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WO2013035562A1 - Structure fine à phases séparées et son procédé de fabrication - Google Patents

Structure fine à phases séparées et son procédé de fabrication Download PDF

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Publication number
WO2013035562A1
WO2013035562A1 PCT/JP2012/071520 JP2012071520W WO2013035562A1 WO 2013035562 A1 WO2013035562 A1 WO 2013035562A1 JP 2012071520 W JP2012071520 W JP 2012071520W WO 2013035562 A1 WO2013035562 A1 WO 2013035562A1
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group
chain segment
polymer chain
integer
block copolymer
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Japanese (ja)
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片岡一則
岸村顕広
安楽泰孝
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Japan Science and Technology Agency
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Japan Science and Technology Agency
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L101/00—Compositions of unspecified macromolecular compounds
    • C08L101/02—Compositions of unspecified macromolecular compounds characterised by the presence of specified groups, e.g. terminal or pendant functional groups

Definitions

  • the present invention relates to a fine phase separation structure having a regular pattern structure obtained by using a block copolymer, and a method for producing the same.
  • Non-Patent Document 1 S.-C. Chen, et al. Macromolecules 2010, vol.43, p.1083.
  • Non-Patent Document 2 T. Higuchi, et al.
  • a fine phase separation structure (structure having an ordered fine structure) having a regular pattern structure utilizing the self-assembly of a block copolymer and phase separation in a solution
  • the present invention has been made in consideration of the above situation, and provides a fine phase separation structure, a manufacturing method thereof, and the like shown below. That is, the present invention is as follows.
  • a block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment and a polymer containing a cationic polymer chain segment are mixed, or uncharged
  • a block copolymer containing a hydrophilic polymer chain segment and a cationic polymer chain segment is mixed with a polymer containing an anionic polymer chain segment, and a salt compound is added to the solvent after the mixing or during the mixing.
  • the fine phase-separated structure which has a regular pattern structure obtained by this.
  • the fine phase separation structure according to the above (1) includes, for example, a total charge of a block copolymer including an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment and a polymer including a cationic polymer chain segment.
  • the ratio is not 1, or the total charge ratio between the block copolymer containing the non-charged hydrophilic polymer chain segment and the cationic polymer chain segment and the polymer containing the anionic polymer chain segment is not 1. It is done.
  • the fine phase separation structure of (1) is obtained, for example, such that when the salt compound is added to the aqueous solvent, the concentration of the salt compound in the aqueous solvent is 0.1 to 1000 mM. Can be mentioned.
  • the salt compound include at least one selected from the group consisting of alkali halides, alkaline earth metal halide salts, and transition metal halide salts.
  • the fine phase separation structure of (1) includes, for example, a total ion concentration of a block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment in an aqueous solvent, and a cationic polymer.
  • the total ionic concentration of the polymer containing the chain segment is substantially the same, or the total ionic concentration of the block copolymer comprising the uncharged hydrophilic polymer chain segment and the cationic polymer chain segment, and the anionic Examples thereof include those obtained in such a manner that the total ion concentration of the polymer including the polymer chain segment is substantially the same.
  • the block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment is, for example, represented by the following general formula (I) and / or (II): What is shown.
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represent a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protecting group, a hydrophobic group, or a polymerizable group
  • m is 5
  • n is an integer of 2 to 5,000
  • y is an integer of 0 to 5,000
  • y is not larger than n
  • the formula (I) and Although each repeating unit in (II) is shown in the order specified for convenience of description, each repeating unit can exist in a random order.
  • Examples of the polymer containing a cationic polymer chain segment include those represented by the following general formula (VII) and / or (VIII).
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represent a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protective group, a hydrophobic group or a polymerizable group
  • R 5a , R 5b , R 5c and R 5d each independently represent a hydroxyl group, an oxybenzyl group, or an NH— (CH 2 ) a —X group (where a is an integer of 1 to 5, and X is each independently
  • R 5a and R 5b are amine compound residues containing one or more of primary, secondary, tertiary
  • T is an integer of 2 to 6
  • n is an integer of 2 to 5,000
  • y is an integer of 0 to 5,000
  • z is 0 to 5,000. It is an integer
  • y + z is not larger than n
  • each repeating unit in general formulas (VII) and (VIII) is shown in the order specified for convenience of description, but each repeating unit exists in random order can do.
  • the block copolymer containing an uncharged hydrophilic polymer chain segment and a cationic polymer chain segment is, for example, represented by the following general formula (III) and / or (IV): What is shown.
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represent a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protective group, a hydrophobic group or a polymerizable group
  • R 5a , R 5b , R 5c and R 5d each independently represent a hydroxyl group, an oxybenzyl group, or an NH— (CH 2 ) a —X group (where a is an integer of 1 to 5, and X is each independently
  • R 5a and R 5b are amine compound residues containing one or more of primary, secondary, tertiary amines or quaternary ammonium salts, or non-amine compound residues) the total number and R 5c and R 5d of Of the total number,
  • z is an integer of 0 to 5,000, y + z is not larger than n, and each repeating unit in the general formulas (III) and (IV) is shown in the order specified for convenience of description. Each repeating unit can exist in a random order.
