WO2006115293A1 - NOUVEAU COPOLYMERE SEQUENCE UTILISE DANS LA PREPARATION D'UNE MICELLE DE POLYMERE REAGISSANT AU pH, ET SON PROCEDE DE FABRICATION - Google Patents

NOUVEAU COPOLYMERE SEQUENCE UTILISE DANS LA PREPARATION D'UNE MICELLE DE POLYMERE REAGISSANT AU pH, ET SON PROCEDE DE FABRICATION Download PDF

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WO2006115293A1
WO2006115293A1 PCT/JP2006/309064 JP2006309064W WO2006115293A1 WO 2006115293 A1 WO2006115293 A1 WO 2006115293A1 JP 2006309064 W JP2006309064 W JP 2006309064W WO 2006115293 A1 WO2006115293 A1 WO 2006115293A1
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group
polymer
integer
acid derivative
compound
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Kazunori Kataoka
Younsoo Bae
Shigeto Fukushima
Woo-Dong Jang
Nobuhiro Nishiyama
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The University Of Tokyo
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    • 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
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/10—Polyimides; Polyester-imides; Polyamide-imides; Polyamide acids or similar polyimide precursors
    • C08G73/1092—Polysuccinimides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a drug delivery system aimed at enhancing therapeutic effects and reducing side effects by targeting an anticancer agent to tumor tissue.
  • anticancer drugs In cancer chemotherapy, the serious side effects of anticancer drugs are a major limitation of their use. If anticancer drugs can be collected selectively in tumor tissue and not as much as possible in normal tissue, it will be possible to enhance the effect and reduce side effects. In tumor tissue, neovascularization and vascular wall permeability are markedly increased compared to normal tissue, and because the lymphatic system is underdeveloped, even high molecular weight substances can be transferred from blood to tissue. Nanoparticles such as liposome micelles encapsulating anticancer agents due to the so-called EPR effect that polymer or nano-sized particles tend to accumulate in tumor tissue as a result. Particles of size are known to accumulate in tumor tissue.
  • D o X i 1 ® a ribosome formulation encapsulating adriamycin, with NK 9 1 1, a polymeric micelle formulation
  • D o X i 1 ® is more stable in blood and tumors. It was excellent.
  • NK 91 1 was excellent in the drug release ability after reaching the local area (Tetsuya Higuchi, clinical trial of micelle inclusion agent, Drug Delivery System, 19-5, 429-437 (2004)). Ideally, a system in which the drug is stably bound to the carrier in the blood and releases the drug immediately after reaching the tumor tissue is desired.
  • the present inventors have reported a system in which adriamycin (doxorubicin hydrochloride) is bound to a polyethylene glycol (hereinafter also referred to as PEG) monopolyaspartate hydrazide block copolymer by Schiff base formation (Younsoo Bae, Shigeto Fukushima, Atsushi Harada, and Kazunori Kataoka, Design 01
  • PEG-polyaspartic acid hydrazide block copolymer is prepared according to the following scheme. I was synthesizing.
  • the present invention provides a method for easily and reproducibly producing a drug carrier useful for delivery of an anticancer drug to a tissue or cell, and further a drug carrier incorporating a ligand or an antibody for active targeting.
  • the purpose is to provide
  • the present inventor has made aspartic hydrazide in a single step by reacting hydrazine with a polymer containing the aspartic acid benzyl ester structure. It was found that this reaction proceeds quantitatively with good reproducibility. It was also found that the drug release rate can be controlled by changing the conversion rate to aspartic hydrazide. Furthermore, a drug carrier into which a ligand was introduced was manufactured, and an excellent function over that of a conventional drug carrier was confirmed, and the present invention was completed. That is, the present invention is as follows.
  • the aspartic acid hydrazide is characterized in that the aspartic acid benzyl ester moiety is converted to aspartic acid hydrazide by reacting hydrazine with the polymer containing the aspartic acid benzyl ester structure.
  • a method for producing a polymer containing a hydrazide structure is provided.
  • the polymer containing the aspartic acid benzyl ester structure may be polyaspartic acid benzyl ester, a polyamino acid derivative, and a part of the constituting amino acid derivative may be aspartic acid benzyl ester. Furthermore, it is a graft copolymer, and at least one of its main chain or graft chain may contain an aspartic acid benzyl ester structure, is a block copolymer, and a part of its constituent segments It may contain a benzyl ester aspartate structure.
  • the block copolymer is a block copolymer of polyethylene dalycol or its derivative and a polyamino acid derivative, and the amino acid constituting the polyamino acid derivative It is more preferable that a part of the derivative is aspartate benzyl ester or a block copolymer of polyethylene glycol or its derivative and polyaspartate benzyl ester.
