WO2022080364A1 - Particules d'administration de médicament et composition pharmaceutique - Google Patents

Particules d'administration de médicament et composition pharmaceutique Download PDF

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WO2022080364A1
WO2022080364A1 PCT/JP2021/037726 JP2021037726W WO2022080364A1 WO 2022080364 A1 WO2022080364 A1 WO 2022080364A1 JP 2021037726 W JP2021037726 W JP 2021037726W WO 2022080364 A1 WO2022080364 A1 WO 2022080364A1
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plga
drug delivery
sirna
polymer compound
component
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PCT/JP2021/037726
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Japanese (ja)
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舞 櫨川
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学校法人福岡大学
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    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to drug delivery particles and pharmaceutical compositions.
  • nucleic acid drugs have many problems for practical use, despite their high usefulness. In general, nucleic acid drugs have problems such as in vivo stability and cell permeability. For example, Journal of Pharmacological Sciences 139 (2019) 231-239. Has proposed a hybrid micelle in which siRNA and PLGA are covalently bound, and is said to be able to suppress the expression of the glypican-3 (GPC3) gene in ovarian cancer. Further, Japanese Patent Application Laid-Open No. 2019-518040 proposes nanocarriers for encapsulating an active agent and to which a targeting portion that targets DNA is bound.
  • An object of the present invention is to provide drug delivery particles having excellent accumulation in target cells.
  • the first aspect is a drug delivery particle comprising a first component comprising a biodegradable polymer compound covalently bonded to a drug molecule and a second component comprising a biodegradable polymer compound covalently bonded to a target recognition molecule.
  • the drug molecule may include oligonucleotides and may include siRNA.
  • Target recognition molecules may include antibody fragments or functional peptides.
  • the biodegradable polymer compound may contain at least one selected from the group consisting of polyester compounds, polyamide compounds and polycarbonate compounds.
  • the drug delivery particles may have a volume average particle size of 10 nm or more and 1000 nm or less, and preferably 10 nm or more and 300 nm or less.
  • the drug delivery particles may further contain a charge modifier placed on the surface thereof.
  • the second aspect is a pharmaceutical composition containing the drug delivery particles.
  • the drug delivery particles constituting the pharmaceutical composition may contain oligonucleotides as drug molecules and may contain siRNA.
  • the drug delivery particle may contain an antibody fragment as a target recognition molecule.
  • the drug delivery particles may contain at least one selected from the group consisting of polyester compounds, polyamide compounds and polycarbonate compounds as the biodegradable polymer compound.
  • the drug delivery particles may have a volume average particle size of 10 nm or more and 1000 nm or less, and preferably 10 nm or more and 300 nm or less.
  • the drug delivery particles may further contain a charge modifier placed on the surface thereof.
  • the third aspect is to covalently bond the drug molecule and the biodegradable polymer compound to obtain the first component, and to covalently bond the target recognition molecule and the biodegradable polymer compound to obtain the second component.
  • a method for producing a drug delivery particle which comprises mixing the first component and the second component.
  • a fourth aspect is a method of treating a disease, which comprises administering the pharmaceutical composition to a subject.
  • FIG. 3 is a fluorescence microscope image showing the distribution of siRNA in target cells by drug delivery particles. It is the result of flow cytometry showing the introduction of siRNA into target cells by drug delivery particles. It is the result of flow cytometry showing the introduction of siRNA into target cells by drug delivery particles. It is the result of flow cytometry showing the introduction of siRNA into target cells by drug delivery particles. It is the result of flow cytometry showing the introduction of siRNA into target cells by drug delivery particles.
  • the term "process” is included in this term not only as an independent process but also as long as the intended purpose of the process is achieved even if it cannot be clearly distinguished from other processes. ..
  • the content of each component in the composition means the total amount of the plurality of substances present in the composition when a plurality of substances corresponding to each component are present in the composition, unless otherwise specified.
  • the upper limit and the lower limit of the numerical range described in the present specification can be arbitrarily selected and combined with the numerical values exemplified as the numerical range.
  • embodiments of the present invention will be described in detail. However, the embodiments shown below exemplify the drug delivery particles and the pharmaceutical composition for embodying the technical idea of the present invention, and the present invention is the drug delivery particles and the pharmaceutical composition shown below. Not limited to.
  • the drug delivery particles include a first component containing a biodegradable polymer compound covalently bound to a drug molecule and a second component containing a biodegradable polymer compound covalently bound to a target recognition molecule. Consists of.
  • the drug delivery particles may be self-associating particles formed from a biodegradable polymer compound.
  • the first component, in which the drug molecule is covalently bonded to the biodegradable polymer compound forms drug delivery particles, thereby improving the in vivo stability of the drug molecule and further improving the permeability of the drug molecule to cells. ..
  • the drug delivery particle contains the second component in which the target recognition molecule is covalently bonded to the biodegradable polymer compound, the directivity and accumulation of the drug delivery particle to the target cell are improved.
  • the first component contains a biodegradable polymer compound (hereinafter, also referred to as a drug-modified polymer compound) in which a drug molecule is covalently bonded.
  • the drug molecule in the first component is a drug molecule to be delivered, and examples thereof include a physiologically active substance, a diagnostic agent, and a nucleic acid for genetic manipulation.
  • a bioactive substance is a chemical substance having a desired biological activity, for example, therapeutic, prophylactic activity, diagnostic activity, etc. in the living body.
  • the diagnostic agent is a chemical substance used for diagnosing a disease and testing the function of an organ.
  • Nucleic acids for genetic engineering are oligonucleotides that are introduced into cells for research purposes. These drug molecules may be used alone or in combination of two or more.
  • physiologically active substances include oligonucleotides, proteins, peptides, polysaccharides, small molecule organic compounds and the like.