  • Examples of the polymer containing an anionic polymer chain segment include those represented by the following general formula (V) and / or (VI).
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represents a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • n is 2 It is an integer of ⁇ 5,000
  • y is an integer of 0 to 5,000
  • y is not larger than n
  • each repeating unit in the general formulas (V) and (VI) is specified for convenience of description.
  • the fine phase separation structure (1) may be, for example, in the form of a lump, fine particle or film, and in the case of a fine particle, the average particle size is, for example, 10 nm to 100 ⁇ m.
  • Examples of the fine phase separation structure (1) include those having a regular co-continuous channel structure.
  • a block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment and a polymer containing a cationic polymer chain segment are mixed, or uncharged
  • a block copolymer containing a hydrophilic polymer chain segment and a cationic polymer chain segment is mixed with a polymer containing an anionic polymer chain segment, and a salt compound is added to the solvent after the mixing or during the mixing.
  • the total charge ratio of a block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment to a polymer containing a cationic polymer chain segment is The total charge ratio between the block copolymer containing non-charged hydrophilic polymer chain segment and the cationic polymer chain segment and the polymer containing the anionic polymer chain segment is not 1. it can.
  • the concentration of the salt compound in the aqueous solvent can be 0.1 to 1000 mM.
  • the salt compound examples include at least one selected from the group consisting of alkali halides, alkaline earth metal halide salts, and transition metal halide salts.
  • the total ion concentration of a block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment in an aqueous solvent, and a cationic polymer chain segment for example, the total ion concentration of a block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment in an aqueous solvent, and a cationic polymer chain segment.
  • the total ion concentration of the polymer containing the segments can be substantially the same.
  • the block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment is, for example, one represented by the following general formula (I) and / or (II) Can be used.
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represent a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protecting group, a hydrophobic group, or a polymerizable group
  • m is 5
  • n is an integer of 2 to 5,000
  • y is an integer of 0 to 5,000
  • y is not larger than n
  • the formula (I) and Although each repeating unit in (II) is shown in the order specified for convenience of description,
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represent a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protective group, a hydrophobic group or a polymerizable group
  • R 5a , R 5b , R 5c and R 5d each independently represent a hydroxyl group, an oxybenzyl group, or an NH— (CH 2 ) a —X group (where a is an integer of 1 to 5, and X is each independently R 5a and R 5b are amine compound residues containing one or more of primary
  • T is an integer of 2 to 6
  • n is an integer of 2 to 5,000
  • y is an integer of 0 to 5,000
  • z is 0 to 5,000. It is an integer, y + z is not larger than n, and each repeating unit in general formulas (VII) and (VIII) is shown in the order specified for convenience of description, but each repeating unit exists in random order can do.
  • the block copolymer containing an uncharged hydrophilic polymer chain segment and a cationic polymer chain segment is, for example, one represented by the following general formula (III) and / or (IV) Can be used.
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represent a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protective group, a hydrophobic group or a polymerizable group
  • R 5a , R 5b , R 5c and R 5d each independently represent a hydroxyl group, an oxybenzyl group, or an NH— (CH 2 ) a —X group (where a is an integer of 1 to 5, and X is each independently
  • R 5a and R 5b are amine compound residues containing one or more of primary, secondary, tertiary amines or quaternary ammonium salts, or non-amine compound residues) the total number and R 5c and R 5d of Of the total number,
  • z is an integer of 0 to 5,000, y + z is not larger than n, and each repeating unit in the general formulas (III) and (IV) is shown in the order specified for convenience of description. Each repeating unit can exist in a random order.
  • general formula (V) and / or (VI) can be used for the polymer containing an anionic polymer chain segment, for example.
  • R 1a and R 1b each independently represent a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 alkyl group
  • L 1 and L 1 2 represents a linking group
  • R 2a and R 2b each independently represents a methylene group or an ethylene group
  • R 3 and R 4 represent a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • n is 2 It is an integer of ⁇ 5,000
  • y is an integer of 0 to 5,000
  • y is not larger than n
  • each repeating unit in the general formulas (V) and (VI) is specified for convenience of description. Although shown in the order shown, each repeating unit can exist in a random order.
  • FIG. 1 is a diagram showing an example (added with 10 mM NaCl) of the fine phase separation structure of the present invention.
  • the middle and lower figures are schematic views showing the structure of the obtained fine phase separation structure
  • the left figure is a cross section (cross section 1) corresponding to the horizontal cross section of the structure of the schematic view.
  • the right side figure is a TEM image of a cross section (cross section 2) corresponding to a cross section in the vertical direction of the structure of the schematic diagram.
  • FIG. 2 is a diagram showing an example (addition of 50 mM NaCl) of the fine phase separation structure of the present invention, and is a TEM image of a cross section of the obtained fine phase separation structure.
