WO2016114397A1 - コンドロイチン硫酸架橋体、並びにこれを含有する組成物、及び眼疾患処置剤 - Google Patents

コンドロイチン硫酸架橋体、並びにこれを含有する組成物、及び眼疾患処置剤 Download PDF

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Publication number
WO2016114397A1
WO2016114397A1 PCT/JP2016/051176 JP2016051176W WO2016114397A1 WO 2016114397 A1 WO2016114397 A1 WO 2016114397A1 JP 2016051176 W JP2016051176 W JP 2016051176W WO 2016114397 A1 WO2016114397 A1 WO 2016114397A1
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Prior art keywords
group
chondroitin sulfate
polyvalent amine
main chain
cross
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English (en)
French (fr)
Japanese (ja)
Inventor
奨 舩山
梨紗 野寺
貴弘 畠中
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Seikagaku Corp
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Seikagaku Corp
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Priority to JP2016533212A priority Critical patent/JP6110037B2/ja
Priority to EP16737468.5A priority patent/EP3246037A4/en
Priority to EP21150701.7A priority patent/EP3831394B1/en
Priority to US15/543,748 priority patent/US10420796B2/en
Publication of WO2016114397A1 publication Critical patent/WO2016114397A1/ja
Anticipated expiration legal-status Critical
Priority to US16/536,779 priority patent/US10716804B2/en
Priority to US16/896,823 priority patent/US11207345B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/738—Cross-linked polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof

Definitions

  • the present invention relates to a chondroitin sulfate crosslinked product, a composition containing the same, and an eye disease treatment agent.
  • Dry eye '' is an international organization, Dry Eye WorkShop (DEWS), that is ⁇ a multifactorial disease of tears and the surface of the eye, resulting in discomfort, with potential damage to the surface of the eye, '' Symptoms such as visual impairment, tear film instability, etc., are associated with increased tear film osmotic pressure and inflammation of the ocular surface ”(The Ocular Surface Vol.5, No.2: 75 -92, 2007).
  • DEWS Dry Eye WorkShop
  • CS chondroitin sulfate
  • CS crosslinked product a CS derivative having a crosslinked structure via a crosslinking group
  • CS crosslinked product WO 91/16881, JP-A-6-73102, Amnon ⁇ Sintov et al., Biomaterials, 16). : 473-478, 1995
  • Rubinstein et al. who tried to produce a CS derivative using 1,12-diaminododecane as a cross-linking agent
  • International Publication No. 91/16881, Amnon Sintov et al., Biomaterials 16: 473-478, 1995.
  • cross-linking is used to change the water-soluble nature of CS into a water-insoluble one and form a film or tablet.
  • an object of the present invention is to provide a CS derivative having a cross-linked structure through a group derived from a polyvalent amine. It is another object of the present invention to provide a composition containing the CS derivative. Another object of the present invention is to provide an eye disease treatment agent and treatment method having a therapeutic effect on corneal epithelial disorder and / or dry eye. The present invention solves at least one or more of these problems.
  • the inventors of the present invention have produced the CS derivative having a cross-linked structure through a group derived from a polyvalent amine for the first time, thereby completing the present invention. Contrary to the conventional knowledge that crosslinking of CS is used to make CS hardly soluble, a composition containing a crosslinked CS can be used unexpectedly in the form of a solution.
  • the present invention has been completed by finding out that it has an excellent therapeutic effect on disorders and / or dry eyes.
  • the present invention includes the following aspects.
  • A3 The chondroitin sulfate derivative according to [A1] or [A2], wherein the crosslinking group is a group derived from a polyvalent amine.
  • the polyvalent amine is a substituted or unsubstituted polyvalent amine having 1 to 20 carbon atoms in the main chain, which may or may not have a hetero atom on the main chain.
  • the chondroitin sulfate derivative according to any one of [A7] The polyvalent amine is a substituted or unsubstituted polyvalent amine having 1 to 20 main chain atoms, which may or may not have a hetero atom on the main chain.
  • the chondroitin sulfate derivative according to any one of [A8] The chondroitin sulfate derivative according to any one of [A3] to [A7], wherein the polyvalent amine is an aliphatic polyvalent amine.
  • [A9] The chondroitin sulfate derivative according to any one of [A3] to [A8], wherein the polyvalent amine is a diamine.
  • the polyvalent amine is ethane-1,2-diamine, 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, 1,6-diaminohexane, 1,8-diamino.
  • the crosslinked structure is represented by the following general formula (I): Y-CO-NH-R-NH-CO-Z (I) (Wherein Y—CO— represents a moiety derived from a constituent disaccharide unit in the chondroitin sulfate molecule, -CO-Z represents a moiety derived from a constituent disaccharide unit of the same or different chondroitin sulfate molecule as described above, R represents a substituted or unsubstituted hydrocarbon group with or without heteroatoms on the main chain; -CO-NH- and -NH-CO- represent an amide bond between the carboxy group of glucuronic acid, which is a constituent sugar of chondroitin sulfate, and the amino group of a polyvalent amine)
  • R represents a substituted or unsubstituted hydrocarbon group having or not having a heteroatom on the main chain;
  • the heteroatom is 1 to 3 atoms selected from the group consisting of nitrogen, oxygen, and sulfur,
  • the substituent is an alkyl group having 1 to 3 carbon atoms, an aminoalkyl group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, an alkyl ester group having 1 to 3 carbon atoms, or 1 carbon atom.
  • the hydrocarbon group is a hydrocarbon group having 1 to 10 carbon atoms in the main chain.
  • [A20] The chondroitin sulfate derivative according to any one of [A11] to [A14], wherein the hydrocarbon group is a hydrocarbon group having 1 to 8 atoms in the main chain.
  • [A21] The chondroitin sulfate derivative according to any one of [A11] to [A20], wherein the hydrocarbon group is an aliphatic hydrocarbon group.
  • [A22] The chondroitin sulfate derivative according to any one of [A1] to [A21], which is water-soluble.
  • a composition comprising the chondroitin sulfate derivative according to any one of [A1] to [A22] and a pharmaceutically acceptable carrier.
  • [A24] The composition according to [A23], which is an aqueous solution.
  • [A25] The composition according to [A23] or [A24], which has a filter passage rate of 80% or more when passed through a porous filter (pore size: 5.0 ⁇ m, diameter: 25 mm) at 25 ° C.
  • [A26] The composition according to any one of [A23] to [A25], which has a viscosity of 5 to 11,000 mPa ⁇ s.
  • [A27] The composition according to any one of [A23] to [A26], wherein the concentration of the chondroitin sulfate derivative is 0.1 to 15% by weight based on the total amount of the composition.
  • [A28] A medicament containing the chondroitin sulfate derivative according to any one of [A1] to [A22].
  • [A29] The composition according to any one of [A23] to [A27], which is an eye disease treatment agent.
  • [A31] The composition according to any one of [A23] to [A27], which is a dry eye treatment agent.
  • An eye disease treatment agent comprising the chondroitin sulfate derivative according to any one of [A1] to [A22] as an active ingredient.
  • [B2] The eye disease treatment agent according to [B1], which is an eye drop.
  • [B3] The eye disease treatment agent according to [B1] or [B2], which is an aqueous eye drop.
  • [B4] The eye disease treatment agent according to any one of [B1] to [B3], which is an aqueous solution.
  • [B5] The eye according to any one of [B1] to [B4], which has a filter passage rate of 80% or more when passed through a porous filter (pore diameter: 5.0 ⁇ m, diameter: 25 mm) at 25 ° C. Disease treatment agent.
  • [B6] The eye disease treatment agent according to any one of [B1] to [B5], wherein the eye disease is corneal epithelial disorder.
  • [B7] The eye disease treatment agent according to any one of [B1] to [B5], wherein the eye disease is dry eye.
  • [B8] The eye disease treatment agent according to any one of [B1] to [B7], wherein the treatment is treatment.
  • [C1] A method for treating an eye disease, comprising administering to the eye the composition according to any one of [A23] to [A27].
  • [C2] The method of [C1], wherein the administration method to the eye is eye drop.
  • [C3] The method according to [C1] or [C2], wherein the composition is an aqueous eye drop.
  • [C4] The method according to any one of [C1] to [C3], wherein the composition is an aqueous solution.
  • the filter passage rate is 80% or more.
  • [C6] The method according to any one of [C1] to [C5], wherein the eye disease is corneal epithelial disorder.
  • [C7] The method according to any one of [C1] to [C5], wherein the eye disease is dry eye.
  • [C8] The method according to any one of [C1] to [C7], wherein the treatment is treatment.
