[go: up one dir, main page]

USRE46190E1 - High-molecular weight conjugate of steroids - Google Patents

High-molecular weight conjugate of steroids Download PDF

Info

Publication number
USRE46190E1
USRE46190E1 US14/594,748 US200814594748A USRE46190E US RE46190 E1 USRE46190 E1 US RE46190E1 US 200814594748 A US200814594748 A US 200814594748A US RE46190 E USRE46190 E US RE46190E
Authority
US
United States
Prior art keywords
group
steroids
molecular weight
weight conjugate
integer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US14/594,748
Inventor
Masayuki Kitagawa
Toshitaka Murata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Nippon Kayaku Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Kayaku Co Ltd filed Critical Nippon Kayaku Co Ltd
Priority to US14/594,748 priority Critical patent/USRE46190E1/en
Application granted granted Critical
Publication of USRE46190E1 publication Critical patent/USRE46190E1/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K47/48215—
    • A61K47/48315—
    • 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
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a high-molecular weight conjugate of steroids in which a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety is ester-bonded to a hydroxy group in the steroids, a method for producing the same, and the use thereof.
  • Steroid pharmaceuticals are a therapeutic agent for various disorders including many inflammatory disorders such as rheumatism and collagen disease, allergic diseases, serious infections and cancer, and they have excellent therapeutic effects on these disorders.
  • various actions of steroids are manifested as side effects on normal sites other than lesions to be treated, and as a result a dosage amount may be limited in some cases.
  • the number of repeated doses may be also limited.
  • the steroids are an excellent pharmaceutical compound which exhibits efficacy in treating various disorders
  • the use of steroids tends to be avoided at clinical settings due to their side effects.
  • studies for example, to accumulate the steroids selectively on a lesion and to release them at the lesion over a long period of time are carried out.
  • Limethasone manufactured by Mitsubishi Pharma Corporation
  • palmitic acid ester of dexamethasone in a lipid sphere is known in the art (Adv. Drug Delivery Rev., vol. 20, p. 195 (1996)).
  • Patent Document 1 describes a formulation comprising nano particles of phosphoric acid ester of betamethasone formed with zinc, polylactic acid, and polyethylene glycolpolylactic acid.
  • Patent Document 2 discloses a polymer compound comprising a drug bonded to a block copolymer of polyethylene glycol and polyaspartic acid, which forms micelles and has water solubility.
  • Patent Document 3 describes a polymer derivative of camptothecins in which a side chain carboxylic acid group of a block copolymer of polyethylene glycol and polyglutamic acid is bonded to a phenolic hydroxy group of camptothecins. It is known that these polymer compounds accumulate in tumors due to an EPR effect.
  • neither Patent Document 2 nor Patent Document 3 discloses a polymer compound to which steroids are bonded.
  • Limethasone described above releases palmitic acid ester of dexamethasone from lipid spheres, and then steroids produced by hydrolysis of the ester bond by enzymes in the body exhibit their activity.
  • the nano particles described in Patent Document 1 release phosphoric acid ester of betamethasone from the particles, and then steroids produced by hydrolysis of the ester bond by enzymes in the body exhibit their activity.
  • activities of hydrolyzing enzymes in the body vary not only among different species but also among individuals of the same species, and thus there is also a concern that the effect of the drug release from the conjugate would be greatly different among individuals when the cleavage of the bond to drug depends on the hydrolyzing enzymes.
  • steroids including prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone and alclometasone are a useful drug for treating disorders such as rheumatism, asthma, nephritis. ulcerative colitis, autoimmune diseases, allergy, psoriasis, eczema, stomatits, granuloma and malignant lymphoma, the side effects are very frequently manifested.
  • a novel drug which does not depend on hydrolyzing enzymes present in the body and delivers the steroids only to desired site to manifest fewer side effects.
  • the inventors of the present invention noticed the higher permeability of blood vessels around cancer lesions or inflammation sites, and, as a consequence of studies to solve the problems described above.
  • the high-molecular weight conjugate of steroids can also be used as a prodrug.
  • the present invention by introducing a moiety of succinic acid monoamide bonded to steroids into a polymer, intends to chemically hydrolyze the conjugate under physiological condition. Specifically, the inventors found a phenomenon that a compound having a hydroxy group is easily released as the structure of succinic acid monoamide changes to a cyclized structure (i.e., succinic imide) when the compound having a hydroxy group is ester-bonded to a free carboxylic acid of succinic acid monoamide, and attempted to apply the phenomenon to a block copolymer including polyethylene glycol.
  • a cyclized structure i.e., succinic imide
  • the ester bond can be cleaved without depending on hydrolyzing enzymes to release the steroids that are the active entities and to exhibit the pharmacological effects and have completed the present invention.
  • the present invention is related to the following (1) to (14).
  • a high-molecular weight conjugate of steroids comprising a structure in which a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is ester-bonded to a hydroxy group in the steroids.
  • R1 represents a hydrogen atom or a (C1-C6) alkyl group
  • R2 represents a linking group
  • R3 represents a hydrogen atom or a (C1-C6) acyl group
  • R4 represents a residue of the hydroxy group of the —OR4 represents an alcoholic hydroxy group of said steroids
  • R5 represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with a protected carboxy group and —N(R6)CONH(R7)
  • R6 and R7 which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amine group
  • t represents an integer from 5
  • R1 represents a (C1-C6) alkyl group
  • R2 represents a (C2-C6) alkylene group
  • R3 represents a (C1-C6) acyl group
  • t represents an integer of 100 to 300
  • d, e, f, g, h, i or j each independently represents an integer from 0 to 100, provided that d+e represents an integer from 1 to 100 and d+e+f+g+h+i+j represents an integer from 6 to 100.
  • R1 represents a (C1-C3) alkyl group
  • R2 represents a (C2-C4) alkylene group
  • R3 represents a (C1-C3) acyl group
  • t represents an integer from 100 to 300
  • d, e, f, g, h, i or j each independently represents an integer from 0 to 90, provided that d+e represents an integer from 1 to 90 and d+e+f+g+h+i+j represents an integer from 15 to 90.
  • steroids are prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone or alclometasone.
  • a high-molecular weight conjugate of steroids which is obtained by ester-bonding a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units to a hydroxy group in the steroids having hydroxy groups by using a dehydrating condensation agent in an organic solvent.
  • (9) A method of manufacturing the high-molecular weight conjugate of steroids described in any one of (1) to (7) above, the method comprising ester-bonding a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units to a hydroxy group of the steroids having the hydroxy group, by using a dehydrating condensation agent in an organic solvent.
  • a pharmaceutical composition comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
  • An anti-inflammatory agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
  • An anti-rheumatism agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
  • An agent for treating collagen disease comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
  • An anti-allergy agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
  • the high-molecular weight conjugate of steroids of the present invention can deliver the steroids only to a desired site and release the steroids without depending on hydrolyzing enzymes in the body. Thus, without being affected by difference among individuals, the steroids are expected to achieve efficacious therapeutic effects.
  • the high-molecular weight conjugate of steroids of the present invention is characterized in that a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is ester-bonded to a hydroxy group in the steroids.
  • succinic acid monoamide moiety refers to the structure of —HNCO—C—C—CO 2 H, and examples thereof include succinic acid monoamide (—HNCO—CH 2 —CH 2 —CO 2 H) and a structure in which one of the two carboxylic acid groups of aspartic acid is amidated (—HNCO—CH(—NH—)—CH 2 —CO 2 H or —HNCO—CH 2 —CH(—NH—)—CO 2 H).
  • succinic acid monoamide moieties may constitute a polymer backbone, for example, as in the case of polyaspartic acid, or may be bound to a functional group of the backbone polymer composed of a polyalcohol such as dextran, a polyamine such as polylysine, or a polycarboxylic acid other than polyaspartic acid (for example, polylactic acid, etc.).
  • a polyalcohol such as dextran
  • a polyamine such as polylysine
  • a polycarboxylic acid other than polyaspartic acid for example, polylactic acid, etc.
  • Examples of the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units include a graft-type polymer in which the polyethylene glycol moiety and the succinic acid monoamide moiety branch from the polymer backbone in a comb-like form, and a block-type polymer (block copolymer) in which the polymers having a polyethylene glycol moiety and a succinic acid monoamide moiety are tandemly aligned.
  • the graft-type polymer also includes a polymer in which the polyethylene glycol moiety is partially bonded to the polyaspartic acid backbone.
  • the block-type polymer includes a polymer in which the terminal of polyaspartic acid is bonded to the terminal of polyethylene glycol moiety.
  • the polyethylene glycol moiety in the polymer of the high-molecular weight conjugate of steroids of the present invention includes polyethylene glycol in which both terminals or a single terminal is modified.
  • the modifying groups can be identical or different from each other.
  • the modifying group include a (C1-C6) alkyl group optionally having a substituent group.
  • Examples of the alkyl group of the (C1-C6) alkyl group optionally having a substituent group include an alkyl group set forth as R1 in Formula (I) below.
  • Examples of a substituent group included in the (C1-C6) alkyl group optionally having a substituent group include, for example, an amino group, a methylamino group, a dimethylamino group, an ethylamino group and a diethylamino group.
  • the molecular weight of the polyethylene glycol moiety is about 300 to 500,000, preferably about 500 to 100,000, more preferably about 1,000 to 50,000.
  • the molecular weight of the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety is about 500 to 600,000, preferably about 600 to 110,000, more preferably about 800 to 80,000.
  • the term “molecular weight” refers to the weight average molecular weight determined by the GPC method.
  • the amount of the steroids bonded to the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is 1 to 100%, preferably 1 to 90%, more preferably 2 to 60%, based on the total number of carboxylic acid groups.
  • the steroids are not particularly limited, provided that they are the steroids having an alcoholic hydroxy group.
  • the steroids include prednisolone represented by the following formula (II), methyl prednisolone represented by the following formula (III), dexamethasone represented by the following formula (IV), betamethasone represented by the following formula (V), clobetasol represented by the following formula (VI), diflorasone represented by the following formula (VII), diflucortolone represented by the following formula (VIII), fluocinolone acetonide represented by the following formula (IX), hydrocortisone represented by the following formula (X), a deacylated product of difluprednate represented by the following formula (XI), beclometasone represented by the following formula (XII), triamcinolone represented by the following formula (XIII) and alclometasone represented by the following formula (XIV).
  • examples of the hydroxy group of steroids include, for example, a primary hydroxy group of prednisolone represented by the following formula (II) or a secondary hydroxy group of clobetasol represented by the following formula (VI).
  • the position for substitution is not limited.
  • the steroids indicated above and derivatives thereof are commercially available as an anti-allergic agent, an anti-inflammatory agent, an agent for treating autoimmune diseases, an anti-tumor agent, etc.
  • the succinic acid monoamide moiety having two or more succinic acid monoamide units is preferably polyaspartic acid.
  • a preferred high-molecular weight conjugate of steroids of the present invention includes a compound represented by formula (I) above, wherein R1 represents a hydrogen atom or a (C1-C6) alkyl group; R2 represents a linking group; R3 represents a hydrogen atom or a (C1-C6) acyl group; R4 represents a residue of the hydroxy group of the —OR4 represents an alcoholic hydroxy group of said steroids; R5 represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with protected carboxy group and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group
  • Examples of the (C1-C6) alkyl group for R1 in the general formula (I) include a straight-chain or branched (C1-C6) alkyl group, including a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group and a t-butyl group.
  • a straight-chain or branched (C1-C4) alkyl group and particularly preferred is a straight-chain or branched (C1-C3) alkyl group including a methyl group, an ethyl group, an n-propyl group, and an i-propyl group, and more particularly preferred is a methyl group.
  • Examples of the linking group represented by R2 in the general formula (I) include, but are not particularly limited to, a (C2-C6) alkylene group.
  • a (C2-C4) alkylene group including, for example, an ethylene group, a trimethylene group and a tetramethylene group, and particularly preferred is a trimethylene group.
  • Examples of the (C1-C6) acyl group for R3 in the general formula (I) include, but not particularly limited to, a formyl group, an acetyl group, a propionyl group and a pivaloyl group. Preferred is a (C1-C3) acyl group, and more preferred is an acetyl group.
  • examples of the steroids include the steroids enumerated above.
  • R5 in the general formula (I) represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with protected carboxy group, and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amino group.
  • R5 in the general formula (I) may be identical or different from each other in one molecule, and a polymer in the high-molecular weight conjugate of steroids may include a single-type R5 or mixed type R5.
  • a substituent group can be introduced to R5 as necessary.
  • Physical properties of the high-molecular weight conjugate of steroids can be controlled by the introduction of the substituent groups to R5.
  • the release rate of the steroids can be freely controlled.
  • Examples of the (C1-C30) alkoxy group include a straight-chain or branched (C1-C30) alkoxy group, and preferred is a straight-chain or branched (C1-C10) alkoxy group, including, for example, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group and a t-butoxy group.
  • Examples of the (C7-C30) aralkyloxy group include a straight-chain or branched (C7-C30) aralkyloxy group, and preferred is a straight-chain or branched (C7-C12) aralkyloxy group, including, for example, a 4-phenylbutoxy group.
  • Examples of the (C1-C30) alkylamino group or di(C1-C30) alkylamino group include a straight-chain or branched (C1-C30) alkylamino group or a straight-chain or branched di(C1-C30) alkylamino group, and preferred is a straight-chain or branched (C1-C20) alkylamino group or a straight-chain or branched di(C1-C20) alkylamino group, including, for example, an methylamino group, an ethyl amino group, an n-propylamino group, an i-propylamino group, an n-butylamino group, a t-butylamino group, a dimethylamino group, a diethylamino group and a dibutylamino group.
  • amino acid with protected carboxy group examples include an amino acid generally used in peptide synthesis, in which a carboxyl group is protected, including, for example, a phenylalanine benzyl ester.
  • Examples of the group —N(R6) CONH(R7) for R5 in the general formula (I), wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group optionally substituted with a tertiary amine group include. but not particularly limited to, for example, a cyclohexylaminocarbonylcyclohexylamino group and an isopropylaminocarbonylisopropylamino group.
  • Polyaspartic acid which is a succinic acid monoamide moiety in the high-molecular weight conjugate of steroids represented by the general formula (I) of the present invention, includes constituent units of ⁇ -amino acid type, ⁇ -amino acid type and cyclized type. These constituent units are bound in any order, and may be bound to form a block-type form or a random-type form.
  • the total number of aspartic acid residues in the high-molecular weight conjugate of steroids represented by the aforementioned general formula (I) is represented by “d+e+f+g+h+i+j”, and is about 3 to 200, preferably about 6 to 100, more preferably about 15 to 90.
  • the proportion of the number of aspartic acid residues bonded to the steroids (d+e) based on the total number of aspartic acid residues (d+e+f+g+h+i+j) is 1 to 100%, preferably 3 to 90%, more preferably 4 to 60%.
  • the number of aspartic acid residues (d+e) is about 1 to 200, preferably about 1 to 100, more preferably about 1 to 90.
  • the proportion of ⁇ -amino acid type (d+f+h) based on the total number of aspartic acid residues (d+e+f+g+h+i+j) is 10 to 100%, preferably 20 to 100%.
  • the proportion can be appropriately changed, for example, by suitably selecting a deprotection condition for a protecting group in the polyaspartic acid which was produced by using the protecting group.
  • t is an integer from about 5 to 11,500, preferably an integer from about 8 to 2300, more preferably, an integer from about 100 to 300.
  • the high-molecular weight conjugate of steroids of the present invention represented by the aforementioned general formula (I) may form micelles with the polyethylene glycol moiety as the outer shell in water.
  • the high-molecular weight conjugate of steroids of the present invention is obtained by ester-bonding a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units to a hydroxy group of steroids by using a dehydrating condensation agent in an organic solvent, and the present invention also includes this manufacturing method; that is, a manufacturing method of subjecting, for example, a block copolymer of a polyethylene glycol moiety-polyaspartic acid produced by the method described in Japanese Patent Application Laid-Open No.
  • a dehydrating condensation agent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt (WSC) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinolinone (EEDQ) at a temperature of 0 to 180° C., preferably 5 to 50° C.
  • DCC dicyclohexylcarbodiimide
  • DIPC diisopropylcarbodiimide
  • WSC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt
  • EEDQ 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinolinone
  • aprotic polar solvent such as N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI) and N-methylpyrrolidone (NMP).
  • DMF N,N-dimethylformamide
  • DI 1,3-dimethyl-2-imidazolidinone
  • NMP N-methylpyrrolidone
  • a reaction aid such as N,N-dimethylaminopyridine (DMAP) may also be used for the condensation reaction. After condensation reaction, deprotection is carried out as necessary, and conventional operations for separation and purification, etc., are applied to obtain a high-molecular weight conjugate of steroids.
  • DMAP N,N-dimethylaminopyridine
  • a high-molecular weight conjugate of steroids in which R5 is a —N(R6)CONH(R7) group wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group optionally substituted with a tertiary amine group may also be obtained by a reaction using the aforementioned carbodiimides as an condensation agent.
  • a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group or an amino acid with protected carboxy group may be introduced.
  • the method of manufacturing the high-molecular weight conjugate of steroids of the present invention is not intended to be limited to the aforementioned methods.
  • the high-molecular weight conjugate of steroids of the present invention releases steroids under the condition in the body to exhibit the pharmacological activity of the steroids, and therefore functioning as a drug, it can be used as an anti-inflammatory agent, an anti-rheumatism agent, an agent for treating collagen disease, an anti-allergic agent, an anti-cancer agent, etc.
  • the high-molecular weight conjugate of steroids of the present invention can be used in a dosage form which is conventionally used, including, for example, injections, tablets, powders and the like.
  • a pharmaceutically acceptable carriers which are conventionally used, for example, binding agents, lubricating agents, disintegrating agents, solvents, vehicles, solubilizing agents, dispersing agents, stabilizing agents.
  • suspending agents can also be used.
  • the use as an injection is preferred, and usually, for example, water, physiological saline, 5% glucose or mannitol solution, water-soluble organic solvent (for example. glycerol, ethanol, dimethylsulfoxide, N-methylpyrrolidone, polyethylene glycol, Cremophor and the like, or a mixture thereof), or a mixture of water and water-soluble organic solvents can be used.
  • water-soluble organic solvent for example. glycerol, ethanol, dimethylsulfoxide, N-methylpyrrolidone, polyethylene glycol, Cremophor and the like, or a mixture thereof
  • the dosage of the high-molecular weight conjugate of steroids of the present invention can varies as a matter of course, depending on sex, age, physiological conditions, pathology and the like of patients. It is parenterally administered, typically at a does of 0.01 to 500 mg/m 2 , preferably 0.1 to 250 mg/m 2 , as an active ingredient per day. Administration by injection is carried out intravenously, intraarterially, to the affected site (inflammation site), for example.
  • the content of prednisolone in Compound 1 was determined as 25.4% (w/w), and the proportion of d+e based on d+e+f+g+h+i+j was determined as 44%. In Compound 1, free prednisolone was not detected.
  • an isopropylaminocarbonyl-isopropylamino group can be added as R5, and the abundance ratio of the group was determined by 1 H-NMR (hydrogen nuclear magnetic resonance spectrum) using Compound 1 dissolved in sodium deuteroxide/deuterium oxide/deuterated acetonitrile.
  • the proportion of isopropylaminocarbonylisopropylamino group to polyaspartic acid of Compound 1, that is, the proportion of f+g based on d+e+f+g+h+i+j was 9%.
  • the remaining aspartic acid residues are in the form of a free carboxylic acid (corresponding to h+i) or a cyclic structure (corresponding to j).
  • N-acetylated product of a copolymer of polyethylene glycol with methoxy at one terminal-polyaspartic acid produced according to the manufacturing method described in Japanese Patent Application Laid-open No. 6-206815 (a polymerization number of aspartic acid is 35; 100 mg) and commercially available prednisolone (manufactured by Tokyo Chemical Industry Co., Ltd.; 42 mg) were dissolved in DMF (2.0 ml), and DMAP in a DMF solution (0.773 mmol/ml solution, 27.7 ⁇ l) and DIPC (67.0 ⁇ l) were added thereto. The mixture was stirred for 43 hrs at 15° C.
  • Compound 2 was collected and treated with alkali to cleave the bonded dexamethasone.
  • HPLC high performance liquid chromatography
  • the content of dexamethasone in Compound 2 was determined as 20.7% (w/w) and the proportion of d+e based on d+e+f+g+h+i+j was determined as 31%.
  • free dexamethasone was found to be 0.3% (w/w).
  • N-acetylated product of methoxypolyethylene glycol with methoxy at one terminal-polyaspartic acid copolymer (polymerization number of aspartic acid 35; 100 mg) prepared according to the manufacturing method described in Japanese Patent Application Laid-open No. 6-206815 and commercially available dexamethasone (manufactured by Tokyo Chemical Industry Co., Ltd.; 42 mg) were dissolved in DMF (2.0 ml), and DMAP in a DMF solution (0.773 mmol/ml solution, 27.7 ⁇ l) and DIPC (33.5 ⁇ l) were added thereto. The mixture was stirred for 20 hrs at 15° C.
  • Comparative compound 1 conjugate of prednisolone and a block copolymer consisting of methoxypolyethylene glycol moiety having molecular weight of 12,000 and polyglutamic acid moiety having a polymerization number of 23
  • N-acetylated product of polyethylene glycol with methoxy at one terminal-polyglutamic acid copolymer (a block copolymer consisting of a methoxypolyethylene glycol moiety having a molecular weight of 12,000 and a polyglutamic acid moiety having a polymerization number of 23; 128 mg) prepared according to the manufacturing method described in Japanese Patent Application Laid-Open publication No. 5-955 and commercially available prednisolone (50 mg) were dissolved in DMF (1.3 ml), and DMAP (2.4 mg) and DIPC (0.06 ml) were added thereto. The mixture was stirred for 20 hrs at 25° C.
  • Compound 1 or Comparative compound 1, or Compound 2 or Compound 3 was dissolved in PBS (phosphate buffered physiological saline; pH 7.1) to a polymer concentration of 1 mg/ml, and the solution was incubated at 37° C.
  • PBS phosphate buffered physiological saline
  • Prednisolone or dexamethasone released from Compound 1, Compound 2, Compound 3 or Comparative compound 1 was separated and quantified by HPLC in comparison with a standard curve. The proportion of the quantified value based on the total amount of the drug determined from the drug content in the high-molecular weight conjugate is shown in FIGS. 1 and 2 .
  • Comparative compound 1 As shown in FIG. 1 , the high-molecular weight conjugate of the present invention (Compound 1) released almost 98% of prednisolone within 24 hrs even in the absence of hydrolyzing enzymes. However, Comparative compound 1 including no succinic acid monoamide moiety hardly released prednisolone even after 24 hrs.
  • the high-molecular weight conjugate of the present invention (Compounds 2 and 3) was found to be capable of releasing almost 60 to 90% of dexamethasone within 24 hrs even in the absence of hydrolyzing enzymes. It was also shown that the linking of phenylalanine benzyl ester to the high-molecular weight conjugate allowed to control the release rate of dexamethasone.
  • FIG. 1 illustrates a proportion of the amount of the released prednisolone based on the total amount of the prednisolone in the conjugate in PBS solution (pH 7.1; 37° C.) containing Compound 1 of the present invention (the high-molecular weight conjugate in which prednisolone is bonded to a polyaspartic acid moiety) or Comparative compound 1 (the high-molecular weight conjugate in which prednisolone is bonded to a polyglutamic acid moiety).
  • - ⁇ - indicates the proportion of the drug released from Compound 1 of the present invention
  • - ⁇ - indicates the proportion of the drug released from Comparative compound 1.
  • FIG. 2 illustrates a proportion of the amount of the released dexamethasone based on the total amount of the dexamethasone in the conjugate in PBS solution (pH 7.1; 37° C.) containing Compound 2 of the present invention (the high-molecular weight conjugate in which dexamethasone is bonded to a polyaspartic acid moiety) or Compound 3 of the present invention (the high-molecular weight conjugate in which dexamethasone and phenylalanine benzyl ester are bonded to a polyaspartic acid moiety).
  • - ⁇ - indicates the proportion of the drug released from Compound 2 of the present invention
  • - ⁇ - indicates the proportion of the drug released from Compound 3 of the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polyethers (AREA)
  • Steroid Compounds (AREA)