  • R la and R lb represent a hydrogen atom or an unsubstituted or substituted linear, branched or cyclic d. 12 alkyl group, 1 ⁇ and L 2 represent a linking group, R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group, R 3 represents a hydroxyl group or an initiator residue, R 4a and R 4b each independently represents various protecting groups, where Is, for example, a benzyl group and a methyl group, which are usually used as protecting groups for carboxyl groups, and R 5a and R 5b each independently represent various protecting groups, where the protecting groups are, for example, usually amino Z group, B oc group, F moc group, acetyl group and trifluoroacetyl group used as a protecting group for groups, m is an integer of 5 to 20 and 0 0 0, and n is 2 to 5 , 0 0 0, y is an integer from 0 to 4, 9 9 9
  • It contains a functional group into which an antibody or antibody fragment selected from the group consisting of a group, an amino group, a thiol group, and an active ester group can be introduced, or a ligand structure (eg, saccharides, peptides, folic acid, etc.). May be.
  • an antibody or antibody fragment selected from the group consisting of a group, an amino group, a thiol group, and an active ester group can be introduced, or a ligand structure (eg, saccharides, peptides, folic acid, etc.). May be.
  • R la and Rib may be folic acid derivatives represented by the following formula.
  • R 2 is preferably a acetyl group.
  • R 3 is NH—X, where X preferably represents an unsubstituted or substituted Ci. 12 alkyl group.
  • Li is (CH 2 ) a — NH, where a is preferably an integer from 1 to 5.
  • L 2 is (CH 2 ) b — CO, where b is: Preferable to be an integer of ⁇ 5.
  • At least one of y and z may be 0.
  • a block copolymer of polyethylene dallicol or a derivative thereof and polybenzyl aspartate is obtained.
  • a polymer containing an aspartic hydrazide structure is provided.
  • the conversion rate was about 75% at the maximum, so it was a polymer containing the aspartic acid derivative structure, which was 8% or more, more than 90%, or even 95% of the aspartic acid derivative.
  • the above is a novel high molecular weight aspartic hydrazide.
  • the type of polymer containing the aspartic acid derivative structure may be a polyaspartic acid derivative, which is a polyamino acid derivative, and a part of the constituting amino acid derivative is an aspartic acid derivative. It may be a graft copolymer, and may contain an aspartic acid derivative structure in at least one of its main chain or graft chain, and is a block copolymer, a part of which The segment may contain an aspartic acid derivative structure.
  • the block copolymer is a block copolymer of polyethylene dalycol or its derivative and a polyamino acid derivative, and part of the amino acid derivative constituting the polyamino acid derivative. It is more preferable that is an aspartic acid derivative or a block copolymer of polyethylene glycol or a derivative thereof and a polyaspartic acid derivative.
  • R la and R lb represent a hydrogen atom or an unsubstituted or substituted linear, branched or cyclic d. 12 alkyl group, and L 2 represents a linking group
  • R 2 represents Represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • R 3 represents a hydroxyl group or an initiator residue
  • R 6a and R 6b each independently represent a hydroxyl group, an oxybenzyl group
  • 1 NH—NH 2 or 1 represents a NH- Y
  • Ri least one one NH _ NH 2 der where Y is independently an unsubstituted or substituted C i.
  • R 7a and R 7b each independently represent a hydroxyl group, an oxy-protecting group, one NH—NH 2 or one NH—Y, where the protecting group is, for example, usually used as a protecting group for a carboxyl group Benzyl group, methyl group, etc., Y is each independently an unsubstituted or substituted C 1.20 alkyl group, R 8a and R 8 b each independently represents a hydrogen atom or a protecting group, and protected here Examples of the group include a Z group, a Boc group, a Fmoc group, a acetyl group and a trifluoroacetyl group, which are usually used as a protecting group for an amino group, and m is an integer of 5 to 20 and 0 0 0.
  • N is an integer from 2 to 5 0 0
  • X is an integer from 0 to 5 and 0 0
  • y is an integer from 0 to 4 and 9 9
  • z is 0 to 4 and 9 9 It is an integer of 9, but y + z is smaller than n, and each repeating unit in the above general formula is Yibin shows above specified order and force the repeating units may be present randomly.
  • R la and R lb may be a methyl group or a substituted linear, branched or cyclic d. 12 alkyl group, and the substituent may be protected. It contains a functional group into which an antibody or antibody fragment selected from the group consisting of a group, an amino group, a thiol group and an active ester group can be introduced, or a ligand structure (eg, saccharides, peptides, folic acid, etc.). There may be.
  • shaku may be a folic acid derivative represented by the following formula.
  • R la and R lb are substituted linear, branched or cyclic d. 12 alkyl groups, the substituents of which may be protected maleimide group, amino group, thiol group and active ester
  • the block copolymer, which is a conductor, is novel if it includes the aspartic hydrazide structure, regardless of the proportion in the aspartic acid derivative.
  • R 2 is preferably a acetyl group.