  • a CS derivative having a crosslinked structure through a group derived from a polyvalent amine can be provided.
  • the composition containing the said CS crosslinked body can be provided.
  • an eye disease treatment agent having a therapeutic effect on corneal epithelial disorder and / or dry eye can be provided.
  • a method for treating an eye disease can be provided.
  • the HPLC chart of the digestive liquid by chondroitinase ABC is shown.
  • An example of the result of multistage mass spectrometry is shown.
  • An example of the result of multistage mass spectrometry is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • the average value of the degree of fluorescein staining when the model animal is instilled twice a day is shown.
  • Chondroitin sulfate (also referred to as “CS”) means chondroitin sulfate or a salt thereof.
  • Chodroitin sulfate cross-linked product (also referred to as “CS cross-linked product”) means a CS derivative having a cross-linked structure via a cross-linking group between CS constituent disaccharide units or a salt thereof. The cross-linked structure may exist within the same CS molecule and / or between different CS molecules.
  • substitution means that one or more hydrogen atoms in a compound are replaced with other atoms or atomic groups.
  • the atom or atomic group introduced instead of the hydrogen atom is referred to as “substituent”.
  • Heteroatom means an atom other than carbon and hydrogen contained in a compound, and examples thereof include nitrogen, oxygen, sulfur and the like.
  • “Has a heteroatom” means having 1 or 2 or more heteroatoms, respectively, unless otherwise specified.
  • “Has a heteroatom on the chain” means that at least one carbon atom constituting the chain is replaced with a heteroatom.
  • Carbon chain means an atomic chain composed primarily of carbon, which may optionally be branched and may have heteroatoms on the chain.
  • Reactive functional group means a functional group having the ability to react with the functional group of chondroitin sulfate.
  • Main chain means a straight carbon chain connecting two reactive functional groups unless otherwise specified. When there are three or more reactive functional groups, the longest carbon chain among the carbon chains connecting the reactive functional groups is the main chain. When the carbon chain has a branch, the carbon chain constituting the branch is not included in the main chain unless otherwise specified. The main chain may have 1 or 2 or more heteroatoms except for the position directly bonded to the reactive functional group. When a cyclic structure is present in the carbon chain connecting the reactive functional groups, the cyclic structure has at least one branch and a structure in which at least two of the branched carbon chains share an end point atom.
  • the “number of atoms in the main chain” means the number of atoms constituting the main chain, and when the main chain has a hetero atom, it indicates the number of atoms including the hetero atom.
  • the “main chain” in a polyvalent amine or a group derived from a polyvalent amine means a linear carbon chain connecting two primary amino groups which are reactive functional groups.
  • hydrocarbon refers to a group or compound having carbon and hydrogen, and unless otherwise specified, may have a heteroatom and / or a substituent.
  • the “hydrocarbon” may be linear or branched.
  • Aliphatic means a group or compound having no aromaticity.
  • Cyclic means a group or compound having a cyclic structure in the molecule.
  • Acyclic means a group or compound having no cyclic structure in the molecule.
  • alkyl group refers to a monovalent linear or branched saturated aliphatic hydrocarbon group
  • alkylene group refers to a divalent linear or branched saturated aliphatic hydrocarbon group.
  • alkenylene group refers to a divalent linear or branched unsaturated aliphatic hydrocarbon group having at least one double bond.
  • alkynylene group refers to a divalent linear or branched unsaturated aliphatic hydrocarbon group having at least one triple bond.
  • aryl group refers to a monovalent monocyclic or polycyclic aromatic hydrocarbon group.
  • arylene group refers to a divalent monocyclic or polycyclic aromatic hydrocarbon group.
  • arylalkylene group refers to a divalent group in which one hydrogen atom of an aryl group is substituted with an alkylene group, or a divalent group in which two hydrogen atoms in an aromatic ring are substituted with an alkylene group.
  • Cycloalkyl group refers to a monovalent cycloaliphatic hydrocarbon group.
  • Cycloalkylene group refers to a divalent cyclic aliphatic hydrocarbon group.
  • the “cycloalkylalkylene group” refers to a divalent group in which one hydrogen atom of a cycloalkyl group is substituted with an alkylene group, or a divalent group in which two hydrogen atoms of a cycloalkane are substituted with an alkylene group.
  • Aminoalkyl group refers to a group in which an amino group is substituted on an alkyl group.
  • “Hydroxyalkyl group” refers to a group in which a hydroxy group is substituted on an alkyl group.
  • polyvalent amine means an amine having two or more primary amino groups (—NH 2 ).
  • diamine means an amine having two primary amino groups
  • triamine means an amine having three primary amino groups.
  • aliphatic polyvalent amine means a polyvalent amine in which two or more hydrogen atoms of an aliphatic hydrocarbon are substituted with a primary amino group.
  • “Aromatic polyvalent amine” means a polyvalent amine in which two or more hydrogen atoms of an aromatic hydrocarbon are substituted with a primary amino group or an aminoalkyl group.
  • a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the content of each component in the composition means the total amount of the plurality of substances present in the composition unless there is a specific notice when there are a plurality of substances corresponding to each component in the composition. .
  • the “CS cross-linked product” in the present invention has a cross-linked structure via a cross-linking group between CS constituent disaccharide units, and the cross-linked structure is within the same CS molecule and / or between different CS molecules. May be formed.
  • the CS used as the raw material for the crosslinked CS has a basic skeleton of a disaccharide structure of D-glucuronic acid and N-acetyl-D-galactosamine, and a part of the hydroxy groups of the constituent sugars are mainly sulfated.
  • this CS crosslinked body and CS used as the raw material are in a free state in which no salt is formed, they may form a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt examples include salts with alkali metal ions such as sodium salt and potassium salt, salts with alkaline earth metal ions such as magnesium salt and calcium salt, and the like.
  • the CS crosslinked product in the present invention is preferably a pharmaceutically acceptable salt with an alkali metal ion, and more preferably a sodium salt, from the viewpoint of applicability to a living body and affinity.
  • the CS crosslinked product in the present invention and the CS used for the raw material thereof may take the form of a hydrate or a solvate.
  • the type of CS used for the raw material of the crosslinked CS is not particularly limited, and examples thereof include chondroitin sulfate C (hereinafter also referred to as “CSC”).
  • CSC chondroitin sulfate C
  • the origin of CS used for the raw material of the crosslinked CS is not particularly limited, and any of those derived from natural products and chemically synthesized can be used.
  • the natural product to be used as a raw material can be appropriately selected according to the desired type of CS.
  • a natural product-derived substance may be appropriately modified by a chemical synthesis method to obtain a target CS.
  • the weight average molecular weight of CS used for the raw material of the crosslinked CS is not particularly limited, but is preferably 10,000 to 100,000, more preferably 10,000 to 80,000, and 10,000 to It is more preferably 60,000, particularly preferably 15,000 to 45,000.
  • the weight average molecular weight of CS can be measured by size exclusion chromatography or a conventional method using a light scattering method.
  • a crosslinked CS can be produced by covalently bonding a crosslinking agent to such CS.
  • the “crosslinking group” refers to a group derived from a compound having two or more groups that can be covalently bonded to a group of CS.
  • a compound preferably has at least two groups selected from the group consisting of an amino group, an epoxy group, a vinyl group, and a haloalkyl group.
  • the CS crosslinked product of the present invention it is preferable that these groups are crosslinked.
  • the compound having two or more groups that can be covalently bonded to the group of CS is at least one compound selected from the group consisting of a polyvalent amine, a polyvalent epoxy compound, a polyvalent vinyl compound, and an epihalohydrin. More preferably.
  • the number of carbons of the crosslinking group in the present invention and the number of carbon atoms of the polyvalent amine, polyvalent epoxy compound, polyvalent vinyl compound, and epihalohydrin of the present invention are not particularly limited, but 1 to 20, 1 to 12, 1-10, 1-8, 1-6, 1-4, 2-12, 2-10, 2-8, 2-6, 2-4, 4-12, 4-10, 4-8.
  • the amino group can form an amide bond with the carboxy group of CS.
  • Epoxy groups, vinyl groups, and haloalkyl groups can form ether bonds with the hydroxy groups of CS.
  • the crosslinking group preferably has a group derived from an amino group.
  • a group derived from a divalent amine is particularly preferred.
  • the polyvalent amine is not particularly limited as long as it has two or more primary amino groups (—NH 2 ), and examples thereof include triamine and diamine. From the viewpoint of reducing the diversity of the structure of the CS crosslinked product. A diamine is preferred.