  • therapeutic and prophylactic activity of the physiologically active substance include antisense activity, antitumor activity, antiviral activity, antibacterial activity, antifungal activity, hormonal activity, immunomodulatory activity and the like.
  • diagnostic activity the detection activity of the analysis target can be mentioned.
  • An example of a diagnostic agent is a contrast agent.
  • Drug molecules can be mentioned. Diagnostic agents can be detected using standard techniques and commercially available equipment available in the art.
  • nucleic acids for genetic manipulation include oligonucleotides such as siRNA, shRNA, miRNA.
  • the amount of drug molecule contained in the drug delivery particles may be appropriately selected according to the purpose and the like. For example, it may be 0.1% by mass or more and 20% by mass or less, preferably 0.2% by mass or more and 10% by mass or less with respect to the mass of the drug delivery particles.
  • the drug molecule may contain at least an oligonucleotide.
  • the oligonucleotide include siRNA, ThenRNA, miRNA, antisense nucleic acid, decoy nucleic acid, aptamer, CpG oligo and the like.
  • the oligonucleotide preferably contains at least siRNA.
  • the base sequence of the oligonucleotide is not particularly limited, and may be appropriately selected depending on the purpose of the drug delivery particles and the like.
  • the oligonucleotide may be single-stranded or double-stranded.
  • SiRNA is a double-stranded RNA consisting of 21 to 23 base pairs. siRNA is involved in a phenomenon called RNA interference (RNAi), and by degrading mRNA, expression of a target gene can be suppressed in a sequence-specific manner.
  • RNAi RNA interference
  • siRNA is a double-stranded RNA, the 3'portion of each RNA strand has a structure protruding by 2 bases. It is known that siRNA is produced by excising from a hairpin-shaped RNA or a long double-stranded RNA by an enzyme called a dicer, and as a result, each strand has a phosphate group at the 5'end and a 3'. It has a structure having a hydroxy group at the end.
  • the siRNA may have, for example, a function of suppressing cell proliferation, a function of suppressing infiltration, a function of suppressing migration, a function of suppressing immunity, and the like.
  • Examples of the target gene of siRNA include Glypcian-3, Cyclin B1 and the like.
  • MiRNA is a functional nucleic acid with a length of 20 to 25 bases.
  • MiRNAs are functional ncRNAs (non-coding RNAs) and are thought to play an important role in the biological phenomenon of regulating the expression of other genes.
  • MiRNAs are thought to regulate target gene expression by binding to the 3'untranslated region (UTR) of the target mRNA and inhibiting translation.
  • the miRNA may have, for example, a function of suppressing cell proliferation, a function of suppressing infiltration, a function of suppressing migration, a function of suppressing immunity, and the like.
  • Examples of the target gene of miRNA include Glypcian-3, Cyclin B1 and the like.
  • ShRNA is a hairpin-type RNA used for gene silencing by RNA interference.
  • the hairpin structure of shRNA is cleaved into siRNA by a cellular mechanism and suppresses the expression of the target gene.
  • the shRNA may have, for example, a function of suppressing cell proliferation, a function of suppressing infiltration, a function of suppressing migration, a function of suppressing immunity, and the like.
  • the oligonucleotide constituting the drug delivery particle may be a vector expressing at least one of siRNA, miRNA and shRNA.
  • siRNA siRNA
  • miRNA miRNA
  • shRNA shRNA
  • Oligonucleotides may be composed of naturally occurring nucleotide residues or may be composed of non-naturally occurring modified nucleotide residues.
  • Non-natural modified nucleotide residues include, for example, modified phosphodiester bonds between nucleosides, modified 2'hydroxyl groups of ribose, those containing intramolecularly crosslinked ribose, purine bases and pyrimidine bases. At least one of which is modified is included. Examples of modification of the phosphodiester bond moiety include phosphorothioation, methylphosphonate, methylthiophosphonate, phosphorodithioate, phosphoramidate, peptide bond substitution and the like.
  • Examples of modification of the 2'hydroxyl group of ribose are 2'-O-methylation, 2'-O-methoxyethylation, 2'-O-aminopropyl (AP), 2'-fluoromation, 2'-. Examples thereof include O-methylcarbamoylethylation and 3,3-dimethylallylation.
  • Examples of intramolecular crosslinked ribose include nucleotides crosslinked at the 2'and 4'positions (2', 4'-BNA).
  • 2', 4'-BNA includes, for example, locked nucleic acid ( ⁇ -L-methyleneoxy (4'-CH 2 -O-2') BNA or ⁇ -D-methyleneoxy (4'-), which is also called LNA.
  • CH 2 -O-2') BNA ethyleneoxy (4'-(CH 2 ) 2 -O-2') BNA, also known as ENA), ⁇ -D-thio (4'-CH 2 -S-2) ') BNA, Aminooxy (4'-CH 2 -ON (R) -2') BNA (R is H or CH 3 ), 2', 4'-Oxyamino (4'also called BNANC -CH 2 -N (R) -O-2') BNA (R is H or CH 3 ), 2', 4'-BNACOC, 3'amino-2', 4'-BNA, 5'-methyl BNA , Also called cEt-BNA (4'-CH (CH 3 ) -O-2') BNA, also called cMOE-BNA (4'-CH (CH 2 OCH 3 ) -O-2') BNA , AmNA, as well as amide type BNA (4'-C (O) -N (R) -2')
  • modification of the base moiety examples include halogenation; methylation, ethylation, n-propylation, isopropylization, cyclopropylation, n-butylation, isobutylation, s-butylation, t-butylation, cyclobutylation.
  • Alkylation such as; hydroxylation; amination; deaminolation; demethylation and the like.
  • the amount of oligonucleotide contained in the drug delivery particles may be appropriately selected according to the purpose and the like. For example, it may be 0.1% by mass or more and 70% by mass or less, preferably 0.2% by mass or more and 60% by mass or less with respect to the mass of the drug delivery particles.