  • R 3 is —NH—X, where X preferably represents an unsubstituted or substituted Ci. 12 alkyl group.
  • L i is one (CH 2 ) a —NH—, where a is preferably an integer from 1 to 5.
  • L 2 is one (CH 2 ) b—CO—, where b is preferably an integer of 1-5.
  • At least one of y and z may be 0.
  • a block copolymer of polyethylene dallicol or a derivative thereof and a polyaspartic acid derivative is obtained.
  • a method for producing a block copolymer into which a folic acid ligand is introduced is provided.
  • L! And L 2 represent a linking group
  • R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • R 3 represents a hydroxyl group or an initiator residue
  • R 6a And R 6b each independently represent a hydroxyl group, an oxybenzyl group, 1 NH—NH 2 or 1 NH—Y, but at least one is —NH—NH 2
  • Y is independently An unsubstituted or substituted d.20 alkyl group
  • R 7a and R 7b each independently represent a hydroxyl group, an oxy-protecting group, _NH—NH 2 or one NH—Y
  • the protecting group is For example, a benzyl group and a methyl group that are usually used as protecting groups for carboxyl groups
  • Y is independently an unsubstituted or substituted C! .20 alkyl group
  • R 8 a and R 8 b are each Independently represents a hydrogen atom or a
  • B oc group, Fmo c group, acetyl group, trifluoroacetyl group, etc. m is an integer of 5 to 20,000, n is an integer of 2 to 5,000, x is 0 to 5 000 Y is an integer from 0 to 4,999, z is an integer from 0 to 4,999, y + z is smaller than n, and each repeating unit in the above general formula Are shown in the order specified for convenience of description, but each repeating unit can exist randomly.
  • L 2 represents a linking group
  • R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group
  • R 3 represents a hydroxyl group or an initiator residue
  • R 4a and R 2 4b each independently represents various protecting groups, where the protecting groups are, for example, a benzyl group and a methyl group that are usually used as protecting groups for carboxyl groups
  • R 5a and R 5b are each independently
  • the protecting group is, for example, a Z group, a Boc group, a Fnioc group, a acetyl group or a trifluoroacetyl group, which is usually used as a protecting group for an amino group
  • m is 5 to 5
  • each repeating unit in the above general formula is shown in
  • R 2 is preferably a acetyl group.
  • R 3 is one NH—X, where X preferably represents an unsubstituted or substituted CH 2 alkyl group.
  • Li is one (CH 2 ) a _NH—, where a is preferably an integer from 1 to 5.
  • the polymer provided in the second aspect of the present invention or the polymer produced by the production method provided in the first aspect or the third aspect of the present invention, and a carbonyl group A polymer one-compound complex with a compound having an aspartic acid hydrazide in the polymer and a force sulfonyl group in the compound bound by forming a Schiff base, or A polymer micelle formed by the polymer-one compound complex is provided.
  • the polymer When the polymer is a block copolymer of polyethylene dallicol or its derivative and a polyamino acid derivative, it is a core-shell type polymer micelle formed by a polymer compound complex with a compound having a carbocyclic group.
  • the aspartic acid hydrazide in which the aspartic acid hydrazide in the polymer is bonded to the force ruponyl group in the compound by forming a Schiff base In some cases, a high molecular micelle is formed, in which a segment containing is mainly present in the core and polyethylene glycol or a derivative segment thereof is mainly present in the shell.
  • a core-shell type formed by a polymer compound complex with a compound having a carbonyl group.
  • the complex is formed by binding the aspartic hydrazide in the polymer and the force sulfonyl group in the compound to form a Schiff base, and the compound is bonded to the complex.
  • a segment containing aspartic hydrazide is mainly present in the core, polyethylene dallicol or its derivative segment is mainly present in the shell, and an antibody or antibody fragment or ligand bound to a functional group is present near the surface layer.
  • polymer micelles are formed.
  • polymer-single compound complexes or polymer micelles are preferably freed from the compound by cleavage of the Schiff base bond under acidic conditions.
  • the compound is preferably a drug having physiological activity.
  • the drug is an anticancer drug
  • a useful system for cancer treatment is provided.
  • anticancer agent examples include adriamycin.
  • a polymer-one compound complex a method for controlling the release or release rate of a compound from a polymer micelle, or a polymer-one compound complex in which the release or release rate of a compound is controlled. Or micelles are provided.
  • a pharmaceutical composition comprising the polymer single compound complex provided in the fourth aspect or the fifth aspect of the present invention, or a polymer micelle.
  • the polymer micelle of the present invention has pH responsiveness and can be used for drug targeting and the like.
  • FIG. 1 shows the relationship between the hydrazide substitution rate and the drug release behavior.
  • Figure 2 shows that adriamycin (ADR), folic acid surface-mounted micelles (FMA), and non-folic acid surface-mounted micelles (MA) were contacted with human pharyngeal cancer cells (KB cells) for 24 hours, respectively. It is a figure which shows the in-vitro cytocidal evaluation result.