Abstract

Enzymes in the body vary among different species, and also vary among individuals of the same species. Thus, it has been demanded to develop a novel steroid-containing pharmaceutical preparation which can release a drug in a manner independent of the enzymes present in the body, and which is expected to have an efficacious therapeutic effect.
Disclosed is a high-molecular weight conjugate of a steroid, comprising a structure in which a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is ester-bonded to a hydroxy group in the steroid.

Description

TECHNICAL FIELD
The present invention relates to a high-molecular weight conjugate of steroids in which a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety is ester-bonded to a hydroxy group in the steroids, a method for producing the same, and the use thereof.
BACKGROUND ART
Steroid pharmaceuticals are a therapeutic agent for various disorders including many inflammatory disorders such as rheumatism and collagen disease, allergic diseases, serious infections and cancer, and they have excellent therapeutic effects on these disorders. However, when they are prescribed for a certain disorder, various actions of steroids are manifested as side effects on normal sites other than lesions to be treated, and as a result a dosage amount may be limited in some cases. In addition, it is easily expected that the longer it remains on a lesion, the more efficacious the steroid would be on the lesion. However, due to the concern regarding the side effect as described above, the number of repeated doses may be also limited. In other words, although the steroids are an excellent pharmaceutical compound which exhibits efficacy in treating various disorders, the use of steroids tends to be avoided at clinical settings due to their side effects. Currently, as an attempt to solve this problem, studies, for example, to accumulate the steroids selectively on a lesion and to release them at the lesion over a long period of time are carried out.
One of such studies relates to a drug delivery system, and as an example of the system, Limethasone (manufactured by Mitsubishi Pharma Corporation), which comprises palmitic acid ester of dexamethasone in a lipid sphere is known in the art (Adv. Drug Delivery Rev., vol. 20, p. 195 (1996)).
Patent Document 1 describes a formulation comprising nano particles of phosphoric acid ester of betamethasone formed with zinc, polylactic acid, and polyethylene glycolpolylactic acid.
Meanwhile, Patent Document 2 discloses a polymer compound comprising a drug bonded to a block copolymer of polyethylene glycol and polyaspartic acid, which forms micelles and has water solubility. Patent Document 3 describes a polymer derivative of camptothecins in which a side chain carboxylic acid group of a block copolymer of polyethylene glycol and polyglutamic acid is bonded to a phenolic hydroxy group of camptothecins. It is known that these polymer compounds accumulate in tumors due to an EPR effect. However, neither Patent Document 2 nor Patent Document 3 discloses a polymer compound to which steroids are bonded.
  • [Patent Document 1] Japanese Patent Application Laid-open Publication (Kohyo) No. 2006-521367
  • [Patent Document 2] Japanese Patent Publication No. 2694923
  • [Patent Document 3] WO 2004/39869
  • [Non-Patent Document 1] Adv. Drug Delivery Rev., vol. 20, p. 195 (1996)
DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
Limethasone described above releases palmitic acid ester of dexamethasone from lipid spheres, and then steroids produced by hydrolysis of the ester bond by enzymes in the body exhibit their activity. Similarly, the nano particles described in Patent Document 1 release phosphoric acid ester of betamethasone from the particles, and then steroids produced by hydrolysis of the ester bond by enzymes in the body exhibit their activity. However, it has been known that activities of hydrolyzing enzymes in the body vary not only among different species but also among individuals of the same species, and thus there is also a concern that the effect of the drug release from the conjugate would be greatly different among individuals when the cleavage of the bond to drug depends on the hydrolyzing enzymes.
In the case of the adriamycin conjugate described in Patent Document 2 in which a block copolymer is bonded to adriamycin via an amide bond, the efficacy is questionable since the release of the drug by hydrolysis is slow due to the amide bond, a chemically stable bonding form.
Although steroids including prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone and alclometasone are a useful drug for treating disorders such as rheumatism, asthma, nephritis. ulcerative colitis, autoimmune diseases, allergy, psoriasis, eczema, stomatits, granuloma and malignant lymphoma, the side effects are very frequently manifested. Thus, there has been a demand for a novel drug which does not depend on hydrolyzing enzymes present in the body and delivers the steroids only to desired site to manifest fewer side effects.
Means for Solving the Problems
The inventors of the present invention noticed the higher permeability of blood vessels around cancer lesions or inflammation sites, and, as a consequence of studies to solve the problems described above. we considered that, as result of the circulation in the body of a drug administered in the vessels, the drug would be more easily accumulated in cancer lesions or inflammation sites around which the vessels are highly permeable. Consequently, they achieved an invention of a high-molecular weight conjugate of steroids in which the steroids are chemically bonded to a polymer carrier of a block copolymer including polyethylene glycol. The high-molecular weight conjugate of steroids can also be used as a prodrug.
Efficacy of conventional prodrugs may be likely to vary among individuals as the hydrolyzing enzymes of a patient are used for the release of the drug. On the other hand, the present invention, by introducing a moiety of succinic acid monoamide bonded to steroids into a polymer, intends to chemically hydrolyze the conjugate under physiological condition. Specifically, the inventors found a phenomenon that a compound having a hydroxy group is easily released as the structure of succinic acid monoamide changes to a cyclized structure (i.e., succinic imide) when the compound having a hydroxy group is ester-bonded to a free carboxylic acid of succinic acid monoamide, and attempted to apply the phenomenon to a block copolymer including polyethylene glycol. As a result, they have found that, in the high-molecular weight derivative of steroids in which a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety is ester-bonded to a hydroxy group of the steroids having a hydroxy group, the ester bond can be cleaved without depending on hydrolyzing enzymes to release the steroids that are the active entities and to exhibit the pharmacological effects and have completed the present invention.
Specifically, the present invention is related to the following (1) to (14).
(1) A high-molecular weight conjugate of steroids, comprising a structure in which a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is ester-bonded to a hydroxy group in the steroids.
(2) The high-molecular weight conjugate of steroids according to (1) above, wherein the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety is a block copolymer.
(3) The high-molecular weight conjugate of steroids according to (1) or (2) above, wherein the succinic acid monoamide moiety is polyaspartic acid.
(4) The high-molecular weight conjugate of steroids according to any one of (1) to (3) above represented by formula (I)
Figure USRE046190-20161101-C00001
wherein R1 represents a hydrogen atom or a (C1-C6) alkyl group; R2 represents a linking group; R3 represents a hydrogen atom or a (C1-C6) acyl group; R4 represents a residue of the hydroxy group of the —OR4 represents an alcoholic hydroxy group of said steroids; R5 represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with a protected carboxy group and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amine group; t represents an integer from 5 to 11500; and d, e, f, g, h, i or j each independently represents an integer from 0 to 200; provided that d+e represents an integer from 1 to 200, d+e+f+g+h+i+j represents an integer from 3 to 200; and respective units of the polyaspartic acid are bonded in any order.
(5) The high-molecular weight conjugate of steroids according to (4) above, wherein R1 represents a (C1-C6) alkyl group, R2 represents a (C2-C6) alkylene group, R3 represents a (C1-C6) acyl group, t represents an integer of 100 to 300, and d, e, f, g, h, i or j each independently represents an integer from 0 to 100, provided that d+e represents an integer from 1 to 100 and d+e+f+g+h+i+j represents an integer from 6 to 100.
(6) The high-molecular weight conjugate of steroids according to (5) above, wherein R1 represents a (C1-C3) alkyl group, R2 represents a (C2-C4) alkylene group, R3 represents a (C1-C3) acyl group, t represents an integer from 100 to 300, and d, e, f, g, h, i or j each independently represents an integer from 0 to 90, provided that d+e represents an integer from 1 to 90 and d+e+f+g+h+i+j represents an integer from 15 to 90.
(7) The high-molecular weight conjugate of steroids according to any one of (1) to (6) above, in which the steroids are prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone or alclometasone.
(8) A high-molecular weight conjugate of steroids which is obtained by ester-bonding a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units to a hydroxy group in the steroids having hydroxy groups by using a dehydrating condensation agent in an organic solvent.
(9) A method of manufacturing the high-molecular weight conjugate of steroids described in any one of (1) to (7) above, the method comprising ester-bonding a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units to a hydroxy group of the steroids having the hydroxy group, by using a dehydrating condensation agent in an organic solvent.
(10) A pharmaceutical composition comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
(11) An anti-inflammatory agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
(12) An anti-rheumatism agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
(13) An agent for treating collagen disease comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
(14) An anti-allergy agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to any one of (1) to (8) above.
Effect of the Invention
The high-molecular weight conjugate of steroids of the present invention can deliver the steroids only to a desired site and release the steroids without depending on hydrolyzing enzymes in the body. Thus, without being affected by difference among individuals, the steroids are expected to achieve efficacious therapeutic effects.
BEST MODE FOR CARRYING OUT THE INVENTION
The high-molecular weight conjugate of steroids of the present invention is characterized in that a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is ester-bonded to a hydroxy group in the steroids.
According to the present invention, the term “succinic acid monoamide moiety” refers to the structure of —HNCO—C—C—CO2H, and examples thereof include succinic acid monoamide (—HNCO—CH2—CH2—CO2H) and a structure in which one of the two carboxylic acid groups of aspartic acid is amidated (—HNCO—CH(—NH—)—CH2—CO2H or —HNCO—CH2—CH(—NH—)—CO2H). These succinic acid monoamide moieties may constitute a polymer backbone, for example, as in the case of polyaspartic acid, or may be bound to a functional group of the backbone polymer composed of a polyalcohol such as dextran, a polyamine such as polylysine, or a polycarboxylic acid other than polyaspartic acid (for example, polylactic acid, etc.).
Examples of the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units include a graft-type polymer in which the polyethylene glycol moiety and the succinic acid monoamide moiety branch from the polymer backbone in a comb-like form, and a block-type polymer (block copolymer) in which the polymers having a polyethylene glycol moiety and a succinic acid monoamide moiety are tandemly aligned.
When the succinic acid monoamide moiety forms polyaspartic acid, the graft-type polymer also includes a polymer in which the polyethylene glycol moiety is partially bonded to the polyaspartic acid backbone. The block-type polymer includes a polymer in which the terminal of polyaspartic acid is bonded to the terminal of polyethylene glycol moiety.
The polyethylene glycol moiety in the polymer of the high-molecular weight conjugate of steroids of the present invention includes polyethylene glycol in which both terminals or a single terminal is modified. When both terminals are modified, the modifying groups can be identical or different from each other. Examples of the modifying group include a (C1-C6) alkyl group optionally having a substituent group. Examples of the alkyl group of the (C1-C6) alkyl group optionally having a substituent group include an alkyl group set forth as R1 in Formula (I) below. Preferred is a (C1-C4) alkyl group including, for example, a methyl group, an ethyl group, an n-propyl group and an n-butyl group. Examples of a substituent group included in the (C1-C6) alkyl group optionally having a substituent group include, for example, an amino group, a methylamino group, a dimethylamino group, an ethylamino group and a diethylamino group.
The molecular weight of the polyethylene glycol moiety is about 300 to 500,000, preferably about 500 to 100,000, more preferably about 1,000 to 50,000.
The molecular weight of the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety is about 500 to 600,000, preferably about 600 to 110,000, more preferably about 800 to 80,000.
According to the present invention, the term “molecular weight” refers to the weight average molecular weight determined by the GPC method.
In the high-molecular weight conjugate of steroids of the present invention, the amount of the steroids bonded to the polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units is 1 to 100%, preferably 1 to 90%, more preferably 2 to 60%, based on the total number of carboxylic acid groups.
According to the present invention, the steroids are not particularly limited, provided that they are the steroids having an alcoholic hydroxy group. Examples the steroids include prednisolone represented by the following formula (II), methyl prednisolone represented by the following formula (III), dexamethasone represented by the following formula (IV), betamethasone represented by the following formula (V), clobetasol represented by the following formula (VI), diflorasone represented by the following formula (VII), diflucortolone represented by the following formula (VIII), fluocinolone acetonide represented by the following formula (IX), hydrocortisone represented by the following formula (X), a deacylated product of difluprednate represented by the following formula (XI), beclometasone represented by the following formula (XII), triamcinolone represented by the following formula (XIII) and alclometasone represented by the following formula (XIV). Preferably, examples of the hydroxy group of steroids include, for example, a primary hydroxy group of prednisolone represented by the following formula (II) or a secondary hydroxy group of clobetasol represented by the following formula (VI). However, the position for substitution is not limited.
Figure USRE046190-20161101-C00002
Figure USRE046190-20161101-C00003
Figure USRE046190-20161101-C00004
The steroids indicated above and derivatives thereof are commercially available as an anti-allergic agent, an anti-inflammatory agent, an agent for treating autoimmune diseases, an anti-tumor agent, etc.
According to the present invention, the succinic acid monoamide moiety having two or more succinic acid monoamide units is preferably polyaspartic acid.
A preferred high-molecular weight conjugate of steroids of the present invention includes a compound represented by formula (I) above, wherein R1 represents a hydrogen atom or a (C1-C6) alkyl group; R2 represents a linking group; R3 represents a hydrogen atom or a (C1-C6) acyl group; R4 represents a residue of the hydroxy group of the —OR4 represents an alcoholic hydroxy group of said steroids; R5 represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with protected carboxy group and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amine group; t represents an integer from 5 to 11,500; and d, e, f, g, h, i or j each independently represents an integer from 0 to 200; provided that d+e represents an integer from 1 to 200 and that d+e+f+g+h+i+j represents an integer from 3 to 200.
Examples of the (C1-C6) alkyl group for R1 in the general formula (I) include a straight-chain or branched (C1-C6) alkyl group, including a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group and a t-butyl group. Preferred is a straight-chain or branched (C1-C4) alkyl group, and particularly preferred is a straight-chain or branched (C1-C3) alkyl group including a methyl group, an ethyl group, an n-propyl group, and an i-propyl group, and more particularly preferred is a methyl group.
Examples of the linking group represented by R2 in the general formula (I) include, but are not particularly limited to, a (C2-C6) alkylene group. Preferred is a (C2-C4) alkylene group including, for example, an ethylene group, a trimethylene group and a tetramethylene group, and particularly preferred is a trimethylene group.
Examples of the (C1-C6) acyl group for R3 in the general formula (I) include, but not particularly limited to, a formyl group, an acetyl group, a propionyl group and a pivaloyl group. Preferred is a (C1-C3) acyl group, and more preferred is an acetyl group.
With regard to the residue of the hydroxy group of the steroids for R4 alcoholic hydroxy group of the steroids for —OR4 in the general formula (I), examples of the steroids include the steroids enumerated above.
R5 in the general formula (I) represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with protected carboxy group, and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amino group. R5 in the general formula (I) may be identical or different from each other in one molecule, and a polymer in the high-molecular weight conjugate of steroids may include a single-type R5 or mixed type R5.
A substituent group can be introduced to R5 as necessary. Physical properties of the high-molecular weight conjugate of steroids can be controlled by the introduction of the substituent groups to R5. For example, the release rate of the steroids can be freely controlled.
Examples of the (C1-C30) alkoxy group include a straight-chain or branched (C1-C30) alkoxy group, and preferred is a straight-chain or branched (C1-C10) alkoxy group, including, for example, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group and a t-butoxy group. Examples of the (C7-C30) aralkyloxy group include a straight-chain or branched (C7-C30) aralkyloxy group, and preferred is a straight-chain or branched (C7-C12) aralkyloxy group, including, for example, a 4-phenylbutoxy group.
Examples of the (C1-C30) alkylamino group or di(C1-C30) alkylamino group include a straight-chain or branched (C1-C30) alkylamino group or a straight-chain or branched di(C1-C30) alkylamino group, and preferred is a straight-chain or branched (C1-C20) alkylamino group or a straight-chain or branched di(C1-C20) alkylamino group, including, for example, an methylamino group, an ethyl amino group, an n-propylamino group, an i-propylamino group, an n-butylamino group, a t-butylamino group, a dimethylamino group, a diethylamino group and a dibutylamino group.
Examples of the amino acid with protected carboxy group include an amino acid generally used in peptide synthesis, in which a carboxyl group is protected, including, for example, a phenylalanine benzyl ester.
