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WO2020209379A1 - Composition pharmaceutique destinée à être administrée à des femmes enceintes ou à des femmes pouvant être enceintes - Google Patents

Composition pharmaceutique destinée à être administrée à des femmes enceintes ou à des femmes pouvant être enceintes Download PDF

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WO2020209379A1
WO2020209379A1 PCT/JP2020/016186 JP2020016186W WO2020209379A1 WO 2020209379 A1 WO2020209379 A1 WO 2020209379A1 JP 2020016186 W JP2020016186 W JP 2020016186W WO 2020209379 A1 WO2020209379 A1 WO 2020209379A1
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pharmaceutical composition
group
drug
integer
block copolymer
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PCT/JP2020/016186
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English (en)
Japanese (ja)
Inventor
オラシオ カブラル
拓也 宮崎
静羽 万
和恵 水野
健 永松
研資 鈴木
紘子 小田
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国立大学法人 東京大学
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Priority to JP2021513726A priority Critical patent/JP7289155B2/ja
Publication of WO2020209379A1 publication Critical patent/WO2020209379A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a pharmaceutical composition for administration to a pregnant woman or a woman who may become pregnant.
  • Medications for pregnant women are avoided as much as possible to avoid affecting the fetus. Effects on the fetus include teratogenicity, miscarriage, premature birth and fetal stunting.
  • the number of drugs for which safety has been established is limited, and it is necessary to discontinue medication when pregnancy is known. Pregnant women may also suffer from excessive labor due to the discovery of pregnancy during medication. On the other hand, discontinuation of medication often has an adverse effect on pregnant women, and development of a drug that can be used even during pregnancy is desired.
  • Cancer is one of the diseases that becomes a problem during pregnancy. Approximately 200,000 pregnant women worldwide suffer from cancer, of which breast cancer has been reported to be associated with exposure to endogenous estrogen and progesterone and develops with pregnancy. There is also.
  • breast cancer The risk of breast cancer increases with age, but the number of cases of breast cancer in pregnant women increases with increasing age of pregnancy. Generally, for breast cancer, anticancer agents, hormone therapy, antibody therapeutic agents, radiation therapy, surgery, etc. are performed, but the anticancer agents that can be used for pregnant women are limited.
  • Inflammation during pregnancy especially bacterial inflammation, is known to increase the risk of preterm birth, and non-steroidal anti-inflammatory drugs such as indomethacin can be used for treatment.
  • non-steroidal anti-inflammatory drugs such as indomethacin affect the fetus and cause renal failure and digestive failure, and sufficient caution is required for their use.
  • Preeclampsia is known as a disease that occurs frequently in pregnant women, and it occurs in about 1 in 20 people. Preeclampsia impairs renal and hepatic function, is dangerous to the mother, and can also cause fetal growth restriction. Antihypertensive agents such as hydralazine, methyldopa, labetalol, and nifedipine are commonly used to treat preeclampsia. Recent studies have reported that statins are useful for the treatment and / or prevention of preeclampsia (Non-Patent Document 1: Plos One (2010) vol. 5, Issue 10, e13663). The use of statins in pregnant women is contraindicated. In addition, some psychiatric drugs administered for the treatment of psychiatric disorders may cause teratogenicity or neonatal maladaptation syndrome, and the medication may be discontinued.
  • the purpose is to develop a drug that can be used during pregnancy.
  • the present inventors conducted research focusing on the placental permeability of the drug for the purpose of developing a drug that can be used during pregnancy.
  • placental permeability can be controlled by controlling the size with a hydrophilic polymer, and have reached the present invention. Therefore, the present invention relates to the following:
  • a pharmaceutical composition for administration to a pregnant woman or a woman of childbearing potential which comprises particles having a hydrophilic polymer on the surface to which a therapeutic agent is bound or coordinated, and has a dynamic particle size.
  • the pharmaceutical composition having a diameter of 10 to 100 nm as measured by a light scattering method.
  • the pharmaceutical composition according to item 1, wherein the particles are micelles containing a polyethylene glycol-polyamino acid block copolymer.
  • the polyethylene glycol-polyamino acid block copolymer has the following general formula (I) or (II):
  • R 1a and R 1b represent hydrogen atoms, hydroxyl groups or unsubstituted or substituted linear or branched C 1-12 alkyl groups or C 1-12 alkoxy groups.
  • L 1 represents-(CH 2 ) b- NH-, and b is an integer of 1 to 5.
  • L 2 represents ⁇ (CH 2 ) c ⁇ CO ⁇ , and c is an integer from 1 to 5.
  • R 2a , and R 2c independently on each appearance, either do not exist or represent a methylene group.
  • R 2b and R 2d represent a carboxy group or any amino acid side chain.
  • R 3 represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
  • R 4 represents a hydroxyl group, an oxybenzyl group, an -NH- (CH 2 ) a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amine or quaternary ammonium salt, or a compound residue that is not an amine.
  • m is an integer from 20 to 2,000
  • n is an integer from 1 to 200) Item 2.
  • [4] The pharmaceutical composition according to any one of items 1 to 3, wherein the particle size is 25 to 75 nm.
  • the therapeutic agent is administered at a dosage and / or dosage that is contraindicated for pregnant women when administered only with the therapeutic agent.
  • the therapeutic agent is selected from the group consisting of an anticancer drug, an anti-inflammatory drug, an antihypertensive drug, and a psychotropic drug.
  • the anticancer drug is a platinum preparation.