  • ADR adriamycin
  • FMA folic acid surface-mounted micelles
  • MA non-folic acid surface-mounted micelles
  • the polymer containing the aspartate benzyl ester structure in the first aspect of the present invention may be a polyaspartate benzyl ester, a polyamino acid derivative, and a part of the constituent amino acid derivative is aspartate benzyl ester. There may be.
  • other amino acid derivatives include, but are not limited to, for example, glutamic acid derivatives and lysine derivatives.
  • the polymer constituting the main chain or graft chain on the side, which does not include the aspartate benzyl ester structure is not particularly limited, but for example, polyethylene glycol, polypropylene glycol, such as polyethylene glycol.
  • Polyolylene oxide Polysaccharide, Polyacrylamide, Polysubstituted acrylamide, Polyacrylamide, Polysubstituted methacrylate J, Lumiamide, Polybutylpyrrolidone, Polyvinyl alcohol, Polyacrylate, Poly Examples include various polymers derived from methacrylic acid esters, uncharged polyamino acids, or derivatives thereof.
  • the polymer constituting the segment not containing the aspartic acid benzyl ester structure is not particularly limited.
  • polyalkylene glycol such as polyethylene glycol and polypropylene glycol, polyalkylene oxide, polysaccharide and polyacrylamid.
  • Various polymers are mentioned.
  • a method for producing these polymers is not particularly limited.
  • a method of polymerizing N-force rubonic acid anhydride (NCA), which is a protected amino acid is used.
  • NCA N-force rubonic acid anhydride
  • a block copolymer is preferred.
  • the block copolymer is a block copolymer composed of polyethylene dallicol or its derivative and a polyamino acid derivative, and the amino acid derivative constituting the polyamino acid derivative is a block copolymer. It is more preferable that a part thereof is aspartic acid benzyl ester, or a block copolymer composed of polyethylene glycol or a derivative thereof and polyaspartic acid benzyl ester.
  • R LA and R LB represent a hydrogen atom or an unsubstituted or substituted linear, branched, or cyclic CH 2 alkyl group, but they do not introduce an antibody or antibody fragment and a ligand. If not considered, it is preferably a methyl group.
  • R LA and R LB are substituted linear, branched or cyclic C H2 alkyl groups, and the substituent is an antibody or antibody.
  • the fragment is a functional group that can be introduced.
  • the functional group is a group consisting of a maleimide group, an amino group, a thiol group, and an active ester group. Preferred functional groups may be mentioned, and these functional groups may be protected by various protective groups.
  • R la and R lb are substituted linear, branched or cyclic d. 12 alkyl groups, and the substituents include a ligand structure. preferable.
  • the “antibody” is not particularly limited as long as it specifically recognizes a cell surface antigen, and a monoclonal antibody that recognizes a cancer cell surface antigen is particularly preferable.
  • the length of the fragment is not limited as long as it can specifically recognize surface antigens of cells (particularly cancer cells), and (Fab ') 2 or Fab is particularly preferred.
  • Ligand means a molecule that specifically binds to a receptor present on the cell surface and can promote uptake into cells by receptor-mediated endcytosis. Examples of the ligand include, but are not limited to, saccharides, peptides, and folic acid.
  • the folic acid derivative represented by the following formula is a preferred example of a compound in which the substituent includes a ligand structure.
  • R la and R lb are the above-described substituted alkyl groups
  • protected functional groups may be used.
  • Polyethylene glycol segments are synthesized by a known method using polyethylene glycol, and then a block copolymer can be synthesized by the method disclosed in the present specification (described later).
  • Protecting groups can be deprotected depending on the need for introduction of functional groups.
  • an antibody or antibody fragment when introduced (bonded) to the functional group, it can be introduced by a known method suitable for each functional group. For example, when introducing an antibody or fragment thereof into a polyethylene dallicol segment having a maleimide group end as a functional group, a thiol group is introduced into the antibody or fragment thereof, and a known method is used. Can be introduced. When an antibody or fragment thereof is introduced into a polyethylene diol segment having an amino group terminal as a functional group, a schiff base is formed in the aldehyde of the antibody or fragment thereof and reduced, or the carboxyl of the antibody or fragment thereof is formed. It can be introduced by a condensation reaction with a group.
  • an antibody or fragment thereof When introducing an antibody or fragment thereof into a polyethylene dallicol segment that has a thiol group end as a functional group, introduce it by disulfide bonding the thiol group and the thiol group of the antibody or fragment thereof. be able to.
  • an antibody or a fragment thereof into a polyethylene dallicol segment having an active ester group end as a functional group it may be introduced by reacting the active ester group with an amine of the antibody or fragment thereof. it can.
  • 1 ⁇ and L 2 represent a linking group, but are derived from a terminal structure of polyethylene dalycol suitable for the method for producing a block copolymer.