  • the upper limit of the amount of oligonucleotide contained in the drug delivery particles may be 50% by mass or less, 10% by mass or less, 2% by mass or less, or 1% by mass or less with respect to the mass of the drug delivery particles.
  • the drug molecule may contain at least a peptide.
  • Peptides constituting drug delivery particles include a fragment of the human antibacterial peptide LL-37, a peptide having antibacterial activity and anticancer activity (CKR12) in which cysteine is introduced into the N-terminal of petitdo KR12, and a fragment of the human antibacterial peptide LL-37.
  • Peptides such as LLAA, which is a petite and has anticancer activity, can be mentioned.
  • the amount of peptide contained in the drug delivery particles may be appropriately selected according to the purpose and the like. For example, it may be 0.1% by mass or more and 50% by mass or less, preferably 0.2% by mass or more and 10% by mass or less with respect to the mass of the drug delivery particles.
  • biodegradable polymer compound to which the drug molecule is covalently bonded examples include polyester compounds, polyamide compounds, polycarbonate compounds, polysaccharides and the like, and at least one selected from the group consisting of these is preferable, and at least polyester. It is more preferable to contain a compound.
  • biodegradable polymer compounds can be used alone or in combination of two or more.
  • polyester compound examples include polylactic acid, polyglycolic acid, polycaproic acid, and copolymers thereof, as well as polybutylene succinate, polyethylene succinate, poly (butylene succinate / adipate), and poly (butylene succinate /).
  • the copolymer may be a random copolymer or a block copolymer.
  • polyamide compound examples include polyleucine, a polyamide compound consisting of a single amino acid residue such as polylysine, insulin, a physiologically active peptide such as growth hormone, a water-soluble protein such as albumin, and a protein which is a polyamide compound. Examples thereof include glycoproteins bound to sugar.
  • polysaccharide examples include cellulose, chitosan, hydroxypropyl cellulose chemically modified from cellulose, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethyl cellulose, and lipopolysaccharide containing polysaccharide and lipid.
  • the release rate of drug molecules and the biodegradation rate of particles can be controlled.
  • the biodegradable polymer compound is PLGA
  • the molecular weight may be, for example, 1000 or more and 50,000 or less, preferably 5000 or more and 20000 or less.
  • the biodegradable polymer compound is a copolymer
  • the release rate of drug molecules and the biodegradation rate of particles can be controlled by appropriately selecting the composition ratio of the monomers.
  • the molar ratio (L / G) of lactic acid to glycolic acid may be, for example, 0.3 or more and 5 or less, preferably 1 or more and 4 or less. ..
  • the first component contains a drug-modified polymer compound formed by covalently bonding a drug molecule and a biodegradable polymer compound.
  • the covalent bond between the drug molecule and the biodegradable polymer compound can be formed by a commonly used method depending on the structure of the drug molecule and the biodegradable polymer compound.
  • the molar ratio of the covalent bond between the drug molecule and the biodegradable polymer compound may be, for example, 2: 1 to 1: 4, or 1: 1.
  • the first component may contain an oligonucleotide as a drug molecule and a polyester compound as a biodegradable hole molecular compound.
  • the first component of such a configuration may have self-association capable of forming micelles.
  • the critical micelle concentration (CMC) of the first component may be, for example, 100 nM or more and 50 mM or less, preferably 1 ⁇ M or more and 10 mM or less.
  • the first component may further contain a biodegradable polymer compound to which the drug molecule is not covalently bonded, in addition to the drug-modified polymer compound.
  • the content of the drug-modified polymer compound in the first component may be, for example, 1 ⁇ 10 -7 % or more and 1% or less, preferably 1 ⁇ 10 -6 % or more and 0.1% or less.
  • the second component may be a biodegradable polymer compound (hereinafter, also referred to as a target recognition polymer compound) to which a target recognition molecule is covalently bonded, as long as it can recognize the molecule existing on the surface of the target cell.
  • the molecule present on the surface of the target cell may be a surface antigen, and examples thereof include receptors, adhesion factors, proteins such as membrane proteins, sugar chains, and the like.
  • the target recognition molecule include functional peptides such as antibodies, antibody fragments, receptor agonists, receptor antagonists, ligand-like peptides, and coiled coil peptides, which consist of a group consisting of antibody fragments, ligand-like peptides, and coiled coil peptides.
  • the target recognition molecule contained in the second component may be one kind alone or a combination of two or more kinds.
  • the target recognition molecule may contain at least one of the antibody fragments as a functional peptide.
  • the antibody fragment may be an antigen-binding fragment, and examples thereof include F (ab') 2, Fab', Fab, Fv, scFv, and the like, and may be at least one selected from the group consisting of these.
  • the antibody fragment can be prepared by treating a desired antibody (for example, IgG) with a protease such as papain, pepsin, or ficin, and if necessary, treating with a reducing agent.
  • the target recognition molecule may contain at least one of the ligand-like peptides as a functional peptide.
  • the ligand-like peptide may be a peptide that can interact with the receptor, may be a ligand peptide, or may be a fragment of the ligand peptide. Specifically, for example, transferrin, transferrin fragment and the like can be mentioned.
  • the target recognition molecule may contain at least one of the coiled coil peptides as a functional peptide.
  • the coiled coil peptide is a coiled peptide having an ⁇ -helix structure, and unlike a ligand, it is a peptide having no physiological activity by itself.
  • the target cell expressing the peptide to which the coiled coil peptide can bind can be recognized.
  • E4 / K4 peptide and the like can be mentioned.
  • biodegradable polymer compound to which the target recognition molecule in the second component is covalently bonded are the same as that in the biodegradable polymer compound in the first component.
  • biodegradable polymer compound in the second component may be the same as or different from the biodegradable polymer compound in the first component.