  • the polyvalent amine in the present invention may be a bond that can be degraded in a living body, that is, a polyvalent amine having no biodegradation point.
  • the polyvalent amine in the present invention may be a polyvalent amine having no biodegradation point on the main chain in the molecule.
  • the polyvalent amine in the present invention may be a polyvalent amine having no disulfide bond.
  • the polyvalent amine may be a polyvalent amine having no disulfide bond on the main chain.
  • Examples of the polyvalent amine in the present invention include an aliphatic polyvalent amine and an aromatic polyvalent amine, and among these, an aliphatic polyvalent amine is preferable.
  • the aliphatic polyvalent amine may be either an acyclic aliphatic polyvalent amine or a cycloaliphatic polyvalent amine, but is preferably an acyclic aliphatic polyvalent amine.
  • the aliphatic polyvalent amine may be either a saturated aliphatic polyvalent amine or an unsaturated aliphatic polyvalent amine.
  • the aliphatic polyvalent amine is an acyclic saturated aliphatic polyvalent amine, an acyclic unsaturated aliphatic polyvalent amine, a cyclic saturated aliphatic polyvalent amine, or a cyclic unsaturated aliphatic polyvalent amine. Any of them may be used, but among these, an acyclic saturated aliphatic polyvalent amine is preferable.
  • the same substance as the biological component or a derivative thereof may be a polyvalent amine.
  • the polyvalent amine may be a basic amino acid or a derivative thereof.
  • Examples of the polyvalent amine in the present invention include substituted or unsubstituted aliphatic polyvalent amines and aromatic polyvalent amines having or not having a hetero atom on the main chain.
  • Examples of the substituent in the present invention include an alkyl group, an aminoalkyl group, a hydroxyalkyl group, an alkyl ester group, an alkoxy group, an amino group, a formyl group, a hydroxy group, a carboxy group, and a carbonyl group. When a group containing a reactive functional group such as a group becomes a substituent, the substituent is substituted so as not to constitute the main chain.
  • an alkyl group, an aminoalkyl group, an alkyl ester group, or a hydroxy group is preferable.
  • the alkyl group, aminoalkyl group, hydroxyalkyl group, alkyl ester group, and alkoxy group each independently preferably have 1 to 5 carbon atoms, and more preferably 1 to 3 carbon atoms.
  • the alkyl group is preferably an alkyl group having 1 to 3 carbon atoms, that is, a methyl group, an ethyl group, or a propyl group.
  • an aminoalkyl group an aminomethyl group, an aminoethyl group, or an aminopropyl group is preferable.
  • alkyl ester group examples include a methyl ester group, an ethyl ester group, a propyl ester group, and a butyl ester group, and among them, a methyl ester group or an ethyl ester group is preferable.
  • the number of substituents is not particularly limited, but may be 1 to 5 at a substitutable position, and preferably 1 to 3. When two or more substituents are present, each substituent may be the same or different.
  • the hetero atom in the present invention include nitrogen, oxygen, sulfur and the like. When the main chain has a heteroatom, the number of the heteroatom is not particularly limited, but 1 to 5 or 1 to 3 is exemplified.
  • each heteroatom may be the same or different.
  • they may be positioned so that these heteroatoms are not directly bonded to each other.
  • it may have a hetero atom other than the position directly bonded to the reactive functional group, particularly the primary amino group.
  • the number of carbons in the main chain of the polyvalent amine in the present invention is 1 or more, or 2 or more, and is 20 or less, 12 or less, 10 or less, 8 or less, 6 or less, or 4 or less.
  • the carbon number is, for example, 1-20, 1-12, 1-10, 1-8, 1-6, 1-4, 2-20, 2-12, 2-10, 2-8, 2-6, 2-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
  • the number of carbon atoms in the main chain of the polyvalent amine is preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, and particularly preferably 2 to 4.
  • the number of carbon atoms in the main chain of the polyvalent amine is preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 2 to 5, and more preferably 2 to 4. More preferred.
  • the number of atoms of the main chain of the polyvalent amine in the present invention is 1 or more, or 2 or more, and 20 or less, 12 or less, 11 or less, 10 or less, 8 or less, 6 or less, or 4 or less.
  • the number of atoms is, for example, 1 to 20, 1 to 12, 1 to 11, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 2 to 20, 2 to 12, 2 to 11, 2 to 10, 2-8, 2-6, 2-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
  • the number of atoms in the main chain of the polyvalent amine is preferably 1 to 11, more preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, and more preferably 2 to 4. Particularly preferred.
  • the number of atoms in the main chain of the polyvalent amine is preferably 1 to 11, more preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, and more preferably 2 to 5. More preferably, 2 to 4 is more preferable.
  • the polyvalent amine in the present invention is preferably a triamine or a diamine, and more preferably a diamine.
  • the polyvalent amine in the present invention is preferably an aliphatic diamine or an aromatic diamine, and more preferably an aliphatic diamine.
  • Examples of the aliphatic diamine include acyclic aliphatic diamine or cycloaliphatic diamine, and among them, acyclic aliphatic diamine is preferable.
  • Examples of the cycloaliphatic diamine include cycloalkylenediamine and bis (aminoalkyl) cycloalkane, and examples of the acyclic aliphatic diamine include alkylenediamine, alkenylenediamine, and alkynylenediamine. Among these, alkylene diamine or alkenylene diamine is preferable, and alkylene diamine is particularly preferable.
  • Examples of the aromatic diamine include arylene diamine and bis (aminoalkyl) benzene.
  • polyvalent amine in the present invention examples include ethane-1,2-diamine, 1,3-diaminopropane, 1,4-diaminobutane (putrescine), 1,5-diaminopentane (cadaverine), 1,6 -Diaminohexane, 1,7-diaminoheptane, 1,8-diaminooctane, 1,9-diaminononane, 1,10-diaminodecane, 1,11-diaminoundecane, 1,12-diaminododecane, 1,3-diamino -2-propanol, 2,2'-thiodietaneamine, 2,2'-oxydiethanamine, 1,11-diamino-3,6,9-trioxaundecane, L-lysine ethyl ester, L-ornithine Ethyl ester, N- (2-aminoethyl
  • the polyvalent epoxy compound in the present invention is not particularly limited as long as it has two or more epoxy groups.
  • a diepoxy compound a diglycidyl compound is mentioned, for example.
  • the polyvalent vinyl compound in the present invention is not particularly limited as long as it has two or more vinyl groups.
  • examples of the divinyl compound include divinyl sulfone.
  • examples of the epihalohydrin in the present invention include epichlorohydrin.
  • the “crosslinked structure” means a structure in which the same or different CS molecules are linked by a covalent bond via a crosslinking group.
  • the crosslinking group is a group derived from a polyvalent amine
  • the CS crosslinked product of the present invention has the following general formula (I); Y-CO-NH-R-NH-CO-Z (I) (Wherein Y—CO— represents a moiety derived from a constituent disaccharide unit in the chondroitin sulfate molecule, -CO-Z represents a moiety derived from a constituent disaccharide unit of the same or different chondroitin sulfate molecule as described above, R represents a substituted or unsubstituted hydrocarbon group with or without heteroatoms on the main chain; -CO-NH- and -NH-CO- represent an amide bond between the carboxy group of glucuronic acid, which is a constituent sugar of chondroitin
  • the crosslinking group is a group derived from a polyvalent amine
  • the CS crosslinked product of the present invention has the following general formula (III); Y-CO-NH-R-NH 2 (III) (Wherein Y—CO—, R and —CO—NH— are as defined above for formula (I)).
  • one of the amino groups of the polyvalent amine may be covalently bonded to CS.
  • —NH—R—NH— and —NH—R—NH 2 are groups derived from polyvalent amines.
  • the descriptions, examples, and preferred ranges in the description of the polyvalent amine in the invention can be applied as they are.
  • R in general formulas (I) and (III) may be a substituted or unsubstituted hydrocarbon group with or without heteroatoms on the main chain.
  • the hydrocarbon group here may be an aliphatic hydrocarbon group or an aromatic hydrocarbon group, but is preferably an aliphatic hydrocarbon group.
  • the aliphatic hydrocarbon group may be either an acyclic aliphatic hydrocarbon group or a cyclic aliphatic hydrocarbon group, but is preferably an acyclic aliphatic hydrocarbon group.
  • the aliphatic hydrocarbon group may be either a saturated aliphatic hydrocarbon group or an unsaturated aliphatic hydrocarbon group.