  • the block copolymer of the above formula (I) can be obtained, for example, by polymerizing a protected amino acid N-force sulfonic acid anhydride (NCA) using an amino terminal polyethylene glycol as an initiator.
  • NCA N-force sulfonic acid anhydride
  • 1 ⁇ is one (CH 2 ) a — NH—, where a is: It is an integer of ⁇ 5, more preferably 2 or 3.
  • the block copolymer of the above formula (II) is obtained by, for example, bonding a terminal amino group of a polyprotected amino acid polymerized with an appropriate initiator and a carboxyl group at the end of polyethylene glycol using a condensing agent or the like. Is obtained.
  • L 2 is one (CH 2 ) b —CO—, where b is an integer of 1 to 5, more preferably an integer of 1 to 3.
  • R 2 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group.
  • the protecting group include a dealkylcarbonyl group, preferably a acetyl group.
  • the hydrophobic group include derivatives such as benzene, naphthalene, anthracene and pyrene.
  • the polymerizable group include a methacryloyl group and an acryloyl group.
  • a method for introducing these protecting groups, hydrophobic groups or polymerizable groups into the ends of the copolymer a method using an acid halide, an acid anhydride may be used.
  • Examples of the method used in the conventional synthesis include a method used and a method using an active ester.
  • R 3 represents a hydroxyl group or an initiator residue.
  • N-force rubonic acid anhydride NAA
  • R 1 and R 2 each independently represent various protecting groups, where the protecting groups are a benzyl group, a methyl group, and the like that are usually used as protecting groups for lpoxyl groups.
  • R 5 a and R3 ⁇ 4 each independently represent a variety of protecting groups, where Z group used as a protecting group for normal ⁇ amino groups with protecting groups, B oc group, F moc group, Asechiru group and triflate Ruo b acetyl
  • Z group used as a protecting group for normal ⁇ amino groups with protecting groups B oc group, F moc group, Asechiru group and triflate Ruo b acetyl
  • a trifluoroacetyl group is more preferable because it is a group and the like and can be deprotected under mild conditions.
  • m is an integer of 5 to 20 and 0 0 0, preferably an integer of 2 0 to 1 and 0 0 0, more preferably an integer of 1 0 0 to 5 0 0.
  • n is an integer of 2 to 5, 0 0 0, preferably an integer of 5 to 1, 0 0 0, and more preferably an integer of 1 0 to 2 0 0.
  • each repeating unit in the above general formula is Although shown in the order specified for convenience of description, each repeating unit can exist randomly.
  • a block copolymer of the above formula (I) is produced by polymerizing a protected amino acid N-carboxylic acid anhydride (NCA) using an amino-terminated polyethylene glycol as an initiator, the reaction is usually carried out in a solvent. Done.
  • the solvent an aliphatic or aromatic organic solvent is used, and a solvent in which both polyethylene dalycol and NCA are soluble is preferable, but not necessarily limited thereto.
  • N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, black mouth form, or a mixed solvent thereof is preferably used.
  • the reaction is carried out in a temperature range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C, more preferably 30 ° C to 50 ° C.
  • the pressure may be, for example, normal pressure.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but it is usually 8 hours to 4 days. ' More preferably, the N-terminal of the block copolymer is blocked by acetylation or the like so that no side reaction occurs.
  • acetylation is performed by mixing a block copolymer and acetic anhydride in a solvent.
  • Acetic anhydride is usually used in an amount of 1 to 10 equivalents with respect to the block copolymer.
  • the solvent an aliphatic or aromatic organic solvent is used, and a solvent in which the block copolymer and acetic anhydride are dissolved is preferable.
  • the solvent N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, dichloromethane, black mouth form, or a mixed solvent thereof is preferably used.
  • the reaction is performed in a temperature range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C, more preferably 30 ° C to 50 ° C.
  • the pressure may be normal pressure, for example.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but it is usually 30 minutes to 2 hours.
  • the reaction for converting the aspartate benzyl ester moiety to aspartate hydride by reacting the block copolymer of the above formula (I) or (II) with hydrazine is usually carried out in a solvent.
  • a solvent an aliphatic or aromatic organic solvent is used, and it is preferable that both the block copolymer and hydrazine are dissolved.
  • N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dichloromethane, black mouth form, or a mixed solvent thereof is preferably used.
  • the solvent used contains as little water as possible.
  • the amount of hydrazine to be charged is usually the amount to be introduced into the aspartic benzyl ester. For example, when 5% is introduced relative to the benzyl ester, 0.5 times the equivalent amount of hydrazine is charged, and when 75% is introduced, 0.75 times the equivalent amount of hydrazine is charged. In the case of introducing 100%, hydrazine may be added in an excessive amount.
  • the reaction is carried out in the temperature range of 0 ° C to 100 ° C, preferably in the range of 20 ° C to 80 ° C, more preferably in the temperature range of 30 ° C to 50 ° C. Done.