  • any one of the composition, molecular weight, charge and the like of the polymer compound may be different.
  • the second component contains a target recognition polymer compound formed by covalently bonding a target recognition molecule and a biodegradable polymer compound.
  • the covalent bond between the target recognition molecule and the biodegradable polymer compound can be formed by a commonly used method depending on the structure of the target recognition molecule and the biodegradable polymer compound.
  • the molar ratio of the covalent bond between the target recognition molecule and the biodegradable polymer compound may be, for example, 2: 1 to 1: 1 or 1: 1.
  • the second component may contain an antibody fragment or a functional peptide as a target recognition molecule and a polyester compound as a biodegradable polymer compound.
  • the second component having such a configuration may have self-association capable of forming micelles.
  • the critical micelle concentration (CMC) of the second component may be, for example, 100 nM or more and 50 mM or less, preferably 1 ⁇ M or more and 10 mM or less.
  • the second component may further contain a biodegradable polymer compound to which the target recognition molecule is not covalently bonded, in addition to the target recognition polymer compound.
  • the content of the target recognition polymer compound in the second component may be, for example, 1 ⁇ 10 -7 % or more and 1% or less, preferably 1 ⁇ 10 -6 % or more and 0.1% or less.
  • the molar ratio of the content of the second component to the content of the first component in the drug delivery particles may be, for example, 0.2 or more and 1 or less, preferably 0.25 or more and 0. It may be 5.5 or less.
  • the drug delivery particles may be composite particles containing the first component and the second component, and may be self-associating composite particles or mixed micelles. When the first component and the second component constituting the drug delivery particles are formed from a hydrophobic polymer compound and a water-soluble drug molecule or target recognition molecule, mixed micelles can be easily formed.
  • the drug delivery particles may contain other components in addition to the first component and the second component.
  • examples of other components include charge regulators and the like.
  • the charge regulator may be placed, for example, on the surface of the drug delivery particles.
  • the charge adjuster may be any as long as it can adjust the particle surface charge of the drug delivery particles to a desired range, for example.
  • the charge adjusting agent include chargeable polymer compounds such as cationic polymers and anionic polymers, cationic polypeptides, and anionic polypeptides.
  • the cationic polymer compound include polyamino acids such as polyethyleneimine; chitosan; polylysine, polyarginine, and polyhistidine.
  • the anionic polymer compound include poly (meth) acrylic acid derivatives such as poly (meth) acrylic acid and (meth) acrylic acid- (meth) acrylic acid ester copolymer.
  • the charge regulator may preferably contain at least one of the cationic polymer compounds.
  • the content of the charge adjusting agent may be appropriately selected so that the desired particle surface charge can be obtained.
  • a cationic polymer compound may be used as a charge regulator.
  • the content of the cationic polymer compound is, for example, the ratio (N / P ratio) of the number of moles of basic nitrogen atoms contained in the cationic polymer compound to the number of moles of phosphorus atoms contained in the oligonucleotide. It may be 10 or more and 80 or less, preferably 10 or more and 40 or less, or 10 or more and 20 or less.
  • the volume average particle size of the drug delivery particles may be, for example, 10 nm or more and 500 nm or less, preferably 50 nm or more and 200 nm or less.
  • the zeta potential of the drug delivery particles may be, for example, -60 mV or more and 60 mV or less, preferably -60 mV or more and -20 mV or less, or 20 mV or more and 60 mV or less.
  • the method for producing drug delivery particles is a first step of covalently bonding a drug molecule and a biodegradable polymer compound to obtain a first component, and a target recognition molecule and a biodegradable polymer compound.
  • a second step of covalently bonding the above to obtain a second component, and a third step of mixing the first component and the second component are included.
  • the drug molecule and the biodegradable polymer compound are covalently bonded to obtain the first component.
  • the first component contains a drug-modified polymer compound in which a drug molecule and a biodegradable polymer compound are covalently bonded.
  • the covalent bond between the drug molecule and the biodegradable polymer compound can be formed by a conventional method selected according to the structure of the drug molecule and the biodegradable polymer compound.
  • the biodegradable polymer compound is a polyester compound
  • the drug molecule can be covalently bonded to the carboxy group or the hydroxyl group of the polyester compound via an appropriate linking group.
  • a bifunctional compound having a functional group capable of forming an amide group with a carboxy group such as an amino group or a hydrazide group in the molecule and a disulfide group is amide-bonded to the carboxy group of the polyester compound. And get an intermediate.
  • a drug-modified polymer compound can be obtained by reacting the obtained intermediate with a drug molecule having a thiol group.
  • the target recognition molecule and the biodegradable polymer compound are covalently bonded to obtain the second component.
  • the second component contains a target recognition polymer compound in which a target recognition molecule and a biodegradable polymer compound are covalently bonded.
  • the covalent bond between the target recognition molecule and the biodegradable polymer compound can be formed by a conventional method selected according to the structure of the target recognition molecule and the biodegradable polymer compound.
  • the biodegradable polymer compound is a polyester compound
  • the target recognition molecule can be covalently bonded to the carboxy group or the hydroxyl group of the polyester compound via an appropriate linking group.
  • a bifunctional compound having a functional group capable of forming an amide group with a carboxy group such as an amino group or a hydrazide group in the molecule and a disulfide group is amide-bonded to the carboxy group of the polyester compound. And get an intermediate.
  • a target recognition polymer compound can be obtained by reacting the obtained intermediate with a target recognition molecule having a thiol group.
  • the drug delivery particles are obtained as composite particles containing the first component and the second component by mixing the first component and the second component.
  • the drug delivery particles may be formed, for example, by the self-association of a biodegradable polymer compound.