  • the aliphatic hydrocarbon group is an acyclic saturated aliphatic hydrocarbon group, an acyclic unsaturated aliphatic hydrocarbon group, a cyclic saturated aliphatic hydrocarbon group, or a cyclic unsaturated aliphatic hydrocarbon group. Any of them may be used, but among them, an acyclic saturated aliphatic hydrocarbon group is preferable.
  • the acyclic aliphatic hydrocarbon group include an alkylene group, an alkenylene group, and an alkynylene group. Among them, an alkylene group or an alkenylene group is preferable, and an alkylene group is more preferable.
  • Examples of the cycloaliphatic hydrocarbon group include a cycloalkylene group and a cycloalkylalkylene group.
  • Examples of the aromatic hydrocarbon group include an arylene group and an arylalkylene group.
  • R in the general formulas (I) and (III) may be a hydrocarbon group other than an unsubstituted hydrocarbon group having no hetero atom on the main chain.
  • the substituents and heteroatoms in the present invention the description, illustrations, and preferred ranges in the description of the polyvalent amine in the present invention in the above-mentioned ⁇ Bridged group> item can be applied as they are.
  • R in the general formulas (I) and (III) may be a hydrocarbon group having no biodegradation point.
  • the R may be a hydrocarbon group having no biodegradation point on the main chain.
  • the biodegradation point include an ester bond or a thioester bond. That is, R may be a hydrocarbon group having no ester bond or thioester bond on the main chain.
  • R in the general formulas (I) and (III) may be a hydrocarbon group having no disulfide bond.
  • the R may be a hydrocarbon group having no disulfide bond on the main chain.
  • the R may be positioned so that these heteroatoms are not directly bonded to each other.
  • atoms at both ends thereof, that is, atoms bonded to nitrogen atoms may be carbon atoms.
  • the carbon number and the number of atoms of the main chain of R in the general formulas (I) and (III) are the description and illustration regarding the number of carbons and the number of atoms of the main chain of the polyvalent amine in the present invention in the above ⁇ Bridge group> item.
  • the preferred range can be applied as it is.
  • R in the general formulas (I) and (III) is —CH 2 CH 2 — (R 1 —CH 2 CH 2 ) n —.
  • R 1 represents any one of an oxygen atom, a sulfur atom, and —NH, and when n is 2 or more, each R 1 may be the same or different.
  • N represents an integer of 1 to 5, or 1 to 3.
  • R in the general formulas (I) and (III) is — (CH 2 ) 1 — (CR 2 R 3 ) — (CH 2 ) m —.
  • R 2 and R 3 are each independently a hydrogen atom, —OH, —NH 2 , an alkyl group having 1 to 3 carbon atoms, an alkyl ester group, or an aminoalkyl group, and l is 1 to 5 An integer, and m is an integer of 0 to 5.
  • R is represented by the formula — (CH 2 ) 1 — (CR 2 R 3 ) — (CH 2 ) m —, wherein R 2 , R 3 , l and m are as defined above. And when R 2 is a hydrogen atom, R 3 is not a hydrogen atom.
  • R is represented by the formula — (CH 2 ) 1 — (CR 2 R 3 ) — (CH 2 ) m —, wherein R 2 , R 3 and l are as defined above.
  • M is an integer of 1 to 5, and when R 2 is a hydrogen atom, R 3 is not a hydrogen atom.
  • R in the general formulas (I) and (III) is — (CH 2 ) p —CH ⁇ CH— (CH 2 ) q —.
  • p and q are each independently an integer of 0 to 3, or 1 to 2.
  • R in the general formulas (I) and (III) include — (CH 2 ) 2 —, — (CH 2 ) 3 —, — (CH 2 ) 4 —, — (CH 2 ) 5 —, — (CH 2 ) 6 —, — (CH 2 ) 7 —, — (CH 2 ) 8 —, — (CH 2 ) 9 —, — (CH 2 ) 10 —, — (CH 2 ) 11 —, — (CH 2 ) 12 —, —CH 2 CH ⁇ CHCH 2 —, —CH 2 CH (OH) CH 2 —, —CH 2 CH 2 —S—CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2- , —CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH (NH 2 ) CH 2 —, —CH 2 CH 2 CH ( NH 2 ) CH 2 —, —CH
  • a group derived from a polyvalent amine when selected as a crosslinking group, not all of the carboxy groups in CS need to be amide-bonded to the crosslinking group, and a part of them may be amide-bonded.
  • R in the general formula (I) may be a hydrocarbon group having no biodegradation point and / or disulfide bond on the main chain.
  • the CS crosslinked product in the present invention can be produced by covalently bonding two functional groups possessed by CS and two reactive functional groups possessed by a crosslinking agent by a commonly used method.
  • the two functional groups of CS may be the same CS molecule group or different CS molecule groups.
  • a polyfunctional crosslinking agent such as a polyvalent amine, a polyvalent epoxy compound, a polyvalent vinyl compound, or an epihalohydrin may be used. Applicable.
  • the concentration of CS in the solvent when reacting CS with the crosslinking agent is preferably 2 to 20% by weight (hereinafter also referred to as “wt%”), more preferably 2 to 15% by weight, and more preferably 3 to 15% by weight. Is particularly preferred.
  • the solvent at the time of the crosslinking reaction is not particularly limited as long as CS and the crosslinking agent are soluble, but a mixed solvent of water and a water-miscible organic solvent is preferable.
  • the water-miscible organic solvent is not particularly limited, but examples thereof include lower alcohols such as methanol, ethanol, isopropanol, n-propanol and tertiary butanol, glycol ethers such as ethylene glycol monomethyl ether and ethylene glycol monoethyl ether, Acetone, 1,4-dioxane, tedrahydrofuran, and acetonitrile may be mentioned.
  • methanol, ethanol, acetone, tetrahydrofuran, and 1,4-dioxane are preferable.
  • These water-miscible organic solvents may be used alone or in combination of two or more with respect to water.
  • the crosslinking reaction time is not particularly limited, and examples thereof include 1 to 48 hours, 1 to 24 hours, 2 to 20 hours, and all night. In this specification, “all night” means 10 to 24 hours. In addition, you may stop reaction in the middle of a crosslinking reaction by adding 10% sodium carbonate aqueous solution.
  • the temperature during the crosslinking reaction is not particularly limited and is appropriately selected depending on the solvent used, but is preferably 5 to 60 ° C, more preferably 15 to 30 ° C.
  • an alkali treatment step can be appropriately added.
  • the alkali treatment for making the reaction solution after the crosslinking reaction alkaline is not particularly limited as long as the reaction solution is alkalinized. Specifically, it is preferable to use an inorganic base for the alkali treatment, and it is particularly preferable to use sodium hydroxide, sodium bicarbonate, or sodium carbonate. Examples of pH conditions for the alkali treatment include 7.2 to 11, preferably 7.5 to 10.
  • the treatment time with alkali is not particularly limited, but is exemplified by 2 to 12 hours, preferably 2 to 6 hours.
  • the temperature during the alkali treatment is preferably 5 to 60 ° C, more preferably 15 to 30 ° C.
  • a crosslinked CS in a dry powder state is obtained.
  • the stirring step, the precipitation step, the washing step, and the drying step can be carried out by methods generally performed by those skilled in the art, and are not particularly limited.
  • ⁇ Crosslinking method of CS using polyvalent amine as crosslinking agent When a polyvalent amine is used as a crosslinking agent, it can be crosslinked by covalently bonding the carboxy group of CS and the amino group of the crosslinking agent by a commonly used amidation method.
  • Examples of the amidation method in this case include water-soluble carbodiimide (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), dicyclohexylcarbodiimide (DCC), 4- (4,6-dimethoxy) in a solvent.
  • -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride N hydrate (DMT-MM) and the like a symmetric acid anhydride method, a mixed acid anhydride method, An active ester method can be mentioned.
  • the reaction conditions for the amidation method are appropriately selected according to the CS and the crosslinking agent used.
  • the concentration of CS in the solvent is preferably 2 to 20% by weight, more preferably 2 to 15% by weight, and particularly preferably 3 to 15% by weight.
  • the molar equivalent of the polyvalent amine crosslinking agent with respect to CS is preferably 0.005 to 0.500 eq, more preferably 0.005 to 0.300 eq with respect to 1.00 molar equivalent (eq) of CS disaccharide unit. 0.005 to 0.250 eq is more preferable, 0.005 to 0.200 eq is more preferable, and 0.005 to 0.100 eq is particularly preferable.
  • the molar equivalent of the condensing agent with respect to the polyvalent amine crosslinking agent is preferably (0.50 to 5.00) ⁇ valence eq with respect to 1.00 molar equivalent (eq) of the polyvalent amine crosslinking agent, (1 0.000 to 4.00) ⁇ valence eq, more preferably (1.00 to 3.00) ⁇ valence eq.
  • the “valence” means the valence of the polyvalent amine.
  • the solvent during the crosslinking reaction As for the solvent during the crosslinking reaction, the crosslinking reaction time, and the temperature during the crosslinking reaction, the above examples and preferred ranges are applied as they are.
  • the amidation method during the crosslinking reaction, the concentration of CS, the structure of the polyvalent amine crosslinking agent, the addition amount of the crosslinking agent, the addition amount of the condensing agent, and the solvent are appropriately selected depending on the properties required for the CS crosslinked product.
  • CS cross-linked bodies having various structures can be generated depending on the position of the hydroxy group used. For this reason, in order to reduce the diversity of the structure of the CS cross-linked product, it is preferable to select the cross-linking utilizing the carboxy group of CS. That is, a polyvalent amine is preferable as the crosslinking agent in that it forms an amide bond with the carboxy group of CS. In addition, diamine is particularly preferable in order to reduce the diversity of the structure of the crosslinked CS.
  • the crosslinked structure of the CS crosslinked product can be confirmed, for example, by the method described in Example 12A.
  • the crosslinking rate of the crosslinked CS in the present invention means a value expressed as a percentage of the number of crosslinking groups in which two or more functional groups are bonded to CS per CS disaccharide unit.
  • the crosslinking rate of a CS derivative having a crosslinked structure through a group derived from diamine is calculated by the following formula (A).
  • R represents —OH, —OM (M represents a metal element of Group 1 or Group 2 of the periodic table) or a group derived from diamine.)
  • the crosslinking rate of the CS crosslinked product of the present invention is not particularly limited, 0.01% or more, 0.05% or more, 0.1% or more, 0.5% or more, 30% or less, 10% or less, 5% or less 3% or less, 1% or less is exemplified, 0.01 to 30% is preferable, 0.05 to 10% is more preferable, 0.1 to 5% is more preferable, and 0.25 to 4% is more preferable 0.5 to 3% is particularly preferable.
  • the crosslinking rate of a CS derivative having a crosslinked structure via a group derived from diamine can be measured, for example, by the following method. After adding dilute sulfuric acid to the test substance and heating at 60 ° C for 6 hours, basify the resulting solution, add propylene oxide, and heat at 60 ° C overnight. The strongly acidified solution is heated at 110 ° C. overnight, the resulting solution is made basic, the amino group of the crosslinking group is labeled with phenyl isothiocyanate, and the labeled crosslinking group is converted to LC / Quantify by MS. Then, the number of moles of crosslinking groups relative to the number of moles of CS disaccharide units is calculated as a percentage.
  • ⁇ Pharmaceutically acceptable carrier examples include physiological saline, phosphate buffered saline, purified water, and water for injection.
  • conventionally used additives such as pH adjusters, buffers, isotonic agents, stabilizers, preservatives and the like may be used as appropriate.
  • the additive include sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, monopotassium hydrogen phosphate, sodium edetate, benzalkonium chloride, and the like.
  • composition containing the CS crosslinked product of the present invention (also referred to as “the composition of the present invention”) is not particularly limited.
  • the CS crosslinked product of the present invention is combined with a pharmaceutically acceptable carrier. It can be prepared by mixing and shaking on a shaker for 4-24 hours or longer.
  • the composition containing the CS crosslinked product of the present invention is preferably in a liquid state, and more preferably an aqueous solution in that it is considered that the solute is sufficiently finely dispersed in the solvent.
  • the “aqueous solution” in the present specification refers to a composition having water as a medium and having a clear property (hereinafter also referred to as “solution state”).
  • the solution state can be determined by a “solution state confirmation test” described later.
  • the composition of the present invention is preferably an aqueous solution.
  • composition using water as a medium include a composition obtained by mixing the crosslinked CS of the present invention with physiological saline, phosphate buffered saline, purified water, or water for injection.
  • the CS crosslinked product of the present invention is preferably water-soluble. Whether or not the CS crosslinked product is water-soluble can be determined by a “water solubility confirmation test” described later.
  • the composition containing the CS crosslinked product of the present invention preferably has a filter passage rate of the CS crosslinked product of 50% or more, more preferably 60% or more, and more preferably 70% or more, It is more preferably 80% or more, and particularly preferably 85% or more.
  • the viscosity of the composition containing the crosslinked CS of the present invention may be 5 to 11,000, 10 to 5,000, 20 to 1,000, 30 to 300, or 30 to 250 mPa ⁇ s.
  • the concentration of the crosslinked CS in the composition containing the crosslinked CS of the present invention is 0.1 to 15% by weight, 0.3 to 13% by weight, or 1 to 10% by weight based on the total amount of the composition. It may be.
  • ⁇ Solution confirmation test> The absorbance at 600 nm of the prepared composition is measured using an ultraviolet-visible spectrophotometer (UV-1800, manufactured by Shimadzu Corporation). When the absorbance value is 0.1 or less, the solution is determined to be “clear”, and when it exceeds 0.1, “white turbidity” is determined.
  • UV-1800 ultraviolet-visible spectrophotometer
  • CS crosslinked product is dissolved in water or PBS so that the concentration becomes 2.0% (w / w), and the absorbance of the composition at 600 nm is measured with an ultraviolet-visible spectrophotometer (UV-1800, Shimadzu Corporation). To make measurements. When the absorbance value is 0.1 or less, the CS crosslinked product is determined to be “water-soluble”.
  • CS concentration CS disaccharide unit equivalent concentration
  • the “filter pass rate” in this specification is calculated by the following formula (B) as measured by the carbazole sulfate method.
  • the pressure when passing through the filter is 5.3 kgf / cm 2 or less. For example, when the CS concentration in the sample before passing through the filter is 1.00% and the CS concentration in the sample after passing through the filter is 0.90%, the filter passing rate is 90%.
  • CS concentration (mol / L) is calculated from the following formula (C) from the carbazole sulfate method using a 20.0 ⁇ g / mL aqueous solution of D-glucuronolactone (molecular weight: 176.12) as a standard product.
  • OD530 represents the optical density at a wavelength of 530 nm
  • the CS cross-linked product of the present invention and the composition of the present invention can be used as a medicine, an eye disease treatment agent and the like. That is, the CS cross-linked product of the present invention can be used as an active ingredient of a pharmaceutical agent or an eye disease treating agent.
  • the eye disease treatment agent of the present invention is an eye disease treatment agent containing the crosslinked CS of the present invention as an active ingredient.
  • the crosslinked CS include the crosslinked CS described earlier in this specification, and in particular, the CS derivatives of the above-described embodiments as any of [A1] to [A22].
  • the “eye disease” in the present specification is not particularly limited as long as it is any abnormality in the anterior segment.
  • the anterior ocular segments the ocular surface is preferable, the cornea is more preferable, and the corneal epithelium is particularly preferable.
  • the “anterior segment” in the present specification includes tear fluid.
  • corneal epithelial disorder corneal epithelial disorder, tear film abnormality, or dry eye is preferable, and corneal epithelial disorder or dry eye is particularly preferable.
  • dry eye may be both dry eye disease and / or dry eye syndrome.
  • Abnormal tear film means that the tear film is broken or that the tear film is prone to breakage. The definition of dry eye by DEWS (The Ocular Surface Vol.5, No. 2) : 75-92, 2007), which means that the tear film is unstable.
  • causes of abnormalities in the tear film include increased tear evaporation and decreased tear fluid. Abnormalities in the tear film can also be evaluated using the Schirmer method, tear film breakage time (BUT), corneal spherical surface irregularity index (SRI), and the like.
  • corneal epithelial disorder is not particularly limited as long as it is a disorder that occurs in the corneal epithelium.
  • examples include corneal epithelial defect, corneal epithelial erosion, corneal ulcer, corneal perforation, and the like, including corneal epithelial disorders due to punctate superficial keratopathy, keratitis, and the like.
  • corneal epithelial disorder associated with endogenous diseases such as dry eye, Sjogren's syndrome, Stevens-Johnson syndrome, or corneal epithelium associated with extrinsic diseases such as contact lens wearing, trauma, surgery, infectivity, and drug properties. Includes obstacles.
  • corneal epithelial disorder associated with dry eye is preferable.
  • Treatment in this specification includes treatment. “Treatment” includes improving, healing, and promoting healing. That is, the “treatment agent” includes a therapeutic agent, and the “therapeutic agent” includes an improving agent and a healing promoter. In the present specification, treating a tear film abnormality is also referred to as “tear layer stabilization”.
  • the “eye disease treatment agent” is preferably a treatment agent for abnormalities in the anterior segment of the eye, especially abnormalities in the ocular surface or tears.
  • a corneal epithelial disorder treatment agent, a tear film stabilizer, and a dry eye treatment agent are exemplified.
  • the dosage form of the eye disease treatment agent (hereinafter, also referred to as “the agent of the present invention”) containing the CS crosslinked product of the present invention as an active ingredient is not particularly limited, and examples thereof include eye drops and eye ointments. Agents, creams, lotions, and the like. Among them, eye drops are preferable, and aqueous eye drops are particularly preferable.
  • the “aqueous eye drop” means an eye drop containing 50% by weight or more of water. As the aqueous eye drop of the present invention, an eye drop containing 80% by weight or more of water is preferable, and an eye drop containing 90% by weight or more is more preferable.
  • the water contained in the aqueous eye drop of the present invention may be pharmaceutically or physiologically acceptable.
  • distilled water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like can be used. These definitions are based on the 16th revised Japanese Pharmacopoeia. Saline, phosphate buffered saline and the like may be used, and appropriately used commonly used additives such as pH adjusters, buffers, isotonic agents, stabilizers, preservatives and the like. It's okay.
  • the additive examples include sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, monopotassium hydrogen phosphate, sodium edetate, benzalkonium chloride, and the like.
  • the pH and osmotic pressure ratio of the eye drops are not particularly limited as long as they are within the range acceptable for ophthalmic preparations.
  • the agent of the present invention may not contain hyaluronic acid.
  • the agent of the present invention is preferably in the form of a liquid, and more preferably an aqueous solution in that it is considered that the solute is sufficiently finely dispersed and homogeneously dispersed in the solvent.
  • the agent of the present invention is an aqueous solution because the presence of an insoluble substance may lead to a foreign body sensation.
  • the agent of the present invention preferably has a CS cross-linked product having a filter passage rate of 60% or more, more preferably 70% or more, more preferably 80% or more, and particularly preferably 85% or more.
  • the concentration of the cross-linked CS contained in the agent of the present invention is not particularly limited, but may be an effective concentration exhibiting a desired medicinal effect, 0.01 to 20% by weight, 0.1 to 15% by weight, 0.3% ⁇ 10% by weight is exemplified.
  • the subject of application of the agent of the present invention is preferably a mammal.
  • mammals include, but are not limited to, humans, horses, cows, dogs, cats, rabbits, hamsters, guinea pigs, mice, and the like.
  • the agent of the present invention can be a human or veterinary drug, and is preferably a human drug.
  • the dosage of the agent of the present invention can be appropriately changed according to the severity of the patient's symptoms, age, weight, doctor's judgment and the like.
  • the number of administrations per day and the administration period of the agent of the present invention are not particularly limited. Examples of the number of administrations per day include 1 to 8 times, 1 to 6 times, 1 to 4 times, 1 to 3 times, 1 or 2 times, and may be “adjustable as appropriate”.
  • the administration period is not particularly limited, and examples include one week to several months. Moreover, daily administration is preferable. Examples of eye drops include 1 to 2 drops at a time, or 1 to 3 drops at a time.
  • 1 to 3 drops per day 1 to 8 drops per day, 1 to 3 drops per day, 1 to 6 drops per day, 1 to 3 drops per day, 1 to 4 drops per day, 1 time per day Illustrated are 1 to 3 drops of 1 to 3 drops per day, 1 to 3 drops of 1 to 2 drops per day, and these daily drops.
  • the agent of the present invention can be used by administering it to human or animal eyes.
  • Administration of the agent of the present invention to human or animal eyes is not particularly limited as long as it is carried out in a medically acceptable manner and can exhibit the effects of the present invention.
  • the specific method of administration is not particularly limited, and may be appropriately administered according to the dosage form or formulation, but eye drops can be preferably exemplified.
  • the treatment method of the present invention is an ophthalmic disease treatment method comprising administering an agent of the present invention or a composition containing a crosslinked CS of the present invention to the eyes of a human or an animal.
  • the treatment method of the present invention can be carried out in the same manner according to the explanations of ⁇ Application object>, ⁇ Dosage and administration>, ⁇ Method of using the agent of the present invention> and the like.
  • Example 1 Production of cross-linked CS-NC2N
  • Representative example CS CSC, extraordinary sodium chondroitin sulfate, weight average molecular weight 40,000, Seikagaku Corporation
  • 2.00 g 3.91 mmol of disaccharide units [calculated assuming the average molecular weight of disaccharide units as 511], 1.00 eq) was dissolved in water for injection (WFI) to a concentration of 10%, and 20.0 mL of ethanol (EtOH) was mixed.
  • WFI water for injection
  • EtOH ethanol
  • Ethanol-1,2-diamine dihydrochloride (NC2N ⁇ 2HCl, Wako Pure Chemical Industries, Ltd.) 10.4 mg (0.0783 mmol, 0.0200 eq) 50% ethanol solution as a cross-linking agent and DMT-MM as a condensing agent (TRIAZIMOCH, Tokuyama Corporation) 86.6 mg (0.313 mmol, 0.0800 eq) in 50% ethanol solution (4.00 mL) was successively added dropwise and stirred overnight at room temperature (crosslinking reaction). 20 mL of 10% aqueous sodium carbonate solution (Na2CO3 / WFI) was added and stirred vigorously for 2-4 hours.
  • Na2CO3 / WFI 10% aqueous sodium carbonate solution
  • Example 2 Production of cross-linked CS-NC2N
  • 10 g Scale CS amount is 10 g
  • the molar equivalent of NC2N ⁇ 2HCl is 0.020 eq
  • the molar equivalent of DMT-MM is 0.080 eq.
  • 8.94 g of CS-NC2N crosslinked product, compound 9 was obtained as a white powder.
  • B Example 1 (A) except that the amount of 20 g scale CS was 20 g, the molar equivalent of NC2N ⁇ 2HCl was 0.02375 eq, the molar equivalent of DMT-MM was 0.0950 eq, and the crosslinking reaction time was 3 hours 46 minutes.
  • 19.1 g of a CS crosslinked product (CS-NC2N crosslinked product, Compound 10) was obtained as a white powder.
  • Example 3 Production of CS-NC3N cross-linked product 1g of CS amount, 1,3-diaminopropane dihydrochloride (NC3N ⁇ 2HCl, Tokyo Chemical Industry Co., Ltd.) as the cross-linking agent (molar equivalents are 0.0150, 0.0200, 0.0300, 0.0400eq) Except that the molar equivalent of DMT-MM was 0.0600, 0.0800, 0.120, 0.160 eq, the CS crosslinked product (CS-NC3N crosslinked compound, compounds 11 to 14) was white in the same manner as in Example 1 (A). Obtained as a powder (approximately 0.84 g each).
  • Example 4 Production of CS-NC4N crosslinked product 4g CS amount, 1,4-diaminobutane dihydrochloride (NC4N ⁇ 2HCl, Wako Pure Chemical Industries, Ltd.) (molar equivalent is 0.0300, 0.0425, 0.0450, 0.0475eq) ), Except that the molar equivalents of DMT-MM were changed to 0.120, 0.170, 0.180, 0.190 eq, and the CS crosslinked product (CS-NC4N crosslinked product, compounds 15 to 18) was obtained in the same manner as in Example 1 (A). Obtained as a white powder (about 3.85 g each).
  • Example 5 Production of CS-NC5N crosslinked product 1g CS amount, 1,5-diaminopentane dihydrochloride (NC5N ⁇ 2HCl, Tokyo Chemical Industry Co., Ltd.) (molar equivalent is 0.0250, 0.0350, 0.0450, 0.0550eq)
  • NMT-MM 1,5-diaminopentane dihydrochloride
  • Example 6 Production of CS-NC6N crosslinked product 4g CS amount, 1,6-diaminohexane dihydrochloride (NC6N ⁇ 2HCl, Wako Pure Chemical Industries, Ltd.) as a crosslinking agent (molar equivalents are 0.0400, 0.0525, 0.0550, 0.0575eq) ), Except that the molar equivalents of DMT-MM were changed to 0.160, 0.210, 0.220, 0.230 eq, and the CS crosslinked product (CS-NC6N crosslinked product, compounds 23 to 26) was obtained in the same manner as in Example 1 (A). Obtained as a white powder (about 3.83 g each).
  • Example 7 Production of CS-NC8N cross-linked product 4g of CS, 1,8-diaminooctane dihydrochloride (NC8N ⁇ 2HCl, 1,8-diaminooctane [Wako Pure Chemical Industries, Ltd.]) and 2N of 1N hydrochloric acid Example 1 (A) except that the molar equivalent was 0.0500, 0.0650, 0.0700, 0.0725 eq) and the molar equivalent of DMT-MM was 0.200, 0.260, 0.280, 0.290 eq.
  • a CS crosslinked product (CS-NC8N crosslinked product, compounds 27 to 30) was obtained as a white powder (about 3.88 g each).
  • Example 8 Production of CS-NC12N cross-linked product 1 g of CS, 1,12-diaminododecane dihydrochloride (NC12N ⁇ 2HCl, 1,12-diaminododecane [Sigma-Aldrich]) as the cross-linking agent and 2.00 eq of 1N hydrochloric acid (The molar equivalent was 0.0550, 0.0700 eq), and the DMT-MM molar equivalent was changed to 0.220, 0.280 eq, in the same manner as in Example 1 (A). (CS-NC12N crosslinked product, compounds 31 and 32) were obtained as white powder (about 0.82 g each).
  • Example 9 Production of CS-LysEt cross-linked product 1 g of CS, cross-linking agent L-lysine ethyl ester dihydrochloride (LysEt ⁇ 2HCl, Sigma-Aldrich) (molar equivalent is 0.0450 eq), molar equivalent of DMT-MM is 0.180
  • the cross-linking reaction time was 2 hours, 3 hours, 3 hours 40 minutes, 4 hours 20 minutes, 5 hours, 5 hours 50 minutes.
  • a cross-linked product (CS-LysEt cross-linked product, compounds 33 to 38) was obtained as a white powder (each about 1.04 g).
  • Example 10 Production of CS-OrnEt cross-linked product 2 g of CS, ornithine ethyl ester dihydrochloride (OrnEt ⁇ 2HCl, Chem-Impex International) (molar equivalent is 0.0200, 0.0300, 0.0325, 0.0350 eq), DMT- A CS crosslinked product (CS-OrnEt crosslinked product, compounds 39 to 42) was obtained as a white powder in the same manner as in Example 1 (A) except that the molar equivalent of MM was changed to 0.0800, 0.120, 0.130, 0.140 eq. (About 1.99 g each).
  • Example 11 Production of CS-Spermidine cross-linked product 1 or 2 g of CS, spermidine trihydrochloride (Spermidine 3HCl, Sigma-Aldrich) (molar equivalent is 0.0100, 0.0200, 0.0220 eq)
  • a CS cross-linked product (CS-Spermidine cross-linked product, compounds 43, 44 and 67) was obtained as a white powder in the same manner as in Example 1 (A) except that the equivalent weight was changed to 0.0400, 0.0800, 0.0880 eq (respectively, respectively) About 0.77, 0.77, and 1.75 g).
  • Example A1 Production of CS-triAmine cross-linked product 2 g of CS, and 2- (aminomethyl) -2-methylpropane-1,3-diamine ⁇ 3 hydrochloride (triAmine ⁇ 3HCl, Aldrich) as the cross-linking agent (molar equivalent is 0.0091) , 0.0092, 0.0097 eq), and a cross-linked CS product (CS-triAmine cross-linked product, compound 48-) in the same manner as in Example 1 (A) except that the molar equivalent of DMT-MM was changed to 0.0364, 0.0368, 0.0388 eq. 50) as a white powder (about 1.74 g each).
  • Example A2 Production of CS-NC3 (OH) N crosslinked product 2g CS amount, 1,3-diamino-2-propanol dihydrochloride as the cross-linking agent (NC3 (OH) N ⁇ 2HCl, 1,3-diamino-2-propanol Prepared by adding 2.00 eq of 1N hydrochloric acid to [Aldrich] (molar equivalents are 0.0220, 0.0240, 0.0260 eq) and DMT-MM molar equivalents were 0.0880, 0.0960, 0.1040 eq.
  • a CS crosslinked product (CS-NC3 (OH) N crosslinked product, compounds 51 to 53) was obtained as a white powder (about 1.75 g each).
  • Example A3 Production of CS-NC4 ( ) N crosslinked body
  • the amount of CS is 2 g
  • Example A4 Production of CS-Xylylene crosslinked body Add 2.00 eq of 1N hydrochloric acid to 2 g of CS, 1,4-bis (aminomethyl) benzene dihydrochloride (Xylylene ⁇ 2HCl, 1,4-bis (aminomethyl) benzene [Aldrich] as the cross-linking agent (The molar equivalent was 0.0135, 0.0145, 0.0150 eq), and the CS crosslinking was carried out in the same manner as in Example 1 (A) except that the molar equivalent of DMT-MM was 0.0540, 0.0580, 0.0600 eq.
  • the product (CS-Xylylene crosslinked product, compounds 56 to 58) was obtained as a white powder (about 1.77 g each).
  • Example A5 Production of cross-linked CS-Cyclohex CS amount 2g, crosslinker 1,4-bis (aminomethyl) cyclohexane dihydrochloride (Cyclohex ⁇ 2HCl, 1,4-bis (aminomethyl) cyclohexane [Kanto Chemical Co., Ltd.], 1N hydrochloric acid 2.00eq (The molar equivalent was 0.0410, 0.0425 eq), and the molar equivalent of DMT-MM was changed to 0.1640, 0.1700 eq in the same manner as in Example 1 (A), except that the crosslinked CS (CS -Cyclohex cross-linked products, compounds 59 and 60) were obtained as white powders (about 1.80 g each).
  • Example A6 Production of crosslinked CS-NC5 (S) N 2g of CS, 2,2'-thiodietaneamine dihydrochloride (NC5 (S) N ⁇ 2HCl, 2,2'-thiodiethanamine [Tokyo Kasei Co., Ltd.] and 1N hydrochloric acid to 2.00 prepared by adding eq) (molar equivalent is 0.0170, 0.0180 eq), and CS crosslinked product in the same manner as in Example 1 (A) except that the molar equivalent of DMT-MM is 0.0680, 0.0720 eq. (Cs-NC5 (S) N crosslinked product, compounds 61 and 62) were obtained as white powder (about 1.77 g each).
  • Example A7 Production of CS-Glycol (C5) crosslinked product 2 g of CS and 2,2′-oxydiethanamine dihydrochloride (Glycol (C5) ⁇ 2HCl, Wako Pure Chemical Industries) (molar equivalent is 0.0290) , 0.0310eq), and a cross-linked CS (CS-Glycol (C5) cross-linked compound, compounds 63 and 64) in the same manner as in Example 1 (A) except that the molar equivalents of DMT-MM were 0.1160 and 0.1240 eq. ) As a white powder (about 1.76 g each).
  • a CS cross-linked product (CS-Glycol (C11) cross-linked product, compounds 65 and 66) was obtained as a white powder in the same manner as in Example 1 (A) except that eq was used (each about 1.87 g).
  • Comparative Example 1 Production of CS-NC12N Derivative (Comparative Example) A powder of CS derivative modified with 1,12-diaminododecane was produced by the following procedure. In addition, according to the literature from which this production method is cited, the modification is aimed at reducing the hydrophilicity of CS. 1.00 g of chondroitin sulfate A (CSA, Sigma-Aldrich) according to the method described in Example 5 of WO 91/16881, “A. Modification of Chondroitin” and Biomaterials, 16: 473-478, 1995.
  • CSA chondroitin sulfate A
  • Tables 1 to 4 show a list of compounds produced in the above examples and comparative examples.
  • Example 12A Analysis (confirmation of cross-linked structure) Analysis of the CS-NC12N derivative produced by the method described in WO 91/16881 revealed no cross-linking of CS using various analytical methods (C. Bourie, et al. , J. Biomater. Appl., 12, (1998), 201-221). Therefore, in order to verify the crosslinking of the CS crosslinked product of the present invention, the enzyme digest of the CS crosslinked product of the present invention was analyzed by liquid chromatography (HPLC) / multistage mass spectrometry.
  • HPLC liquid chromatography
  • CS CSC, external standard chondroitin sulfate, weight average molecular weight 40,000, Seikagaku Corporation
  • CS-NC2N cross-linked product compound 9
  • Method 1 Enzymatic digestion of CS and CS-NC2N cross-linked product and 20 ⁇ L each of 1% w / v aqueous solution of CS-NC2N cross-linked product in 50 mM Tris-HCl buffer (pH 7.5) -0.1% BSA solution 10 ⁇ L of diluted chondroitinase ABC (C-ABC) (Seikagaku Corporation) (50 U / mL) was added. The reaction solution was heated at 37 ° C.
  • C-ABC diluted chondroitinase ABC
  • C-ABC digested liquid was analyzed with 20 mM aqueous ammonium formate solution (Solvent A) and acetonitrile (Solvent B) (Detect: 232 nm and MS).
  • the ESI-MS was operated with an interface voltage of ⁇ 3.5 kV, a CDL temperature of 200 ° C. and a heat block temperature, respectively.
  • the operation was performed with the flow rate of 10 ⁇ L / h, the interface voltage of ⁇ 1.5 kV, the CDL temperature of 200 ° C., and the heat block temperature.
  • Example 12B Measurement of cross-linking ratio A part of the sample prepared in Examples 1 and 2 was weighed, 10 mg was added, and 1 mL of 20 mM sulfuric acid was added to perform deaeration and dissolution. The resulting solution was heated at 60 ° C. for 6 hours and then made basic, ethanol and propylene oxide were added, and the mixture was heated at 60 ° C. overnight. After acidifying the cooled solution, the solution was evaporated to dryness. Diaminobutane was added thereto as an internal standard, 6M hydrochloric acid was further added, and the resulting solution was heated at 110 ° C. overnight.
  • Example 13 Preparation of Composition Containing CS Crosslinker
  • PBS phosphate buffered saline solution
  • Each sample of the cross-linked product was mixed with the PBS so as to have the concentrations shown in Tables 7, 8 and 9, and each sample was prepared by shaking with a shaker overnight (Samples 1 to 43, Samples 55 to 71, and Samples 75-77). Thereafter, the absorbance at 600 nm of some samples was measured using an ultraviolet-visible spectrophotometer (UV-1800, manufactured by Shimadzu Corporation). The results are shown in Tables 7, 8 and 9.
  • Comparative Example 2 Preparation of a composition containing CS Using CS (CSC [Seikagaku Corporation] and CSA [Sigma-Aldrich]), the concentrations shown in Table 10 are obtained according to the method of Example 13. Each sample was prepared (Samples 47-54). Thereafter, the absorbance of the sample 53 at 600 nm was measured using an ultraviolet-visible spectrophotometer (UV-1800, manufactured by Shimadzu Corporation). The results are shown in Table 10.
  • Comparative Example 3 Preparation of Composition Containing CS-NC12N Derivative (Comparative Example) Using the CS-NC12N derivative (Comparative Example) produced in Comparative Example 1, the concentrations shown in Table 8 are obtained according to the method of Example 13. Each sample was prepared as described above (Samples 44 to 46, 72 to 74). Thereafter, the absorbance at 600 nm was measured for each sample using an ultraviolet-visible spectrophotometer (UV-1800, manufactured by Shimadzu Corporation). The results are shown in Table 8.
  • Example 14 Viscosity measurement of each sample About the sample prepared in Example 13 and Comparative Example 2, E type rotational viscometer (TV-L / H, Toki Sangyo Co., Ltd.), standard cone (CORD-1, 1 ° 34'xR24) was used to measure the value of 5 rpm at 25 ° C. to obtain the viscosity (mPa ⁇ s). When the 5 rpm value was out of the detection range, an extrapolated value was calculated from the other rotational speed, and was used as the viscosity (mPa ⁇ s). The results are shown in Tables 7-10.
  • Example 15 Filter permeability test Some of the samples prepared in Example 13 were equipped with a porous filter (pore size 5.0 ⁇ m, diameter 25 mm, Millex (registered trademark) -SV 5.00 ⁇ m (Millipore Ireland)). The 1 mL syringe (SS-01T, Terumo) was filled. Under the condition of 25 ° C., the sample was extruded with a piston at a pressure of 5.3 kgf / cm 2 or less and passed through a filter.
  • a porous filter pore size 5.0 ⁇ m, diameter 25 mm, Millex (registered trademark) -SV 5.00 ⁇ m (Millipore Ireland)
  • the 1 mL syringe (SS-01T, Terumo) was filled. Under the condition of 25 ° C., the sample was extruded with a piston at a pressure of 5.3 kgf / cm 2 or less and passed through a filter.
  • the CS concentration of the sample before passing through the filter and the sample passing through the filter after passing 0.5 mL or more were measured by the carbazole sulfate method using a 20.0 ⁇ g / mL aqueous solution of D-glucuronolactone as a standard product. From this value, the ratio of the CS concentration after passing to the CS concentration before passing was calculated, and the filter passing rate was calculated. The results are shown in Table 11.
  • Example 16 Verification of corneal epithelial disorder healing promotion effect of CS cross-linked body (1) Using a SD rat (Nippon Charles River Co., Ltd.), a dry eye model was prepared according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci. 42 (1): 96-100 (2001)). After creating the model, the test substance was instilled to verify the corneal epithelial disorder healing promoting effect.
  • CS CSC, external standard chondroitin sulfate, weight average molecular weight 40,000, Seikagaku Corporation
  • test substances were prepared by mixing and shaking on a shaker overnight.
  • the degree of staining with fluorescein was scored according to the following criteria for each of the upper part, middle part, and lower part of the corneal epithelium, and the total score of each part was calculated. Individuals with an average score of 5 or more in both eyes were instilled with 5 ⁇ L of each test substance twice a day for 3 weeks. The same operation as described above was performed using PBS as a control.
  • Table 12 and FIG. 4 show the transition and average value of scores after 1, 2, and 3 weeks after instillation.
  • the 2% CS-NC2N cross-linked product, 2% CS-NC4N cross-linked product, and 2% CS-OrnEt cross-linked product exhibited a significant corneal epithelial disorder healing promoting effect on PBS. Further, the 2% CS-NC2N cross-linked product and the 2% CS-NC4N cross-linked product showed a significant corneal epithelial disorder healing promoting effect on 2% CS.
  • Example 17 Verification of corneal epithelial disorder healing promotion effect of CS cross-linked body (2) According to the method of Example 16, the corneal epithelial disorder healing promoting effect was verified.
  • a test substance was prepared by mixing Compound 49 or Compound 52 with PBS so that the concentration of the CS cross-linked product was 2% and shaking with a shaker overnight.
  • 2% CS-triAmine cross-linked product and 2% CS-NC3 (OH) N cross-linked product were used as test substances, and PBS was used as a control (Example 17A).
  • Compound 55 or Compound 60 was mixed with PBS to prepare a test substance.
  • Example 18 Verification of corneal epithelial disorder healing promotion effect of cross-linked CS (3) According to the method of Example 16, the corneal epithelial disorder healing promoting effect was verified.
  • a test substance was prepared by mixing Compound 26, Compound 62, Compound 64, Compound 66, or Compound 67 with PBS so that the concentration of the CS cross-linked product was 2% and shaking with a shaker overnight.
  • Example 18D ⁇ Test results> Table 15 and FIG. 7 (Example 18A), Table 16 and FIG. 8 (Example 18B), Table 17 and FIG. 9 (Example 18C) are shown in FIG. The results are shown in Table 18 and FIG. 10 (Example 18D).
  • the CS crosslinked product of the present invention can be used as a therapeutic agent for eye diseases, in particular, a therapeutic agent for corneal epithelial disorder and / or a therapeutic agent for dry eye.
  • the CS crosslinked product of the present invention and a composition containing the CS crosslinked product can be industrially utilized as an eye disease treatment agent, and the method of the present invention can be industrially utilized as a treatment method for eye diseases.

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PCT/JP2016/051176 2015-01-16 2016-01-15 コンドロイチン硫酸架橋体、並びにこれを含有する組成物、及び眼疾患処置剤 Ceased WO2016114397A1 (ja)

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EP16737468.5A EP3246037A4 (en) 2015-01-16 2016-01-15 Crosslinked chondroitin sulfate, composition containing same, and treatment agent for eye disease
EP21150701.7A EP3831394B1 (en) 2015-01-16 2016-01-15 Cross-linked chondroitin sulfate, composition containing same, and treatment agent for eye disease
US15/543,748 US10420796B2 (en) 2015-01-16 2016-01-15 Crosslinked chondroitin sulfate, composition containing same, and treatment agent for eye disease
US16/536,779 US10716804B2 (en) 2015-01-16 2019-08-09 Crosslinked chondroitin sulfate, composition containing same, and treatment agent for eye disease
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US12310981B2 (en) 2021-05-10 2025-05-27 Surface Ophthalmics, Inc. Use of chondroitin sulfate for relieving ocular pain
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