  • the pressure is preferably normal pressure.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but it is usually 2 hours to 2 days.
  • a polymer containing an aspartic hydrazide structure is provided.
  • the conversion rate was about 75% at the maximum, so that the polymer containing the aspartic acid derivative structure was 80% or more, further 90% or more in the aspartic acid derivative, 9 High molecular weights with more than 5% aspartic hydrazide are novel.
  • the type of polymer containing the aspartic acid derivative structure may be a polyaspartic acid derivative corresponding to the first embodiment, or may be a polyamino acid derivative, and a part of the constituent amino acid derivative is aspartic acid. It may be a derivative, a graft copolymer, may contain an aspartic acid derivative structure in either the main chain or the graft chain, is a block copolymer, and part of its structure. The aspartic acid derivative structure may be included in the synthetic segment. These polymer components are the same as those described in the first embodiment of the present invention.
  • the block copolymer is a block copolymer composed of polyethylene dallicol or a derivative thereof and a polyamino acid derivative, and the amino acid derivative constituting the polyamino acid derivative. It is more preferable that a part of is a aspartic acid derivative, or a block copolymer composed of polyethylene glycol or a derivative thereof and a polyaspartic acid derivative.
  • a more specific structure of the block copolymer includes the following formula (III) or (IV) force s.
  • RGa and Reb are each independently a hydroxyl group, an oxybenzyl group, —NH—NH 2 ,
  • _NH— represents Y, at least one is NH—NH2, where Y is each independently an unsubstituted or substituted d.20 alkyl group.
  • R 7a and R 7b each independently represent a hydroxyl group, an oxy-protecting group, or one NH_NH 2 _NH—Y, but most (usually 85% or more, preferably 95% or more, more preferably 98% or more) Is preferably a hydroxyl group.
  • the protecting group is a benzyl group, a methyl group or the like, which is usually used as a protecting group for a carboxyl group
  • Y is independently an unsubstituted or substituted C 1-20 alkyl group.
  • RSa and R each independently represent a hydrogen atom or a protecting group, but it is preferable that most (usually 85% or more, preferably 95% or more, more preferably 98% or more) are hydrogen atoms.
  • the protecting group includes a Z group, a Boc group, an Fmoc group, a acetyl group, a trifluoroacetyl group and the like which are usually used as a protecting group for an amino group.
  • X is an integer of 0 to 5,000, and each repeating unit in the above general formula is shown in the order specified for convenience of description, but each repeating unit can be present at random.
  • y + z is assumed to be smaller than n.
  • the block copolymer may form a salt.
  • the counter ions forming the salt include Na +, K +, NH4 +, (l / 2Mg) + , (1/2 C a) +, (1/2 B a) +, CI-, Br-, I -, (1/2 S 0 4) _, N0 3 -, (1/2 C 0 3) _, (1/3 P0 4) -, CH 3 COO-, CF 3 COO-, CH 3 S_ ⁇ 3 —, CF 3 S O3-and the like.
  • a method for producing a block copolymer into which a folic acid ligand is introduced is provided.
  • R4a, R4b, R5a, R5b, R6a, R6b, R7a, R7b, R8a, R8b m , n, X, y, z are the same as described in the first or second aspect of the present invention. .
  • each repeating unit in the above general formula is shown in the order specified for convenience of description, but each repeating unit can exist at random.
  • a block copolymer having a benzaldehyde group at the end of polyethylene dalycol can be obtained by subjecting a block copolymer having a benzyl acetal group at the end of polyethylene dalycol to deacetalization in an acidic solution.
  • hydrochloric acid sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid and the like are used. It is also possible to carry out deacetalization simultaneously with the acetylation reaction.
  • the Schiff base formation and the reduction reaction are usually performed in a solvent.
  • a solvent a lunar alicyclic or aromatic organic solvent is used, and a solvent in which both the block copolymer and the folic acid derivative are soluble is preferable.
  • N, N-dimethylformamide, N, N-dimethylacetamide, methanol, or a mixed solvent thereof is preferably used as the solvent.
  • the reaction is carried out in a temperature range of 0 ° C to 10 ° C, preferably 10 ° C to 70 ° C, more preferably 20 ° C to 40 ° C.
  • the pressure is preferably normal pressure.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but is usually 1 day to 10 days.
  • a dehydrating agent such as molecular sieves may coexist.
  • the folic acid derivative is usually used in an excess amount, that is, 1 to 20 times equivalent to the block copolymer. Unreacted folic acid derivatives can be removed by treatment such as gel filtration.
  • the reducing agent Li A 1 H 4 , Na bH 4, Na bH 3 CN and the like can be used, but it is preferable to use Na bH 3 CN. Good.
  • the reducing agent is used in an excess amount relative to the block copolymer, that is, 1 to 20 times equivalent.