  • FIG. 1 is a diagram showing an example (added with 10 mM NaCl) of the fine phase separation structure of the present invention.
  • the middle and lower figures are schematic views showing the structure of the obtained fine phase separation structure
  • the left figure is a cross section (cross section 1) corresponding to the horizontal cross section
  • FIG. 3 is a diagram showing an example of a structure (0 mM NaCl) as a comparative example of the present invention.
  • FIG. 4 is a view showing one example of the fine phase separation structure of the present invention (addition of 10 mM NaCl, crosslinking after centrifugation), and is a TEM image of a cross section of the obtained fine phase separation structure.
  • the present invention is a microphase-separated structure (ordered) having a regular pattern structure that directly and easily utilizes self-assembly of a block copolymer in an aqueous solvent (for example, in a buffer solution close to physiological conditions).
  • the present invention relates to a method for manufacturing a structure having a fine structure.
  • the fine phase separation structure has a phase separation structure in which, for example, a channel structure derived from a hydrophilic segment (hydrophilic block portion) (a so-called communication structure such as a cylinder) has a high regularity such as hexagonal close-packed packing. Examples include a structure that exists as a continuous structure and has a structure that is oriented in one direction (see, for example, FIG.
  • the fine phase separation structure of the present invention includes, for example, an aqueous solution of a charged polymer (cationic and anionic polymer) having a PEG segment and an aqueous solution of a charged polymer (cationic or anionic polymer) having no PEG segment. And after the mixing or at the time of mixing, the salt compound is added to the aqueous solution at an appropriate concentration, and the manufacturing process is performed at room temperature for a short time (for example, one step and several minutes). ).
  • the production conditions are such that the charge ratios of the two polymers to be mixed (cationic polymer and anionic polymer) are not substantially the same, and the salt compound is added to the aqueous solution at an appropriate concentration after or during the mixing.
  • the obtained structure can be controlled to be a structure having an ordered fine structure (a fine phase separation structure having a regular pattern structure).
  • the fine phase separation structure having a regular pattern structure can be specifically referred to as a structure having a regular channel-like fine channel structure. 2.
  • the method for producing a fine phase-separated structure having a regular pattern structure includes, as described above, (i) an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment in an aqueous solvent. Or a polymer containing a cationic polymer chain segment, and a salt compound is added to the solvent after the mixing or during the mixing, or (ii) an uncharged hydrophilic polymer A block copolymer containing a chain segment and a cationic polymer chain segment is mixed with a polymer containing an anionic polymer chain segment, and a salt compound is added to the solvent after or during the mixing. Manufacturing method.
  • the present invention relates to a fine phase separation structure having a regular pattern structure obtained by the production method, and (i) an uncharged hydrophilic polymer chain segment for producing the fine phase separation structure.
  • a block copolymer comprising an anionic polymer chain segment and a polymer comprising a cationic polymer chain segment, or (ii) comprising an uncharged hydrophilic polymer chain segment and a cationic polymer chain segment
  • block copolymers and polymers containing anionic polymer chain segments is also encompassed.
  • uncharged hydrophilic polymer chain segment in each of the above block copolymers “uncharged” means that the segment is neutral as a whole.
  • non-charged hydrophilic polymer chain segment examples include, but are not limited to, polyethylene glycol (PEG), poly (2-methyl-2-oxazoline), poly (2-ethyl-2-oxazoline), poly (2 -Isopropyl-2-oxazoline), polyacrylamide, polymethacrylamide, polyvinyl alcohol, hydroxyethyl polyacrylate, poly (hydroxyethyl methacrylate) and poly (2-methacryloyloxyethyl phosphorylcholine) water-soluble
  • PEG polyethylene glycol
  • poly (2-methyl-2-oxazoline) poly (2-ethyl-2-oxazoline
  • polyacrylamide polymethacrylamide
  • polyvinyl alcohol hydroxyethyl polyacrylate
  • poly (hydroxyethyl methacrylate) poly (2-methacryloyloxyethyl phosphorylcholine) water-soluble
  • PEG polyethylene glyco
  • the uncharged hydrophilic polymer chain segment is hydrophilic, biocompatibility can be imparted to the fine phase separation structure of the present invention.
  • the non-charged hydrophilic polymer chain segment is present in the above-described channel structure (communication structure) portion. Therefore, for example, the segment has ionic conductivity.
  • the fine phase separation structure of the present invention can be applied as a conductive material.
  • the structure is such that the non-charged hydrophilic polymer chain segment can be separated from the block copolymer (particularly designed so that the linker moiety with the cationic or anionic polymer chain segment can be decomposed or cleaved).
  • the non-charged hydrophilic polymer chain segments are separated (thinned out from the entire structure), thereby forming a fine structure with voids in the channel structure.
  • a phase separation structure can be obtained.
  • Such a structure can be used for various purposes as a functional material having substance permeability and a porous material.
  • the polymer containing a cationic polymer chain segment and the polymer containing an anionic polymer chain segment described above may be a block copolymer containing an uncharged hydrophilic polymer chain segment.