Examples of the group —N(R6) CONH(R7) for R5 in the general formula (I), wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group optionally substituted with a tertiary amine group include. but not particularly limited to, for example, a cyclohexylaminocarbonylcyclohexylamino group and an isopropylaminocarbonylisopropylamino group.
Polyaspartic acid which is a succinic acid monoamide moiety in the high-molecular weight conjugate of steroids represented by the general formula (I) of the present invention, includes constituent units of α-amino acid type, β-amino acid type and cyclized type. These constituent units are bound in any order, and may be bound to form a block-type form or a random-type form.
The total number of aspartic acid residues in the high-molecular weight conjugate of steroids represented by the aforementioned general formula (I) is represented by “d+e+f+g+h+i+j”, and is about 3 to 200, preferably about 6 to 100, more preferably about 15 to 90.
The proportion of the number of aspartic acid residues bonded to the steroids (d+e) based on the total number of aspartic acid residues (d+e+f+g+h+i+j) is 1 to 100%, preferably 3 to 90%, more preferably 4 to 60%. In addition, the number of aspartic acid residues (d+e) is about 1 to 200, preferably about 1 to 100, more preferably about 1 to 90.
The proportion of α-amino acid type (d+f+h) based on the total number of aspartic acid residues (d+e+f+g+h+i+j) is 10 to 100%, preferably 20 to 100%. The proportion can be appropriately changed, for example, by suitably selecting a deprotection condition for a protecting group in the polyaspartic acid which was produced by using the protecting group.
In the aforementioned general formula (I), t is an integer from about 5 to 11,500, preferably an integer from about 8 to 2300, more preferably, an integer from about 100 to 300.
The high-molecular weight conjugate of steroids of the present invention represented by the aforementioned general formula (I) may form micelles with the polyethylene glycol moiety as the outer shell in water.
The high-molecular weight conjugate of steroids of the present invention is obtained by ester-bonding a carboxylic acid group of a polymer having a polyethylene glycol moiety and a succinic acid monoamide moiety having two or more succinic acid monoamide units to a hydroxy group of steroids by using a dehydrating condensation agent in an organic solvent, and the present invention also includes this manufacturing method; that is, a manufacturing method of subjecting, for example, a block copolymer of a polyethylene glycol moiety-polyaspartic acid produced by the method described in Japanese Patent Application Laid-Open No. 6-206815, and steroids in which the functional groups other than the group to be reacted are protected as necessary, to a reaction using a dehydrating condensation agent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt (WSC) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinolinone (EEDQ) at a temperature of 0 to 180° C., preferably 5 to 50° C. in an organic solvent in which both of the block copolymer and the steroids are dissolved, preferably in an aprotic polar solvent such as N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI) and N-methylpyrrolidone (NMP). Furthermore, a reaction aid such as N,N-dimethylaminopyridine (DMAP) may also be used for the condensation reaction. After condensation reaction, deprotection is carried out as necessary, and conventional operations for separation and purification, etc., are applied to obtain a high-molecular weight conjugate of steroids.
In addition, a high-molecular weight conjugate of steroids in which R5 is a —N(R6)CONH(R7) group wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group optionally substituted with a tertiary amine group may also be obtained by a reaction using the aforementioned carbodiimides as an condensation agent.
As a method of introducing as R5 a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group or an amino acid with protected carboxy group into a compound of the general formula (I), there can be mentioned a method in which a carboxylic acid of the polymer is first activated according to the aforementioned method, and then reacted with a corresponding alcohol, a corresponding amine or an amino acid with protected carboxy group in a an amount to be introduced under basic conditions; and a method in which a corresponding alcohol, a corresponding amine or an amino acid with a protected carboxy group is first activated, and then reacted with a polymer. After purification of the polymer, it is also possible to re-activate any unreacted carboxylic acid groups of the polymer by the same reaction, and the re-activated carboxylic acid groups may be condensed with the hydroxyl group of the steroids. Alternatively, different alcohols, amines, etc. are repeatedly reacted to synthesize a mixture of polymers having various substituents as R5, with which the hydroxy group of steroids may subsequently condensed. Furthermore, after condensation of steroids, a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group or an amino acid with protected carboxy group may be introduced.
However, the method of manufacturing the high-molecular weight conjugate of steroids of the present invention is not intended to be limited to the aforementioned methods.
The high-molecular weight conjugate of steroids of the present invention releases steroids under the condition in the body to exhibit the pharmacological activity of the steroids, and therefore functioning as a drug, it can be used as an anti-inflammatory agent, an anti-rheumatism agent, an agent for treating collagen disease, an anti-allergic agent, an anti-cancer agent, etc. The high-molecular weight conjugate of steroids of the present invention can be used in a dosage form which is conventionally used, including, for example, injections, tablets, powders and the like. For formulation process, a pharmaceutically acceptable carriers which are conventionally used, for example, binding agents, lubricating agents, disintegrating agents, solvents, vehicles, solubilizing agents, dispersing agents, stabilizing agents. suspending agents, preservatives, soothing agents, colorants and flavors can also be used. Among various dosage forms, the use as an injection is preferred, and usually, for example, water, physiological saline, 5% glucose or mannitol solution, water-soluble organic solvent (for example. glycerol, ethanol, dimethylsulfoxide, N-methylpyrrolidone, polyethylene glycol, Cremophor and the like, or a mixture thereof), or a mixture of water and water-soluble organic solvents can be used.
The dosage of the high-molecular weight conjugate of steroids of the present invention can varies as a matter of course, depending on sex, age, physiological conditions, pathology and the like of patients. It is parenterally administered, typically at a does of 0.01 to 500 mg/m2, preferably 0.1 to 250 mg/m2, as an active ingredient per day. Administration by injection is carried out intravenously, intraarterially, to the affected site (inflammation site), for example.
EXAMPLES
Hereinafter, the present invention will be illustrated more specifically with reference to Examples, but is not intended to be limited to the Examples. Conditions for analysis by HPLC (high performance liquid chromatography) is as follows:
column: ODS (inertsil ODS-3 4.6×150 mm)
detection: UV 254 nm
elution: A) 0.1% aqueous phosphate solution,
B) acetonitrile/1% aqueous phosphate solution (9/1)
B %=30%.
Example 1
Synthesis of Compound 1 (conjugate of prednisolone and a block copolymer consisting of methoxypolyethylene glycol moiety having molecular weight of 12,000 and polyaspartic acid moiety having a polymerization number of 33: in the general formula (I), R1=Me (methyl group), R2=trimethylene group, R3=Ac (acetyl group), R4=prednisolone residue —OR4=the alcoholic hydroxy group of prednisolone, R5=isopropylaminocarbonylisopropylamino group, d+e+f+g+h+i+j=33, t=273)
An N-acetylated product of a copolymer of polyethylene glycol with methoxy at one terminal-polyaspartic acid (a block copolymer consisting of a methoxypolyethylene glycol moiety having a molecular weight of 12,000 and a polyaspartic acid moiety having a polymerization number of 33, and in the general formula (I), R1=Me (methyl group), R2=trimethylene group, R3=Ac (acetyl group), d=e=f=g=j=0; 265 mg) produced according to the production method described in Japanese Patent Application Laid-open No. 6-206815, and commercially available prednisolone (manufactured by Tokyo Chemical Industry Co., Ltd.; 100 mg) were dissolved in DMF (3.7 ml), and DMAP (7 mg) and DIPC (0.2 ml) were added thereto. The mixture was stirred for 40 hrs at 15° C. To the reaction solution, ethanol (5.6 ml), ethyl acetate (5.6 ml) and diisopropyl ether (45 ml) were added, and the mixture was stirred for 3 hrs at room temperature. Subsequently, the precipitate was collected by filtration and washed with ethanol/diisopropyl ether (1/4 (v/v); 10 ml). The resulting precipitate was dissolved in acetonitrile/water (1/1 (v/v); 20 ml), and then the solution was applied to a column of an ion exchange resin (DOWEX50 (H+), manufactured by The Dow Chemical Company; 3 ml), and then eluted with acetonitrile/water (1/1 (v/v); 6 ml). After water (20 ml) was added to the eluted fraction thus obtained, acetonitrile was distilled off under reduced pressure, and then the residue was freeze-dried to obtain Compound 1 (340 mg).
On the basis of the amount of unreacted prednisolone present in the reaction liquid determined by HPLC (high performance liquid chromatography), the content of prednisolone in Compound 1 was determined as 25.4% (w/w), and the proportion of d+e based on d+e+f+g+h+i+j was determined as 44%. In Compound 1, free prednisolone was not detected.
According to this method, an isopropylaminocarbonyl-isopropylamino group can be added as R5, and the abundance ratio of the group was determined by 1H-NMR (hydrogen nuclear magnetic resonance spectrum) using Compound 1 dissolved in sodium deuteroxide/deuterium oxide/deuterated acetonitrile. The proportion of isopropylaminocarbonylisopropylamino group to polyaspartic acid of Compound 1, that is, the proportion of f+g based on d+e+f+g+h+i+j was 9%. The remaining aspartic acid residues are in the form of a free carboxylic acid (corresponding to h+i) or a cyclic structure (corresponding to j).
Example 2
Synthesis of Compound 2 (conjugate of dexamethasone and a block copolymer consisting of a methoxypolyethylene glycol moiety having a molecular weight of 12,000 and a polyaspartic acid moiety having a polymerization number of 35: in the general formula (I), R1=Me (methyl group), R2=trimethylene group, R3=Ac (acetyl group), R4=dexamethasone residue —OR4=the alcoholic hydroxy group of dexamethasone, R5=isopropylaminocarbonylisopropylamino group, d+e+f+g+h+i+j=35, t=273)
An N-acetylated product of a copolymer of polyethylene glycol with methoxy at one terminal-polyaspartic acid produced according to the manufacturing method described in Japanese Patent Application Laid-open No. 6-206815 (a polymerization number of aspartic acid is 35; 100 mg) and commercially available prednisolone (manufactured by Tokyo Chemical Industry Co., Ltd.; 42 mg) were dissolved in DMF (2.0 ml), and DMAP in a DMF solution (0.773 mmol/ml solution, 27.7 μl) and DIPC (67.0 μl) were added thereto. The mixture was stirred for 43 hrs at 15° C. DIPC (17.0 μl) was further added and stirred for 4 hrs at 30° C. To the reaction solution, ethyl acetate (4.0 ml) and diisopropyl ether (16 ml) were added, and the mixture was stirred for 3 hrs at room temperature. Subsequently, the precipitate was collected by filtration and washed with ethyl acetate/diisopropyl ether (1/4 (v/v); 10 ml). The resulting precipitate was dissolved in acetonitrile/water (1/1 (v/v); 12 ml), and then the solution was applied to a column of an ion exchange resin (DOWEX50 (H+), manufactured by The Dow Chemical Company; 10 ml) and eluted with acetonitrile/water (1/1 (v/v); 20 ml). Acetonitrile in the eluted fraction thus obtained was distilled off under reduced pressure, and the residue was freeze-dried to obtain Compound 2 (108 mg).
Compound 2 was collected and treated with alkali to cleave the bonded dexamethasone. By HPLC (high performance liquid chromatography), the content of dexamethasone in Compound 2 was determined as 20.7% (w/w) and the proportion of d+e based on d+e+f+g+h+i+j was determined as 31%. In the isolated Compound 2, free dexamethasone was found to be 0.3% (w/w).
Example 3
Synthesis of Compound 3 (conjugate of dexamethasone and a block copolymer consisting of a methoxypolyethylene glycol moiety having a molecular weight of 12,000 and a polyaspartic acid moiety having a polymerization number of 35 to which phenylalanine benzyl ester is further bonded: in the general formula (I), R1=Me (methyl group), R2=trimethylene group, R3=Ac (acetyl group), R4=dexamethasone residue —OR4=the alcoholic hydroxy group of dexamethasone, R5=phenylalanine benzyl ester and isopropylaminocarbonylisopropylamino group, d+e+f+g+h+i+j=35, t=273)
An N-acetylated product of methoxypolyethylene glycol with methoxy at one terminal-polyaspartic acid copolymer (polymerization number of aspartic acid 35; 100 mg) prepared according to the manufacturing method described in Japanese Patent Application Laid-open No. 6-206815 and commercially available dexamethasone (manufactured by Tokyo Chemical Industry Co., Ltd.; 42 mg) were dissolved in DMF (2.0 ml), and DMAP in a DMF solution (0.773 mmol/ml solution, 27.7 μl) and DIPC (33.5 μl) were added thereto. The mixture was stirred for 20 hrs at 15° C. To the reaction solution, a DMF solution of phenylalanine benzyl ester (0.612 mmol/ml, 140.0 μl) and DIPC (33.5 μl) were further added and stirred for 23 hrs at 30° C. Thereafter, DIPC (17.0 μl) was further added, and the mixture was stirred for 4 hrs at 30° C. To the reaction liquid, ethyl acetate (4.0 ml) and diisopropyl ether (16 ml) were added. After stirring for 3 hrs at room temperature, the precipitate was collected by filtration and washed with ethyl acetate/diisopropyl ether (1/4 (v/v); 10 ml). The resulting precipitate was dissolved in acetonitrile/water (1/1 (v/v); 12 ml), and the solution was applied to a column of an ion exchange resin (DOWEX50 (H+), manufactured by The Dow Chemical Company; 10 ml), and then eluted with acetonitrile/water (1/1 (v/v); 20 ml). Acetonitrile in the eluted fraction thus obtained was distilled off under reduced pressure, and the residue was freeze-dried to obtain Compound 3 (112 mg).
Compound 3 was collected and treated with alkali to cleave the bonded dexamethasone. By HPLC (high performance liquid chromatography), the content of dexamethasone in Compound 3 was determined as 20.5% (w/w). In the isolated Compound 3, free dexamethasone was found to be 0.2% (w/w).
Comparative Example 1
Synthesis of Comparative compound 1 (conjugate of prednisolone and a block copolymer consisting of methoxypolyethylene glycol moiety having molecular weight of 12,000 and polyglutamic acid moiety having a polymerization number of 23)
An N-acetylated product of polyethylene glycol with methoxy at one terminal-polyglutamic acid copolymer (a block copolymer consisting of a methoxypolyethylene glycol moiety having a molecular weight of 12,000 and a polyglutamic acid moiety having a polymerization number of 23; 128 mg) prepared according to the manufacturing method described in Japanese Patent Application Laid-Open publication No. 5-955 and commercially available prednisolone (50 mg) were dissolved in DMF (1.3 ml), and DMAP (2.4 mg) and DIPC (0.06 ml) were added thereto. The mixture was stirred for 20 hrs at 25° C. To the reaction solution, ethanol (2 ml), ethyl acetate (2 ml) and diisopropyl ether (12 ml) were added, and the mixture was stirred for 30 minutes at room temperature. Subsequently, the precipitate was collected by filtration and washed with ethanol/diisopropyl ether (1/4 (v/v); 2 ml). The resulting precipitate was dissolved in acetonitrile/water (1/1 (v/v); 7 ml) and applied to a column of anion exchange resin (DOWEX50 (H+), manufactured by The Dow Chemical Company; 1 ml), and then eluted with acetonitrile/water (1/1 (v/v); 2 ml). After water (10 ml) was added to the eluted fraction thus obtained, acetonitrile was distilled off under reduced pressure, and then the residue was freeze-dried to obtain Comparative compound 1 (160 mg).
On the basis of the amount of unreacted prednisolone present in the reaction solution determined by HPLC (high performance liquid chromatography), the content of prednisolone in Comparative compound 1 was determined as 25.8% (w/w). In the isolated Comparative compound 1, no free prednisolone was detected.
Test Example Drug Release in the Absence of Enzymes
Compound 1 or Comparative compound 1, or Compound 2 or Compound 3 was dissolved in PBS (phosphate buffered physiological saline; pH 7.1) to a polymer concentration of 1 mg/ml, and the solution was incubated at 37° C. Prednisolone or dexamethasone released from Compound 1, Compound 2, Compound 3 or Comparative compound 1 was separated and quantified by HPLC in comparison with a standard curve. The proportion of the quantified value based on the total amount of the drug determined from the drug content in the high-molecular weight conjugate is shown in FIGS. 1 and 2.
As shown in FIG. 1, the high-molecular weight conjugate of the present invention (Compound 1) released almost 98% of prednisolone within 24 hrs even in the absence of hydrolyzing enzymes. However, Comparative compound 1 including no succinic acid monoamide moiety hardly released prednisolone even after 24 hrs.
As shown in FIG. 2, the high-molecular weight conjugate of the present invention (Compounds 2 and 3) was found to be capable of releasing almost 60 to 90% of dexamethasone within 24 hrs even in the absence of hydrolyzing enzymes. It was also shown that the linking of phenylalanine benzyl ester to the high-molecular weight conjugate allowed to control the release rate of dexamethasone.
These results demonstrate the excellent drug release performance of the high-molecular weight conjugate of steroids of the present invention under a neutral condition even in the absence of enzymes, and thus a capability of the high-molecular weight conjugate of steroids of the present invention to release steroid under a physiological condition observed, for example, in blood or body fluids. It is further demonstrated that, the appropriate linking of a substituent group including, for example, phenylalanine benzyl ester, allows to control the release rate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a proportion of the amount of the released prednisolone based on the total amount of the prednisolone in the conjugate in PBS solution (pH 7.1; 37° C.) containing Compound 1 of the present invention (the high-molecular weight conjugate in which prednisolone is bonded to a polyaspartic acid moiety) or Comparative compound 1 (the high-molecular weight conjugate in which prednisolone is bonded to a polyglutamic acid moiety). In FIG. 1, -●- indicates the proportion of the drug released from Compound 1 of the present invention, and -∘- indicates the proportion of the drug released from Comparative compound 1.
FIG. 2 illustrates a proportion of the amount of the released dexamethasone based on the total amount of the dexamethasone in the conjugate in PBS solution (pH 7.1; 37° C.) containing Compound 2 of the present invention (the high-molecular weight conjugate in which dexamethasone is bonded to a polyaspartic acid moiety) or Compound 3 of the present invention (the high-molecular weight conjugate in which dexamethasone and phenylalanine benzyl ester are bonded to a polyaspartic acid moiety). In FIG. 2, -▴- indicates the proportion of the drug released from Compound 2 of the present invention, and -▪- indicates the proportion of the drug released from Compound 3 of the present invention.