  • the mixing ratio of the first component and the second component in the third step may be, for example, 1:10 or more and 10: 1 or less, preferably 1: 1 based on the molar standard of the biodegradable polymer compound contained therein. It may be 5: 1 or less.
  • the method for producing the drug delivery particles includes a fourth step of bringing the charge adjuster into contact with the composite particles containing the first component and the second component obtained in the third step and arranging the charge adjuster on the surface of the composite particles. Further may be included.
  • the contact between the composite particles and the charge adjusting agent in the fourth step can be performed by mixing the suspension containing the composite particles and the charge adjusting agent.
  • the mixing ratio of the composite particles and the charge adjusting agent in the fourth step may be 1:10 or more and 1:80 or less, preferably 1:10 or more and 1:80 or less, for example, the charge adjusting agent with respect to the first component. It may be 20 or less.
  • compositions contain at least one of the above-mentioned drug delivery particles as an active ingredient. By including the drug delivery particles, the desired drug molecule can be efficiently delivered to the target cells.
  • the pharmaceutical composition is used for the treatment of diseases.
  • diseases examples include various metastatic cancers and neurodegenerative diseases.
  • the treatment of the disease may be any treatment given to the disease, and examples thereof include treatment, improvement, suppression of progression (prevention of deterioration), prevention, and alleviation of symptoms caused by the disease.
  • the subject of administration of the pharmaceutical composition may be, for example, a mammal, and the mammal includes a human. Moreover, the administration subject may be a non-human animal.
  • the pharmaceutical composition may further contain a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier any carrier commonly used in pharmaceutical preparations can be used.
  • the carrier include a solvent, a solubilizing agent, a suspending agent, an tonicity agent, a buffering agent or a pH adjusting agent, a pain-relieving agent, and the like in a semi-solid preparation or a liquid preparation.
  • additives such as preservatives, antioxidants, colorants, sweeteners, refreshing agents or flavoring agents, defoaming agents, and thickening agents may be contained.
  • Examples of the solvent in the liquid preparation include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizing agent include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • Examples of the suspending agent include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate and the like.
  • Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
  • Examples of the buffer or pH adjuster include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • Examples of the soothing agent include benzyl alcohol and the like.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • Examples of the antioxidant include sodium sulfite, ascorbic acid and the like.
  • Examples of the colorant include edible pigments (eg, edible red No. 2 or 3, edible yellow No. 4 or 5, etc.), ⁇ -carotene and the like.
  • Examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame and the like.
  • Examples of the refreshing agent or flavoring agent include l-menthol or mint water.
  • Examples of the defoaming agent include dimethylpolysiloxane and silicon defoaming agents.
  • Examples of the thickener include xanthan gum, tragant, methyl cellulose, dextrin and the like.
  • the pharmaceutical composition may contain a drug such as an anticancer drug, or may be used in combination with a drug such as an anticancer drug, if necessary.
  • anticancer agents include antimetabolites, molecular targeting agents, alkylating agents, plant alkaloid agents, anticancer antibiotics, platinum preparations, hormone agents, biological response regulators, immune checkpoint inhibitors and the like. Can be mentioned.
  • anticancer agents for example, antimetabolites include gemcitabine, cytarabine, enocitabine, tegafur, carmofur and the like.
  • Molecular-targeted drugs include imatinib, gefitinib, sunitinib, cetuximab and the like.
  • alkylating agent include ifosfamide, cyclophosphamide, dacarbacin and the like.
  • plant alkaloid agent include docetaxel, vincristine, vindesine, and vinblastine.
  • anticancer antibiotic include pirarubibicin, bleomycin, mitomycin, peplomycin and the like.
  • platinum preparation examples include cisplatin, carboplatin, oxaliplatin and the like.
  • hormonal agents include exemestane, tamoxifen, prednisolone and the like.
  • biological response regulator examples include interferon and interleukin.
  • Immune checkpoint inhibitors include nivolumab, pembrolizumab, ipilimumab and the like.
  • the content of the active ingredient in the pharmaceutical composition varies depending on the dosage form, dosage and the like, and is, for example, 0.1% by mass or more and 20% by mass or less, or 0.1% by mass or more and 10% by mass or less of the whole composition. ..
  • the administration dose of the pharmaceutical composition is appropriately selected depending on the administration subject, disease, symptom, dosage form, administration route and the like.
  • the administration dose is, for example, when orally administered to an adult cancer patient, the active ingredient is usually about 0.1 mg or more and 500 mg or less, or about 0.5 mg or more and 100 mg or less, once or several times per day. It can be administered separately.
  • the pharmaceutical composition can be administered parenterally or orally depending on its dosage form.
  • Dosage forms that are administered parenterally include, for example, injections, infusions, eye drops, nasal agents, transpulmonary agents, and the like.
  • Examples of the dosage form to be orally administered include liquid preparations such as syrups, emulsions and suspensions, and semi-solid preparations such as jellies.
  • Treatment of Disease comprises administering to the subject an effective amount of the pharmaceutical composition.
  • the details of the pharmaceutical composition and the administration method are as described above.
  • the subject of treatment is, for example, a mammal, which includes a human.
  • the target of treatment may be a non-human animal.
  • the disease may be, for example, various metastatic cancers, neurodegenerative diseases and the like.
  • the present invention includes the use of drug delivery in the manufacture of pharmaceutical compositions used in the treatment of a disease, the use of drug delivery particles in the treatment of a disease, and the use of drug delivery particles in the treatment of a disease.
  • siRNA-PLGA As a drug molecule, siRNA (sense strand: 5' ⁇ 3') in which a sulfanyl group (-SH group) is modified on the 3'side of siRNA with respect to human cyclin B1 (hCyclin B1). ) was obtained from Thermo Fisher Scientific.
