 90:10 to 10:90, and for example, 80:20 to 20:80.
　上記式（Ｉ）中、ｘ：（ｂ＋ｄ）は、例えば２０：８０～８０：２０であり、また例えば２５：７５～７５：２５であり、また例えば３０：７０～７０：３０である。 In the above formula (I), 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.
　上記式（Ｉ）中、（ｘ＋ａ＋ｂ＋ｃ＋ｄ）に対する（ａ＋ｃ）の比率（％）は、例えば２％以上、さらには７％以上であってよく、また例えば５０％以下、さらには３５％以下であってよい。 In the above formula (I), 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.
　上記式（Ｉ）中、（ａ＋ｃ）：（ｂ＋ｄ）は、例えば９０：１０～３０：７０であり、また例えば８０：２０～３０：７０である。 In the above formula (I), (a + c) :( b + d) is, for example, 90:10 to 30:70, and for example, 80:20 to 30:70.
　上記式（Ｉ）中、ｘ／（ａ＋ｃ）は、例えば０．５以上、さらには１以上であってよく、また例えば１５以下、さらには１０以下であってよい。 In the above formula (I), x / (a + c) may be 0.5 or more, further 1 or more, for example, 15 or less, or 10 or less.
［２．ブロック共重合体］
　本発明の１つの実施形態によるブロック共重合体について以下に述べる。上記ブロック共重合体は下記一般式（ＩＩ）で表される。
Figure JPOXMLDOC01-appb-C000014
 　上記式（ＩＩ）中、Ｒ１、Ｒ２、Ｒ３、Ｌ、ｍ、ｘ、ａ、ｂ、ｃ、ｄについては、上記式（Ｉ）において説明した通りである。上記コ－ポリアミノ酸鎖セグメントにおける各反復単位の結合順は任意である。 [2. 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).
Figure JPOXMLDOC01-appb-C000014
 In the above 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.
　１つの実施形態において、上記式（ＩＩ）で表されるブロック共重合体は、式（ＩＩＩ）で表わされるブロック共重合体である。
Figure JPOXMLDOC01-appb-C000015
 　上記式（ＩＩＩ）中、Ｒ１、Ｒ２、Ｒ３、Ｌ、ｍ、ｘについては、上記式（Ｉ）において説明した通りであり、ｅおよびｆはそれぞれ独立して、０～２００の整数であり、ｅ＋ｆは、１～２００の整数である。また、上記コ－ポリアミノ酸鎖セグメントにおける各反復単位の結合順は任意である。 In one embodiment, the block copolymer represented by the formula (II) is a block copolymer represented by the formula (III).
Figure JPOXMLDOC01-appb-C000015
 In the above 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.
　上記式（ＩＩＩ）中、ｅおよびｆはそれぞれ独立して、例えば０以上の整数、さらには２以上の整数、またさらには１０以上の整数であってよく、また例えば２００以下の整数、さらには１２０以下の整数、またさらには８０以下の整数であってよい。 In the above formula (III), 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.
　上記式（ＩＩＩ）中、ｅ＋ｆは、例えば５以上の整数、さらには１０以上の整数であってよく、また例えば１００以下の整数、さらには６０以下の整数であってよい。 In the above formula (III), 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.
　上記式（ＩＩＩ）中、（ｘ＋ｅ＋ｆ）は、例えば１０以上、さらには２０以上であってよく、また例えば２００以下、さらには１００以下であってよい。 In the above formula (III), (x + e + f) may be, for example, 10 or more, further 20 or more, for example, 200 or less, or 100 or less.
　上記式（ＩＩＩ）中、ｘ：（ｅ＋ｆ）は、例えば９０：１０～１０：９０であってよく、また例えば８０：２０～２０：８０であってよい。 In the above formula (III), x: (e + f) may be 90:10 to 10:90, for example, and may be 80:20 to 20:80, for example.
［３．薬物複合化ブロック共重合体の製造方法］
　本発明の１つの実施形態による薬物複合化ブロック共重合体の製造方法について以下に述べる。上記製造方法は上記一般式（Ｉ）で表される薬物複合化ブロック共重合体の製造方法である。 [3. Method for producing drug-conjugated block copolymer]
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).
　薬物複合化ブロック共重合体の製造方法の具体例を以下に説明する。 Specific examples of the method for producing the drug-conjugated block copolymer will be described below.
　上記製造方法は、上述のように、上記一般式（ＩＩ）で表されるブロック共重合体のコ－ポリアミノ酸鎖セグメントの側鎖の水酸基の全部または一部と、カルボキシル基を有し、連結基を有していてもよい薬物の該カルボキシル基とを反応させてエステル結合を形成させる工程を含む。 As described above, 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.
　上記製造方法は、さらに、ポリエチレングリコール－コ－ポリグルタミン酸Ｒ２エステル－ポリアスパラギン酸（ＰＥＧ－ＰＲ２ＬＧ－ｐＡｓｐ）を準備する工程を有し得る。上記コ－ポリアミノ酸鎖セグメントにおいては、側鎖にＲ２がエステル結合したグルタミン酸残基とアスパラギン酸残基とが任意に配置されている。 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). In the co-polyamino acid chain segment, a glutamic acid residue and an aspartic acid residue in which R 2 is ester-bonded to the side chain are arbitrarily arranged.
　上記製造方法は、さらに、ＰＥＧ－ＰＲ２ＬＧ－ｐＡｓｐのアスパラギン酸側鎖のカルボキシル基を還元し、水酸基とする工程を有し得る。その結果、ポリエチレングリコール－コ－ポリアミノ酸において、側鎖にＲ２がエステル結合したグルタミン酸残基と還元型アスパラギン酸残基とが任意に配置されたコポリマー（ＰＥＧ－ＰＲ２ＬＧ－ｐＡｓｐ（ｒｅｄ））（すなわち、一般式（ＩＩ）で表されるブロック共重合体）が得られ得る。 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. As a result, 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.
（エステル結合形成工程）
　上記水酸基と上記カルボキシル基を有する薬物の該カルボキシル基とを反応させてエステル結合を形成させる方法としては、任意の適切な方法を採用し得る。 (Ester bond formation process)
Any appropriate method can be adopted as a method of forming an ester bond by reacting the hydroxyl group with the carboxyl group of the drug having the carboxyl group.
（ＰＥＧ－ＰＲ２ＬＧ－ｐＡｓｐ準備工程）
　ＰＥＧ－ＰＲ２ＬＧ－ｐＡｓｐを準備する方法の一例として、ポリエチレングリコール（ＰＥＧ）鎖を有するポリマーとコ－ポリグルタミン酸Ｒ２エステル－ポリアスパラギン酸（ＰＲ２ＬＧ－ｐＡｓｐ）を有するポリマーとを、任意の適切な方法によりカップリングする方法が挙げられる。 (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－ＰＲ２ＬＧ－ｐＡｓｐを準備する方法の別の例として、片末端が保護され、もう一方の末端がアミノ基であるポリエチレングリコールを開始剤として、アスパラギン酸無水物（Ａｓｐ－ＮＣＡ）およびＮ－カルボキシ－γ－Ｒ２－Ｌ－グルタミン酸無水物（Ｒ２ＬＧ－ＮＣＡ）を所望の重合度（アミノ酸ユニット数）となるように添加し、反応させる方法が挙げられる。上記開始剤としては、任意の適切な開始剤を採用し得る。上記開始剤としては、例えばＭｅＯ－ＰＥＧ－ＣＨ２ＣＨ２ＣＨ２－ＮＨ２が挙げられる。上記反応は、好ましくは脱水された有機溶媒中で行われる。 As another example of a method for preparing PEG-PR 2 LG-pAsp, 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-γ-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. Examples of 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－ＰＲ２ＬＧ－ｐＡｓｐ還元工程）
　アスパラギン酸側鎖のカルボキシル基を還元し、水酸基とする方法としては、任意の適切な方法を採用し得る。 (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.
［４．ポリマーミセル医薬組成物］
　本発明の１つの実施形態による薬物複合化ブロック共重合体（以下、ブロックコポリマーユニットαと称する場合がある。）を含むポリマーミセル医薬組成物について以下に述べる。上記ポリマーミセル医薬組成物は、標的結合部位が結合したポリエチレングリコール鎖セグメントとポリアミノ酸鎖セグメントとを有し、かつ、ブロックコポリマーユニットαではないブロックコポリマーユニットβをさらに含んでいてもよい。上記ポリマーミセル医薬組成物は、標的結合部位も薬物も含有せず、ポリエチレングリコール鎖セグメントと、ポリアミノ酸鎖セグメントとを有するブロックコポリマーユニットγをさらに含んでいてもよい。 [4. Polymer micelle pharmaceutical composition]
A polymer micelle pharmaceutical composition comprising a drug-conjugated block copolymer (hereinafter sometimes referred to as block copolymer unit α) according to one embodiment of the present invention is described below. The polymer micelle pharmaceutical composition may further include a block copolymer unit β 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 α. The polymer micelle pharmaceutical composition contains neither a target binding site nor a drug, and may further include a block copolymer unit γ having a polyethylene glycol chain segment and a polyamino acid chain segment.
　代表的には、上記ポリマーミセル医薬組成物において、ブロックコポリマーユニットα、ならびに存在する場合にはβおよびγは、ポリエチレングリコール鎖セグメントを外側に向けた状態で放射状に配列している。本明細書において、ブロックコポリマーが放射状に配列しているとは、ポリエチレングリコール鎖セグメントを外側に向けるとともに、ポリエチレングリコール鎖セグメントと反対側のセグメント（コーポリアミノ酸鎖セグメント）が内側に向けて凝集した状態にあればよい。 Typically, in the polymer micelle pharmaceutical composition described above, the block copolymer unit α and, if present, β and γ are arranged radially with the polyethylene glycol chain segment facing outward. In this specification, 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.
　上記ポリマーミセル医薬組成物の多分散指数（ＰＤＩ：Polydispersity　Index）は、任意の適切な値をとり得る。上記多分散指数は、例えば０．０１以上、さらには０．０２以上であってよく、また例えば０．８以下、さらには０．５以下であってよい。 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.
　上記ポリマーミセル医薬組成物におけるブロックコポリマーユニットαの含有量としては、任意の適切な値をとり得る。上記含有量としては、例えば２０重量％以上であり、また例えば３０重量％以上である。上記含有量が所定値以上であることにより、ポリマーミセル医薬組成物に十分量の薬物を搭載することがより容易になる。一方、上記含有量としては、例えば９０重量％以下であり、また例えば８０重量％以下であり、また例えば７０重量％以下である。 The content of the block copolymer unit α 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.
　上記ブロックコポリマーは、上記のブロックコポリマーユニットα、ならびに存在する場合にはβおよびγをそれぞれ２種類以上含んでいてもよい。 The block copolymer may contain two or more kinds of the above-mentioned block copolymer unit α and, if present, β and γ.
　ブロックコポリマーユニットβおよびγのポリアミノ酸鎖セグメントは、それぞれ好ましくは側鎖に疎水性基を有するアミノ酸残基を含む。上記アミノ酸残基としては、任意の適切なアミノ酸残基を採用し得る。上記アミノ酸残基としては、例えば、側鎖に疎水性基が導入されたグルタミン酸残基、およびアスパラギン酸残基が挙げられる。上記疎水性基としては、任意の適切な疎水性基を採用し得る。上記疎水性基としては、例えば、薬物複合化ブロック共重合体について述べた疎水性基が挙げられる。 The polyamino acid chain segments of the block copolymer units β and γ 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.
　ブロックコポリマーユニットγのポリアミノ酸鎖セグメントは、好ましくは側鎖に親水性基を有するアミノ酸残基を含む。上記アミノ酸残基としては、任意の適切なアミノ酸残基を採用し得る。上記アミノ酸残基としては、例えば、グルタミン酸残基、およびアスパラギン酸残基が挙げられる。上記親水性基としては、任意の適切な親水性基を採用し得る。上記親水性基としては、例えばカルボキシル基が挙げられる。 The polyamino acid chain segment of the block copolymer unit γ 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.
　以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例には限定されない。実施例における試験および評価方法は以下のとおりである。また、特に明記しない限り、実施例における「部」および「％」は重量基準である。 Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples. The tests and evaluation methods in the examples are as follows. Unless otherwise specified, “parts” and “%” in the examples are based on weight.
［試験例１］
　薬物としてイブプロフェンを搭載したポリマーミセルを次のようにして形成した。 [Test Example 1]
Polymer micelles loaded with ibuprofen as a drug were formed as follows.
（薬物複合化ブロック共重合体の調製）
　上記一般式（Ｉ）で表される薬物複合化ブロック共重合体を、次のようにして調製した。コ－ポリアミノ酸の片末端がアセチル化されたポリエチレングリコール－コ－ポリグルタミン酸ベンジルエステル－ポリ還元型アスパラギン酸（ＰＥＧ－ＰＢＬＧ－ｐＡｓｐ（ｒｅｄ））の還元型アスパラギン酸残基の側鎖の水酸基と、イブプロフェンのカルボキシル基とを反応させてエステル結合を形成させた。その結果、上記一般式（Ｉ）で表される薬物複合化ブロック共重合体を得た。得られた薬物複合化ブロック共重合体（表１中、「ＰＥＧ－ＰＢＬＧ－ｐＡｓｐ（ｒｅｄ）－ＩＢ」として示される）についてＮＭＲによりイブプロフェン残基数を測定した結果を表１に示す。表１において、「ＡＡ」は、上記薬物複合化ブロック共重合体のアミノ酸残基数の平均値を表し、「ＰＥＧ　ＭＷ」は、ＰＥＧの平均分子量（Ｍｗ）を表す（平均分子量（Ｍｗ）が１０，０００であるＰＥＧの重合度は、２２６～２２７程度と算出される）。「Ｂｎ：ＯＨ比率」は、薬物複合化前のブロック共重合体における（側鎖がベンジルエステル化されたグルタミン酸残基数の平均値）：（還元型アスパラギン酸残基の水酸基数の平均値）を表す。「ＩＢ数」は、薬物複合化ブロック共重合体におけるＮＭＲにより測定されたイブプロフェン残基数の平均値を表す。 (Preparation of drug-conjugated block copolymer)
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). In Table 1, “AA” represents the average value of the number of amino acid residues of the drug-conjugated block copolymer, and “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). “Bn: 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.
（ミセルの調製）
　上記薬物複合化ブロック共重合体にメタノールまたはアセトンを添加して溶解した。その後、ロータリーエバポレーター（ビュッヒ製、Rotavapor　R-205、Vac(R)　V-513）で溶媒留去してポリマーのフィルムを形成し、更に一昼夜乾燥した。１００ｍＭ　ＰＢＳ（pH7.4）を加えてフィルムを分散させた後、ナノヴェイタ（吉田機械興業製、NM2-L200）を用いて高圧分散処理してポリマーミセルを得た。当該ミセル画分には、上記薬物複合化ブロック共重合体が放射状に配列したポリマーミセルが含有されている。得られたポリマーミセル（表２中、「ｐＡｓｐ（ｒｅｄ）ミセル」として示される）および上記薬物複合化ブロック共重合体についてイブプロフェン含有量を測定した結果を表２に示す。表２において、「ＩＢＮＭＲ」は、ＮＭＲにより測定された薬物複合化ブロック共重合体におけるイブプロフェン含有量（％）を表す。また、「ＩＢＨＰＬＣ」は、ＨＰＬＣにより測定されたポリマーミセルにおけるイブプロフェン含有量（％）を表す。 (Preparation of micelles)
Methanol or acetone was added to the drug-conjugated block copolymer and dissolved. Thereafter, the solvent was distilled off with a rotary evaporator (Buch, Rotavapor R-205, Vac (R) V-513) to form a polymer film, which was further dried overnight. After adding 100 mM PBS (pH 7.4) to disperse the film, polymer micelles were obtained by high-pressure dispersion treatment using Nanovaita (NM2-L200, manufactured by Yoshida Kikai Kogyo Co., Ltd.). The micelle fraction contains polymer micelles in which the drug-conjugated block copolymer is radially arranged. 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. In Table 2, “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.
［試験例２］
　ＰＥＧ－ＰＢＬＧ－ｐＡｓｐ（ｒｅｄ）に代えて、コ－ポリアミノ酸の片末端がアセチル化されたポリエチレングリコール－コ－ポリグルタミン酸ベンジルエステル－ポリ還元型グルタミン酸（ＰＥＧ－ＰＢＬＧ－ｐＧｌｕ（ｒｅｄ））を用いた以外は、試験例１と同一の方法で薬物複合化ブロック共重合体を調製した。得られた薬物複合化ブロック共重合体（表１中、「ＰＥＧ－ＰＢＬＧ－ｐＧｌｕ（ｒｅｄ）－ＩＢ」として示される）についてＮＭＲによりイブプロフェン残基数を測定した結果を表１に示す。また、上記薬物複合化ブロック共重合体を用いて試験例１と同一の方法でポリマーミセルを得た。得られたポリマーミセル（表２中、「ｐＧｌｕ（ｒｅｄ）ミセル」として示される）および上記薬物複合化ブロック共重合体についてイブプロフェン含有量を測定した結果を表２に示す。 [Test Example 2]
In place of PEG-PBLG-pAsp (red), polyethylene glycol-co-polyglutamic acid benzyl ester-polyreduced glutamic acid (PEG-PBLG-pGlu (red)) in which one end of the co-polyamino acid is acetylated is used A drug-conjugated block copolymer was prepared in the same manner as in Test Example 1 except that. 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-pGlu (red) -IB” in Table 1). In addition, 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.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
（イブプロフェン放出試験）
　３７℃で湯浴したＰＢＳ中にイブプロフェン濃度が１μｇ／ｍＬになるように試験例１および２のミセル製剤を添加して、緩やかに振とうさせた。２４時間後にＰＢＳの一部を回収して、ミセルからＰＢＳ中に放出されたイブプロフェンの濃度を測定した。イブプロフェンの総量に対する放出されたイブプロフェン量の比率（％）を算出した。結果を表２に「薬物放出率」として示す。 (Ibuprofen release test)
The micelle preparations of Test Examples 1 and 2 were added to PBS bathed in water at 37 ° C. so that the concentration of ibuprofen was 1 μg / mL, and gently shaken. A portion of PBS was collected after 24 hours and the concentration of ibuprofen released from micelles into PBS was measured. The ratio (%) of the amount of ibuprofen released to the total amount of ibuprofen was calculated. The results are shown in Table 2 as “drug release rate”.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
［試験例３］
　薬物として、下記式（ｉｉｉ）で表わされるヘミアステリン誘導体であるＥ７９７４を搭載したポリマーミセルを次のようにして形成した。
Figure JPOXMLDOC01-appb-C000018
 [Test Example 3]
As a drug, a polymer micelle loaded with E7974, which is a hemiasterin derivative represented by the following formula (iii), was formed as follows.
Figure JPOXMLDOC01-appb-C000018
（薬物複合化ブロック共重合体の調製）
　薬物としてＥ７９７４を用いたこと以外は試験例１と同一の方法で薬物複合化ブロック共重合体を調製した。得られた薬物複合化ブロック共重合体（表３中、「ＰＥＧ－ＰＢＬＧ－ｐＡｓｐ（ｒｅｄ）－Ｅ７９７４」として示される）についてＥ７９７４残基数を測定した結果を表３に示す。表３において「ＡＡ」、「ＰＥＧ　ＭＷ」、「Ｂｎ：ＯＨ比率」は、表１と同様の意味である。「Ｅ７９７４数」は、加水分解後、ＨＰＬＣにより測定された薬物複合化ブロック共重合体におけるＥ７９７４残基数の平均値を表す。 (Preparation of 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). 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.
（ミセルの調製）
　上記薬物複合化ブロック共重合体を用いて、試験例１と同様の方法でポリマーミセルを得た。当該ミセル画分には、上記薬物複合化ブロック共重合体が放射状に配列したポリマーミセルが含有されている。得られたポリマーミセル（表４中、「ｐＡｓｐ（ｒｅｄ）ミセル」として示される）についてＥ７９７４含有量を測定した結果を表４に示す。表４において、「Ｅ７９７４含有量（ＨＰＬＣ）」は、ＨＰＬＣにより測定されたポリマーミセルにおけるＥ７９７４含有量（％）を表す。 (Preparation of micelles)
Polymer micelles were obtained in the same manner as in Test Example 1 using the drug-conjugated block copolymer. The micelle fraction contains polymer micelles in which the drug-conjugated block copolymer is radially arranged. Table 4 shows the results of measuring the E7974 content of the obtained polymer micelle (shown as “pAsp (red) micelle” in Table 4). In Table 4, “E7974 content (HPLC)” represents the E7974 content (%) in polymer micelles measured by HPLC.
［試験例４］
　ＰＥＧ－ＰＢＬＧ－ｐＡｓｐ（ｒｅｄ）に代えて、コ－ポリアミノ酸の片末端がアセチル化されたポリエチレングリコール－コ－ポリグルタミン酸ベンジルエステル－ポリ還元型グルタミン酸（ＰＥＧ－ＰＢＬＧ－ｐＧｌｕ（ｒｅｄ））を用いた以外は、試験例３と同一の方法で薬物複合化ブロック共重合体を調製した。得られた薬物複合化ブロック共重合体（表３中、「ＰＥＧ－ＰＢＬＧ－ｐＧｌｕ（ｒｅｄ）－Ｅ７９７４」として示される）についてＥ７９７４残基数を測定した結果を表３に示す。また、上記薬物複合化ブロック共重合体を用いて試験例１と同一の方法でポリマーミセルを得た。得られたポリマーミセル（表４中、「ｐＧｌｕ（ｒｅｄ）ミセル」として示される）についてＥ７９７４含有量を測定した結果を表４に示す。 [Test Example 4]
In place of PEG-PBLG-pAsp (red), polyethylene glycol-co-polyglutamic acid benzyl ester-polyreduced glutamic acid (PEG-PBLG-pGlu (red)) in which one end of the co-polyamino acid is acetylated is used A drug-conjugated block copolymer was prepared in the same manner as in Test Example 3 except that. Table 3 shows the results of measuring the number of E7974 residues for the obtained drug-conjugated block copolymer (shown as “PEG-PBLG-pGlu (red) -E7974” in Table 3). In addition, 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).
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
（Ｅ７９７４放出試験）
　３７℃で湯浴したＰＢＳ中にＥ７９７４濃度が１μｇ／ｍＬになるように試験例３および４のミセル製剤を添加して、緩やかに振とうさせた。２４時間後にＰＢＳの一部を回収して、ミセルからＰＢＳ中に放出されたＥ７９７４の濃度を測定した。Ｅ７９７４の総量に対する放出されたＥ７９７４量の比率（％）を算出した。結果を表４に「薬物放出率」として示す。 (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 μg / 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”.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　表２および表４からわかるように、ポリエチレングリコール－コ－ポリアミノ酸共重合体を薬物複合化ブロック共重合体として用いるポリマーミセル医薬組成物において、上記コ－ポリアミノ酸鎖セグメントの還元型アスパラギン酸側鎖に薬物が結合しているポリエチレングリコール－コ－ポリアミノ酸共重合体を用いることにより、カルボキシル基を有する薬物の放出制御が可能となる。 As can be seen from Table 2 and Table 4, in the polymer micelle pharmaceutical composition using a polyethylene glycol-co-polyamino acid copolymer as a drug-conjugated block copolymer, the reduced aspartic acid side of the co-polyamino acid chain segment is used. By using a polyethylene glycol-co-polyamino acid copolymer in which a drug is bonded to a chain, release of a drug having a carboxyl group can be controlled.
　本発明は、抗がん剤等の医薬製剤等の分野で、好適に利用することができる。 The present invention can be suitably used in the field of pharmaceutical preparations such as anticancer agents.

Claims (20)

  1. 　一般式：Ａ－Ｂで表される薬物複合化ブロック共重合体：
    　ここで、
    　Ａは、ポリエチレングリコール鎖セグメントを表し、
    　Ｂは、下記一般式（ｉ）で表される繰り返し単位、および／または、下記一般式（ｉｉ）で表される繰り返し単位を含むコ－ポリアミノ酸鎖セグメントを表し、
    　下記一般式（ｉ）および下記一般式（ｉｉ）中、
    　Ｘは、連結基を有していてもよい薬物の残基を表す。
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
         Drug-conjugated block copolymer represented by the general formula: AB:
    here,
    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 including a repeating unit represented by the following general formula (ii):
    In the following general formula (i) and the following general formula (ii),
    X represents a drug residue optionally having a linking group.
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
  2. 　前記コ－ポリアミノ酸鎖セグメントが、側鎖に疎水性基が導入されたグルタミン酸残基を繰り返し単位としてさらに含む、請求項１に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 1, wherein the co-polyamino acid chain segment further contains a glutamic acid residue having a hydrophobic group introduced in a side chain as a repeating unit.
  3. 　下記一般式（Ｉ）で表される、請求項１または２に記載の薬物複合化ブロック共重合体：
    Figure JPOXMLDOC01-appb-C000003
     　上記式中、
    　Ｒ１は、水素原子、非置換もしくは置換された炭素数１～１２の直鎖または分枝状のアルキル基、あるいは標的結合部位を有する基を表し、
    　Ｒ２は、疎水性基を表し、
    　Ｒ３は、水素原子、飽和もしくは不飽和の非置換もしくは置換された炭素数１～３０の直鎖または分枝状の脂肪族カルボニル基またはアリールカルボニル基、あるいは炭素数１～１２の非置換もしくは置換された直鎖または分枝状のアルキル基を表し、
    　Ｌは、リンカーを表し、
    　ｍは、３０～２０，０００の整数であり、
    　ｘは、５～１００の整数であり、
    　ａは、０～１００の整数であり、
    　ｂは、０～１００の整数であり、
    　ｃは、０～１００の整数であり、
    　ｄは、０～１００の整数であり、
    　ａとｃとの和は、１～２００であり、
    　前記コ－ポリアミノ酸鎖セグメントにおける各反復単位の結合順は任意である。     The drug-conjugated block copolymer according to claim 1 or 2, represented by the following general formula (I):
    Figure JPOXMLDOC01-appb-C000003
     In the above formula,
    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. Represents a substituted linear or branched alkyl group,
    L represents a linker;
    m is an integer from 30 to 20,000,
    x is an integer of 5 to 100,
    a is an integer of 0 to 100;
    b is an integer from 0 to 100;
    c is an integer from 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.
  4. 　前記式（Ｉ）中、ｘとａとｂとｃとｄとの和が、１０～２００である、請求項３に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 3, wherein in the formula (I), the sum of x, a, b, c and d is 10 to 200.
  5. 　前記式（Ｉ）中、ａとｃとの和が、３～４０である、請求項３または４に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 3 or 4, wherein in the formula (I), the sum of a and c is 3 to 40.
  6. 　前記式（Ｉ）中、ａとｃとの和が、４～２０である、請求項５に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 5, wherein in the formula (I), the sum of a and c is 4 to 20.
  7. 　前記式（Ｉ）中、ｘが、５～６０である、請求項３から６のいずれかに記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to any one of claims 3 to 6, wherein x is 5 to 60 in the formula (I).
  8. 　前記式（Ｉ）中、ｘが、１０～６０である、請求項７に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 7, wherein x is 10 to 60 in the formula (I).
  9. 　前記式（Ｉ）中、ｘ：（ｂ＋ｄ）が、２０：８０～８０：２０である、請求項３から８のいずれかに記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to any one of claims 3 to 8, wherein in the formula (I), x: (b + d) is 20:80 to 80:20.
  10. 　Ｘが、カルボキシル基を有する薬物の残基である、請求項１から９のいずれかに記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to any one of claims 1 to 9, wherein X is a residue of a drug having a carboxyl group.
  11. 　Ｘが、その活性ドメイン部分とカルボキシル基との間に連結基が配置された状態にある薬物の残基である、請求項１０に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 10, wherein X is a drug residue in a state where a linking group is arranged between the active domain portion and the carboxyl group.
  12. 　前記連結基が、アミド結合、エステル結合、エーテル結合、および／またはヒドラジド結合を含んでいてもよい炭素数０～５の２価の連結基である、請求項１１に記載の薬物複合化ブロック共重合体。 The drug-conjugated block copolymer according to claim 11, wherein the linking group is a divalent linking group having 0 to 5 carbon atoms, which may include an amide bond, an ester bond, an ether bond, and / or a hydrazide bond. Polymer.
  13. 　Ｘが、下記式（ｉｉｉ）で表されるヘミアステリン誘導体の残基である、請求項１から１２のいずれかに記載の薬物複合化ブロック共重合体。
    Figure JPOXMLDOC01-appb-C000004
         The drug-conjugated block copolymer according to any one of claims 1 to 12, wherein X is a residue of a hemiasterin derivative represented by the following formula (iii).
    Figure JPOXMLDOC01-appb-C000004
  14. 　Ｘが、下記式（ｉｉｉ）で表されるヘミアステリン誘導体の残基であり、
    Figure JPOXMLDOC01-appb-C000005
     　Ｒ１は、水素原子、非置換もしくは置換された炭素数１～１２の直鎖または分枝状のアルキル基、あるいは標的結合部位を有する基であり、
    　Ｒ２は、Ｃ４～Ｃ１６の直鎖、分岐鎖または環状構造を有するアルキル基、Ｃ６～Ｃ２０のアリール基、およびＣ７～Ｃ２０のアラルキル基またはステロール残基であり、
    　Ｒ３は、水素原子、飽和もしくは不飽和の非置換もしくは置換された炭素数１～３０の直鎖または分枝状の脂肪族カルボニル基またはアリールカルボニル基、あるいは炭素数１～１２の非置換もしくは置換された直鎖または分枝状のアルキル基であり、
    　Ｌは、－ＮＨ－、－Ｏ－、－Ｏ－Ｚ－ＮＨ－、－ＣＯ－、－ＣＨ２－、－Ｏ－Ｚ－Ｓ－Ｚ－および－ＯＣＯ－Ｚ－ＮＨ－（ここで、Ｚは独立してＣ１～Ｃ６アルキレン基である。）からなる群より選ばれるリンカーであり、
    　ｍは、５０～５０００の整数であり、
    　ｘは、５～１００の整数であり、
    　ａとｃの和は、２～４０であり、
    　ｘとａとｂとｃとｄとの和は、１０～２００である、
    　請求項３に記載の薬物複合化ブロック共重合体。     X is a residue of a hemiasterin derivative represented by the following formula (iii):
    Figure JPOXMLDOC01-appb-C000005
     R 1 is 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 is a C 4 to C 16 linear, branched or cyclic alkyl group, a C 6 to C 20 aryl group, and a C 7 to C 20 aralkyl group or a sterol residue,
    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 substituted linear or branched alkyl group,
    L represents —NH—, —O—, —O—Z—NH—, —CO—, —CH 2 —, —O—Z—S—Z— and —OCO—Z—NH— (where Z Is independently a C 1 -C 6 alkylene group), and is a linker selected from the group consisting of:
    m is an integer of 50 to 5000,
    x is an integer of 5 to 100,
    The sum of a and c is 2-40,
    The sum of x, a, b, c, and d is 10 to 200.
    The drug-conjugated block copolymer according to claim 3.
  15. 　Ｘが、前記式（ｉｉｉ）で表されるヘミアステリン誘導体の残基であり、
    　Ｒ１は、水素原子、非置換もしくは置換された炭素数１～１２の直鎖または分枝状のアルキル基、あるいは標的結合部位を有する基であり、
    　Ｒ２は、Ｃ４～Ｃ１６の直鎖、分岐鎖または環状構造を有するアルキル基、Ｃ６～Ｃ２０のアリール基、およびＣ７～Ｃ２０のアラルキル基またはステロール残基であり、
    　Ｒ３は、水素原子、飽和もしくは不飽和の非置換もしくは置換された炭素数１～３０の直鎖または分枝状の脂肪族カルボニル基またはアリールカルボニル基、あるいは炭素数１～１２の非置換もしくは置換された直鎖または分枝状のアルキル基であり、
    　Ｌは、－ＮＨ－、－Ｏ－、－Ｏ－Ｚ－ＮＨ－、－ＣＯ－、－ＣＨ２－、－Ｏ－Ｚ－Ｓ－Ｚ－および－ＯＣＯ－Ｚ－ＮＨ－（ここで、Ｚは独立してＣ１～Ｃ６アルキレン基である。）からなる群より選ばれるリンカーであり、
    　ｍは、１００～５００の整数であり、
    　ｘは、１０～６０の整数であり、
    　ａとｃの和は、４～２０であり、
    　ｘとａとｂとｃとｄとの和は、２０～１００である、
    　請求項１４に記載の薬物複合化ブロック共重合体。     X is a residue of a hemiasterin derivative represented by the formula (iii),
    R 1 is 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 is a C 4 to C 16 linear, branched or cyclic alkyl group, a C 6 to C 20 aryl group, and a C 7 to C 20 aralkyl group or a sterol residue,
    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 substituted linear or branched alkyl group,
    L is —NH—, —O—, —O—Z—NH—, —CO—, —CH 2 —, —O—Z—S—Z— and —OCO—Z—NH— (where Z Is independently a C 1 -C 6 alkylene group), and is a linker selected from the group consisting of:
    m is an integer from 100 to 500;
    x is an integer of 10 to 60,
    The sum of a and c is 4-20,
    The sum of x, a, b, c and d is 20-100.
    The drug-conjugated block copolymer according to claim 14.
  16. 　Ｘが、前記式（ｉｉｉ）で表されるヘミアステリン誘導体の残基であり、
    　Ｒ１は、メチル基であり、
    　Ｒ２は、ベンジル基であり、
    　Ｒ３は、アセチル基であり、
    　Ｌは、－ＮＨ－であり、
    　ｍは、２００～３００であり、
    　ｘは、１５～２５であり、
    　ａとｃの和は５～１０であり、
    　ｘとａとｂとｃとｄとの和は、３０～５０である、
    　請求項１４に記載された薬物複合化ブロック共重合体。     X is a residue of a hemiasterin derivative represented by the formula (iii),
    R 1 is a methyl group;
    R 2 is a benzyl group,
    R 3 is an acetyl group,
    L is —NH—
    m is 200 to 300,
    x is 15-25,
    The sum of a and c is 5-10,
    The sum of x, a, b, c and d is 30-50,
    The drug-conjugated block copolymer according to claim 14.
  17. 　Ｘが、前記式（ｉｉｉ）で表されるヘミアステリン誘導体の残基であり、
    　Ｒ１は、メチル基であり、
    　Ｒ２は、ベンジル基であり、
    　Ｒ３は、アセチル基であり、
    　Ｌは、－ＮＨ－であり、
    　ｍは、２２６であり、
    　ｘは、２０であり、
    　ａとｃの和は６～８であり、
    　ｘとａとｂとｃとｄとの和は４０である、
    　請求項１４に記載された薬物複合化ブロック共重合体。     X is a residue of a hemiasterin derivative represented by the formula (iii),
    R 1 is a methyl group;
    R 2 is a benzyl group,
    R 3 is an acetyl group,
    L is —NH—
    m is 226,
    x is 20,
    The sum of a and c is 6-8,
    The sum of x, a, b, c and d is 40.
    The drug-conjugated block copolymer according to claim 14.
  18. 　下記一般式（ＩＩ）で表される、ブロック共重合体：
    Figure JPOXMLDOC01-appb-C000006
     　上記式中、
    　Ｒ１は、水素原子、非置換もしくは置換された炭素数１～１２の直鎖または分枝状のアルキル基、あるいは標的結合部位を有する基を表し、
    　Ｒ２は、疎水性基を表し、
    　Ｒ３は、水素原子、飽和もしくは不飽和の非置換もしくは置換された炭素数１～３０の直鎖または分枝状の脂肪族カルボニル基またはアリールカルボニル基、あるいは炭素数１～１２の非置換もしくは置換された直鎖または分枝状のアルキル基を表し、
    　Ｌは、リンカーを表し、
    　ｍは、３０～２０，０００の整数であり、
    　ｘは、５～１００の整数であり、
    　ａは、０～１００の整数であり、
    　ｂは、０～１００の整数であり、
    　ｃは、０～１００の整数であり、
    　ｄは、０～１００の整数であり、
    　ａとｃとの和は、１～２００であり、
    　前記コ－ポリアミノ酸鎖セグメントにおける各反復単位の結合順は任意である。     A block copolymer represented by the following general formula (II):
    Figure JPOXMLDOC01-appb-C000006
     In the above formula,
    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. Represents a substituted linear or branched alkyl group,
    L represents a linker;
    m is an integer from 30 to 20,000,
    x is an integer of 5 to 100,
    a is an integer of 0 to 100;
    b is an integer from 0 to 100;
    c is an integer from 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.
  19. 　請求項３に記載の前記一般式（Ｉ）で表される薬物複合化ブロック共重合体の製造方法であって、
    　請求項１８に記載の前記一般式（ＩＩ）で表されるブロック共重合体のコ－ポリアミノ酸鎖セグメントの側鎖の水酸基の全部または一部と、
    　カルボキシル基を有し、連結基を有していてもよい薬物の該カルボキシル基と、を反応させてエステル結合を形成させる工程、
    　を含む製造方法。     A method for producing a drug-conjugated block copolymer represented by the general formula (I) according to claim 3,
    All or part of the hydroxyl groups in the side chain of the co-polyamino acid chain segment of the block copolymer represented by the general formula (II) according to claim 18;
    A step of reacting the carboxyl group of a drug having a carboxyl group and optionally having a linking group to form an ester bond;
    Manufacturing method.
  20. 　請求項１から１７のいずれかに記載の薬物複合化ブロック共重合体を含む、ポリマーミセル医薬組成物。
          A polymer micelle pharmaceutical composition comprising the drug-conjugated block copolymer according to any one of claims 1 to 17.
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