Claims (10)

The invention claimed is:
1. A high-molecular weight conjugate of steroids, comprising a structure in which a carboxylic acid group of a block copolymer having a polyethylene glycol moiety and polyaspartic acid is ester-bonded to an alcoholic hydroxy group in the steroids, and
wherein the conjugate is represented by formula (I)
Figure USRE046190-20161101-C00005
wherein R1 represents a (C1-C6) alkyl group; R2 represents a (C2-C6) alkylene group; R3 represents a (C1-C6) acyl group; R4 —OR4 represents an alcoholic hydroxy group of said steroids; R5 represents a group selected from the group consisting of a (C1-C30) alkoxy group, a (C7-C30) aralkyloxy group, a (C1-C30) alkylamino group, a di(C1-C30) alkylamino group, an amino acid with a protected carboxy group and —N(R6)CONH(R7) wherein R6 and R7, which may be identical or different from each other, represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amine group; t represents an integer from 100 to 300; and d, e, f, g, h, i or j each independently represents an integer from 0 to 100; provided that d+e represents an integer from 1 to 100, d+e+f+g+h+i+j represents an integer from 6 to 100; and respective units of the polyaspartic acid are bonded in any order.
2. The high-molecular weight conjugate of steroids according to claim 1, wherein R1 represents a (C1-C3) alkyl group, R2 represents a (C2-C4) alkylene group, R3 represents a (C1-C3) acyl group, t represents an integer from 100 to 300, and d, e, f, g, h, i or j each independently represents an integer from 0 to 90, provided that d+e represents an integer from 1 to 90 and d+e+f+g+h+i+j represents an integer from 15 to 90.
3. The high-molecular weight conjugate of steroids according to claim 1 or 2, in which the steroids are prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone or alclometasone.
4. A method of manufacturing the high-molecular weight conjugate of steroids described in claim 1, the method comprising ester-bonding a carboxylic acid group of a block copolymer having a polyethylene glycol moiety and polyaspartic acid to an alcoholic hydroxy group of the steroids, by using a dehydrating condensation agent in an organic solvent.
5. A pharmaceutical composition comprising as an active ingredient the high-molecular weight conjugate of steroids according to claim 1.
6. An anti-inflammatory agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to claim 1.
7. An anti-rheumatism agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to claim 1.
8. An agent for treating collagen disease comprising as an active ingredient the high-molecular weight conjugate of steroids according to claim 1.
9. An anti-allergy agent comprising as an active ingredient the high-molecular weight conjugate of steroids according to claim 1.
10. The high-molecular weight conjugate of steroids according to claim 2, in which the steroids are prednisolone, methyl prednisolone, dexamethasone, betamethasone, clobetasol, diflorasone, diflucortolone, fluocinolone acetonide, hydrocortisone, difluprednate, beclometasone, triamcinolone or alclometasone.
US14/594,748 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids Expired - Fee Related USRE46190E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/594,748 USRE46190E1 (en) 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2007-254904 2007-09-28
JP2007254904 2007-09-28
PCT/JP2008/067413 WO2009041570A1 (en) 2007-09-28 2008-09-26 Polymer conjugate of steroid
US14/594,748 USRE46190E1 (en) 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids
US12/678,620 US8703878B2 (en) 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids

Publications (1)

Publication Number Publication Date
USRE46190E1 true USRE46190E1 (en) 2016-11-01

Family

ID=40511450

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/594,748 Expired - Fee Related USRE46190E1 (en) 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids
US12/678,620 Ceased US8703878B2 (en) 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/678,620 Ceased US8703878B2 (en) 2007-09-28 2008-09-26 High-molecular weight conjugate of steroids

Country Status (5)

Country Link
US (2) USRE46190E1 (en)
EP (1) EP2206502B1 (en)
JP (1) JP5349318B2 (en)
CN (1) CN101808651B (en)
WO (1) WO2009041570A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101064901B1 (en) * 2003-03-20 2011-09-16 나노캐리어 가부시키가이샤 Micellar preparations containing poorly water-soluble anticancer agents and novel block copolymers
BRPI0515573A (en) * 2004-09-22 2008-07-29 Nippon Kayaku Kk block copolymer, micelle preparation and anticancer agent containing it as the active ingredient
WO2007111211A1 (en) * 2006-03-28 2007-10-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
EP2019122A4 (en) 2006-05-18 2009-07-01 Nippon Kayaku Kk Polymer conjugate of podophyllotoxin
ES2584840T3 (en) * 2006-10-03 2016-09-29 Nippon Kayaku Kabushiki Kaisha Compound of a resorcinol derivative with a polymer
US8334364B2 (en) * 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
JP5548365B2 (en) * 2006-11-08 2014-07-16 日本化薬株式会社 Polymer derivatives of nucleic acid antimetabolites
WO2009041570A1 (en) 2007-09-28 2009-04-02 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of steroid
WO2009045539A2 (en) 2007-10-05 2009-04-09 Nektar Therapeutics Al, Corporation Oligomer-corticosteroid conjugates
WO2009116509A1 (en) 2008-03-18 2009-09-24 日本化薬株式会社 Polymer conjugate of physiologically active substance
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
EP2431403B1 (en) * 2009-05-15 2016-09-28 Nipponkayaku Kabushikikaisha Polymer conjugate of bioactive substance having hydroxy group
EP2641605B1 (en) * 2010-11-17 2018-03-07 Nippon Kayaku Kabushiki Kaisha Polymer derivative of cytidine metabolism antagonist
AU2012305405B2 (en) * 2011-09-11 2016-01-14 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer
AU2016224760B2 (en) 2015-02-23 2021-01-28 Nippon Kayaku Kabushiki Kaisha Block copolymer conjugate of physiologically active substance
WO2018025657A1 (en) 2016-07-30 2018-02-08 日本化薬株式会社 Novel polymer derivatives, and novel polymer derivative imaging probe using same
CN109642024A (en) 2016-08-02 2019-04-16 日本化药株式会社 Active targeting type polymeric derivative, the composition comprising the polymeric derivative and their purposes
CN115844823B (en) * 2022-12-20 2024-12-13 武威市人民医院 Dexamethasone polymeric micelle and preparation method thereof