  • DCC dicyclohexylcarbodiimide
  • the volume-based particle size distribution was measured by a dynamic light scattering method, and the volume average particle size was calculated as the particle size corresponding to the volume accumulation of 50% from the small diameter side. It was 0.09 nm. Moreover, when the zeta potential was measured by the electrophoretic light scattering method, it was -22.1 mV. The particle size distribution and zeta potential were measured using a zetasizer (manufactured by Malvern).
  • a reaction mixture was obtained by mixing a solution prepared in the same manner as above in which 40 nmol of PLGA-PDPH was dissolved in 100 ⁇ l of DMSO and a solution in which 10 nmol of Fab'was dissolved in 20 ⁇ l of PBS.
  • the resulting reaction mixture was dialyzed in DMSO for 12 hours and then further dialyzed in distilled water for 12 hours.
  • the insoluble PLGA was removed by filtration through a 0.2 ⁇ m filter.
  • ultrafiltration was performed 5 times with purified water to remove unreacted Fab'to obtain a Fab'-PLGA dispersion in which Fab'and PLGA were covalently bonded.
  • the volume average particle size of the Fab'-PLGA dispersion was calculated to be 170 ⁇ 0.26 nm. Moreover, when the zeta potential was measured, it was -68.5 mV.
  • siRNA-PLGA / Fab'-PLGA complex particles The prepared siRNA-PLGA and the prepared Fab'-PLGA are mixed at a PLGA molar ratio of 4: 1 (siRNA-PLGA: Fab'-PLGA). , A dispersion of siRNA-PLGA / Fab'-PLGA composite particles was obtained as drug delivery particles.
  • the volume average particle size of the dispersion of siRNA-PLGA / Fab'-PLGA composite particles was calculated to be 112.8 ⁇ 0.30 nm. Moreover, when the zeta potential was measured, it was -42.5 mV.
  • siRNA-PLGA (hCyclinB1) significantly suppressed cell proliferation (p ⁇ 0.01) with respect to the control.
  • siRNA-PLGA (hCyclinB1) / Fab'-PLGA significantly (p ⁇ 0.01) suppressed cell proliferation as opposed to siRNA-PLGA (hCyclinB1).
  • the significance test was performed by Bonferroni / Dunnett test.
  • siRNA-PLGA (hCyclinB1) significantly suppressed the expression of (p ⁇ 0.01) hCyclinB1 with respect to the control.
  • siRNA-PLGA (hCyclinB1) / Fab'-PLGA significantly suppressed the expression of (p ⁇ 0.01) hCyclinB1 with respect to siRNA-PLGA (hCyclinB1).
  • siRNA * -PLGA siRNA labeled with the fluorescent dye Alexa488 (green) was used for hCyclinB1 (hereinafter referred to as siRNA * ). bottom.
  • siRNA * -PLGA siRNA labeled with the fluorescent dye Alexa488 (green) was used for hCyclinB1 (hereinafter referred to as siRNA * ). bottom.
  • siRNA * -PLGA siRNA * -PLGA was used.
  • siRNA * -PLGA / Fab'-PLGA composite particles obtained by mixing at a PLGA molar ratio of 4: 1 (siRNA * -PLGA: Fab'-PLGA) were used.
  • the cell introduction rate of siRNA by the siRNA * -PLGA / Fab'-PLGA composite particles was higher than that when siRNA * -PLGA was used. This showed that the use of iRNA * -PLGA / Fab'-PLGA composite particles improved the accumulation of siRNA in target cells.
  • siRNA * -PLGA micelles (equivalent to 80 pmol as siRNA), siRNA * -PLGA micelles and IgG (0.25 ⁇ g) mixed solution, siRNA * -PLGA micelles
  • siRNA * -PLGA micelles The procedure was the same as in Experiment 4A, except that a mixed solution of Fab'(0.25 ⁇ g) and a mixed solution of siRNA * -PLGA micelle and F (ab') 2 (0.25 ⁇ g) were used. The results are shown in FIG. 6B.
  • siRNA of siRNA-PLGA was fluorescently labeled with Cy5, and the PLGA was fluorescently labeled with FITC.
  • siRNA of the siRNA-PLGA / Fab'-PLGA composite particle was fluorescently labeled with Cy5, and the PLGA of Fab'-PLGA was fluorescently labeled with FITC.
  • SiRNA-PLGA / Fab'-PLGA composite particles containing siRNA for mouse glypican 3 (GPC-3) and Fab'for mouse CD71 as drug molecules were prepared in the same manner as above.
  • LPEI-coated siRNA-PLGA / Fab'-PLGA composite particles were prepared by adding a PLEI solution to the obtained composite particles.
  • B16C3F1 female mice (6 to 7 weeks old) were transplanted with 1 ⁇ 10 6 mouse ovarian cancer cell lines HM-1 intraperitoneally. Twenty-four hours after transplantation, intraperitoneally carboplatin (50 mg / kg), paclitaxel (2.5 mg / kg), siRNA-PLGA / Fab'-PLGA composite particles (also called micelles; 100 pmol as siRNA), or LPEI-coated siRNA-PLGA. / Fab'-PLGA composite particles (also referred to as LPEI-micelles; 100 pmol as siRNA) were administered. Two weeks later, the abdomen was opened and the number of tumors in the peritoneum was counted.
  • FIG. 8A The state of the laparotomy mesentery is shown in FIG. 8A, the survival rate is shown in FIG. 8B, and the number of tumors is shown in FIG. 8C.
  • the white triangle in FIG. 8A refers to the tumor.
  • siRNA-PLGA / Fab'-PLGA composite particles show a remarkable prolongation of survival rate and a suppressive effect on the number of metastatic colonies in the abdominal cavity as compared with the standard therapeutic agent.