  • the polymer does not include an uncharged hydrophilic polymer chain segment (such as a homopolymer) and is not particularly limited.
  • the anionic polymer chain segment may be derived from a polymer having an anionic group in the side chain.
  • those derived from polypeptides having an anionic group in the side chain are preferred.
  • the cationic polymer chain segment is derived from a polymer having a cationic group in the side chain.
  • what is necessary is not limited, what originates in the polypeptide which has a cationic group in a side chain is mentioned preferably, for example.
  • examples of the block copolymer containing an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment used in the production method of the present invention include, for example, the following general formulas (I) and / or (II): ) Is preferred.
  • the segment whose number of repeating units (polymerization degree) is “m” is an uncharged hydrophilic polymer chain segment derived from PEG (hereinafter referred to as PEG segment).
  • PEG segment uncharged hydrophilic polymer chain segment derived from PEG
  • the segment in which the number of repeating units of “ny” and the portion of “y” are combined is a polyanion-derived anionic polymer chain segment (hereinafter, polyanion segment).
  • R 1a And R 1b Each independently represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 Represents an alkyl group.
  • Linear or branched C 1-12 Examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, decyl, undecyl and the like.
  • the acetalization means that the acetal part formed by the reaction of a carbonyl of formyl with two molecules of an alkanol having 1 to 6 carbon atoms or an alkylene diol having 2 to 6 carbon atoms which may be branched. Meaning formation, and also a method for protecting the carbonyl group.
  • L 1 And L 2 represents a linking group. Specifically, L 1 Is-(CH 2 ) b -NH- (where b is an integer of 1 to 5) is preferred, and L 2 Is-(CH 2 ) c It is preferably —CO— (where c is an integer of 1 to 5).
  • R 2a , R 2b , R 2c And R 2d Each independently represents a methylene group or an ethylene group.
  • R 2a And R 2b When each of them is a methylene group, it corresponds to a poly (aspartic acid derivative), and when it is an ethylene group, it corresponds to a poly (glutamic acid derivative).
  • 2c And R 2d When both are methylene groups, they correspond to poly (aspartic acid derivatives), and when they are ethylene groups, they correspond to poly (glutamic acid derivatives).
  • R 2a And R 2b (R 2b And R 2a ) Represents both a methylene group and an ethylene group
  • R 2c And R 2d (R 2d And R 2c ) Represents both a methylene group and an ethylene group
  • the repeating units of the aspartic acid derivative and the glutamic acid derivative may each be present in a block form or may be present randomly.
  • R 3 Represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group. Specifically, R 3 Is preferably an acetyl group, an acryloyl group or a methacryloyl group.
  • R 4 Is a hydroxyl group, an oxybenzyl group, -NH- (CH 2 ) a -Represents an X group or an initiator residue.
  • a is an integer of 1 to 5
  • X is an amine compound residue containing one or more of primary, secondary, tertiary amine or quaternary ammonium salt, or a compound which is not an amine It is preferably a residue.
  • R 4 -NH-R 9 (Where R 9 Is unsubstituted or substituted linear or branched C 1-20 Represents an alkyl group).
  • m is an integer of 5 to 2,000, preferably an integer of 5 to 270, and more preferably an integer of 10 to 100.
  • N is an integer of 2 to 5,000, y is an integer of 0 to 5,000, and n and y are preferably integers of 5 to 300, more preferably an integer of 10 to 100. It is. However, y is not larger than n.
  • each repeating unit in general formula (I) and (II) is shown in the order specified for convenience of description, each repeating unit can exist in random order. In particular, it is preferable that only each repeating unit in the polyanion segment can be present in a random order as described above.
  • the molecular weight (Mw) of the block copolymer represented by the general formulas (I) and (II) is not limited, but is preferably 3,000 to 30,000, more preferably 5,000 to 20,000. is there.
  • the molecular weight (Mw) of the PEG segment is preferably 500 to 15,000, more preferably 1,000 to 5,000
  • the molecular weight (Mw) of the polyanion segment is The total is preferably 500 to 50,000, more preferably 1,000 to 20,000.
  • R 1a O- or R 1b A segment (PEG segment) containing O- and the block part of the PEG chain was synthesized in advance, and one end (R 1a O- or R 1b A method in which a predetermined monomer is sequentially polymerized at a terminal opposite to O-, and then the side chain is substituted or converted so as to include an anionic group as necessary, or the PEG segment and the anionic group are included.
  • R 1a O- or R 1b A method in which a predetermined monomer is sequentially polymerized at a terminal opposite to O-, and then the side chain is substituted or converted so as to include an anionic group as necessary, or the PEG segment and the anionic group are included. Examples include a method of previously synthesizing a block part having a side chain and linking them together. Methods and conditions for various reactions in the production method can be appropriately selected or set in consideration of conventional methods.
  • the PEG segment can be prepared, for example, using the method for producing a PEG segment portion of a block copolymer described in WO 96/32434, WO 96/33233, WO 97/06202, and the like.
  • Block copolymer was synthesized by polymerizing N-carboxylic acid anhydride (NCA) of protected amino acids such as aspartate (BLA) and N ⁇ -ZL-lysine, and then the side chain of each segment was anionic as described above A method of substitution or conversion so as to be a side chain having a group is preferred.
  • NCA N-carboxylic acid anhydride
  • BLA aspartate
  • N ⁇ -ZL-lysine N ⁇ -ZL-lysine
  • specific examples of the block copolymer represented by the general formulas (I) and (II) include, for example, a block copolymer represented by the following formula (PEG-P (Asp)).
  • PEG-P those having a molecular weight (MW) of PEG segment: 2,000 and a P (Asp) unit number (m) representing a polyanion segment: 70 or 75 are particularly preferable.
  • x and y each represent the ratio of each repeating unit to the number of units (m) (for example, 0.50 for 50%).
  • block copolymer containing an uncharged hydrophilic polymer chain segment and a cationic polymer chain segment used in the production method of the present invention include those represented by the following general formulas (III) and / or (IV). Preferred are those mentioned above.
  • the segment whose number of repeating units (polymerization degree) is “m” is a non-charged hydrophilic polymer chain segment (PEG segment) derived from PEG, and is repeated
  • a segment obtained by combining the “nyz” portion, the “y” portion, and the “z” portion is a polycation-derived cationic polymer chain segment (hereinafter, polycation segment).
  • R 1a And R 1b Each independently represents a hydrogen atom or an unsubstituted or substituted linear or branched C 1-12 Represents an alkyl group.
  • Linear or branched C 1-12 Examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, decyl, undecyl and the like.
  • An alkylsiloxy group, a siloxy group, or a silylamino group can be mentioned.
  • the acetalization means that the acetal part formed by the reaction of a carbonyl of formyl with two molecules of an alkanol having 1 to 6 carbon atoms or an alkylene diol having 2 to 6 carbon atoms which may be branched. Meaning formation, and also a method for protecting the carbonyl group.
  • the substituent when the substituent is an acetalized formyl group, it can be converted to another formyl group (—CHO: or aldehyde group) by hydrolysis under acidic mild conditions.
  • L 1 And L 2 Represents a linking group.
  • L 1 Is-(CH 2 ) b -NH- (where b is an integer of 1 to 5) is preferred
  • L 2 Is-(CH 2 ) c It is preferably —CO— (where c is an integer of 1 to 5).
  • R 2a , R 2b , R 2c And R 2d Each independently represents a methylene group or an ethylene group.
  • R 2a And R 2b When each of them is a methylene group, it corresponds to a poly (aspartic acid derivative), and when it is an ethylene group, it corresponds to a poly (glutamic acid derivative).
  • R 2c And R 2d When both are methylene groups, they correspond to poly (aspartic acid derivatives), and when they are ethylene groups, they correspond to poly (glutamic acid derivatives).
  • R 2a And R 2b (R 2b And R 2a ) Represents both a methylene group and an ethylene group
  • R 2c And R 2d (R 2d And R 2c ) Represents both a methylene group and an ethylene group
  • the repeating units of the aspartic acid derivative and the glutamic acid derivative may each be present in a block form or may be present randomly.
  • R 3 Represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group. Specifically, R 3 Is preferably an acetyl group, an acryloyl group or a methacryloyl group. In the general formulas (III) and (IV), R 4 Is a hydroxyl group, an oxybenzyl group, -NH- (CH 2 ) a -Represents an X group or an initiator residue.
  • a is an integer of 1 to 5
  • X is an amine compound residue containing one or more of primary, secondary, tertiary amine, quaternary ammonium salt or guanidino group, or A compound residue that is not an amine is preferred.
  • R 4 -NH-R 9 (Where R 9 Is unsubstituted or substituted linear or branched C 1-20 Represents an alkyl group).
  • R 5a , R 5b , R 5c And R 5d Each independently represents a hydroxyl group, an oxybenzyl group, -NH- (CH 2 ) a -X group is represented.
  • a is an integer of 1 to 5
  • X is an amine compound residue containing one or more of primary, secondary, tertiary amine, quaternary ammonium salt or guanidino group, or A compound residue that is not an amine is preferred.
  • R 5a And R 5b And the total number and R 5c And R 5d -NH- (CH 2 ) a -X group (where X is (NH (CH 2 ) 2 ) e -NH 2 (Where e is an integer from 0 to 5), preferably at least 2 or more, more preferably 50% or more of the total number, and 85% or more of the total number. Is more preferable.
  • R 5a , R 5b , R 5c And R 5d All or a part of —NH— (CH 2 ) a -X group (where a is 2 and X is (NH (CH 2 ) 2 ) e -NH 2 (Where e is 1)).
  • R 4 And R 5a , R 5b , R 5c And R 5d As an example of -NH- (CH 2 ) a In the -X group, the case where X is selected from the groups represented by the following formulas is particularly preferred.
  • X 2 Is a hydrogen atom or C 1-6 Alkyl group or amino C 1-6 Represents an alkyl group
  • R 7a , R 7b And R 7c Each independently represents a hydrogen atom or a methyl group
  • d1, d2 and d3 each independently represent an integer of 1 to 5
  • e1, e2 and e3 each independently represents an integer of 1 to 5.
  • F represents an integer of 0 to 15
  • g represents an integer of 0 to 15
  • R 8a And R 8b Each independently represents a hydrogen atom or a protecting group.
  • the protecting group is preferably a group selected from the group consisting of a Z group, a Boc group, an acetyl group, and a trifluoroacetyl group, which are usually used as a protecting group for an amino group.
  • t is preferably an integer of 2 to 6, more preferably 3 or 4.
  • m is an integer of 5 to 2,000, preferably an integer of 5 to 270, and more preferably an integer of 10 to 100.
  • N is an integer of 2 to 5,000, y is an integer of 0 to 5,000, and z is an integer of 0 to 5,000.
  • n is preferably an integer of 5 to 300, more preferably 0 or an integer of 10 to 100.
  • y and z are preferably 0 or an integer of 5 to 300, more preferably 0 or an integer of 10 to 100.
  • the sum (y + z) of y and z is not larger than n.
  • each repeating unit in general formula (III) and (IV) is shown in the order specified for convenience of description, each repeating unit can exist in random order. In particular, it is preferable that only the repeating units in the polycation segment can be present in a random order as described above.
  • the molecular weight (Mw) of the block copolymers represented by the general formulas (III) and (IV) is not limited, but is preferably 3,000 to 40,000, more preferably 5,000 to 25,000. is there.
  • the molecular weight (Mw) of the PEG segment is preferably 500 to 15,000, more preferably 1,000 to 5,000
  • the molecular weight (Mw) of the polycation segment is The total is preferably 500 to 50,000, more preferably 1,000 to 30,000.
  • R 1a O- or R 1b A segment (PEG segment) containing O- and the block part of the PEG chain was synthesized in advance, and one end (R 1a O- or R 1b A method in which a predetermined monomer is polymerized in order at a terminal opposite to O-, and then the side chain is substituted or converted to include a cationic group as necessary, or the PEG segment and the cationic group are included.
  • R 1a O- or R 1b A method in which a predetermined monomer is polymerized in order at a terminal opposite to O-, and then the side chain is substituted or converted to include a cationic group as necessary, or the PEG segment and the cationic group are included. Examples include a method of previously synthesizing a block part having a side chain and linking them together. Methods and conditions for various reactions in the production method can be appropriately selected or set in consideration of conventional methods.
  • the PEG segment can be prepared, for example, using the method for producing a PEG segment portion of a block copolymer described in WO 96/32434, WO 96/33233, WO 97/06202, and the like.
  • N-carboxylic anhydride N-carboxylic anhydride
  • BLA aspartate
  • N ⁇ -ZL-lysine N-carboxylic anhydride
  • a method of substitution or conversion with diethylenetriamine (DET) or the like so as to be a side chain having a group is preferred.
  • specific examples of the block copolymer represented by the general formulas (III) and (IV) include a block copolymer represented by the following formula (PEG-P (Asp-AP)) and the like.
  • PEG-P As PEG-P (Asp-AP), those in which the molecular weight (MW) of the PEG segment is 2,000 and the number of P (Asp-AP) units indicating the polycation segment (m) is 70 or 75 are particularly preferable. .
  • x and y each represent the ratio of each repeating unit to the number of units (m) (for example, 0.50 for 50%).
  • a polymer containing the anionic polymer chain segment used in the manufacturing method of this invention what is shown by the following general formula (V) and / or (VI) is mentioned preferably, for example.
  • the polymer containing the anionic polymer chain segment may be a homopolymer or a block copolymer, and is not limited.
  • it may be a block copolymer including an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment.
  • polymers represented by the general formulas (V) and (VI) include, for example, a block copolymer (Homo-P (Asp)) represented by the following formula.
  • Homo-P (Asp) is particularly preferably a P (Asp) unit number (m) showing a polyanion segment: 70 or 82.
  • x and y each represent the ratio of each repeating unit to the number of units (m) (for example, 0.50 for 50%).
  • a polymer containing the anionic polymer chain segment used in the manufacturing method of this invention what is shown by the following general formula (VII) and / or (VIII) is mentioned preferably, for example.
  • the polymer containing the cationic polymer chain segment may be a homopolymer or a block copolymer, and is not limited.
  • it may be a block copolymer containing an uncharged hydrophilic polymer chain segment and a cationic polymer chain segment.
  • specific examples of the polymers represented by the general formulas (VII) and (VIII) preferably include a block copolymer (Homo-P (Asp-AP)) represented by the following formula.
  • Homo-P (Asp-AP) is particularly preferably a P (Asp-AP) unit number (m) showing a polycation segment: 70 or 82.
  • x and y each represent the ratio of each repeating unit to the number of units (m) (for example, 0.50 for 50%).
  • the aqueous solvent used in the production method of the present invention is not limited.
  • a buffer solution used under physiological conditions is preferable.
  • HEPES 4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid is used.
  • a buffer solution containing Tris, phosphate and the like is preferable.
  • the pH of the aqueous solvent is not limited, but is preferably 5.5 to 9.5, and more preferably 6.5 to 8.5, for example.
  • the total charge ratio (a2) is not 1.
  • the total charge ratio (a2 / a1) is preferably, for example, 0.7 to 1.2 (excluding 1), and more preferably 0.9 to 1.1 (excluding 1).
  • a block copolymer (b1) containing an uncharged hydrophilic polymer chain segment and a cationic polymer chain segment mixed in an aqueous solvent, and an anionic polymer chain segment are mixed.
  • the total charge ratio (b2 / b1) is preferably, for example, 0.7 to 1.2 (excluding 1), and more preferably 0.9 to 1.1 (excluding 1).
  • the total charge ratio of each polymer is controlled, and the total ion concentration of the block copolymer including an uncharged hydrophilic polymer chain segment and an anionic polymer chain segment; It is preferable that the total ion concentration of the polymer containing the cationic polymer chain segment is substantially the same. Also, the total ion concentration of the block copolymer including the non-charged hydrophilic polymer chain segment and the cationic polymer chain segment is substantially the same as the total ion concentration of the polymer including the anionic polymer chain segment. It is preferable to do so.
  • the total charge ratio of each polymer is controlled as described above to mix each polymer in an aqueous solvent, and a salt compound is added to the aqueous solvent after the mixing or at the time of the mixing. It is important to.
  • the salt compound is preferably added so that the concentration of the salt compound in the aqueous solvent is 0.1 to 1000 mM, more preferably 1 to 300 mM, and further preferably 5 to 100 mM. By adding the concentration of the salt compound in the aqueous solvent so as to be within the above range, a fine phase separation structure having a regular pattern structure can be easily obtained.
  • the salt compound added to the aqueous solvent is not particularly limited.
  • alkali halides such as sodium chloride, potassium chloride and sodium bromide
  • halide salts of alkaline earth metals such as magnesium chloride
  • at least one selected from the group consisting of halide salts of transition metals such as manganese chloride, iron chloride and copper chloride is preferred, among which alkali halides are more preferred, and sodium chloride is particularly preferred.
  • the concentration of each polymer described above mixed in an aqueous solvent is not limited, but it is preferably 0.1 to 100 mg / mL, more preferably 0.5 to 10 mg / mL.
  • the method for adding each of the above-described polymers (which are preferably handled in a solution state in advance) to the aqueous solvent is not limited, and may be batch addition, Sequential addition may be used. Further, the mixing time and mixing speed after the addition are not particularly limited. For example, mixing time: 1 minute to 10 minutes (preferably 2 to 8 minutes, more preferably 2 to 3 minutes), mixing speed: 500 It is preferably ⁇ 5,000 rpm. Furthermore, the temperature conditions of the production method of the present invention are not particularly limited, and can be performed at room temperature (for example, about 20 to 30 ° C., preferably about 25 ° C.).
  • Isolation and purification of the fine phase separation structure obtained by the production method of the present invention can be recovered from an aqueous solvent by a conventional method. Typical methods include centrifugation, ultrafiltration, diafiltration, dialysis and the like. Moreover, in the manufacturing method of this invention, the obtained fine phase-separated structure can also be bridge
  • the crosslinking agent various known water-soluble condensing agents (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), glutaraldehyde) and the like can be used.
  • the fine phase separation structure obtained by the production method of the present invention may have a fine particle shape, a lump shape, or a film, and is not limited.
  • the structure that is closed to the outside is not limited, and a structure that is open to the outside may also be included (particularly in the case of fine particles).
  • the average particle diameter by dynamic light scattering measurement (DLS) or laser diffraction method is preferably, for example, 1 nm to 100 ⁇ m, more preferably 10 nm to 30 ⁇ m.
  • the inner diameter size of each channel structure (a so-called communication structure such as a cylinder) in the fine phase separation structure is not limited, but is preferably about 1 to 100 nm, and more preferably 5 It is ⁇ 50 nm, more preferably 10 to 20 nm.
  • the fine phase-separated structure obtained by the production method of the present invention can be used as a constituent element of a composition that can be used for the purpose in various uses to which the characteristic structure described above can be applied.
  • kits containing these various compositions can also be provided.
  • the fine phase separation structure of the present invention includes, for example, a biomaterial typified by a drug carrier for DDS, a nanofilter material (particularly in the case of a thin porous body), and an electrode coating material. It can be used for separators and the like, and in the case of fine particles, it can be applied as fine particles having anisotropic channels, and can be used as a new material for electronic paper and metamaterials.