Citations (123)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979449A (en) 1974-07-11 1976-09-07 Societe D'assistance Technique Pour Produits Nestle S.A. Preparation of an asparagine or a glutamine
US4011317A (en) * 1975-08-22 1977-03-08 Rorer Italiana S.P.A. Steroid derivatives
JPS61243026A (en) 1985-01-04 1986-10-29 チエコスロベンスカ・アカデミ−・ブイイ−デイ− Method for manufacturing polymerizable drugs
JPS6296088A (en) 1985-10-22 1987-05-02 Kanebo Ltd Production of antitumor substance
JPS62145093A (en) 1985-12-05 1987-06-29 ブリストル―マイアーズ　スクイブ　コムパニー Intermediate for producing podophyllotoxin and related compound and its production and utilization
JPS6310789A (en) 1986-07-01 1988-01-18 Nippon Kayaku Co Ltd Novel podophyllotoxin derivative
JPS6323884A (en) 1986-07-17 1988-02-01 Nippon Kayaku Co Ltd Novel podophyllotoxin derivative
JPS63502037A (en) 1985-12-19 1988-08-11 バテル　メモリアル　インステイチユ−ト Biodegradable synthetic polypeptides and their therapeutic uses
JPS6461422A (en) 1987-09-02 1989-03-08 Nippon Kayaku Kk Water-soluble polymeric carcinostatic agent
JPS6461423A (en) 1987-09-02 1989-03-08 Nippon Kayaku Kk Water-soluble polymeric carcinostatic agent
EP0397307A2 (en) 1989-05-11 1990-11-14 Research Development Corporation of Japan Water soluble high molecular polymerized drug preparation
JPH05955A (en) 1990-11-07 1993-01-08 Yasuhisa Sakurai Water-soluble polymeric carcinostatic agent and drug-supporting carrier
US5182203A (en) 1989-03-29 1993-01-26 E. I. Du Pont De Nemours And Company Bifunctional compounds useful in catalyzed reporter deposition
JPH05117385A (en) 1991-10-31 1993-05-14 Res Dev Corp Of Japan Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agent
WO1993024476A1 (en) 1992-06-04 1993-12-09 Clover Consolidated, Limited Water-soluble polymeric carriers for drug delivery
EP0583955A2 (en) 1992-08-14 1994-02-23 Research Development Corporation Of Japan Physical trapping type polymeric micelle drug preparation
JPH06206832A (en) 1992-10-27 1994-07-26 Nippon Kayaku Co Ltd Polymer carrier
JPH06206815A (en) 1992-10-26 1994-07-26 Nippon Kayaku Co Ltd Block copolymer-anticancer drug complex pharmaceutical preparation
JPH06206830A (en) 1992-10-27 1994-07-26 Nippon Kayaku Co Ltd Block copolymer-drug complex and polymer block copolymer
JPH06296088A (en) 1993-04-08 1994-10-21 Canon Inc Electronic equipment
JPH06310789A (en) 1993-04-21 1994-11-04 Sumitomo Heavy Ind Ltd Position regulator of spare ionization pin for excimer laser
JPH06323884A (en) 1993-05-14 1994-11-25 Advance Denki Kogyo Kk Flow sensor
JPH06329085A (en) 1993-05-27 1994-11-29 Hitachi Zosen Corp Jet water inlet structure of water jet catamaran
US5438072A (en) 1992-12-02 1995-08-01 Rhone-Poulenc Rorer S.A. Taxoid-based compositions
JPH0848766A (en) 1994-05-30 1996-02-20 Mitsui Toatsu Chem Inc Polymer and its production
WO1996023794A1 (en) 1995-01-30 1996-08-08 Enzon, Inc. High molecular weight polymer-based prodrugs
JPH08507558A (en) 1993-03-06 1996-08-13 ビーエーエスエフ アクチエンゲゼルシャフト Process for producing reaction product from polyaspartic imide and amino acid and use of the product
US5552517A (en) * 1995-03-03 1996-09-03 Monsanto Company Production of polysuccinimide in an organic medium
US5571889A (en) * 1994-05-30 1996-11-05 Mitsui Toatsu Chemicals, Inc. Polymer containing monomer units of chemically modified polyaspartic acids or their salts and process for preparing the same
JPH08310970A (en) 1995-08-21 1996-11-26 Res Dev Corp Of Japan Water-soluble polymerized pharmaceutical preparation
EP0757049A1 (en) 1995-08-02 1997-02-05 Tanabe Seiyaku Co., Ltd. Camptothecin derivatives
US5614549A (en) 1992-08-21 1997-03-25 Enzon, Inc. High molecular weight polymer-based prodrugs
WO1997038727A1 (en) 1996-04-15 1997-10-23 Asahi Kasei Kogyo Kabushiki Kaisha Medicament composite
WO1998002426A1 (en) 1996-07-15 1998-01-22 Kabushiki Kaisha Yakult Honsha Taxane derivatives and drugs containing the same
WO1998007713A1 (en) 1996-08-20 1998-02-26 Enzon, Inc. High molecular weight polymer-based prodrugs
WO1998008489A1 (en) 1996-08-26 1998-03-05 Transgene S.A. Cationic lipid-nucleic acid complexes
US5877205A (en) 1996-06-28 1999-03-02 Board Of Regents, The University Of Texas System Parenteral paclitaxel in a stable non-toxic formulation
WO1999030727A1 (en) 1997-12-17 1999-06-24 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
WO1999053951A1 (en) 1998-04-17 1999-10-28 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
US5985548A (en) 1993-02-04 1999-11-16 E. I. Du Pont De Nemours And Company Amplification of assay reporters by nucleic acid replication
JPH11335267A (en) 1998-05-27 1999-12-07 Nano Career Kk Polymer micelle system containing poorly water-soluble drug
WO2001019407A2 (en) 1999-09-13 2001-03-22 Nobex Corporation Taxane prodrugs
WO2001019361A2 (en) 1999-09-14 2001-03-22 Tepha, Inc. Therapeutic uses of polymers and oligomers comprising gamma-hydroxybutyrate
WO2001019406A2 (en) 1999-09-13 2001-03-22 Nobex Corporation Amphiphilic prodrugs
CA2383240A1 (en) 1999-09-23 2001-03-29 Yun Hwang Choe Polymer conjugates of ara-c and ara-c derivatives
WO2001026693A2 (en) 1999-10-12 2001-04-19 Cell Therapeutics, Inc. Manufacture of polyglutamate-therapeutic agent conjugates
US20010003779A1 (en) 1999-04-09 2001-06-14 Curran Dennis P. Camptothecin analogs and methods of preparation thereof
US6262107B1 (en) 1996-03-12 2001-07-17 Pg-Txl Company L.P. Water soluble paclitaxel prodrugs
CA2334615A1 (en) 2000-02-09 2001-08-09 Nanocarrier Co., Ltd. Production process for polymeric micelle charged therein with drug and polymeric micelle composition
WO2001064198A2 (en) 2000-02-29 2001-09-07 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives
WO2001070275A2 (en) 2000-03-17 2001-09-27 Cell Therapeutics, Inc. Polyglutamic acid-camptothecin conjugates and methods of preparation
US20010041189A1 (en) 1999-04-13 2001-11-15 Jingya Xu Poly(dipeptide) as a drug carrier
US6322817B1 (en) 1999-02-17 2001-11-27 Dabur Research Foundation Formulations of paclitaxel, its derivatives or its analogs entrapped into nanoparticles of polymeric micelles, process for preparing same and the use thereof
WO2001092584A1 (en) 2000-06-02 2001-12-06 Eidgenossische Technische Hochschule Zurich Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds
US20020009426A1 (en) 1998-04-17 2002-01-24 Greenwald Richard B. Biodegradable high molecular weight polymeric linkers and their conjugates
WO2002006279A1 (en) 2000-07-17 2002-01-24 Oxigene Inc Efficient method of synthesizing combretastatin a-4 prodrugs
JP2002069184A (en) 2000-06-12 2002-03-08 Mitsui Chemicals Inc Polymer and method of producing the same
US20020099013A1 (en) 2000-11-14 2002-07-25 Thomas Piccariello Active agent delivery systems and methods for protecting and administering active agents
WO2002065988A2 (en) 2001-02-20 2002-08-29 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
WO2002065986A2 (en) 2001-02-16 2002-08-29 Cellgate, Inc. Transporters comprising spaced arginine moieties
WO2002066066A1 (en) 2001-02-20 2002-08-29 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
US20020161062A1 (en) 2001-11-06 2002-10-31 Biermann Paul J. Structure including a plurality of cells of cured resinous material, method of forming the structure and apparatus for forming the structure
WO2003000771A1 (en) 2001-06-20 2003-01-03 Nippon Kayaku Kabushiki Kaisha Block copolymer reduced in impurity content, polymeric carrier, pharmaceutical preparations in polymeric form and process for the preparation of the same
US20030054977A1 (en) 1999-10-12 2003-03-20 Cell Therapeutics, Inc. Manufacture of polyglutamate-therapeutic agent conjugates
WO2003035008A2 (en) 2001-10-26 2003-05-01 Oxigene, Inc. Functionalized stilbene derivatives as improved vascular targeting agents
US6573284B1 (en) 1996-12-13 2003-06-03 Phairson Medical Ltd Method of treating melanoma
WO2003055860A1 (en) 2001-12-21 2003-07-10 Vernalis (Cambridge) Limited 3,4-diarylpyrazoles and their use in the therapy of cancer
US6596757B1 (en) 2002-05-14 2003-07-22 Immunogen Inc. Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
JP2003342269A (en) 2002-05-28 2003-12-03 Dai Ichi Seiyaku Co Ltd Method for reducing taxane
JP2003342167A (en) 2002-05-24 2003-12-03 Nano Career Kk Pharmaceutical preparation of camptothecin derivative and method for producing the same
JP2003342168A (en) 2002-05-24 2003-12-03 Nano Career Kk Method for producing polymer micelle preparation containing drug for injection
JP2004039869A (en) 2002-07-03 2004-02-05 Hitachi Ltd Magnetic resistance sensor, magnetic head, and magnetic recording device
US6720304B1 (en) 1997-05-09 2004-04-13 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Conjugate comprising a folic acid antagonist and a carrier
WO2004039869A1 (en) 2002-10-31 2004-05-13 Nippon Kayaku Kabushiki Kaisha High-molecular weight derivatives of camptothecins
WO2004050087A1 (en) 2002-12-05 2004-06-17 Vernalis (Cambridge) Limited 3-(2-hydroxy-phenyl)-1h-pyrazole-4-carboxylic acid amide derivatives as hsp90 inhibitors for the treatment of cancer
WO2004056782A1 (en) 2002-12-19 2004-07-08 Vernalis (Cambridge) Limited Pyrazole compounds
WO2004072051A1 (en) 2003-02-11 2004-08-26 Vernalis (Cambridge) Limited Isoxazole compounds as inhibitors of heat shock proteins
WO2004082718A1 (en) 2003-03-20 2004-09-30 Nippon Kayaku Kabushiki Kaisha Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
WO2004096212A1 (en) 2003-04-28 2004-11-11 Vernalis (Cambridge) Limited Pyrazole compounds as hsp90 inhibitors for the treatment of cancer
EP1489125A1 (en) 2002-03-05 2004-12-22 Beijing Jiankai Technology Co., Ltd. Compound of hydrophilic polymer-polycarboxyl oligopeptide and medicines, medical composite comprising above compound and use of above compound in medicimes
WO2005000300A1 (en) 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
US6858582B2 (en) 1990-11-01 2005-02-22 Oregon Health And Sciences University Composition containing porous microparticle impregnated with biologically-active compound for treatment of infection
JP2005051922A (en) 2003-07-29 2005-02-24 Yokogawa Electric Corp Power supply system and power supply method
WO2005018674A1 (en) 2003-08-22 2005-03-03 Kyowa Hakko Kogyo Co., Ltd. Remedy for diseases associated with immunoglobulin gene translocation
US20050054026A1 (en) 2003-01-10 2005-03-10 Yamanouchi Pharmaceutical Co., Ltd. Lipid-peptide-polymer conjugates for long blood circulation and tumor specific drug delivery systems
US20050119193A1 (en) 2002-06-03 2005-06-02 Jun Motoyama Novel solid preparation containing block copolymer and anthracycline anticancer agent and process for producing the same
WO2005066214A1 (en) 2004-01-07 2005-07-21 Seikagaku Corporation Hyaluronic acid derivative and drug containing the same
US20050171036A1 (en) 2002-03-26 2005-08-04 Banyu Pharmaceutical Co., Ltd. Use of antitumor indolopyrrolocarbazole derivative and other anticancer agent in combination
US20060009622A1 (en) 2002-03-01 2006-01-12 Fuselier Joseph A Conjugates of therapeutic or cytotoxic agents and biologically active peptides
WO2006033296A1 (en) 2004-09-22 2006-03-30 Nippon Kayaku Kabushiki Kaisha Novel block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient
JP2006120914A (en) 2004-10-22 2006-05-11 Matsushita Electric Ind Co Ltd Component suction nozzle, component mounting apparatus, and component mounting method
WO2006055670A2 (en) 2004-11-16 2006-05-26 Hyperion Catalysis International, Inc. Methods for preparing catalysts supported on carbon nanotube networks
WO2006055760A1 (en) 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
CN1800238A (en) 2005-12-05 2006-07-12 中国科学院长春应用化学研究所 Aliphatic polyester-polyamino acids copolymer with biological function and its synthesis method
WO2006095668A1 (en) 2005-03-09 2006-09-14 Toray Industries, Inc. Microparticle and pharmaceutical composition
WO2006095783A1 (en) 2005-03-09 2006-09-14 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor
JP2006521367A (en) 2003-03-26 2006-09-21 株式会社Ｌｔｔバイオファーマ Nanoparticles for intravenous injection for targeting and sustained release
WO2006101052A1 (en) 2005-03-22 2006-09-28 Nippon Kayaku Kabushiki Kaisha Novel acetylene derivative
WO2006115293A1 (en) 2005-04-22 2006-11-02 The University Of Tokyo NOVEL BLOCK COPOLYMER USED FOR PREPARING pH-RESPONSIVE POLYMER MICELLE, AND METHOD FOR PRODUCING SAME
WO2006120915A1 (en) 2005-05-12 2006-11-16 Nipro Corporation Agent for improving circulatory disorder
US20060258569A1 (en) 2003-10-21 2006-11-16 Mctavish Hugh Compounds and methods for treating cancer
WO2006120914A1 (en) 2005-05-11 2006-11-16 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of cytidine metabolic antagonist
US7176185B2 (en) 2003-11-25 2007-02-13 Tsrl, Inc. Short peptide carrier system for cellular delivery of agent
WO2007022493A2 (en) 2005-08-19 2007-02-22 Endocyte, Inc. Ligand conjugates of vinca alkaloids, analogs, and derivatives
JP2007111211A (en) 2005-10-20 2007-05-10 Yamasa Kk Slot machine
JP2007511586A (en) 2003-11-21 2007-05-10 フラメル・テクノロジー Pharmaceutical preparations for the release of active ingredients and their application, in particular therapeutic applications
WO2007080898A1 (en) 2006-01-10 2007-07-19 Medgel Corporation Sustained-release hydrogel preparation
JP2007191643A (en) 2006-01-20 2007-08-02 Mitsui Chemicals Inc Polyamino acid derivative imparted with fixability to living body
WO2007111211A1 (en) 2006-03-28 2007-10-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
WO2007135910A1 (en) 2006-05-18 2007-11-29 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of podophyllotoxin
WO2008010463A1 (en) 2006-07-19 2008-01-24 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of combretastatin
JP2008041610A (en) 2006-08-10 2008-02-21 Mitsubishi Electric Corp Circuit breaker
WO2008041610A1 (en) 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Compound of resorcinol derivative with polymer
WO2008056596A1 (en) 2006-11-06 2008-05-15 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of nucleic acid metabolic antagonist
WO2008056654A1 (en) 2006-11-08 2008-05-15 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of nucleic acid metabolic antagonist
US20080269218A1 (en) 2005-03-09 2008-10-30 Hiroshi Kuramochi Novel Hsp90 Inhibitor
WO2009041570A1 (en) 2007-09-28 2009-04-02 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of steroid
WO2009116509A1 (en) 2008-03-18 2009-09-24 日本化薬株式会社 Polymer conjugate of physiologically active substance
WO2009142326A1 (en) 2008-05-23 2009-11-26 ナノキャリア株式会社 Docetaxel polymer derivative, method for producing same and use of same
WO2010131675A1 (en) 2009-05-15 2010-11-18 日本化薬株式会社 Polymer conjugate of bioactive substance having hydroxy group
US20110294980A1 (en) 2008-05-08 2011-12-01 Nippon Kayaku Kabushiki Kaisha Polymer Conjugate Of Folic Acid Or Folic Acid Derivative
US20130331517A1 (en) 2010-11-17 2013-12-12 Nippon Kayaku Kabushiki Kaisha Novel Polymer Derivative Of Cytidine Metabolic Antagonist
US20140288244A1 (en) 2011-09-11 2014-09-25 Nippon Kayaku Kabushiki Kaisha Method For Manufacturing Block Copolymer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004018494A (en) * 2002-06-19 2004-01-22 Japan Science & Technology Corp Method for producing block copolymer-medicine composite material
ITMI20060494A1 (en) * 2006-03-17 2007-09-18 Sifi Spa PHARMACEUTICAL COMPOSITION OF OPHTHALMIC CONTAINING AMPHIFILE COPOLYMERS OF POLYASPARTAMIDE