  • the reducing agent is preferably added after mixing the folic acid derivative and the block copolymer and reacting for a while, and can be added in several portions.
  • the polymer provided in the second aspect of the present invention, or the polymer produced by the production method provided in the first aspect or the third aspect of the present invention, and a carbonyl group A polymer one-compound complex in which an aspartic hydrazide and a carbonyl group are combined by forming a Schiff base, or a polymer micelle formed by the polymer one-compound complex is provided.
  • the polymer is a block copolymer and the polymer-one compound complex forms micelles.
  • Examples of the compound having a carbonyl group capable of forming a Schiff base bond include aldehydes and ketones.
  • the reaction for bonding the polymer and the compound is usually performed in a solvent.
  • a solvent an aliphatic or aromatic organic solvent is used, and it is preferable that both the polymer and the compound are dissolved.
  • N, N-dimethylformamide, N, N-dimethylacetamide, methanol, or a mixed solvent thereof is preferably used.
  • the reaction is performed in a temperature range of 0 ° C to 100 ° C, preferably 10 ° C to 70 ° C, more preferably 20 ° C to 40 ° C.
  • the pressure is preferably normal pressure.
  • the reaction time is not particularly limited as long as the reaction proceeds sufficiently, but it is usually 1 day to 10 days.
  • the compound is usually used in an excess amount, that is, 1 to 20 times equivalent to aspartic hydrazide.
  • the unreacted compound can be removed by an operation such as gel filtration.
  • polymer micelles can be formed by dissolving a polymer mono-compound complex thus prepared in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide and methanol. Dialyze against water or a buffer, or dissolve the above polymer mono-compound complex in a volatile organic solvent, remove the organic solvent, add an aqueous medium, and vigorously stir. Is called. It is also possible to freeze-dry the polymer micelle solution to obtain a powder formulation.
  • a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide and methanol.
  • polymer-single compound complexes or polymer micelles are preferably freed from the compound by cleavage of the Schiff base bond under acidic conditions.
  • the compound is preferably a drug having physiological activity.
  • the drug include an anticancer agent, an antiviral agent, an anti-inflammatory agent, and the like. If it is an anticancer agent, a system useful for cancer treatment is provided.
  • anticancer agent having a carbonyl group examples include adriamycin, daunorubicin hydrochloride, paclitaxel and docetaxel.
  • the release and release rates of compounds can be controlled in a wide range from those in which most compounds are released on the order of minutes over time to those that are hardly released in several hours.
  • the optimal release and release rate of a drug when used for treatment is thought to vary depending on the type of drug, the purpose of the treatment, the patient's condition, and the administration schedule, and it is very important to have a means that can be widely controlled. Conceivable.
  • Such controlled release performance of drugs in response to pH is useful, for example, for targeting to cancer cells. That is, when the polymer-one compound complex of the present invention or the polymer micelle is administered intravenously, the drug is hardly released in the blood, and is taken up by cancer cells and the acidic environment of endosomes and lysosomes in the cells. The drug release occurs for the first time below. Furthermore, the introduction of an antibody, antibody fragment, or ligand is expected to increase uptake into cells and enhance the drug efficacy.
  • the polymer one-compound complex or polymer micelle of the present invention can be filtered using a filter.
  • a filter having a pore size of 0.22 ⁇ m used for sterilization is used.
  • the micelle structure is maintained without being destroyed even if the filter is filtered once.
  • Such stability can also be controlled by the introduction rate of hydrazide.
  • the amount of the drug contained in the pharmaceutical composition in the sixth aspect of the present invention can be appropriately set by those skilled in the art.
  • the dosage form include injection.
  • normal systemic administration such as intravenous and intraarterial administration, it can be locally administered into muscle, joint, subcutaneous and intradermal. It is also possible to adopt a dosage form using a catheter. Noh.
  • the dosage, dosage form, and dosage schedule can be arbitrarily set according to the purpose.
  • the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the examples. In the following examples, reagents that can be purified by distillation were distilled.
  • MeO-PEG-p (As D_-Hyd) 500 mg of MeO-PEG-PB LA (1 2-40) obtained in Example 1 was dissolved in benzene and freeze-dried. It was dissolved in 0 ml of N, N-dimethylformamide (DMF). 10 times equivalent of anhydrous hydrazine (9.8 mm 01, Mw 32. 05) was added to the benzyl ester and reacted at 40 ° C for 24 hours. After the reaction, an excess amount of unreacted hydrazine contained in the reaction solution is neutralized with acetic acid, then placed in a dialysis membrane with a fractional molecular weight of 6,000 to 8,000, and 0.25% ammonia.
  • DMF N, N-dimethylformamide
  • Dialysis was performed using 1 liter of aqueous solution as an external solution 3 times every 2 hours and then once with water. Polymers were recovered by lyophilization after dialysis. The introduction ratio of hydrazide was 100% when calculated from the area ratio of methyl group to PEG methyl group by NMR using labeling with acetic anhydride.
  • the micelle particle size was determined by dynamic light scattering (DLS_7000, Otsuka Electronics) after 0.45 // ⁇ filter (M i 1 1 e x_HV, M i 1 1 i por e) treatment.
  • Phono Letter (M i 1 1 e X-HV, M i 1 1 ipore) "O" means stable, that is, the micelle particle size does not change significantly before and after filtration,
  • X means unstable, that is, the size of micelles cannot be measured after filtration.
  • ⁇ indicates that drug release is completed within a few hours to a day.
  • N 1 0— (trifluoroacetyl) — pyrofolieacid (5 g) was added to anhydrous DMF (2 5 ml) and then 2 5. Under the condition of C, 1: 2 0 3 was slowly added. The solution was acidified with 5% aqueous hydrochloric acid and the precipitate was washed with water and ether. The obtained pyrofo 1 icacid was recovered by vacuum drying. Subsequently, pyroacid (500 mg) was dissolved in 2 ° m 1 anhydrous DMF, and reacted with 10 equivalents of CA t-BE (1.6 g).
  • fo 1 ate-hydrazide-BOC is reprecipitated in ether, then the BOC protecting group of fo 1 ate- hydrazide- BOC is deprotected with trifluoroaceticacid (TFA), and then the end is activated with ammonia.
  • Folate—hydrazide (F o 1 -Hy d) is recovered.
  • F o 1— P EG— p (A s p_Hy d) — Ac obtained in Example 6 (100 mg) was dissolved in 50 ml of DMF, and 1.5 times the equivalent of adriamycin (ADR) was added to the hydrazide group, and the mixture was allowed to react at room temperature for 5 days under light shielding. Unreacted ADR was removed using LH_20.
  • Purified F o 1 -PEG-p (Asp—Hyd—ADR) — Ac was dissolved in DMF, and then micelles were prepared by dialysis. It was confirmed by dynamic light scattering measurement that the micelle particle size was about 60 nm.
  • the experimental conditions not specifically described here were the same as those in Example 3.
  • folic acid surface-mounted micelles consisting of F o 1-PEG-p (A sp -Hy d -ADR) _ A c block copolymer on the cellular uptake
  • FMA folic acid surface-mounted micelles
  • IC 50 concentration of drug that inhibits cell growth by 50%
  • ADR adriamycin single agent
  • folic acid micelles showed an approximately 8-fold increase in medicinal effect when contacted for 24 hours compared to micelles without folic acid binding, that is, the same cell growth inhibitory effect at a concentration of about 1 Z8. (Fig. 2).
  • its medicinal properties are effective even with a short contact time (3 hours) (Table 2) because the KB cells are said to have overexpressed folate receptors on the surface. From the biological characteristics, it is thought that the intracellular drug transport efficiency is increased by the action of folic acid and its receptor. Table 2
  • b IC 50 is the concentration of drug capable of inhibiting cell growth by 50 %. The value is A
  • the comparison factor is defined as the ratio between the control and the comparison target.
  • the growth inhibition effect of micelles was compared using as a control the value when contacted with ADR for 24 hours.
  • a polymer containing an aspartic hydrazide structure can be easily produced.
  • the present invention also provides a new drug delivery system with pH responsiveness and target orientation. According to this system, the conversion rate of aspartate hydrazide can be controlled by changing the amount of hydrazine or azine added to aspartate benzyl ester. It is possible to control the release or release rate of the compound according to the conversion rate of aspartic hydrazide introduced from the polymer micelle.

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Abstract

L'invention concerne un nouveau copolymère séquencé, utilisé dans la préparation d'une micelle de polymère réagissant au pH. L'invention concerne également un procédé de fabrication d'un tel copolymère séquencé. L'invention concerne en particulier un procédé de fabrication d'un polymère contenant une structure hydrazide d'acide aspartique. Ce procédé est caractérisé en ce qu'un polymère contenant une structure ester de benzyle d'acide aspartique est mis en réaction avec une hydrazine de façon à ce que la partie ester de benzyle d'acide aspartique soit convertie en un hydrazide d'acide aspartique.
PCT/JP2006/309064 2005-04-22 2006-04-24 NOUVEAU COPOLYMERE SEQUENCE UTILISE DANS LA PREPARATION D'UNE MICELLE DE POLYMERE REAGISSANT AU pH, ET SON PROCEDE DE FABRICATION WO2006115293A1 (fr)

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US8529917B2 (en) 2009-09-25 2013-09-10 Wisconsin Alumni Research Foundation Micelle encapsulation of a combination of therapeutic agents
US8858965B2 (en) 2009-09-25 2014-10-14 Wisconsin Alumni Research Foundation Micelle encapsulation of a combination of therapeutic agents
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