  • mice C57BL / 6 male mice (7 to 8 weeks old) were transplanted with mouse melanoma cell line B16 / BL6 subcutaneously in the lower extremities in an amount of 2 ⁇ 10 5 per animal. Mice were bred while administering drugs as described later. The diameter of the formed subcutaneous tumor was measured 7 days, 10 days, 14 days, 17 days, and 21 days after transplantation to calculate the tumor volume. The results are shown in FIG. 9A. The chest was opened 21 days after the melanoma cell transplantation, and the number of metastatic colonies to the lung was visually measured. The results are shown in FIG. 9B.
  • Drug administration was performed as follows. dacarbazine was administered at 10 mg / kg intraperitoneally 5 times a day from 24 hours after melanoma transplantation. In addition, 1 mg / kg of anti-PD-1 antibody was intraperitoneally administered 24 hours after melanoma transplantation and twice on the 15th day.
  • SiRNA-PLGA / Fab'-PLGA composite particles containing siRNA for mouse GPC-3 also referred to as micelles (GPC-3); 100 pmol as siRNA
  • GPC-3 micelles
  • the siRNA-PLGA / Fab'-PLGA composite particles have a higher antitumor effect on the primary lesion than the standard therapeutic agent, and have a metastasis-suppressing effect on the metastatic lesions of the lung as effective as the standard therapeutic agent. You can see that.
  • mice 7 to 8 weeks old were transplanted with 2 ⁇ 10 5 mouse melanoma cell lines B16 / BL6 subcutaneously in the lower extremities. Mice were bred while administering drugs as described later.
  • the breeding was continued, and 14 days after the tumor was resected, the abdomen was opened and the number of lung metastatic colonies was visually measured.
  • the metastatic state to the lung is shown in FIG. 10A, and the number of lung metastasized colonies is shown in FIG. 10B.
  • Drug administration was performed as follows. dacarbazine was administered intraperitoneally at 10 mg / kg once a day for 5 consecutive times from 24 hours after subcutaneous tumor resection. In addition, 1 mg / kg of anti-PD-1 antibody was intraperitoneally administered 24 hours after subcutaneous tumor resection and twice on the 7th day.
  • SiRNA-PLGA / Fab'-PLGA composite particles containing siRNA against GPC-3 also referred to as micelles (GPC-3); 100 pmol as siRNA
  • GPC-3 micelles
  • siRNA-PLGA / Fab'-PLGA composite particles also referred to as micelles (NC)
  • NC micelles
  • siRNA-PLGA / Fab'-PLGA composite particles exert a significant metastasis suppressing effect and have a high superiority as compared with the standard therapeutic agent.
  • mice ovarian cancer cell line HM-1, mouse melanoma cell line B16 / BL6, human cervical cancer cell line HeLa, and human liver cancer cell line HepG2 were seeded on a 24-well plate at 5 ⁇ 10 5 cells / well, respectively. bottom.
  • CKR12 or CKR12-PLGA was added, and 24 hours after the addition, the cells were collected and analyzed by Flow cytometry. The results are shown in FIGS. 11A (HM-1), 11B (B16 / BL6), 11C (HeLa) and 11D (HepG2).
  • the CKR12 peptide was fluorescently labeled with 5-FAM (ex495 / em520 nm).
  • CKR12-PLGA was prepared by covalently binding the CKR12 (SEQ ID NO: 1) peptide as a drug molecule to PLGA in the same manner as above.
  • FIGS. 11A to 11D indicates the distribution of cells in which the fluorescence intensity could be detected in the range indicated by the arrow, that is, cells in which the peptide was incorporated. Further, it can be seen that the intracellular uptake efficiency of CKR12 is improved by micellarization.
  • mice ovarian cancer cell line HM-1, mouse melanoma cell line B16BL6, human cervical cancer cell line HeLa, and human liver cancer cell line HepG2 were each seeded on a 24-well plate at 5 ⁇ 10 5 cells / well. After culturing for 24 hours, pDsRed-Nuc vector was introduced for nuclear staining. Twenty-four hours after the introduction of DsRed, CKR12 or CKR12-PLGA was added. Fluorescence observation was performed with a confocal laser scanning microscope (LMS710, Carl Zeiss) 24 hours after the addition. The results are shown in FIG.
  • mice ovarian cancer cell line HM-1, mouse melanoma cell line B16BL6, human cervical cancer cell line HeLa, and human liver cancer cell line HepG2 were seeded on 96 well plates at 1 ⁇ 10 4 cells / well, respectively. Twenty-four hours after cell seeding, CKR12 or CKR12-PLGA was added as CKR12 to a concentration of 0 to 100 ⁇ M. After culturing for 24 hours, WST-8 assay (CCK-8 reagent) was performed and the absorbance was measured (mes: 450 nm, ref: 655 nm). The results are shown in FIGS. 13A (HM-1), 13B (B16 / BL6), 13C (HeLa) and 13D (HepG2).
  • CKR12 significantly enhances the cell proliferation inhibitory effect by micellarization.
  • CKR (scramble) was obtained from Toray Research Center Co., Ltd.
  • CKR12-PLGA (scramble) was prepared by covalently binding a CKR (scramble) peptide as a drug molecule to PLGA in the same manner as above.
  • CKR12 significantly enhances the cell migration inhibitory effect by micellarization.
  • mice ovarian cancer cell line HM-1, the mouse melanoma cell line B16BL6, the human cervical cancer cell line HeLa, and the human liver cancer cell line HepG2 are each produced by Transwell (manufactured by Platypus Technologies).
  • a culture solution without serum was added and seeded at 3 ⁇ 10 5 cells / well.
  • CKR CKR
  • CKR12-PLGA CKR12-PLGA
  • the culture solution was added to the lower part of the chamber and cultured for another 24 hours.
  • the infiltrated cells were eluted on the bottom side of the transwell, and the number of infiltrated cells was detected as the fluorescence intensity (em: 480 nm, ex: 520 nm) by utilizing the mechanism in which the cell-derived component that correlates with the cell number emits fluorescence. ..
  • the results are shown in FIGS. 15A (HM-1), 15B (B16 / BL6), 15C (HeLa) and 15D (HepG2).
  • CKR12 significantly enhances the cell infiltration ability suppressing effect by micellarization.
  • mice Female mice (6 to 7 weeks old) were transplanted with 1 ⁇ 10 6 mouse ovarian cancer cell lines HM-1 into the abdominal cavity. Once intraperitoneally 24 hours after transplantation of an ovarian cancer cell line, siRNA (NC), siRNA (Gpc3), micelles (NC), micelles (Gpc3), or LPEI-coated micelles are used as siRNA. It was administered at a concentration of 100 pmol. The abdomen was opened 2 weeks after the breeding was continued, and the number of tumors in the peritoneum was counted. In addition, the amount of cytokines (IL-6 and IFN- ⁇ ) in ascites was quantified by the ELISA method.
  • cytokines IL-6 and IFN- ⁇
  • FIG. 16A The state of the mesentery after abdominal opening is shown in FIG. 16A, the number of metastatic colonies in the abdominal cavity is shown in FIG. 16B, the amount of IL-6 in ascites is shown in FIG. 16C, and the amount of IFN- ⁇ in ascites is shown in FIG. 16D.
  • the white triangle in FIG. 16A refers to the tumor.
  • siRNA (NC) is a siRNA that does not have activity as a negative control, and was obtained from Thermo Fisher Scientific.
  • siRNA (Gpc3) is a siRNA for GPC3 and was obtained from Thermo Fisher Scientific.
  • Micelle (NC) is siRNA-PLGA prepared using siRNA having no activity as a negative control, and was prepared according to Example 1.
  • Micelle (Gpc3) is siRNA-PLGA prepared by using siRNA against mouse glypican 3 (Gpc3), and was prepared according to Example 1.
  • the LPEI-coated micelles were prepared by adding an LPEI solution to the micelles (Gpc3).
  • FIGS. 16A and 16B it can be seen that micelles improve the metastasis-suppressing effect of the number of peritoneal metastasis colonies of ovarian cancer by surface modification of LPEI. Further, from FIGS. 16C and 16D, it can be seen that the inhibitory effect on the amount of IL-6 and the amount of IFN- ⁇ associated with the protein knockdown effect of siRNA was enhanced.
  • mice ovarian cancer cell line HM-1 was seeded on a 24-well plate at 5 ⁇ 10 5 cells / well. After culturing for 48 hours, a peptide amount equivalent to 0.3 ⁇ g was added to scramble1-PLGA or scramball2-PLGA. Cells were harvested 24 hours after addition and analyzed by Flow cytometry. The results are shown in FIGS. 17A and 17B.
  • scraple1-PLGA was prepared by covalently linking the scraple1 peptide (SEQ ID NO: 3) with PLGA in the same manner as above.
  • the micelles formed from emulsion1-PLGA had an average particle size of 75.10 nm, a zeta potential of -30.37 mV, and were negatively charged.
  • scraple2-PLGA was prepared by covalently linking the scraple2 peptide (SEQ ID NO: 4) with PLGA in the same manner as above.
  • the micelles formed from emulsion2-PLGA had an average particle size of 56.10 nm, a zeta potential of 18.83 mV, and were positively charged.
  • the scroll1 peptide and the scroll1 peptide were fluorescently labeled with 5-FAM (ex495 / em520 nm).

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Abstract

L'invention concerne des particules d'administration de médicament présentant une excellente accumulation dans des cellules cibles. Les particules d'administration de médicament comprennent un premier constituant qui comprend un composé polymère biodégradable auquel une molécule de médicament est liée de manière covalente et un deuxième constituant qui comprend un composé polymère biodégradable auquel une molécule de reconnaissance de cible est liée de manière covalente.
PCT/JP2021/037726 2020-10-13 2021-10-12 Particules d'administration de médicament et composition pharmaceutique WO2022080364A1 (fr)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DIANNA P.Y. CHAN, GLEN F. DELEAVEY, SHAWN C. OWEN, MASAD J. DAMHA, MOLLY S. SHOICHET: "Click conjugated polymeric immuno-nanoparticles for targeted siRNA and antisense oligonucleotide delivery", BIOMATERIALS, ELSEVIER, vol. 34, no. 33, 1 November 2013 (2013-11-01), pages 8408 - 8415, XP055087734, ISSN: 01429612, DOI: 10.1016/j.biomaterials.2013.07.019 *
HAZEKAWA MAI, NISHINAKAGAWA TAKUYA, KAWAKUBO-YASUKOCHI TOMOYO, NAKASHIMA MANABU: "Glypican-3 gene silencing for ovarian cancer using siRNA-PLGA hybrid micelles in a murine peritoneal dissemination model", JOURNAL OF PHARMACOLOGICAL SCIENCES, JAPANESE PHARMACOLOGICAL SOCIETY , TOKYO, JP, vol. 139, no. 3, 1 March 2019 (2019-03-01), JP , pages 231 - 239, XP055921937, ISSN: 1347-8613, DOI: 10.1016/j.jphs.2019.01.009 *
MAI HAZEKAWA, TAKUYA NISHINAKAGAWA, TOMOYO KAWAKUBO-YASUKOCHI, MANABU NAKASHIMA: "Preparation of Fab'-PLGA/siRNA-PLGA mixed micelles with specific recognition of target cells", PROCEEDINGS OF THE 5TH ANNUAL MEETING OF THE NUCLEIC ACIDS THERAPEUTICS SOCIETY OF JAPAN; JULY 10-12, 2019, vol. 5, 1 July 2019 (2019-07-01) - 12 July 2019 (2019-07-12), JP, pages 160, XP009536295 *

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