Patent Citations (230)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979449A (en) 1974-07-11 1976-09-07 Societe D'assistance Technique Pour Produits Nestle S.A. Preparation of an asparagine or a glutamine
US4011317A (en) * 1975-08-22 1977-03-08 Rorer Italiana S.P.A. Steroid derivatives
US5037883A (en) 1985-01-04 1991-08-06 Ceskoslovenska Akademie Ved Synthetic polymeric drugs
JPS61243026A (en) 1985-01-04 1986-10-29 チエコスロベンスカ・アカデミ−・ブイイ−デイ− Method for manufacturing polymerizable drugs
JPS6296088A (en) 1985-10-22 1987-05-02 Kanebo Ltd Production of antitumor substance
US4734512A (en) 1985-12-05 1988-03-29 Bristol-Myers Company Intermediates for the production of podophyllotoxin and related compounds and processes for the preparation and use thereof
JPS62145093A (en) 1985-12-05 1987-06-29 ブリストル―マイアーズ　スクイブ　コムパニー Intermediate for producing podophyllotoxin and related compound and its production and utilization
US4892733A (en) 1985-12-19 1990-01-09 Imperial Chemical Industries Plc Biodegradable synthesis polypeptide and its therapeutic use
JPS63502037A (en) 1985-12-19 1988-08-11 バテル　メモリアル　インステイチユ−ト Biodegradable synthetic polypeptides and their therapeutic uses
JPS6310789A (en) 1986-07-01 1988-01-18 Nippon Kayaku Co Ltd Novel podophyllotoxin derivative
JPS6323884A (en) 1986-07-17 1988-02-01 Nippon Kayaku Co Ltd Novel podophyllotoxin derivative
JPS6461423A (en) 1987-09-02 1989-03-08 Nippon Kayaku Kk Water-soluble polymeric carcinostatic agent
JPS6461422A (en) 1987-09-02 1989-03-08 Nippon Kayaku Kk Water-soluble polymeric carcinostatic agent
US5182203A (en) 1989-03-29 1993-01-26 E. I. Du Pont De Nemours And Company Bifunctional compounds useful in catalyzed reporter deposition
EP0397307A2 (en) 1989-05-11 1990-11-14 Research Development Corporation of Japan Water soluble high molecular polymerized drug preparation
JPH02300133A (en) 1989-05-11 1990-12-12 Res Dev Corp Of Japan Water-soluble polymerized medical formulation
US5412072A (en) * 1989-05-11 1995-05-02 Research Development Corp. Of Japan Water soluble high molecular weight polymerized drug preparation
US5693751A (en) 1989-05-11 1997-12-02 Research Development Corporation Of Japan Water soluble high molecular weight polymerized drug preparation
US6858582B2 (en) 1990-11-01 2005-02-22 Oregon Health And Sciences University Composition containing porous microparticle impregnated with biologically-active compound for treatment of infection
JPH05955A (en) 1990-11-07 1993-01-08 Yasuhisa Sakurai Water-soluble polymeric carcinostatic agent and drug-supporting carrier
JP3310000B2 (en) 1990-11-07 2002-07-29 靖久 桜井 Water-soluble polymer anticancer agent and carrier for drug support
JPH05117385A (en) 1991-10-31 1993-05-14 Res Dev Corp Of Japan Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agent
WO1993024476A1 (en) 1992-06-04 1993-12-09 Clover Consolidated, Limited Water-soluble polymeric carriers for drug delivery
JPH06107565A (en) 1992-08-14 1994-04-19 Res Dev Corp Of Japan Physical adsorption type polymeric micelle drug
EP0583955A2 (en) 1992-08-14 1994-02-23 Research Development Corporation Of Japan Physical trapping type polymeric micelle drug preparation
US5510103A (en) 1992-08-14 1996-04-23 Research Development Corporation Of Japan Physical trapping type polymeric micelle drug preparation
US5614549A (en) 1992-08-21 1997-03-25 Enzon, Inc. High molecular weight polymer-based prodrugs
JPH06206815A (en) 1992-10-26 1994-07-26 Nippon Kayaku Co Ltd Block copolymer-anticancer drug complex pharmaceutical preparation
JPH06206830A (en) 1992-10-27 1994-07-26 Nippon Kayaku Co Ltd Block copolymer-drug complex and polymer block copolymer
JP3268913B2 (en) 1992-10-27 2002-03-25 日本化薬株式会社 Polymer carrier
JPH06206832A (en) 1992-10-27 1994-07-26 Nippon Kayaku Co Ltd Polymer carrier
JPH08503689A (en) 1992-12-02 1996-04-23 ローン−プーラン・ロレ・ソシエテ・アノニム Novel composition based on taxoid
US5438072A (en) 1992-12-02 1995-08-01 Rhone-Poulenc Rorer S.A. Taxoid-based compositions
US5985548A (en) 1993-02-04 1999-11-16 E. I. Du Pont De Nemours And Company Amplification of assay reporters by nucleic acid replication
JPH08507558A (en) 1993-03-06 1996-08-13 ビーエーエスエフ アクチエンゲゼルシャフト Process for producing reaction product from polyaspartic imide and amino acid and use of the product
US5639832A (en) 1993-03-06 1997-06-17 Basf Aktiengesellschaft Preparation of products of the reaction of polyaspartimide and amino acids and the use thereof
JPH06296088A (en) 1993-04-08 1994-10-21 Canon Inc Electronic equipment
JPH06310789A (en) 1993-04-21 1994-11-04 Sumitomo Heavy Ind Ltd Position regulator of spare ionization pin for excimer laser
JPH06323884A (en) 1993-05-14 1994-11-25 Advance Denki Kogyo Kk Flow sensor
JPH06329085A (en) 1993-05-27 1994-11-29 Hitachi Zosen Corp Jet water inlet structure of water jet catamaran
US5571889A (en) * 1994-05-30 1996-11-05 Mitsui Toatsu Chemicals, Inc. Polymer containing monomer units of chemically modified polyaspartic acids or their salts and process for preparing the same
JPH0848766A (en) 1994-05-30 1996-02-20 Mitsui Toatsu Chem Inc Polymer and its production
JPH10513187A (en) 1995-01-30 1998-12-15 エンゾン，インコーポレーテッド Prodrugs based on high molecular weight polymers
WO1996023794A1 (en) 1995-01-30 1996-08-08 Enzon, Inc. High molecular weight polymer-based prodrugs
US5552517A (en) * 1995-03-03 1996-09-03 Monsanto Company Production of polysuccinimide in an organic medium
EP0757049A1 (en) 1995-08-02 1997-02-05 Tanabe Seiyaku Co., Ltd. Camptothecin derivatives
JP2694923B2 (en) 1995-08-21 1997-12-24 科学技術振興事業団 Water-soluble polymerized pharmaceutical preparation
JPH08310970A (en) 1995-08-21 1996-11-26 Res Dev Corp Of Japan Water-soluble polymerized pharmaceutical preparation
US6262107B1 (en) 1996-03-12 2001-07-17 Pg-Txl Company L.P. Water soluble paclitaxel prodrugs
WO1997038727A1 (en) 1996-04-15 1997-10-23 Asahi Kasei Kogyo Kabushiki Kaisha Medicament composite
US6458347B1 (en) * 1996-04-15 2002-10-01 Asahi Kasei Kabushiki Kaisha Drug complex
US6107333A (en) 1996-06-28 2000-08-22 The University Of Texas System Parenteral paclitaxel in a stable non-toxic formulation
US5877205A (en) 1996-06-28 1999-03-02 Board Of Regents, The University Of Texas System Parenteral paclitaxel in a stable non-toxic formulation
JP2000515132A (en) 1996-06-28 2000-11-14 ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム Parenteral paclitaxel in a stable non-toxic formulation
US6025385A (en) 1996-07-15 2000-02-15 Kabushiki Kaisha Yakult Honsha Taxane derivatives and drugs containing the same
WO1998002426A1 (en) 1996-07-15 1998-01-22 Kabushiki Kaisha Yakult Honsha Taxane derivatives and drugs containing the same
JP2000517304A (en) 1996-08-20 2000-12-26 エンゾン インコーポレーテッド Prodrugs based on high molecular weight polymers
WO1998007713A1 (en) 1996-08-20 1998-02-26 Enzon, Inc. High molecular weight polymer-based prodrugs
JP2000516948A (en) 1996-08-26 2000-12-19 トランジェーヌ、ソシエテ、アノニム Cationic lipid-nucleic acid complex
WO1998008489A1 (en) 1996-08-26 1998-03-05 Transgene S.A. Cationic lipid-nucleic acid complexes
US6573284B1 (en) 1996-12-13 2003-06-03 Phairson Medical Ltd Method of treating melanoma
US6720304B1 (en) 1997-05-09 2004-04-13 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Conjugate comprising a folic acid antagonist and a carrier
US6720306B2 (en) 1997-12-17 2004-04-13 Enzon Pharmaceuticals, Inc. Tetrapartate prodrugs
WO1999030727A1 (en) 1997-12-17 1999-06-24 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
JP2002508400A (en) 1997-12-17 2002-03-19 エンゾン，インコーポレーテッド Polymeric prodrugs of amino and hydroxyl containing bioactive agents
JP2002512265A (en) 1998-04-17 2002-04-23 エンゾン，インコーポレーテッド Terminally branched polymer linker and polymer conjugate containing same
WO1999053951A1 (en) 1998-04-17 1999-10-28 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
US20020009426A1 (en) 1998-04-17 2002-01-24 Greenwald Richard B. Biodegradable high molecular weight polymeric linkers and their conjugates
US6153655A (en) 1998-04-17 2000-11-28 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
JPH11335267A (en) 1998-05-27 1999-12-07 Nano Career Kk Polymer micelle system containing poorly water-soluble drug
US6322817B1 (en) 1999-02-17 2001-11-27 Dabur Research Foundation Formulations of paclitaxel, its derivatives or its analogs entrapped into nanoparticles of polymeric micelles, process for preparing same and the use thereof
US6410731B2 (en) 1999-04-09 2002-06-25 University Of Pittsburgh Camptothecin analogs and methods of preparation thereof
US20010003779A1 (en) 1999-04-09 2001-06-14 Curran Dennis P. Camptothecin analogs and methods of preparation thereof
US20010041189A1 (en) 1999-04-13 2001-11-15 Jingya Xu Poly(dipeptide) as a drug carrier
JP2003511349A (en) 1999-04-13 2003-03-25 ファニン バイオサイエンス、インク． Poly (dipeptide) as drug carrier
JP2003509385A (en) 1999-09-13 2003-03-11 ノベックス・コーポレイション Amphiphilic prodrug
JP2003509386A (en) 1999-09-13 2003-03-11 ノベックス・コーポレイション Taxane prodrug
WO2001019407A2 (en) 1999-09-13 2001-03-22 Nobex Corporation Taxane prodrugs
US6713454B1 (en) 1999-09-13 2004-03-30 Nobex Corporation Prodrugs of etoposide and etoposide analogs
WO2001019406A2 (en) 1999-09-13 2001-03-22 Nobex Corporation Amphiphilic prodrugs
WO2001019361A2 (en) 1999-09-14 2001-03-22 Tepha, Inc. Therapeutic uses of polymers and oligomers comprising gamma-hydroxybutyrate
JP2003524028A (en) 1999-09-23 2003-08-12 エンゾン，インコーポレーテッド Polymer conjugates of ara-C and ara-C derivatives
US6376470B1 (en) 1999-09-23 2002-04-23 Enzon, Inc. Polymer conjugates of ara-C and ara-C derivatives
CA2383240A1 (en) 1999-09-23 2001-03-29 Yun Hwang Choe Polymer conjugates of ara-c and ara-c derivatives
US20030054977A1 (en) 1999-10-12 2003-03-20 Cell Therapeutics, Inc. Manufacture of polyglutamate-therapeutic agent conjugates
JP2003511423A (en) 1999-10-12 2003-03-25 セル・セラピューティックス・インコーポレーテッド Preparation of polyglutamate-therapeutic drug conjugate
WO2001026693A2 (en) 1999-10-12 2001-04-19 Cell Therapeutics, Inc. Manufacture of polyglutamate-therapeutic agent conjugates
CN1307866A (en) 2000-02-09 2001-08-15 那野伽利阿株式会社 Production process of polymerized micelle with injected medicine and polymerized micelle composite
US20010014354A1 (en) 2000-02-09 2001-08-16 Nanocarrier Co., Ltd. Production process for polymeric micelle charged therein with drug and polymeric micelle composition
CA2334615A1 (en) 2000-02-09 2001-08-09 Nanocarrier Co., Ltd. Production process for polymeric micelle charged therein with drug and polymeric micelle composition
EP1127570A2 (en) 2000-02-09 2001-08-29 NanoCarrier Co., Ltd. Production process for polymeric micelle composition charged therein with drug
JP2001226294A (en) 2000-02-09 2001-08-21 Nano Career Kk Method for producing polymer micelle containing included drug and polymer micelle composition
JP2003525238A (en) 2000-02-29 2003-08-26 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Farnesyl protein transferase inhibitor combinations with antitumor podophyllotoxin derivatives
WO2001064198A2 (en) 2000-02-29 2001-09-07 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives
JP2003527443A (en) 2000-03-17 2003-09-16 セル・セラピューティックス・インコーポレーテッド Polyglutamic acid-camptothecin conjugate and method for preparing the same
US20020016285A1 (en) 2000-03-17 2002-02-07 Rama Bhatt Polyglutamic acid-camptothecin conjugates and methods of preparation
WO2001070275A2 (en) 2000-03-17 2001-09-27 Cell Therapeutics, Inc. Polyglutamic acid-camptothecin conjugates and methods of preparation
WO2001092584A1 (en) 2000-06-02 2001-12-06 Eidgenossische Technische Hochschule Zurich Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds
JP2002069184A (en) 2000-06-12 2002-03-08 Mitsui Chemicals Inc Polymer and method of producing the same
US20020119951A1 (en) 2000-07-17 2002-08-29 Faye Seyedi Efficient method of synthesizing combretastatin A-4 prodrugs
WO2002006279A1 (en) 2000-07-17 2002-01-24 Oxigene Inc Efficient method of synthesizing combretastatin a-4 prodrugs
US20020099013A1 (en) 2000-11-14 2002-07-25 Thomas Piccariello Active agent delivery systems and methods for protecting and administering active agents
US20030032593A1 (en) 2001-02-16 2003-02-13 Cellgate, Inc. Transporters comprising spaced arginine moieties
WO2002065986A2 (en) 2001-02-16 2002-08-29 Cellgate, Inc. Transporters comprising spaced arginine moieties
JP2005508832A (en) 2001-02-16 2005-04-07 セルゲイト， インコーポレイテッド Transporter with arginine part at intervals
JP2004532289A (en) 2001-02-20 2004-10-21 エンゾン ファーマシューティカルズ，インコーポレーテッド Terminally branched polymer linker and polymer conjugate containing the same
WO2002066066A1 (en) 2001-02-20 2002-08-29 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
JP2004530736A (en) 2001-02-20 2004-10-07 エンゾン ファーマシューティカルズ，インコーポレーテッド Terminally branched polymer linker and polymer conjugate containing the same
US20020183259A1 (en) 2001-02-20 2002-12-05 Choe Yun Hwang Terminally-branched polymeric linkers and polymeric conjugates containing the same
WO2002065988A2 (en) 2001-02-20 2002-08-29 Enzon, Inc. Terminally-branched polymeric linkers and polymeric conjugates containing the same
WO2003000771A1 (en) 2001-06-20 2003-01-03 Nippon Kayaku Kabushiki Kaisha Block copolymer reduced in impurity content, polymeric carrier, pharmaceutical preparations in polymeric form and process for the preparation of the same
US7138490B2 (en) 2001-06-20 2006-11-21 Nippon Kayaku Kabushiki Kaisha Block copolymer reduced in impurity content, polymeric carrier, pharmaceutical preparations in polymeric form and process for the preparation of the same
WO2003035008A2 (en) 2001-10-26 2003-05-01 Oxigene, Inc. Functionalized stilbene derivatives as improved vascular targeting agents
JP2005507912A (en) 2001-10-26 2005-03-24 オキシジーン， インコーポレイテッド Functionalized stilbene derivatives as improved vascular targeting agents
US20030149003A1 (en) 2001-10-26 2003-08-07 Chaplin David J. Functionalized stilbene derivatives as improved vascular targeting agents
US20020161062A1 (en) 2001-11-06 2002-10-31 Biermann Paul J. Structure including a plurality of cells of cured resinous material, method of forming the structure and apparatus for forming the structure
JP2005517675A (en) 2001-12-21 2005-06-16 ヴァーナリス（ケンブリッジ）リミテッド 3,4-Diarylpyrazoles and their use in the treatment of cancer