  • the fine phase separation structure of the present invention is obtained by a simple method (one step and several minutes) under mild conditions with low environmental load in an aqueous solvent and at room temperature, it is highly environmentally friendly. As a functional material, it is excellent in practicality and future potential.
  • the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
  • PEG-P (Asp) was identified by 1 H NMR and size exclusion chromatography, and used as a polyanion (degree of polymerization 75) for preparing a fine phase separation structure as PIC (polyion complex). In the following experiment, this was described as PEG-P (Asp) (2-75).
  • -Synthesis of Homo-P (Asp-AP) 100 mg of Homo-PBLA was weighed and lyophilized with benzene. Dissolved in 5 mL of NMP and stirred overnight at 35 ° C. for complete dissolution.
  • Homo-P (Asp-AP) was identified by 1 H NMR and size exclusion chromatography, and used as a polycation (degree of polymerization 82) for preparing a fine phase separation structure as PIC. In the following experiment, this was described as Homo-P (Asp-M) (82).
  • the microparticles have a co-continuous regular structure in which a cylindrical channel structure (communication structure) having a diameter of about 10 to 20 nm is packed in a hexagonal close-packed manner.
  • the NaCl concentration was 0 mM, it was revealed that the polymer had a tightly packed internal structure with a tight packing (FIG. 3).
  • a fine phase separation structure having a regular pattern structure (a structure having an ordered fine structure), particularly a structure having a regular co-continuous channel structure,
  • a method for direct and simple production can be provided.
  • the fine phase separation structure obtained by the production method includes, for example, a biomaterial typified by a drug carrier for DDS, a nanofilter material (especially in the case of a thin porous body), an electrode coating material, a separator
  • it can be used as a fine particle with anisotropic channels in the case of fine particles, and can be used as a new material for electronic paper and metamaterials. And is extremely useful.
  • a fine phase separation structure can be produced by a simple method under mild conditions with low environmental impact in an aqueous solvent and at room temperature. Is not only applied as a biomaterial as described above, but also has extremely high practicality and future potential as an environment-friendly high-performance material.

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Abstract

La présente invention concerne un procédé de fabrication d'une structure ayant une structure fine bien ordonnée (une structure fine à phases séparées ayant une structure à motif régulier) directement et d'une manière simple à l'aide de l'auto-assemblage d'un copolymère à blocs et de la séparation de phases dans une solution. Cette structure fine à phases séparées ayant une structure à motif régulier est obtenue par : mélange d'un copolymère à blocs comprenant un segment de chaîne de polymère hydrophile non chargé et un segment de chaîne de polymère anionique avec un polymère comprenant un segment de chaîne de polymère cationique dans un solvant aqueux, ou mélange d'un copolymère à blocs comprenant un segment de chaîne de polymère hydrophile non chargé et un segment de chaîne de polymère cationique avec un polymère comprenant un segment de chaîne de polymère anionique dans un solvant aqueux ; et après le mélange ou pendant le mélange, addition d'un composé sel au solvant.
PCT/JP2012/071520 2011-09-08 2012-08-20 Structure fine à phases séparées et son procédé de fabrication Ceased WO2013035562A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8945408B2 (en) 2013-06-14 2015-02-03 Tokyo Electron Limited Etch process for reducing directed self assembly pattern defectivity
WO2015034600A1 (fr) * 2013-09-04 2015-03-12 Tokyo Electron Limited Procédé de gravure pour la réduction de défectuosité de motifs d'autoassemblage dirigé utilisant une superposition de courant continu
US9153457B2 (en) 2013-06-14 2015-10-06 Tokyo Electron Limited Etch process for reducing directed self assembly pattern defectivity using direct current positioning

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JP7578991B2 (ja) * 2019-08-28 2024-11-07 国立研究開発法人理化学研究所 細胞膜透過性ベシクル

Non-Patent Citations (2)

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Title
AYA KOIDE ET AL.: "Semipermiable Polymer Vesicle(PICsome) Self-Assembled in Aqueous Medium from a pair of Oppositely Charged Block Copolymers: Physiologically Stable Micro-/ Nanocontainers of Water-Soluble Macromolecules", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 128, no. 18, 2006, pages 5988 - 5989 *
YASUTAKA ANRAKU ET AL.: "Kisokuteki Mezo Kozotai o Yusuru Polyion Complex Sosei to Kozo Seigyo", DAI 63 KAI ABSTRACTS OF SYMPOSIUM ON COLLOID AND SURFACE CHEMISTRY, vol. 63, 22 August 2011 (2011-08-22), pages 350 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8945408B2 (en) 2013-06-14 2015-02-03 Tokyo Electron Limited Etch process for reducing directed self assembly pattern defectivity
US9153457B2 (en) 2013-06-14 2015-10-06 Tokyo Electron Limited Etch process for reducing directed self assembly pattern defectivity using direct current positioning
WO2015034600A1 (fr) * 2013-09-04 2015-03-12 Tokyo Electron Limited Procédé de gravure pour la réduction de défectuosité de motifs d'autoassemblage dirigé utilisant une superposition de courant continu

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