  • the therapeutic agent is an anti-inflammatory agent and is used for preventing miscarriage.
  • the anti-inflammatory drug is a non-steroidal anti-inflammatory drug.
  • the therapeutic agent is an antihypertensive agent and is for the treatment of a gestational hypertension agent.
  • the antihypertensive drug is a statin-based antihypertensive drug.
  • R 2a and R 2c independently exist for each occurrence or represent a methylene group.
  • R 2b and R 2d represent a carboxy group or any amino acid side chain.
  • R 3 represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
  • R 4 represents a hydroxyl group, an oxybenzyl group, an -NH- (CH 2 ) a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amine or quaternary ammonium salt, or a compound residue that is not an amine.
  • a drug is a drug-combined block copolymer in which a drug is bound to the block copolymer represented by (1) via R 2b and R 2d of the block copolymer, directly or via a linker, and the drug is , Indomethacin or simvastatin, said drug complex block copolymer.
  • Pharmaceutical composition [17] The pharmaceutical composition according to item 16, wherein the drug contains indomethacin, and the pharmaceutical composition is a miscarriage-preventing pharmaceutical composition.
  • a method for producing micelles which comprises a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated and is to be administered to a pregnant woman or a woman of childbearing potential.
  • the production method is a method for producing micelles, which comprises a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated and is to be administered to a pregnant woman or a woman of childbearing potential.
  • the polyethylene glycol-polyamino acid block copolymer has the following general formula (1-a) or (1-b): (During the ceremony R 1a and R 1b represent hydrogen atoms, hydroxyl groups or unsubstituted or substituted linear or branched C 1-12 alkyl groups or C 1-12 alkoxy groups.
  • L 1 represents-(CH 2 ) b- NH-, and b is an integer of 1 to 5.
  • L 2 represents ⁇ (CH 2 ) c ⁇ CO ⁇ , and c is an integer from 1 to 5.
  • R 2a and R 2c independently exist for each occurrence or represent a methylene group.
  • R 2b and R 2d represent a carboxy group or any amino acid side chain.
  • R 3 represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
  • R 4 represents a hydroxyl group, an oxybenzyl group, an -NH- (CH 2 ) a- X group or an initiator residue.
  • a is an integer of 1 to 5
  • X is an amine compound residue containing one or more of primary, secondary, tertiary amines or quaternary ammonium salts, or a compound that is not an amine.
  • Is a residue m is an integer from 20 to 2,000 n is an integer from 1 to 200)
  • the manufacturing method according to 20. Particles having a hydrophilic polymer on the surface to which a therapeutic agent for use in the treatment or prevention of a disease in a pregnant woman or a woman of childbearing potential is bound or coordinated, and the particle size is dynamic light. The particles having a diameter of 10 to 100 nm as measured by a scattering method.
  • Particles having a hydrophilic polymer on the surface to which an anti-inflammatory drug for use in the prevention, prevention or treatment of miscarriage or premature birth is bound or coordinated in a pregnant woman or a woman of childbearing potential.
  • particles having a hydrophilic polymer on the surface to which an antihypertensive drug for use in the prevention or treatment of preeclampsia is bound or coordinated, and having a particle size of The particles having a diameter of 10 to 100 nm as measured by a dynamic light scattering method.
  • a method for preventing, preventing or treating miscarriage or premature birth in which particles having a hydrophilic polymer on the surface to which an anti-inflammatory agent is bound or coordinated are provided.
  • the method described above comprising administering to a pregnant woman or a woman of childbearing potential, wherein the particle size is 10-100 nm as measured by dynamic light scattering.
  • a method for preventing or treating preeclampsia in which particles having a hydrophilic polymer on the surface to which an antihypertensive drug is bound or coordinated are provided on the surface of the pregnant woman or pregnant woman.
  • the method described above comprising administering to a potential woman, wherein the particle size is 10-100 nm as measured by dynamic light scattering.
  • the surface has a hydrophilic polymer to which a therapeutic agent is bound or coordinated and has a particle size for the manufacture of a medicament for use in the treatment or prevention of a disease in a pregnant woman or a woman of childbearing potential. Use of particles that are 10-100 nm as measured by dynamic light scattering.
  • the hydrophilic polymer In pregnant women or women of childbearing potential, particles to which a therapeutic agent is bound or coordinated to produce a drug for the prevention, prevention or treatment of miscarriage or preterm birth, the hydrophilic polymer. Use of particles on the surface that have a particle size of 10-100 nm as measured by dynamic light scattering. [34] In pregnant women or women of childbearing potential, particles to which a therapeutic agent is bound or coordinated for the manufacture of a pharmaceutical for the prevention or treatment of preeclampsia, with a hydrophilic polymer on the surface. However, the use of particles whose particle size is 10 to 100 nm when measured by dynamic light scattering. [35] The use according to any one of items 32 to 34, wherein the fetal phytotoxicity is reduced. [36] The use according to any one of items 32 to 34, wherein the placental barrier permeability is reduced.
  • the pharmaceutical composition of the present invention has low placental permeability and can reduce the effect of the drug on the fetus. This makes it possible to provide a medicine that can be administered to a pregnant woman or a woman who may become pregnant.
  • FIG. 1 is a photograph showing the accumulation of high molecular weight micelles in the placenta and fetus.
  • FIG. 2 is a photograph showing the analysis of elements (Pt, Fe, K, Ca) after administration of micelles having a size of 30 nm.
  • FIG. 3 is a graph showing the platinum content in the fetus of pregnant mice treated with oxaliplatin and dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm).
  • FIG. 4 is a graph showing the platinum content in the placenta of pregnant mice treated with oxaliplatin and dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm).
  • FIG. 1 is a photograph showing the accumulation of high molecular weight micelles in the placenta and fetus.
  • FIG. 2 is a photograph showing the analysis of elements (Pt, Fe, K, Ca) after administration of micelles having a size of 30 nm.
  • FIG. 5 is a graph showing placental permeability of a drug by a human placental perfusion model.
  • FIG. 5A shows the results for oxaliplatin, 30 nm dahaplatin-encapsulating micelles, 70 nm dahaplatin-encapsulating micelles, and 8-armPEG.
  • FIG. 5B shows the results for 10 nm, 20 nm, and 30 nm PEG-coated gold nanoparticles.
  • FIG. 6 is a graph showing the amount of drug accumulated in the human placenta.
  • FIG. 7 shows the 1 H-NMR spectrum of PEG-poly (Asp-Furan-OH).
  • FIG. 8 is a graph showing the stability of micelles in blood and endosome pH.
  • FIG. 9 is a graph showing the amount of indomethacin released in macrophages.
  • FIG. 10 is a graph showing placental permeability of a drug by a human placental perfusion model.
  • FIG. 11 is a diagram showing the tissue transferability of indomethacin-encapsulating polymer micelles.
  • FIG. 11A shows the location of the recovered organs, and
  • FIGS. 11B-E show the fluorescence of indomethacin-encapsulating polymer micelles at 1, 4, 8 and 24 hours after administration.
  • FIG. 12 is a diagram showing an evaluation of tissue migration of indomethacin-encapsulating polymer micelles.
  • the amount of indomethacin transferred to (A) kidney, (B) liver, (C) spleen, (D) placenta, and (E) fetus after administration of indomethacin-encapsulating polymer micelles to pregnant mice is shown.
  • It is a graph which shows the survival rate by administration of indomethacin, indomethacin-encapsulating polymer micelle in a preterm mouse model.
  • FIG. 14 is a graph showing changes in blood pressure after administration of a drug in a preeclampsia model mouse.
  • FIG. 15 is a graph showing changes in fetal body weight after administration of a drug in a preeclampsia model mouse.
  • FIG. 16 is a graph showing the amount of urinary albumin after drug administration in a preeclampsia model mouse.
  • the present invention relates to a pharmaceutical composition for administration to a pregnant woman or a woman who may become pregnant.
  • the pharmaceutical composition of the present invention contains particles having a hydrophilic polymer to which a therapeutic agent is bound or coordinated on the surface, and the particle size thereof is 10 to 100 nm when measured by a dynamic light scattering method. It is a feature. From the viewpoint of placental permeability, the particle size is usually 10 nm or more, preferably 20 nm or more, and more preferably 25 nm or more. From the viewpoint of exerting the efficacy of the therapeutic agent, the particle size is usually 100 nm or less, preferably 90 nm or less, more preferably 80 nm or less, and even more preferably 75 nm or less.
  • the polydispersity (PDI) of the particle size of the particles is preferably 0.2 or less, and even more preferably 0.1 or less. Since the particles contained in the pharmaceutical composition of the present invention have reduced placental permeability, they can be used as a pharmaceutical composition for reducing fetal phytotoxicity or reducing placental barrier penetration.
  • any particles may be used as long as the particles have a hydrophilic polymer on the surface, and may be micelles or vesicles formed by a block copolymer, liposomes whose surface is covered with a hydrophilic polymer, or the like.
  • hydrophilic polymer any polymer can be used as long as it is a hydrophilic polymer generally used in medicines, particularly drug delivery systems.
  • polyethylene glycol, polylactic acid, polyglycolic acid, polypeptide, polysaccharide and the like can be mentioned.
  • polyethylene glycol-polyamino acid block copolymers can be used.
  • polyethylene glycol-polyamino acid block copolymer any known in the art can be used.
  • amino acid of the polyethylene glycol-polyamino acid block copolymer glutamic acid or aspartic acid having a carboxy group in the side chain can be used.
  • R 1a and R 1b represent a hydrogen atom, a hydroxyl group, or an unsubstituted or substituted linear or branched C 1-12 alkyl group or C 1-12 alkoxy group.
  • L 1 represents-(CH 2 ) b- NH-, and b is an integer of 1 to 5.
  • L 2 represents ⁇ (CH 2 ) c ⁇ CO ⁇ , and c is an integer from 1 to 5.
  • R 2a and R 2c independently exist on each occurrence or represent a methylene group.
  • R 2b and R 2d represent a carboxy group or any amino acid side chain.
  • R 3 represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
  • R 4 represents a hydroxyl group, an oxybenzyl group, an -NH- (CH 2 ) a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amine or quaternary ammonium salt, or a compound residue that is not an amine.
  • m is an integer from 20 to 2,000
  • n is an integer from 1 to 200)
  • Block copolymers represented by can be used. Therapeutic agents are bound or coordinated in R 2b and R 2d either directly or via a linker.
  • R 1a and R 1b are independently hydrogen atoms, hydroxyl groups, or unsubstituted or substituted linear or branched C 1-12 alkyl groups or C 1-12, respectively. Represents an alkoxy group.
  • Linear or branched C 1-12 include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, decyl, undecyl. And so on.
  • the substituents include acetalized formyl group, cyano group, formyl group, carboxyl group, amino group, C 1-6 alkoxycarbonyl group, C 2-7 acylamide group, and the same or different tri-C 1 -6 Alkylsiloxy group, siloxy group or silylamino group can be mentioned.
  • acetalization refers to the reaction of the carbonyl of formyl with, for example, two molecules of an alkanol having 1 to 6 carbon atoms or a branched alkylene diol having 2 to 6 carbon atoms. It means formation and is also a method of protecting the carbonyl group.
  • the substituent when the substituent is an acetalized formyl group, it can be hydrolyzed under mild acidic conditions and converted to another substituent, a formyl group (-CHO) (or aldehyde group).
  • L 1 and L 2 represent a linking group.
  • L 1 is preferably ⁇ (CH 2 ) b ⁇ NH ⁇ (where b is an integer of 1 to 5), and L 2 is ⁇ (CH 2 ) c ⁇ CO ⁇ (here). And c is an integer of 1 to 5).
  • R 2a and R 2c do not exist independently at each appearance or represent a methylene group.
  • aspartic acid is used as the amino acid
  • dehydration condensation occurs between the carboxy group in the side chain of aspartic acid and the nitrogen in the main chain, and a succinimide intermediate is produced. Cleavage of this intermediate can then result in isomerization to isoaspartic acid. Therefore, when aspartic acid is isomerized to isoaspartic acid, a methylene group is generated at the positions of R 2a and R 2c , and R 2b and R 2d become carboxy groups.
  • R 2a and R 2c In the absence of R 2a and R 2c, isomerization does not occur, indicating that the amino acid has a peptide bond in the main chain.
  • the rate of isomerization in the block copolymer can be arbitrary.
  • R 2a and R 2c R 2b and R 2d represent any amino acid side and the drug is coordinated through these groups or the drug, either directly or via a linker.
  • the amino acid side chain may be a side chain of any biological constituent amino acid, but from the viewpoint of binding a drug, it may be a side chain of serine, threonine, arginine, histidine, lysine, cysteine, glutamic acid and aspartic acid. preferable.
  • R 2a and R 2c are present, R 2b and R 2d are carboxy groups. Since the isomerization of aspartic acid to isoaspartic acid in the polyamino acid segment can occur accidentally, the above description is made even when the formula representing only the amide bond between the main chains is described in the present specification. It is not intended to exclude isomerized polymers as in formulas (I) and (II) of. Repetitive units of amino acids can be present in blocks, or can be randomly present.
  • R 3 represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group. Specifically, R 3 is preferably an acetyl group, an acryloyl group, or a methacryloyl group.
  • R 4 represents a hydroxyl group, an oxybenzyl group, an -NH- (CH 2 ) a- X group or an initiator residue.
  • a is an integer of 1 to 5
  • X is an amine compound residue containing one or more of primary, secondary, tertiary amines or quaternary ammonium salts, or a compound that is not an amine. It is preferably a residue.
  • n is an integer of 1 to 200, preferably an integer of 20 to 100, and more preferably an integer of 30 to 50.
  • each repeating unit in the general formulas (I) and (II) is shown in the order specified for convenience of description, but each repeating unit can exist in a random order. In particular, it is preferred that only each repeating unit in the polyamino acid segment can be present in random order as described above.
  • the molecular weight (Mw) of the block copolymer represented by the general formulas (I) and (II) is not limited, but is preferably 5,000 to 40,000, more preferably 8,000 to 22,000. is there.
  • the molecular weight (Mw) of the PEG segment is preferably 1,000 to 20,000, more preferably 2,000 to 12,000, and the molecular weight of the polyamino acid segment (Mw). ) Is preferably 4,000 to 20,000 as a whole, and more preferably 6,000 to 10,000.
  • Method for producing a block copolymer represented by the general formula (I) and (II) include, but are not limited to, for example, R 1a - or R 1b - and previously synthesized segment (PEG segment) comprising a block portion of the PEG chain ; then, one end of the PEG segment (R 1a - - or R 1b opposite ends), and polymerizing a prescribed monomers in sequence, substitution or to include an anionic group to the side chain then optionally Examples thereof include a method of conversion, a method of synthesizing the PEG segment and a block portion having a side chain containing an anionic group in advance, and connecting them to each other.
  • the methods and conditions of various reactions in the production method can be appropriately selected or set in consideration of the conventional method.
  • the PEG segment is a method for producing a PEG segment portion of a block copolymer described in, for example, Patent Document 1: WO96 / 32434, Patent Document 2: WO96 / 33233, and Patent Document 3: WO97 / 06202. Can be prepared using.
  • the bond between the PEG segment portion and the polyamino acid segment portion thus formed can also take an appropriate linking mode depending on the method for producing the block copolymer represented by the general formula (I) or (II), and the present invention As long as it meets the object of the invention, it may be bonded by any linking group.
  • the production method is not particularly limited, but as one method for producing the polymer of the general formula (I) or (II), a PEG derivative having an amino group at the terminal is used, for example, from the amino terminal thereof.
  • ⁇ -benzyl-L-aspartate (BLA), ⁇ -benzyl-L-glutamate and other protected amino acids N-carboxylic acid anhydrides are ring-open polymerized to synthesize block copolymers, followed by Examples thereof include a method of converting a chain benzyl group into another ester group, or partially or completely hydrolyzing the chain benzyl group to obtain the desired block copolymer.
  • the structure of the copolymer is the general formula (I)
  • the linking group L1 is a structure derived from the terminal structure of the PEG segment used, but is preferably ⁇ (CH 2 ) b ⁇ NH ⁇ (here).
  • B is an integer from 1 to 5).
  • the copolymer of the present invention can also be produced by a method of synthesizing a polyamino acid segment portion and then binding it to a PEG segment portion prepared in advance, and in this case, the result is the same as that produced by the above method.
  • the linking group L 2 is not particularly limited, but is preferably ⁇ (CH 2 ) c ⁇ CO ⁇ , as it may have a structure corresponding to the general formula (II). Yes (where c is an integer from 1 to 5).
  • Drugs can be bound or coordinated to the hydrophilic polymers of the present invention.
  • the agent can be attached to or coordinated with the hydrophilic polymer via a linker or directly.
  • the hydrophilic polymer is a block copolymer of formula (I) or (II)
  • the agent can be coordinated or attached at R 2b and R 2d .
  • the drug contains a heavy metal such as platinum, the carboxylate group formed by liberating the proton of the carboxy group of the amino acid side chain coordinates with the heavy metal of the drug.
  • the drug is directly bound, it can be bound via the carboxy group, amino group, thiol group of the amino acid side chain.
  • the linker L 3 can be any linker used in the art, such as C 1-6 alkylene.
  • a drug in which a hydrazine is reacted with a carboxy group of a polyamino acid or a derivative thereof to form a hydrazide group in this case, M is -NH-NH 2
  • M is -NH-NH 2
  • the linker L becomes a hydrazone bond.
  • any linker known in the art can be used from the viewpoint of producing desired particles.
  • the therapeutic agent contained in the pharmaceutical composition of the present invention may be any therapeutic agent. Particularly in pregnant women, the required therapeutic agents are mentioned, and as an example, anticancer agents, anti-inflammatory agents, antihypertensive agents, psychotropic agents and the like can be used.
  • anticancer agents include anticancer agents for treating cancer in any organ such as stomach, skin, larynx, mouth, pharynx, esophagus, digestive organs, pancreas, lung, brain, bone, bone marrow, and breast. Drugs for the treatment of breast cancer, which are more likely to occur in pregnant women.
  • alkylating agent examples include nitrogen mustards such as cyclophosphamide, ifosfamide, melphalan, busulfan and thiotepa, and nitrosoureas such as nimustine, ranimustine, dacarbazine, procarbazine, temozolomide, carmustine, streptozotocin and bendamstin.
  • Antimetabolites include fluorouracil, 6-mercaptopurine, azathioprine, hydroxyurea, thioguanine, fludarabine, cladribine, silatabin, gemcitabine and the like.
  • topoisomerase inhibitors examples include camptothecin, irinotecan, nogitecan, anthracycline, doxorubicin, epirubicin, daunorubicin, bleomycin, levofloxacin, cyprofloxacin and the like.
  • microtubule polymerization inhibitor examples include vincristine, vindesine, paclitaxel, docetaxel and the like.
  • endocrine therapeutic agents include anastrozole, exemestane, tamoxifen, toremifene, fulvestrant, letrozole and the like.
  • an endocrine therapeutic agent and the like can be mentioned.
  • doxorubicin, cyclophosphamide, fluorouracil, etc. which have been proven to have less effect on the fetus, may be used.
  • the present invention relates to a pharmaceutical composition for administration to a pregnant woman or a woman of childbearing potential, which comprises a dahaplatin derivative micelle coordinated to a polyethylene glycol polyamino acid block copolymer.
  • a dahaplatin derivative micelle which is a partial structure in which the oxalate group of oxaliplatin is removed, is coordinated to the carboxylate group of a polyamino acid (particularly glutamic acid or aspartic acid) instead of the oxalate group, and the micelle size is large. It is characterized in that it is 10 to 100 nm, preferably 20 to 90 nm, and more preferably 25 to 75 nm.
  • compositions containing such dahaplatin derivative micelles may be administered in contraindicated doses and dosages to pregnant or potentially pregnant women when the active agent dahaplatin is administered.
  • dahaplatin derivative micelles can be administered at 90-120 mg / m 2 once weekly to pregnant or potentially pregnant women.
  • Anti-inflammatory drugs are non-steroidal anti-inflammatory drugs such as indomethacin, ketoprofen, loxoprofen, diclofenac, ibuprofen, acetylsalicylic acid, selecoxib, etodolac, and meloxicam.
  • the pharmaceutical composition of the present invention containing an anti-inflammatory agent can be used as an analgesic and antipyretic drug, a therapeutic agent for rheumatoid arthritis, and can be used for the treatment or prevention of premature birth or miscarriage.
  • Indomethacin and the like can be designed to be released in response to low pH in the inflamed area, as it is desired to act in the inflamed area.
  • the drug may be designed to be released by the action of esterase possessed by the macrophage by being phagocytosed by the macrophage in the inflamed area.
  • the therapeutic agents for diseases that lead to inflammation such as endometriosis, the therapeutic agents for inflammation associated with infectious diseases, and the therapeutic agents for inflammation associated with immunity are also included in the anti-inflammatory agents in this document. be able to.
  • Examples of antihypertensive drugs include Ca antagonists, ARBs, ACE inhibitors, diuretics, ⁇ -blockers, ⁇ -blockers, and statin-based hyperlipidemia drugs.
  • Calcium channel blockers include dihydropyridines such as amlodipine, nifedipine, nicardipine, benidipine, balnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, ephonidipine, silnidipine and alanidipine, benzothiazepines such as diltiazem, and phenyl such as verapamil. Examples include alkylamine-based agents.
  • Examples of ARB include valsartan, losartan, candesartan, irbesartan, azilsartan and the like.
  • Examples of the ACE inhibitor include imidapril, enalapril, delapril, silazapril, quinapril, temocapril, perindopril, lisinopril, trandolapril and the like.
  • Examples of diuretics include trichloromethiazide, hydrochlorothiazide, furosemide, torasemide, azosemide, spironolactone, triamterene, eplerenone and the like.
  • Examples of ⁇ -blockers include atenololol, bisoprolol, betaxolol, metoprolol, propranolol, nadolol, nipradilol, carteolol, bindrol, amosularol, arotinolol, carvedilol, labetalol, and bevantolol.
  • Examples of the ⁇ blocker include uravidyl, terazosin, prazosin, doxazosin, and bunazosin.
  • Examples of statins include simvastatin, pravastatin, lovastatin, pitavastatin, and atorvastatin.
  • the invention in another aspect of the invention, relates to a drug bound to a polyethylene glycol / polyamino acid block copolymer and micelles formed from the block copolymer.
  • the polyethylene glycol / polyamino acid block copolymer is a polyethylene glycol / polyamino acid block copolymer of the formula (I) or (II) defined in the present specification.
  • the drug bound to the polyethylene glycol / polyamino acid block copolymer any of the above-mentioned drugs may be used, in particular, indomethacin and simvastatin.
  • indomethacin is bound via linker L 3 in R 2b and R 2d of the block copolymers described above, and the carboxyl group of indomethacin is bound to linker L 3 .
  • R 2b and R 2d are aspartic acid side chains or glutamine side chains, and the chemical formulas in that case are shown below: (In the formula, R 1a , R 1b , R 3 , R 4 , m, n, b are as defined herein. c is 1 or 2 and L 3 represents C 1- C 6 alkylene)
  • the indomethacin-bound block copolymer according to the present invention can self-assemble in water to form micelles.
  • furan may be introduced into some drug binding moieties for crosslinking.
  • the furfuryl group in the crosslinked portion can be further crosslinked in the formation of micelles by further acting on a crosslinking agent such as bismaleimide.
  • a crosslinking agent such as bismaleimide.
  • the compound of the present invention in which the therapeutic agent is indomethacin and a furfuryl group is introduced has the following structure as an example: (During the ceremony R 1a , R 3 , R 4 , m, n, b are as already defined herein. k represents the number of bridges introduced, k is an integer from 0 to 199, c is 1 or 2 and L 3 represents C 1- C 6 alkylene. ).
  • the compound of the present invention having a flufuryl group introduced therein is made into micelles and crosslinked by the addition of 1,1- (methylenedi-4,1-phenylene) bismaleimide (BMI). Good.
  • simvastatin can be attached directly to the carboxy group of the side chain of the amino acid by an ester bond.
  • Simvastatin-binding block copolymers are, for example: (During the ceremony R 1a , R 3 , R 4 , m, n, b are as already defined herein. c is 1 or 2).
  • Another aspect of the present invention relates to micelles formed by self-assembling the simvastatin-binding block copolymer according to the present invention in water.
  • the present invention also relates to a method for producing micelles containing a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated.
  • the micelles are predominantly composed of polyethylene glycol-polyamino acid block copolymers to which the therapeutic agent is bound or coordinated, but may contain any other component as long as the desired size can be achieved. Good.
  • the method for producing micelles of the present invention is as follows: A step of reconstitution of a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated in water, and A step of obtaining micelles having a particle size of 20 to 100 nm by performing ultrafiltration using a fractionated molecular weight of 10,000 to 100,000 dialysis membranes. including. Further, a step of purifying through a filter having a membrane size of 0.15 to 0.3 may be included. The size of micelles can be measured by using the dynamic scattering method.
  • Example 1 Evaluation of accumulation in placenta and fetus using polymer micelles of different sizes
  • the accumulation of polymer micelles and low molecular weight compounds of different sizes in placenta and fetus was determined by using a pregnancy model mouse. It was evaluated by the fluorescence analysis, element analysis and mass spectrometry used.
  • Example 2-1 Evaluation of permeability to human placenta
  • the permeability of polymer micelles, low molecular weight compounds, and polymers of different sizes in human placenta was evaluated using a human placenta perfusion model.
  • Non-Patent Document 3 K. Shintaku et. Al., Drug Metab. Dispos. 37 (2009) 962
  • Non-Patent Document 4 J. R. Huston et. Al., Clin. Pharmacol. Ther . 90 (2011) 67.
  • a needle (18 gauge) was introduced into the maternal side of the human placenta provided by the Department of Obstetrics and Gynecology at the University of Tokyo Hospital, and a needle (18 gauge) was introduced into the vein and artery on the fetal side, respectively.
  • Krebs-Ringer carbonate buffer prepared according to M. Nagai et. Al., Drug Metab. Dispos.
  • the platinum content in the collected samples was measured by inductively coupled plasmon mass spectrometry.
  • the fluorescence intensity was quantified by the HPLC method. The ratio of the permeation amount to the dose of each drug was calculated and shown in FIG.
  • 2 mL of 90% nitric acid aqueous solution was added to the placenta, dissolved in 2 mL of 1% nitric acid aqueous solution, and the platinum content in the placenta was quantified by inductively coupled plasmon mass spectrometry.
  • Example 2-2 Assessment of permeability to human placenta
  • PEG-coated gold nanoparticles 10 mL, Nanocs, Inc.
  • an ex vivo human placenta perfusion experiment was performed in the same manner as in Example 2-1.
  • 10 nm gold NP was perfused
  • the amount of gold nanoparticles detected from the fetal side increased in a time-dependent manner, reaching 4.58% of the dose after 60 minutes.
  • 20 nm Gold NP was perfused, the detected dose from the fetal side was 2.21%.
  • Example 3 Preparation of indomethacin-encapsulating micelles for the treatment of preterm birth
  • block copolymers were synthesized and micelles were prepared for the construction of indomethacin-encapsulating micelles.
  • Experimental Method According to a previously reported report (Non-Patent Document 6: M. Yokoyama et. Al., Makromol. Chem. 190 (1989) 2041-2054), an NCA polymerization method using PEG (molecular weight: 12,000 Da) primary amine as an initiator. PEG-poly ( ⁇ -benzyl-L-apartate) (PEG-PVLA) was synthesized.
  • PEG-poly (Asp-Furan-OH) (PEG-P (Asp-furan-OH)) is produced by an aminolysis reaction of 4-amino-1-butanol and 2-aminomethylfuran with the BPLA chain. Synthesized.
  • DMAP dimethylaminopyridine
  • WSC water-soluble carbodiimide
  • indomethacin 2: 3: 1 (mass ratio)
  • DMF dimethylaminopyridine
  • WSC water-soluble carbodiimide
  • indomethacin 2: 3: 1 (mass ratio)
  • DMF dimethylaminopyridine
  • DMF water-soluble carbodiimide
  • the solution was added to PEG-P (Asp-furan-OH) so that the molar ratio of indomethacin to the BPLA chain was 4, and the reaction was carried out overnight at room temperature.
  • the reaction solution was added to an excess amount of diethyl ether to obtain a polymer.
  • the composition of the obtained polymer was measured by 1 1 H-NMR. From 1 1 H-NMR, it was confirmed that the introduction rate of 4-amino-1-butanol was 80% and the introduction rate of 2-aminomethylfuran was 20%.
  • Indomethacin-encapsulating micelles were prepared by dialysis. The polymer was dissolved in DMSO (2,7,14 mg / mL), dialyzed against pure water (MWCO: 3,500 Da), and purified by a filter (0.22 ⁇ m). Then, 1,1- (methylenedi-4,1-phenylene) bismaleimide (BMI) was added to the micelle solution, and the reaction was carried out at 50 ° C. for 2 days. After the reaction, it was purified by ultrafiltration (MWCO: 100,000 Da) and a filter (0.22 ⁇ m). The size and polydispersity (PDI) of the prepared micelles were measured by dynamic light scattering (DLS). From FIG.
  • Example 4 Stability test of indomethacin-encapsulating micelles
  • the scattered light intensity of the micelle after the addition of the surfactant, and the physiological salt condition and the pH condition in the endosome are used as an index of the stability of indomethacin-encapsulating micelles.
  • Indomethacin release amount was measured.
  • Experimental method Sodium dodecylsulfonate (SDS), which is one of the surfactants, was added to the micelle solution as an index of stability. Specifically, SDS (20 g) was dissolved in pure water (80 mL) and stirred at 65 ° C. Then, pure water (100 mL) was added to the SDS solution to prepare a 20% SDS aqueous solution.
  • SDS sodium dodecylsulfonate
  • the prepared 20% SDS aqueous solution (10 ⁇ L) was added to the micellar solution (70 ⁇ L), and after stirring, the size, polydispersity and scattered light intensity (divided count rate (DCR)) were measured by DLS.
  • DCR divided count rate
  • the amount of indomethacin released under physiological salt conditions and endosome pH conditions was used as an index of stability.
  • indomethacin-encapsulating micelles were dialyzed against pure water (MWCO: 3,500 Da), and the amount of indomethacin in the sample after dialysis was measured by the HPLC method.
  • Example 5 Indomethacin release test in macrophages
  • the release of indomethacin from indomethacin-encapsulating micelles was evaluated by measuring the amount of indomethacin in macrophage cells.
  • the amount of indomethacin in the solution was measured by the HPLC method (Fig. 9). From FIG. 9, since the amount of indomethacin released from the indomethacin-encapsulating micelle (CL) is about the same as the amount of uptake of indomethacin alone (FD), the ester bond in the micelle is cleaved by the ester-degrading enzyme in macrophages, and as a result. Efficient release of indomethacin was suggested.
  • Non-Patent Document 3 K. Shintaku et. Al., Drug Metab. Dispos. 37 (2009) 962
  • Non-Patent Document 4 JR Huston et. Al., Clin. Pharmacol. Ther. It was prepared according to 90 (2011) 67). Specifically, a needle (18 gauge) was introduced into the maternal side of the human placenta provided by the Department of Obstetrics and Gynecology at the University of Tokyo Hospital, and a needle (18 gauge) was introduced into the vein and artery on the fetal side, respectively.
  • the Krebs-Ringer carbonate buffer prepared according to M. Nagai et. Al., Drug Metab. Dispos.
  • Example 6-2 Evaluation of tissue migration of indomethacin-encapsulating polymer micelles
  • fluorescently labeled indomethacin micelles IND dose / kg, 10 mg
  • mice are euthanized and the brain, lungs, heart, liver, spleen, pancreas, both kidneys, fetus, umbilical cord, placenta, amniotic membrane, cervix, The cervix, fetus muscle, and femur were harvested and drug distribution was evaluated using the IVIS imaging system.
  • FIG. 11A shows the location of the recovered organs.
  • 11B-E show fluorescence at 1 hour, 4 hours, 8 hours, and 24 hours after administration.
  • Example 6-3 Evaluation of tissue migration of indomethacin-encapsulating polymer micelles Indomethacin (IND dose / kg as 1 mg) and was administered from the tail vein of pregnant mice on the morning of the 18th and 19th days of pregnancy. After 1 hour, 4 hours, 8 hours, and 24 hours, the mice were euthanized and the fetus, placenta, uterine body, uterus, kidneys, liver and spleen were collected. Samples were homogenized and indomethacin concentrations in tissues were measured by HPLC. In the indomethacin micelle-administered group, free indomethacin in tissues and indomethacin in micelle state were detected as the total amount.
  • Indomethacin IND dose / kg as 1 mg
  • indomethacin micelles decompose when sodium hydroxide is used for homogenization.
  • the free indomethacin group 0.57% of the maternal dose was detected in the fetus after 24 hours, which was the maximum.
  • the indomethacin micelle group only 0.013% of the maternal dose was distributed to the fetus, which was also the maximum after 24 hours. Therefore, administration of indomethacin micelles significantly reduced (E) distribution to the fetus compared to administration of free indomethacin (p ⁇ 0.05), thereby preventing indomethacin micelles from crossing the mouse placenta. It has been shown. Furthermore, in organs such as (A) kidney, (B) liver, (C) spleen, and (D) placenta, the amount of indomethacin detected within 24 hours was not sufficient to cause organ damage (Fig. 12A-E).
  • Example 7 Therapeutic effect of indomethacin-encapsulating micelles using preterm birth model mice
  • the preterm birth inhibitory effect and toxicity of indomethacin-encapsulating micelles were evaluated using preterm birth model mice.
  • LPS lipopolysaccharide
  • Table 3 showed that administration of micelles and indomethacin alone reduced the number of preterm mice, suggesting that indomethacin suppresses inflammation in the cervix.
  • administration of micelles increased the survival rate of the fetus, suggesting that the increase in drug size decreased the amount of accumulation in the fetus.
  • Example 8 Preparation of simvastatin-encapsulating micelles for the treatment of preeclampsia
  • simvastatin was introduced into a block copolymer and micelles were prepared for the treatment of preeclampsia.
  • Non-Patent Document 7 A. Harada and K. Kataoka, Macromolecules 28 (1995) 5294-5299
  • PEG-poly ( ⁇ ) was produced by an NCA polymerization method using a primary amine of PEG (molecular weight: 12,000 Da) as an initiator.
  • -Benzyl-L-aspartate) PEG-PVLA
  • PEG-poly (L-aspartate) PEG-PAsp
  • Simvastatin was introduced into the polymer by esterifying the carboxyl group of PEG-PAsp and the hydroxyl group of simvastatin according to the scheme below.
  • PEG-PAsp was dissolved in DMF (10 mg / mL), 10 equivalents of DMAP, EDC and simvastatin were added to the carboxyl group of the PAsp chain, and the reaction was carried out at room temperature for 24 hours. Then, the reaction solution was added to an excess amount of diethyl ether to obtain PEG-P (Asp-simvastatin). 1 From 1 H-NMR, the amount of simvastatin introduced was 1.2 mg / (mg polymer).
  • Simvastatin-encapsulating micelles were prepared by the dialysis method.
  • the polymer was dissolved in DMAc (1 mg / mL), dialyzed against pure water (MWCO: 3,500 Da), and purified by a filter (0.22 ⁇ m).
  • the size and polydispersity (PDI) of the prepared micelles were measured by dynamic light scattering (DLS).
  • the amount of simvastatin introduced was 1.2 mg / (mg polymer). Further, it was confirmed by DLS measurement that micelles having a size of 35 nm and a PDI of 0.23 were obtained.
  • Example 9 Therapeutic effect and toxicity test of simvastatin-encapsulating micelles using preeclampsia model mice
  • the antihypertensive effect and toxicity of simvastatin-encapsulating micelles were evaluated using preeclampsia model mice.
  • AngII angiotensin II
  • Simvastatin-encapsulating micelles (20 ⁇ g / kg: Simvastain Micelle), simvastatin alone (20 ⁇ g / kg: Simvastatin), and pravastatin (20 ⁇ g / kg: Pravastatin) were administered on the 10th to 17th days of pregnancy, and the drug-free group (NS)
  • the maternal blood pressure, urinary protein content and fetal weight were evaluated in comparison with. Blood pressure was evaluated by a sphygmomanometer on days 10, 13, 15, and 17 of pregnancy (Fig. 14).
  • FBW (g) body weight of the fetus
  • the fetus was removed on the 17th day of pregnancy and the body weight was measured (FIG. 15).
  • For urinary protein the amount of albumin in urine on days 10, 11, 16 and 17 of pregnancy was measured (Fig. 16).

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Abstract

L'objet de la présente invention est de développer un produit pharmaceutique qui peut être utilisé pendant la grossesse. Les inventeurs ont découvert que la perméabilité placentaire peut être régulée en régulant, dans des particules ayant sur leur surface un polymère hydrophile auquel est lié ou coordiné un médicament thérapeutique, la taille de particule des particules par le polymère hydrophile. Le problème est résolu par des particules ayant une taille de particule de 10 à 100 nm lorsqu'elles sont mesurées par diffusion dynamique de la lumière.
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