WO2003055860A1 (en) 2001-12-21 2003-07-10 Vernalis (Cambridge) Limited 3,4-diarylpyrazoles and their use in the therapy of cancer
US20060009622A1 (en) 2002-03-01 2006-01-12 Fuselier Joseph A Conjugates of therapeutic or cytotoxic agents and biologically active peptides
EP1489125A1 (en) 2002-03-05 2004-12-22 Beijing Jiankai Technology Co., Ltd. Compound of hydrophilic polymer-polycarboxyl oligopeptide and medicines, medical composite comprising above compound and use of above compound in medicimes
JP2005519122A (en) 2002-03-05 2005-06-30 北京鍵▲凱▼科技有限公司 Hydrophilic polymer-product of binding of multicarboxyl oligopeptide and drug molecule, pharmaceutical composition and pharmaceutical use thereof
US20050147617A1 (en) * 2002-03-05 2005-07-07 Shishan Ji Compounds of hydrophilic polymer-polycarboxyl oligopeptide and medicines, medical composite comprising above compound and use of above compound in medicimes
US20050171036A1 (en) 2002-03-26 2005-08-04 Banyu Pharmaceutical Co., Ltd. Use of antitumor indolopyrrolocarbazole derivative and other anticancer agent in combination
JP2005533026A (en) 2002-05-14 2005-11-04 イミュノジェン・インコーポレーテッド Cytotoxic agent containing taxane containing polyethylene glycol and therapeutic use thereof
US6596757B1 (en) 2002-05-14 2003-07-22 Immunogen Inc. Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
US20060057219A1 (en) 2002-05-24 2006-03-16 Nanocarrier Co., Ltd. Method for preparing a polymer micelle pharmaceutical preparation containing drug for injection
JP2003342168A (en) 2002-05-24 2003-12-03 Nano Career Kk Method for producing polymer micelle preparation containing drug for injection
JP2003342167A (en) 2002-05-24 2003-12-03 Nano Career Kk Pharmaceutical preparation of camptothecin derivative and method for producing the same
JP2003342269A (en) 2002-05-28 2003-12-03 Dai Ichi Seiyaku Co Ltd Method for reducing taxane
US20050119193A1 (en) 2002-06-03 2005-06-02 Jun Motoyama Novel solid preparation containing block copolymer and anthracycline anticancer agent and process for producing the same
JP2004039869A (en) 2002-07-03 2004-02-05 Hitachi Ltd Magnetic resistance sensor, magnetic head, and magnetic recording device
US20060067910A1 (en) 2002-10-31 2006-03-30 Masayuki Kitagawa High-molecular weight derivatives of camptothecins
EP1580216A1 (en) 2002-10-31 2005-09-28 Nippon Kayaku Kabushiki Kaisha High-molecular weight derivatives of camptothecins
CN1708540A (en) 2002-10-31 2005-12-14 日本化药株式会社 High-molecular weight derivatives of camptothecins
US7495099B2 (en) 2002-10-31 2009-02-24 Nippon Kayaku Kabushiki Kaisha High-molecular weight derivatives of camptothecins
WO2004039869A1 (en) 2002-10-31 2004-05-13 Nippon Kayaku Kabushiki Kaisha High-molecular weight derivatives of camptothecins
JP2006510627A (en) 2002-12-05 2006-03-30 ヴァーナリス（ケンブリッジ）リミテッド 3- (2-Hydroxy-phenyl) -1H-pyrazole-4-carboxylic acid amide derivatives as HSP90 inhibitors for cancer treatment
WO2004050087A1 (en) 2002-12-05 2004-06-17 Vernalis (Cambridge) Limited 3-(2-hydroxy-phenyl)-1h-pyrazole-4-carboxylic acid amide derivatives as hsp90 inhibitors for the treatment of cancer
WO2004056782A1 (en) 2002-12-19 2004-07-08 Vernalis (Cambridge) Limited Pyrazole compounds
JP2006511571A (en) 2002-12-19 2006-04-06 ヴァーナリス（ケンブリッジ）リミテッド Pyrazole compounds
US20050054026A1 (en) 2003-01-10 2005-03-10 Yamanouchi Pharmaceutical Co., Ltd. Lipid-peptide-polymer conjugates for long blood circulation and tumor specific drug delivery systems
WO2004072051A1 (en) 2003-02-11 2004-08-26 Vernalis (Cambridge) Limited Isoxazole compounds as inhibitors of heat shock proteins
JP2006517572A (en) 2003-02-11 2006-07-27 ヴァーナリス（ケンブリッジ）リミテッド Isoxazole compounds as inhibitors of heat shock proteins
US20140142167A1 (en) 2003-03-20 2014-05-22 Nanocarrier Kabushiki Kaisha Micellar Preparation Containing Sparingly Water-Soluble Anticancer Agent And Novel Block Copolymer
EP1604687A1 (en) 2003-03-20 2005-12-14 Nippon Kayaku Kabushiki Kaisha Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
WO2004082718A1 (en) 2003-03-20 2004-09-30 Nippon Kayaku Kabushiki Kaisha Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
US7820759B2 (en) 2003-03-20 2010-10-26 Nippon Kayaku Kabushiki Kaisha Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
CN1761485A (en) 2003-03-20 2006-04-19 日本化药株式会社 Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
US20060099265A1 (en) 2003-03-20 2006-05-11 Kazuhisa Shimizu Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
US20090156742A1 (en) 2003-03-20 2009-06-18 Kazuhisa Shimizu Micellar preparation containing sparingly water-soluble anticancer agent and novel block copolymer
JP2006521367A (en) 2003-03-26 2006-09-21 株式会社Ｌｔｔバイオファーマ Nanoparticles for intravenous injection for targeting and sustained release
US20060233883A1 (en) 2003-03-26 2006-10-19 Tsutomu Ishihara Intravenous nanoparticles for targeting drug delivery and sustained drug release
WO2004096212A1 (en) 2003-04-28 2004-11-11 Vernalis (Cambridge) Limited Pyrazole compounds as hsp90 inhibitors for the treatment of cancer
JP2006524673A (en) 2003-04-28 2006-11-02 ヴァーナリス（ケンブリッジ）リミテッド Pyrazole compounds as HSP90 inhibitors for the treatment of cancer
WO2005000300A1 (en) 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
JP2005051922A (en) 2003-07-29 2005-02-24 Yokogawa Electric Corp Power supply system and power supply method
US20070004674A1 (en) 2003-08-22 2007-01-04 Kyowa Hakko Kogyo Co. Ltd. Remedy for diseases associated with immunoglobulin gene translocation
WO2005018674A1 (en) 2003-08-22 2005-03-03 Kyowa Hakko Kogyo Co., Ltd. Remedy for diseases associated with immunoglobulin gene translocation
US20060258569A1 (en) 2003-10-21 2006-11-16 Mctavish Hugh Compounds and methods for treating cancer
JP2007511586A (en) 2003-11-21 2007-05-10 フラメル・テクノロジー Pharmaceutical preparations for the release of active ingredients and their application, in particular therapeutic applications
US20070196497A1 (en) 2003-11-21 2007-08-23 Flamel Technologies, Inc. Pharmaceutical formulations for the prolonged release of active principle(s) and their applications
US7176185B2 (en) 2003-11-25 2007-02-13 Tsrl, Inc. Short peptide carrier system for cellular delivery of agent
WO2005066214A1 (en) 2004-01-07 2005-07-21 Seikagaku Corporation Hyaluronic acid derivative and drug containing the same
US20080221062A1 (en) 2004-01-07 2008-09-11 Kenji Miyamoto Hyaluronic Acid Derivative and Drug Containing the Same
US20140024703A1 (en) 2004-09-22 2014-01-23 Nippon Kayaku Kabushiki Kaisha Novel Block Copolymer, Micelle Preparation, And Anticancer Agent Containing The Same As Active Ingredient
US20080113028A1 (en) 2004-09-22 2008-05-15 Kazuhisa Shimizu Novel Block Copolymer, Micelle Preparation, And Anticancer Agent Containing The Same As Active Ingredient
CN101023119A (en) 2004-09-22 2007-08-22 日本化药株式会社 Novel block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient
US20150259479A1 (en) 2004-09-22 2015-09-17 Nippon Kayaku Kabushiki Kaisha Novel Block Copolymer, Micelle Preparation, And Anticancer Agent Containing The Same As Active Ingredient
EP1792927A1 (en) 2004-09-22 2007-06-06 Nippon Kayaku Kabushiki Kaisha Novel block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient
WO2006033296A1 (en) 2004-09-22 2006-03-30 Nippon Kayaku Kabushiki Kaisha Novel block copolymer, micelle preparation, and anticancer agent containing the same as active ingredient
JP2006120914A (en) 2004-10-22 2006-05-11 Matsushita Electric Ind Co Ltd Component suction nozzle, component mounting apparatus, and component mounting method
WO2006055670A2 (en) 2004-11-16 2006-05-26 Hyperion Catalysis International, Inc. Methods for preparing catalysts supported on carbon nanotube networks
WO2006055760A1 (en) 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US20080145432A1 (en) 2005-03-09 2008-06-19 Yoshinori Kakizawa Fine Particle and Pharmaceutical Preparation
US20080269218A1 (en) 2005-03-09 2008-10-30 Hiroshi Kuramochi Novel Hsp90 Inhibitor
WO2006095668A1 (en) 2005-03-09 2006-09-14 Toray Industries, Inc. Microparticle and pharmaceutical composition
WO2006095783A1 (en) 2005-03-09 2006-09-14 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor
EP1857446A1 (en) 2005-03-09 2007-11-21 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor
WO2006101052A1 (en) 2005-03-22 2006-09-28 Nippon Kayaku Kabushiki Kaisha Novel acetylene derivative
WO2006115293A1 (en) 2005-04-22 2006-11-02 The University Of Tokyo NOVEL BLOCK COPOLYMER USED FOR PREPARING pH-RESPONSIVE POLYMER MICELLE, AND METHOD FOR PRODUCING SAME
US7700709B2 (en) 2005-05-11 2010-04-20 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of cytidine metabolic antagonist
WO2006120914A1 (en) 2005-05-11 2006-11-16 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of cytidine metabolic antagonist
US20090012252A1 (en) 2005-05-11 2009-01-08 Akira Masuda Polymeric Derivative of Cytidine Metabolic Antagonist
WO2006120915A1 (en) 2005-05-12 2006-11-16 Nipro Corporation Agent for improving circulatory disorder
US20090275732A1 (en) 2005-05-12 2009-11-05 Ichiro Hirotsu Agent for improving circulatory disorder
WO2007022493A2 (en) 2005-08-19 2007-02-22 Endocyte, Inc. Ligand conjugates of vinca alkaloids, analogs, and derivatives
US20080280937A1 (en) 2005-08-19 2008-11-13 Christopher Paul Leamon Ligand Conjugates of Vinca Alkaloids, Analogs, and Derivatives
JP2007111211A (en) 2005-10-20 2007-05-10 Yamasa Kk Slot machine
CN1800238A (en) 2005-12-05 2006-07-12 中国科学院长春应用化学研究所 Aliphatic polyester-polyamino acids copolymer with biological function and its synthesis method
WO2007080898A1 (en) 2006-01-10 2007-07-19 Medgel Corporation Sustained-release hydrogel preparation
JP2007191643A (en) 2006-01-20 2007-08-02 Mitsui Chemicals Inc Polyamino acid derivative imparted with fixability to living body
US8323669B2 (en) 2006-03-28 2012-12-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
WO2007111211A1 (en) 2006-03-28 2007-10-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
TW200812572A (en) 2006-03-28 2008-03-16 Nippon Kayaku Kk Polymer conjugate of taxane
US20100234537A1 (en) 2006-03-28 2010-09-16 Masayuki Kitagawa Polymer conjugate of taxane
WO2007135910A1 (en) 2006-05-18 2007-11-29 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of podophyllotoxin
US20090162313A1 (en) 2006-05-18 2009-06-25 Masayuki Kitagawa High-Molecular Weight Conjugate of Podophyllotoxins
US8940332B2 (en) 2006-05-18 2015-01-27 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of podophyllotoxins
WO2008010463A1 (en) 2006-07-19 2008-01-24 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of combretastatin
US20100004403A1 (en) 2006-07-19 2010-01-07 Masayuki Kitagawa High-Molecular Weight Conjugate of Combretastatins
JP2008041610A (en) 2006-08-10 2008-02-21 Mitsubishi Electric Corp Circuit breaker
WO2008041610A1 (en) 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Compound of resorcinol derivative with polymer
US20150011715A1 (en) 2006-10-03 2015-01-08 Nippon Kayaku Kabushiki Kaisha High-Molecular Weight Conjugate Of Resorcinol Derivatives
US20090239782A1 (en) 2006-10-03 2009-09-24 Masaharu Nakamura High-molecular weight conjugate of resorcinol derivatives
WO2008056596A1 (en) 2006-11-06 2008-05-15 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of nucleic acid metabolic antagonist
US20090281300A1 (en) 2006-11-06 2009-11-12 Keiichiro Yamamoto High-molecular weight derivative of nucleic acid antimetabolite
US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
US8188222B2 (en) 2006-11-08 2012-05-29 Nippon Kayaku Kabushiki Kaisha High molecular weight derivative of nucleic acid antimetabolite
WO2008056654A1 (en) 2006-11-08 2008-05-15 Nippon Kayaku Kabushiki Kaisha Polymeric derivative of nucleic acid metabolic antagonist
US20100029849A1 (en) 2006-11-08 2010-02-04 Keiichiro Yamamoto High molecular weight derivative of nucleic acid antimetabolite
CN101808651A (en) 2007-09-28 2010-08-18 日本化药株式会社 polymer conjugate of steroid
US20100292414A1 (en) 2007-09-28 2010-11-18 Nippon Kayaku Kabushiki Kaisha High-Molecular Weight Conjugate Of Steroids
WO2009041570A1 (en) 2007-09-28 2009-04-02 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of steroid
US8703878B2 (en) 2007-09-28 2014-04-22 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
US8920788B2 (en) * 2008-03-18 2014-12-30 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of physiologically active substances
WO2009116509A1 (en) 2008-03-18 2009-09-24 日本化薬株式会社 Polymer conjugate of physiologically active substance
EP2258397A1 (en) 2008-03-18 2010-12-08 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of physiologically active substance
US20110201754A1 (en) 2008-03-18 2011-08-18 Nippon Kayaku Kabushiki Kaisha High-Molecular Weight Conjugate Of Physiologically Active Substances
US20110294980A1 (en) 2008-05-08 2011-12-01 Nippon Kayaku Kabushiki Kaisha Polymer Conjugate Of Folic Acid Or Folic Acid Derivative
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
US20110136990A1 (en) 2008-05-23 2011-06-09 Mitsunori Harada Polymer derivative of docetaxel, method of preparing the same and uses thereof
CN102037058A (en) 2008-05-23 2011-04-27 那野伽利阿株式会社 Docetaxel polymer derivative, method for producing same and use of same
WO2009142326A1 (en) 2008-05-23 2009-11-26 ナノキャリア株式会社 Docetaxel polymer derivative, method for producing same and use of same
US8808749B2 (en) 2009-05-15 2014-08-19 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of bioactive substance having hydroxy group
US20120116051A1 (en) 2009-05-15 2012-05-10 Nippon Kayaku Kabushiki Kaisha Polymer Conjugate Of Bioactive Substance Having Hydroxy Group
WO2010131675A1 (en) 2009-05-15 2010-11-18 日本化薬株式会社 Polymer conjugate of bioactive substance having hydroxy group
US20130331517A1 (en) 2010-11-17 2013-12-12 Nippon Kayaku Kabushiki Kaisha Novel Polymer Derivative Of Cytidine Metabolic Antagonist
US9018323B2 (en) 2010-11-17 2015-04-28 Nippon Kayaku Kabushiki Kaisha Polymer derivative of cytidine metabolic antagonist
US20140288244A1 (en) 2011-09-11 2014-09-25 Nippon Kayaku Kabushiki Kaisha Method For Manufacturing Block Copolymer
US9346923B2 (en) 2011-09-11 2016-05-24 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer

Non-Patent Citations (220)

* Cited by examiner, † Cited by third party
Title
6001 Chemical Abstracts, American Chemical Society, US, vol. 132, No. 2, Oct. 1, 2000, XP-002168038, 1 page abstract, "Polymer Micelle Compositions Containing Poorly Water-Soluble Drugs and their Preparation", Ichiro, et al.
A.V. Shur, "High-Molecular Weight Compounds"; Course for Universities, Third Edition, Revised and supplemented, "Visshaja Shkola" Publishing House, 1981, 656 pages, see p. 265.
Advanced Drug Delivery Reviews 20 (1996) 1995-201; K. Yokoyama et al.; "Limethason as a lipid microsphere preparation: An overview".
Advanced Drug Delivery Reviews, vol. 20, (1996), 195-201, "Limethason as a lipid microsphere preparation: An Overview", Yokoyama, et al.
Advanced Drug Delivery Reviews, vol. 55, No. 2, Feb. 2003, pp. 217-250, "Effective drug delivery by PEGylated drug conjugates", Greenwald, et al.
Anti Cancer Drug Design, vol. 14, No. 6, Dec. 1999, ISSN 0266-9536, pp. 539-548, "Synthesis and antitumor activities of amino acid prodrugs of amino-combretastatins", Ohsumi, et al.
Anti-Cancer Drug Design; vol. 14, No. 6, Dec. 1999-ISSN 0266-9536.
Antimicrobial Agents and Chemotherapy, vol. 2, No. 5, Nov. 1972, pp. 395-401, XP 55016709, ISSN: 0066-4804, "Antiviral Action of Camptothecin", Horwitz, et al.
Arch. Pharm. (Weinheim), Jan. 1995, vol. 328, No. 10, pp. 737-738, "An Improved and Large Scale Synthesis of the Natural Coumarin Scopoletin", Hauer, et al.
Australian Communication dated Oct. 28, 2011 in Australian Patent Application No. 2007252678.
Australian Communication issued May 29, 2015 in co-pending Australian patent application No. 2012305405.
Australian Communication, dated Oct. 28, 2011 in co-pending Australian Patent No. 2007252678.
Bioorganic & Medicinal Chemistry Letters 15 (2005) pp. 3338-3343, "The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors", Cheung, et al.
Bioorganic & Medicinal Chemistry Letters, 2005, vol. 15, 3338-3343, "The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors", Cheung, et al.
Canadian Communication issued Jun. 26, 2013 in co-pending Canadian patent application No. CA 2,664,852.
Cancer Research 44, Jan. 25-30, 1984; Yoshinori Kato et al.; "Anti-tumor Activity of 1-B-D-Arabinofuranosylcytosine Conjugated with Polyglutamic Acid and Its Derivative".
Cancer Research vol. 44, Jan. 25-30, 1984, "Antitumor Activity of 1-B-D-Arabinofuranosylcytosine Conjugated with Polyglutamic Acid and its Derivative", Kato, et al.
Cancer Sci; Feb. 2004; vol. 95; No. 2; 105-111; Akira Matsuda et al.; "Antitumor Activity of Sugar-Modified Cytosine Nucleosides".
Cancer Science, Feb. 2004, V. 95, No. 2, 105-111, "Antitumor Activity of Sugar-Modified Cytosine Nucleosides", Matsuda, et al.
Chemical Abstracts, 6001, vol. 132; Oct. 10, 2000 No. 2-XP-002168038.
Chemistry and Biology, vol. 11, 787-797, Jun. 2004, "Targeting Wide-Range Oncogenic Transformation via PU24FCI, a Specific Inhibitor of Tumor Hsp90", Vilenchik, et al.
Chemistry and Biology, vol. 11, 787-797, Jun. 2004; Maria Vilenchick et al.; "Targeting Wide-Range Oncogenic Transformation via PU24FCI, a specific Inhibitor of Tumor Hsp90".
Chinese Communication dated Apr. 17, 2009 in co-pending Chinese patent application No. CN200480007329.5.
Chinese communication dated Apr. 17, 2009 in co-pending U.S. Appl. No. 10/548,998 (CN200480007329.5).
Chinese Communication dated Aug. 11, 2010 in Chinese patent application No. CN2007800177809.
Chinese communication dated Aug. 11, 2010 in co-pending foreign application (CN2007800177809).
Chinese Communication dated Aug. 31, 2011 in Chinese patent application No. 200980110087.5.
Chinese Communication dated Nov. 10, 2010 in Chinese application No. CN 200780027210.8.
Chinese Communication dated Oct. 10, 2011 in corresponding Chinese Patent Application No. 200880109404.7.
Chinese communication dated Oct. 20, 2006 in co-pending U.S. Appl. No. 10/548,998 (CN200480007329.5).
Chinese Communication dated Sep. 23, 2011 in Chinese patent application No. 2007800177809.
Chinese communication mailed Apr. 29, 2015 in co-pending Chinese patent application No. 201280043928.7.
Chinese Communication mailed Dec. 31, 2013 in Chinese patent application No. CN 200980110087.5.
Chinese Communication mailed Feb. 22, 2013 in Chinese Patent Application No. 201080021960.6.
Chinese communication mailed Jun. 17, 2014 in Chinese patent application No. 200980110087.5.
Chinese Communication, with English translation, dated Aug. 31, 2011 in co-pending Chinese patent application No. 200980110087.5.
Chinese communication, with English translation, dated Jan. 12, 2016 in co-pending Chinese patent application No. 201280043928.7.
Chinese Communication, with English translation, dated Oct. 10, 2011 in corresponding Chinese Patent Application No. 200880109404.7.
Chinese Communication, with English translation, dated Sep. 23, 2011 in co-pending Chinese patent application No. 2007800177809.
Chinese Communication, with English translation, mailed Feb. 22, 2013 in co-pending Chinese Patent Application No. 201080021960.6.
Chinese Communicaton dated Oct. 20, 2006 in co-pending Chinese patent application No. CN200480007329.5.
Chinese Office Action dated Nov. 10, 2010 in co-pending U.S. Appl. No. 12/309,061, filed Mar. 3, 2009 /Foreign Application No. 200780027210.8.
Colloids and Surfaces B: Biointerfaces V 16 (1999) pp. 217-226, "Micelle-like structures of poly(ethyleneoxide)-block-poly(2-hydroxyethyl aspartamide)-methotrexate conjugates", Li, et al.
Colloids and Surfaces B: Biointerfaces V. 16 (1999) pp. 217-226, "Micelle-like structures of poly(ethyleneoxide)-block-poly(2-hydroxethyl aspartamide)-methotrexate conjugates", Li, et al.
Current Cancer Drug Targets, 2003, 3, 385-390; Udai Banerji et al.; "The Clinical Applications of Heat Shock Protein Inhibitors in Cancer Present and Future".
Current Cancer Drug Targets, 2003, vol. 3, 385-390, "The Clinical Applications of Heat Shock Protein Inhibitors in Cancer-Present and Future", Banerji, et al.
English translation of JP 6-206815 (Jul. 26, 1994), "Pharmaceutical Preparation Based on Block Copolymer-Anticancer Drug Complex", by Masayuki Yokoyama, et al., 24 pages, US Patent and Trademark Office, Aug. 2007, Translated by: FLS, Inc.
European Communication dated Feb. 17, 2009 in co-pending European patent application No. EP04721673.4.
European communication dated Feb. 17, 2009 in co-pending U.S. Appl. No. 10/548,998 (EP04721673.4).
European Communication dated Jun. 5, 2009 in co-pending European patent application No. EP04721673.4.
European communication dated Jun. 5, 2009 in co-pending U.S. Appl. No. 10/548,998 (EP04721673.4).
European communication dated Mar. 11, 2015 in co-pending European patent application No. 12830758.4.
European communication dated Oct. 23, 2009 in co-pending U.S. Appl. No. 12/226,962 (EP07743461.1).
European Communication dated Oct. 23, 2009 in European patent application No. EP07743461.1.
European Communication dated Oct. 28, 2011 in co-pending European Patent Application No. EP 05783310.5.
European communication dated Oct. 29, 2014 in co-pending European patent application No. 09742696.9.
European Communication dated Sep. 25, 2008 in European patent application No. EP03769949.3.
European communication dated Sep. 25, 2008 in U.S. Pat. No. 7,495,099 (EP03769949.3).
European communication mailed Apr. 21, 2015 in co-pending European patent application No. 07828587.1.
European Communication mailed Jan. 27, 2012 in co-pending European Patent Application No. 07831039.8.
European Communication mailed Jan. 27, 2012 in European Patent Application No. 07831039.8.
European Communication mailed May 24, 2013 in co-pending European patent application No. 09722008.1.
European Communication mailed May 24, 2013 in European patent application No. 09722008.1
European Communication, dated Oct. 28, 2011 in co-pending European Patent Application No. EP 05783310.5.
Examiner's Answer to Appeal Brief mailed Jul. 29, 2014 in abandoned U.S. Appl. No. 12/311,086.
Final Rejection dated Feb. 16, 2012 in co-pending U.S. Appl. No. 12/226,962.
Final Rejection dated Feb. 28, 2011 in abandoned U.S. Appl. No. 12/309,061.
Final Rejection dated Feb. 28, 2011 in co-pending U.S. Appl. No. 12/309,061.
Final Rejection dated Jul. 27, 2011 in abandoned U.S. Appl. No. 12/311,086.
Final Rejection dated Jul. 27, 2011 in co-pending U.S. Appl. No. 12/311,086.
Final Rejection dated Jun. 8, 2011 in co-pending U.S. Appl. No. 11/662,834.
Final Rejection dated Mar. 4, 2010 in abandoned U.S. Appl. No. 10/548,998.
Final Rejection mailed Apr. 21, 2015 in co-pending U.S. Appl. No. 14/241,924.
Final rejection mailed Apr. 6, 2016 in co-pending U.S. Appl. No. 14/108,875.
Final Rejection mailed Aug. 21, 2012 in co-pending U.S. Appl. No. 11/662,834.
Final Rejection mailed Aug. 28, 2013 in abandoned U.S. Appl. No. 12/311,086.
Final Rejection mailed Aug. 28, 2013 in co-pending U.S. Appl. No. 12/311,086.
Final Rejection mailed Jan. 10, 2014 in co-pending U.S. Appl. No. 13/319,175.
Final rejection mailed Jan. 15, 2016 in co-pending U.S. Appl. No. 14/727,912.
Final rejection mailed Jan. 29, 2016 in co-pending U.S. Appl. No. 11/662,834.
Final Rejection mailed Jul. 14, 2015 in co-pending U.S. Appl. No. 13/971,036.
Final Rejection mailed Mar. 28, 2013 in co-pending U.S. Appl. No. 12/991,041.
Final Rejection mailed Mar. 4, 2015 in co-pending U.S. Appl. No. 11/662,834.
Final Rejection mailed Mar. 5, 2013 in co-pending U.S. Appl. No. 12/922,747.
Final Rejection mailed May 28, 2015 in co-pending U.S. Appl. No. 14/497,703.
Final Rejection mailed Nov. 8, 2011 in co-pending U.S. Appl. No. 12/225,230.
Final Rejection mailed Oct. 17, 2012 in corresponding U.S. Appl. No. 12/678,620.
International Preliminary Report on Patentability issued Apr. 7, 2009 and Apr. 22, 2009 in co-pending PCT application No. PCT/JP2007/068841.
International Preliminary Report on Patentability mailed Mar. 20, 2014 in co-pending PCT application No. PCT/JP2012/072160.
International Preliminary Report on Patentability, with English translation, issued Apr. 7, 2009 and Apr. 22, 2009 in co-pending PCT application No. PCT/JP2007/068841.
International Search Report and Written Opinion mailed Jan. 24, 2012 in co-pending PCT application No. PCT/JP2011/076373.
International Search Report dated Aug. 10, 2010 in co-pending PCT application No. PCT/JP2010/058034.
International Search Report dated Aug. 10, 2010 in PCT application No. PCT/JP2010/058034.
International Search Report dated Aug. 21, 2007 in co-pending U.S. Appl. No. 12/226,962 (PCT/JP2007/060026).
International Search Report dated Aug. 21, 2007 in PCT application No. PCT/JP2007/060026.
International Search Report dated Dec. 24, 2003 in PCT application No. PCT/JP03/13838.
International Search Report dated Dec. 24, 2003 in U.S. Pat. No. 7,495,099 (PCT/JP03/13838).
International Search Report dated Dec. 9, 2008 in co-pending U.S. Appl. No. 12/678,620 (PCT/JP2008/067413).
International Search Report dated Dec. 9, 2008 in corresponding PCT application No. PCT/JP2008/067413.
International Search Report dated Jan. 29, 2008 in co-pending U.S. Appl. No. 12/312,009 (PCT/JP2007/071305).
International Search Report dated Jan. 29, 2008 in co-pending U.S. Appl. No. 12/312,009 (PCT/JP2007/071532).
International Search Report dated Jan. 29, 2008 in co-pending U.S. Appl. No. 12/312,157 (PCT/JP200/071532).
International Search Report dated Jan. 29, 2008 in PCT application No. PCT/JP2007/071305.
International Search Report dated Jan. 29, 2008 in PCT application No. PCT/JP2007/071532.
International Search Report dated Jan. 8, 2008 in co-pending U.S. Appl. No. 12/311,086 (PCT/JP2007/068841).
International Search Report dated Jan. 8, 2008 in PCT application No. PCT/JP2007/068841.
International Search Report dated Jul. 21, 2009 in co-pending international patent application No. PCT/JP2009/058325.
International Search Report dated Jul. 21, 2009 in co-pending PCT application No. PCT/JP2009/058325.
International Search Report dated Jul. 25, 2006 in PCT application No. PCT/JP2006/308826.
International Search Report dated Jul. 25, 2006 in U.S. Pat. No. 7,700,709 (PCT/JP2006/308826).
International Search Report dated May 11, 2004 in co-pending PCT application No. PCT/JP2004/003647.
International Search Report dated May 11, 2004 in co-pending U.S. Appl. No. 10/548,998 (PCT/JP2004/003647).
International Search Report dated May 15, 2007 in co-pending U.S. Appl. No. 12/225,230 (PCT/JP20071055809).
International Search Report dated May 15, 2007 in PCT application No. PCT/JP2007/055809.
International Search Report dated Nov. 15, 2005 in co-pending PCT application No. PCT/JP2005/017127.
International Search Report dated Nov. 15, 2005 in co-pending U.S. Appl. No. 12/322,322 (PCT/JP2005/017127).
International Search Report dated Oct. 16, 2007 in co-pending U.S. Appl. No. 12/309,061 (PCT/JP2007/063990).
International Search Report dated Oct. 16, 2007 in PCT application No. PCT/JP2007/063990.
International Search Report mailed Dec. 4, 2012 in co-pending PCT application No. PCT/JP2012/072160.
International Search Report mailed Jun. 23, 2009 in co-pending PCT application No. PCT/JP2009/055115.
International Search Report mailed Jun. 23, 2009 in PCT application No. PCT/JP2009/055115.
J. of Pharmacokinetics and BioPharmaceutics, vol. 23, No. 4, 1995, pp. 397-406, "In Vivo Pharmacokinetic Study for the Assessment of Poly(L-Aspartic Acid) as a Drug Carrier for Colon-Specific Drug Delivery", Leopold, et al.
J. Org. Chem 2001, 66, 8135-8138, "Novel Syntheses of Cis and Trans Isomers of Combretastatin A-4", Gaukroger, et al.
J. Org. Chem. 2001, 66, 8135-8138; Keirs Gaukroger, et al.; "Novel Synthesis of Cis and Trans Isomers of Combretastatin A-4".
Japanese communication mailed Jul. 8, 2014 in co-pending Japanese patent application No. 2010-503871.
Japanese Communication mailed Mar. 26, 2013 in co-pending Japanese Patent Application No. 2008-537500.
Japanese Communication mailed May 14, 2013 in corresponding Japanese patent application No. JP 2009-534401.
Japanese communication mailed Sep. 24, 2013 in Japanese patent application No. JP 2010-503871.
Japanese Communication, with English translation, mailed Mar. 26, 2013 in co-pending Japanese Patent Application No. 2008-537500.
Japanese communication, with English translation, mailed Sep. 24, 2013 in co-pending Japanese patent application No. JP2010-503871.
Japanese Communication, with partial English translation, mailed May 14, 2013 in corresponding Japanese patent application No. JP 2009-534401.
Journal of Controlled Release 79 (2002) 55-70; Yun H. Choe et al.; "Anticancer Drug Delivery Systems: Multi-Loaded N4-acyl poly-(ethylene glycol) prodrugs of ara-C. II Efficacy in ascites and solid tumors".
Journal of Controlled Release vol. 79 (2002), 55-70, "Anticancer Drug Delivery Systems: Multi-Loaded N4-acyl poly(ethylene glycol) prodrugs of ara-C. II. Efficacy in ascites and solid tumors", Choe, et al.
Journal of Controlled Release, 2001, V. 74, No. 1-3, pp. 295-302, paragraph of "2. Structure of NK911", "Development of the polymer micelle carrier system for doxorubicin", Nakanishi, et al.
Journal of Peptide Science, vol. 3 (1997), 141-144, "Evaluation of Carbodiimides Using a Competition Method", Izdebski, et al.
Journal of Peptide Science, vol. 3, 141-144 (1997); Jan Izdebski et al.; "Evaluation of Carbodiimides Using A Competition Method".
Journal of Pharmaceutical Sciences, vol. 92, No. 7, Jul. 2003, pp. 1343-1355, "MiniReview-Amphiphilic Block Copolymers for Drug Delivery", Adams, et al.
Journal of Pharmaceutical Sciences, vol. 92, No. 7, Jul. 2003; Monica L. Adams et al.; "MiniReview-Amphiphilic Block Copolymers for Drug Delivery".
Journal of Pharmacokinetics and Biopharmaceutics, vol. 23, No. 4, 1995; Claudia S. Leopold; In vivo Pharmacokinetic Study for the Assessment of Poly(L-Aspartic Acid) as a Drug Carrier for Colon-Specific Drug Delivery).
Korean Communication dated Nov. 8, 2010 in co-pending Korean patent application No. 10-2005-7017245.
Korean Office Action dated Nov. 8, 2010 in co-pending U.S. Appl. No. 10/548,998, filed Oct. 31, 2005 /Foreign Application No. 10-2005-7017245.
Matsusaki et al.; "Stably-dispersed and Surface-functional Bionanoparticles Prepared by Self-assembling Amphipathic Polymers of Hydrophilic Poly(y-glutamic acid) Bearing Hydrophobic Amino Acids." 2004, The Chemical Society of Japan; Chemistry Letters, vol. 33, No. 4, pp. 398-399.
Merriam Webster Online Dictionary entry for "Derivative", (http://www.merriam-webster.com/dictionary/derivative), last accessed Feb. 9, 2011, 3 pages.
Merriam-Webster Online Dictionary entry for "Derivative", (http://www.merriam-webster.com/dictionary/derivative), last accessed Feb. 9, 2011, 3 pages.
Merriam-Webster's Collegiate Dictionary-11th Edition, 2004, 22 pages.
Merriam-Webster's Collegiate Dictionary-Eleventh Edition 2004.
Miscellaneous Communication mailed Mar. 19, 2012 in co-pending U.S. Appl. No. 12/312,157.
Molecular Cancer Therapeutics 2006, vol. 5, 1628-1637, "Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors", Smith, et al.
Molecular Cancer Therapeutics, 2006, 5(6), Jun. 2006, pp. 1628-1637, "Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors", Smith, et al.
Notice of Allowance dated Mar. 1, 2012 in co-pending U.S. Appl. No. 12/312,157.
Notice of Allowance mailed Aug. 28, 2012 in co-pending U.S. Appl. No. 12/225,230.
Notice of Allowance mailed Aug. 7, 2012 in co-pending U.S. Appl. No. 12/312,009.
Notice of Allowance mailed Jan. 16, 2014 in corresponding U.S. Appl. No. 12/678,620.
Notice of Allowance mailed Jan. 28, 2015 in co-pending U.S. Appl. No. 13/884,413.
Notice of Allowance mailed Jan. 29, 2016 in co-pending U.S. Appl. No. 14/241,924.
Notice of Allowance mailed Jul. 1, 2016 in co-pending U.S. Appl. No. 13/971,036.
Notice of Allowance mailed May 28, 2015 in co-pending U.S. Appl. No. 12/991,041.
Office Action dated Apr. 17, 2009 in abandoned U.S. Appl. No. 10/548,998.
Office Action dated Apr. 4, 2011 in abandoned U.S. Appl. No. 12/311,086.
Office Action dated Aug. 24, 2010 in co-pending U.S. Appl. No. 11/662,834.
Office Action dated dated Apr. 4, 2011 in co-pending U.S. Appl. No. 12/311,086.
Office Action dated Dec. 15, 2011 in co-pending U.S. Appl. No. 11/662,834.
Office Action dated Feb. 21, 2012 in co-pending U.S. Appl. No. 12/312,009.
Office Action dated Jan. 21, 2009 in abandoned U.S. Appl. No. 10/548,998.
Office Action dated Jul. 10, 2009 in abandoned U.S. Appl. No. 10/548,998.
Office Action dated Jul. 21, 2010 in abandoned U.S. Appl. No. 12/309,061.
Office Action dated Jun. 16, 2011 in co-pending U.S. Appl. No. 12/225,230.
Office Action dated Nov. 12, 2010 in a co-pending U.S. Appl. No. 11/662,834.
Office Action dated Nov. 12, 2010 in co-pending U.S. Appl. No. 11/662,834.
Office Action dated Oct. 12, 2011 in co-pending U.S. Appl. No. 12/312,157.
Office Action dated Sep. 9, 2011 in co-pending U.S. Appl. No. 12/226,962.
Office Action mailed Apr. 18, 2013 in abandoned U.S. Appl. No. 12/311,086.
Office Action mailed Apr. 18, 2013 in co-pending U.S. Appl. No. 12/311,086.
Office Action mailed Apr. 25, 2012 in corresponding U.S. Appl. No. 12/678,620.
Office Action mailed Apr. 6, 2012 in co-pending U.S. Appl. No. 12/225,230.
Office action mailed Aug. 17, 2015 in co-pending U.S. Appl. No. 14/241,924.
Office Action mailed Aug. 22, 2012 in co-pending U.S. Appl. No. 12/991,041.
Office Action mailed Aug. 25, 2014 in co-pending U.S. Appl. No. 11/662,834.
Office Action mailed Dec. 15, 2011 in co-pending U.S. Appl. No. 11/662,834.
Office Action mailed Dec. 31, 2014 in co-pending U.S. Appl. No. 13/971,036.
Office Action mailed Jul. 30, 2012 in co-pending U.S. Appl. No. 12/922,747.
Office Action mailed Jul. 7, 2015 in co-pending U.S. Appl. No. 11/662,834.
Office Action mailed Jun. 12, 2013 in co-pending U.S. Appl. No. 13/319,175.
Office Action mailed Jun. 22, 2015 in co-pending U.S. Appl. No. 14/727,912.
Office Action mailed Nov. 24, 2014 in co-pending U.S. Appl. No. 14/497,703.
Office Action mailed Oct. 1, 2014 in co-pending U.S. Appl. No. 14/241,924.
Office Action mailed Oct. 25, 2011 in co-pending U.S. Appl. No. 12/312,009.
Office action mailed Oct. 5, 2015 in co-pending U.S. Appl. No. 14/108,875.
Office Action mailed Oct. 7, 2013 in abandoned U.S. Appl. No. 10/548,998.
Office Action mailed Oct. 7, 2013 in co-pending U.S. Appl. No. 10/548,998.
Office Action mailed Sep. 6, 2013 in co-pending U.S. Appl. No. 12/922,747.
Office Action-Restriction-mailed Apr. 27, 2012 in co-pending U.S. Appl. No. 12/922,747.
Office Action-Restriction-mailed Jan. 29, 2013 in co-pending U.S. Appl. No. 13/319,175.
Office Action-Restriction-mailed Jul. 11, 2012 in co-pending U.S. Appl. No. 12/991,041.
Office Actions dated Jan. 21, 2009, Apr. 17, 2009, Jul. 10, 2009, Mar. 4, 2010 in co-pending U.S. Appl. No. 10/548,998.
Office Actions dated Jul. 21, 2010 in co-pending U.S. Appl. No. 12/309,061.
Office Actions dated Oct. 19, 2009, Mar. 19, 2010, Jun. 23, 2010, Jul. 7, 2010 in co-pending U.S. Appl. No. 12/322,322.
Pharmaceutical Research, V. 17, No. 5 (2000) pp. 607-611, "Methotrexate Esters of Poly(EthyleneOxide)-Block-Poly(2-Hydroxyethyl-L-Aspartamide). Part I: Effects of the Level of Methotrexate Conjugation on the Stability of Micelles and on Drug Release", Li, et al.
Pharmaceutical Research, V. 17, No. 5 (2000), pp. 607-611, "Methotrexate Esters of Poly (EthyleneOxide)-Block-Poly(2-Hydroxyethyl-L-Aspartamide). Part I: Effects of the Level of Methotrexate Conjugation on the Stability of Micelles and on Drug Release", Li, et al.
Registry Entry for Registry No. 171009-07-07, which entered STN on Dec. 6, 1995, 3 pages.
Registry Entry for Registry No. 171009-07-7, which entered STN on Dec. 6, 1995, 3 pages.
Registry Entry for Registry No. 7689-03-4, which entered STN on Nov. 16, 1984, 3 pages.
Russian Communication dated Apr. 20, 2007 in Russian patent application No. RU2005116309.
Russian communication dated Apr. 20, 2007 in U.S. Pat. No. 7,495,099 (RU2005116309/04).
Russian Communication dated Jun. 27, 2007 in co-pending Russian patent application No. RU2005132309/04.
Russian communication dated Jun. 27, 2007 in co-pending U.S. Appl. No. 10/548,998 (RU2005132309/04).
Russian Communication dated May 16, 2011 in Russian patent application No. RU2008149932/04.
Russian communication, with English translation, dated Jan. 28, 2016 in co-pending Russian patent application No. 2014114264.
Russian Communication, with English translation, dated May 16, 2011 in co-pending foreign patent application No. RU 2008149932/04.
Taiwan Communication, with English translation, dated Jul. 22, 2011 in co-pending Taiwan Patent Application No. 094132581.
Taiwanese Communication dated Dec. 14, 2011 in co-pending Taiwanese patent application No. 094132581.
Taiwanese Communication dated Jul. 22, 2011 in co-pending Taiwanese patent application No. 094132581.
Taiwanese Communication dated Nov. 30, 2006 in Taiwanese patent application No. TW092130275.
Taiwanese communication dated Nov. 30, 2006 in U.S. Pat. No. 7,495,099 (TW092130275).
Taiwanese Communication, with English translation, dated Dec. 14, 2011 in co-pending Taiwanese Application No. 094132581.
Taiwanese communication, with English translation, dated Sep. 10, 2015 in co-pending Taiwanese patent application No. 101133180.
The Merck Index, Fourteenth Edition, 2006, p. 1-16, O'Neil, et al.
Trends in Molecular Medicine vol. 8, No. 4 (Suppl.) 2002; Len Neckers; "Hsp90 inhibitors as novel cancer chemotherapeutic agents".
Trends in Molecular Medicine, vol. 8, No. 4, (Supp.) 2002, p. S55-61, "Hsp90 Inhibitors as Novel Cancer Chemotherapeutic Agents", Neckers.
Written Opinion mailed Dec. 4, 2012 in co-pending PCT application No. PCT/JP2012/072160.

Also Published As

Publication number Publication date
CN101808651A (en) 2010-08-18
EP2206502A4 (en) 2014-01-15
US8703878B2 (en) 2014-04-22
JPWO2009041570A1 (en) 2011-01-27
EP2206502B1 (en) 2018-09-12
JP5349318B2 (en) 2013-11-20
US20100292414A1 (en) 2010-11-18
WO2009041570A1 (en) 2009-04-02
EP2206502A1 (en) 2010-07-14
CN101808651B (en) 2013-03-27

Similar Documents

Publication Publication Date Title
USRE46190E1 (en) High-molecular weight conjugate of steroids
EP1580216B1 (en) High-molecular weight derivatives of camptothecins
EP2258397B1 (en) Polymer conjugate of physiologically active substance
US8323669B2 (en) Polymer conjugate of taxane
US8808749B2 (en) Polymer conjugate of bioactive substance having hydroxy group
US8940332B2 (en) High-molecular weight conjugate of podophyllotoxins
EP2042195A1 (en) Polymer conjugate of combretastatin
CA2816997A1 (en) Novel polymer derivative of cytidine metabolic antagonist
JP2018012694A (en) Rapamycin-bonded block copolymer
JP6851977B2 (en) Polymer derivatives of macrolide immunosuppressants
WO2015002078A1 (en) Novel boronic acid compound preparation
WO2017119272A1 (en) Polymer derivative of macrolide immunosuppressant

Legal Events

Date Code Title Description
FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY