JP2022191362A - Biocompatible medical material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a biocompatible medical material superior in sustained release of inclusion, shape retention of a formed particle, hemolysis-resistance and releasability out of the body.

SOLUTION: A biocompatible medical material contains a biocompatible polymer having a weight-average molecular weight of 1000-90000, including a group represented by the formula: -COOM (M is a hydrogen atom or an alkali metal atom), a hydroxy group, an allyl group, an epoxy group, an aldehyde group or an amino group in at least one molecular end, and formed by the polymerization of a biocompatible monomer, where glycerol methacrylate is used as the biocompatible monomer.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention relates to biocompatible medical materials. More particularly, the present invention relates to a biocompatible medical material useful as a pharmaceutical carrier, coating agent, etc. for holding a drug and introducing it into the body orally or via blood. The biocompatible medical material of the present invention is expected to be used, for example, as a carrier for injectable drugs, a carrier for orally administered drugs, and the like.

As a biocompatible material that does not cause a biological defense reaction when it enters the living body, it has a synthetic polymer compound on the surface that has a repeating unit composed of alkoxyalkyl (meth)acrylate as a constituent, and comes into contact with living tissue or body fluids. Biocompatible medical material used for the purpose (see, for example, Patent Document 1), a polymer synthesized by anionic polymerization from alkoxyalkyl (meth)acrylate, the ratio of the weight average molecular weight to the number average molecular weight (weight average molecular weight / number average molecular weight) of 1.0 to 1.5 and a weight average molecular weight of 40,000 or more (see, for example, Patent Document 2). Both the biocompatible medical material and the biocompatible material can be used for medical devices that come into contact with blood or living tissue. It is not suitable as a carrier for introduction into the body orally or via blood.

As a composite material (conjugate) containing a bioactive agent, a conjugate in which a bioactive agent or a diagnostic agent is linked to an initiator fragment or a terminal group of a polymer arm has been proposed (see, for example, Patent Document 3). . However, the conjugate has a drawback of poor excretion from the body due to its large molecular weight.

JP-A-04-152952 JP-A-2003-012723 Japanese Patent Publication No. 2013-534931

The present invention has been made in view of the above-mentioned prior art, and an object of the present invention is to provide a biocompatible medical material that is excellent in drug sustained release, particle shape retention, hemolysis resistance, and extracorporeal release properties. and

The present invention
(1) A biocompatible medical material comprising a biocompatible polymer having an ester bond or an amide bond between biocompatible polymers having a weight average molecular weight of 1000 to 90000,
(2) a biocompatible medical material comprising a biocompatible polymer having a disulfide bond between the biocompatible polymers having a weight average molecular weight of 1000 to 90000; and (3) a biocompatible medical material having a weight average molecular weight of The present invention relates to a biocompatible medical material comprising a biocompatible polymer having a molecular weight of 1,000 to 90,000 and having a thiol group at at least one molecular terminal.

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a biocompatible medical material which is excellent in drug sustained release properties, particle shape retention properties, hemolysis resistance, and external release properties.

As described above, the biocompatible medical material of the present invention is a biocompatible polymer having an ester bond or an amide bond between biocompatible polymers having a weight average molecular weight of 1,000 to 90,000. A biocompatible polymer having a disulfide bond between biocompatible polymers having a weight average molecular weight of , or a biocompatible polymer having a weight average molecular weight of 1000 to 90000 and having a thiol group at at least one molecular end Contains coalescence.

Both the biocompatible polymer having a weight average molecular weight of 1,000 to 90,000 and the biocompatible polymer having a weight average molecular weight of 1,000 to 90,000 and having a thiol group at at least one molecular terminal are It can be obtained by polymerizing compatible monomers.

Examples of biocompatible monomers include (alkoxy)polyoxyalkylene group-containing unsaturated monomers, hydroxyl group-containing (meth)acrylates, alkoxyalkyl (meth)acrylates, vinyl monomers, alkoxypolyoxyalkylene glycols, carboxybetaine Examples include monomers, sulfobetaine monomers, alkylene oxides, cyclic compounds, amino acids, aspartic acid, glutamic acid, etc., but the present invention is not limited to these examples. These biocompatible monomers may be used alone or in combination of two or more.

In the present invention, "(meth)acrylate" means acrylate or methacrylate, and acrylate and methacrylate may be used alone or in combination. "(Meth)acryloyl" means acryloyl or methacryloyl. Moreover, "(meth)acrylic acid" means acrylic acid and/or methacrylic acid.

The "(alkoxy) polyoxyalkylene group-containing unsaturated monomer" means a polyoxyalkylene group-containing unsaturated monomer or an alkoxypolyoxyalkylene group-containing unsaturated monomer, and a polyoxyalkylene group-containing unsaturated monomer. The saturated monomer and the alkoxypolyoxyalkylene group-containing unsaturated monomer may be used alone or in combination.

(Alkoxy)polyoxyalkylene group-containing unsaturated monomers include, for example, formula (I):

(wherein R ¹ , R ² and R ³ are each independently a hydrogen atom or a methyl group, R ⁴ is a C 2-18 alkylene group, R ⁵ is a hydrogen atom or a C 1-20 a hydrocarbon group, X is an alkylene group having 1 to 5 carbon atoms, a --CO-- group, or a direct bond when the R ¹ R ³ C=CR ² -- group is a vinyl group, m is --(R ⁴ O) - is the average number of added moles of the group, and indicates a number of 1 to 300)
(Alkoxy)polyoxyalkylene group-containing unsaturated monomers represented by.

When two or more types of oxyalkylene groups represented by the formula: —R ⁴ O— are present in one molecule, the oxyalkylene groups may be randomly bonded or may be bonded in blocks. They may be connected alternately.

In formula (I), R ⁵ is a hydrogen atom or a hydrocarbon group having 1-20 carbon atoms. R ⁵ is preferably a saturated hydrocarbon group having 1 to 20 carbon atoms and an unsaturated hydrocarbon group having 2 to 20 carbon atoms, more preferably an alkyl group having 1 to 20 carbon atoms, and an alkyl group having 1 to 10 carbon atoms. groups are more preferred, alkyl groups with 1 to 3 carbon atoms are even more preferred, and alkyl groups with 1 or 2 carbon atoms are even more preferred.

In formula (I), the oxyalkylene group represented by the formula: --R ⁴ O-- is an oxyalkylene group having 2 to 18 carbon atoms. Examples of the oxyalkylene group include oxyethylene group, oxypropylene group, oxybutylene group, oxyisobutylene group, oxy-1-butene group, oxy-2-butene group and the like, but the present invention is limited to such examples only. is not limited to Among these oxyalkylene groups, an oxyalkylene group having 2 to 8 carbon atoms is preferable, and an oxyalkylene group having 2 to 4 carbon atoms such as an oxyethylene group, an oxypropylene group, and an oxybutylene group is more preferable. is more preferred.

In formula (I), m is the average number of added moles of the oxyalkylene group represented by the formula: --R ⁴ O--. The average added mole number of the oxyalkylene group means the average number of moles of the oxyalkylene group in 1 mole of the (alkoxy)polyoxyalkylene group-containing unsaturated monomer. The lower limit of m is preferably 2 or more, more preferably 4 or more, and even more preferably 8 or more. The upper limit of m is preferably 100 or less, more preferably 50 or less.

X is a direct bond when the alkylene group having 1 to 5 carbon atoms, the --CO-- group, or the R ¹ R ³ C=CR ² -- group is a vinyl group. Among these groups, the -CO- group is preferred.

Examples of (alkoxy) polyoxyalkylene group-containing unsaturated monomers include (alkoxy) unsaturated alcohol polyalkylene glycol adducts, (alkoxy) polyalkylene glycol ester monomers, and (alkoxy) polyalkylene glycol monomalein. Examples include acid esters, but the present invention is not limited to such examples.

"(Alkoxy)unsaturated alcohol polyalkylene glycol adduct" means an unsaturated alcohol polyalkylene glycol adduct or an alkoxyunsaturated alcohol polyalkylene glycol adduct, wherein the unsaturated alcohol polyalkylene glycol adduct and the alkoxyunsaturated alcohol Polyalkylene glycol adducts may be used alone or in combination.

The (alkoxy) unsaturated alcohol polyalkylene glycol adduct is a compound in which a polyalkylene glycol chain is added to an alcohol having an unsaturated group. Examples of (alkoxy) unsaturated alcohol polyalkylene glycol adducts include polyethylene glycol monovinyl ether, polyethylene glycol monoallyl ether, polyethylene glycol mono(2-methyl-2-propenyl) ether, polyethylene glycol mono(2-butenyl) ether. , polyethylene glycol mono(3-methyl-3-butenyl) ether, polyethylene glycol mono(3-methyl-2-butenyl) ether, polyethylene glycol mono(2-methyl-3-butenyl) ether, polyethylene glycol mono(2-methyl -2-butenyl) ether, polyethylene glycol mono(1,1-dimethyl-2-propenyl) ether, polyethylene polypropylene glycol mono(3-methyl-3-butenyl) ether, methoxy polyethylene glycol mono(3-methyl-3-butenyl) ) ethers, etc., but the present invention is not limited only to such examples.

"(Alkoxy) polyalkylene glycol ester-based monomer" means a polyalkylene glycol ester-based monomer or an alkoxypolyalkylene glycol ester-based monomer, and a polyalkylene glycol ester-based monomer and an alkoxypolyalkylene glycol The ester-based monomers may be used alone or in combination.

The (alkoxy) polyalkylene glycol ester-based monomer is a monomer in which an unsaturated group and a polyalkylene glycol chain are bonded via an ester bond. As the (alkoxy) polyalkylene glycol ester-based monomer, for example, an ester of an alkoxypolyalkylene glycol obtained by adding 1 to 300 moles of an oxyalkylene group having 2 to 18 carbon atoms to an alcohol and (meth)acrylic acid is preferable. . Among the alkoxypolyalkylene glycols, those containing oxyethylene groups as a main component are preferred. Examples of the alcohol include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, Alicyclic alcohols with 1 to 30 carbon atoms such as 3-hexanol, octanol, 2-ethyl-1-hexanol, nonyl alcohol, lauryl alcohol, cetyl alcohol and stearyl alcohol, and alicyclic groups with 3 to 30 carbon atoms such as cyclohexanol alcohol, (meth)allyl alcohol, 3-buten-1-ol, 3-methyl-3-buten-1-ol and other unsaturated alcohols having 3 to 30 carbon atoms, and each of these may be used alone. may be used, or two or more types may be used in combination. Examples of the ester compound include methoxy mono (meth) acrylate, methoxy (polyethylene glycol polypropylene glycol) mono (meth) acrylate, methoxy (polyethylene glycol polybutylene glycol) mono (meth) acrylate, methoxy (polyethylene glycol polypropylene glycol polybutylene), glycol)mono(meth)acrylates, etc., and these (alkoxy)polyalkylene glycol ester monomers may be used singly or in combination of two or more.

Among (alkoxy) polyalkylene glycol ester-based monomers, it has an alkoxy group having 1 to 4 carbon atoms and an oxyalkylene group having 1 to 4 carbon atoms such as methoxypolyethylene glycol monomethacrylate, and the addition mole of the oxyalkylene group Alkoxypolyalkylene glycol mono(meth)acrylates with numbers from 2 to 30 are preferred.

"(Alkoxy)polyalkylene glycol monomaleate" means polyalkylene glycol monomaleate or alkoxypolyalkylene glycol monomaleate, polyalkylene glycol monomaleate and alkoxypolyalkylene glycol monomaleate may be used alone or in combination.

Examples of hydroxyl group-containing (meth)acrylates include, for example, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, glycerin (meth)acrylate, N-2-hydroxypropyl (meth)acrylamide, and the like. 4, but the present invention is not limited to such examples. These hydroxyl group-containing (meth)acrylates may be used alone or in combination of two or more.

Alkoxyalkyl (meth)acrylates include, for example, methoxymethyl (meth)acrylate, methoxyethyl (meth)acrylate, methoxypropyl (meth)acrylate, ethoxymethyl (meth)acrylate, ethoxyethyl (meth)acrylate, ethoxypropyl (meth)acrylate, ) alkoxy groups such as acrylates having 1 to 4 carbon atoms and alkoxyalkyl (meth)acrylates having alkyl groups having 1 to 4 carbon atoms, but the present invention is limited only to such examples. not a thing These alkoxyalkyl (meth)acrylates may be used alone or in combination of two or more.

A vinyl monomer is a biocompatible compound having a vinyl group other than (alkoxy)polyoxyalkylene group-containing unsaturated monomers, hydroxyl group-containing (meth)acrylates and alkoxyalkyl (meth)acrylates. Examples of the vinyl monomer include 2-(meth)acryloyloxymethylphosphorylcholine, 2-(meth)acryloyloxyethylphosphorylcholine, tetrahydrofurfuryl (meth)acrylate, isopropylacrylamide, vinyl alcohol, vinylformamide, vinylisobutylacrylamide, ( meth)acrylamide, dimethylacrylamide, vinylacetamide, N-vinylpyrrolidone, styrene, diaminomethyl (meth)acrylate, diaminoethyl (meth)acrylate, dimethylamino (meth)acrylate, diethylamino (meth)acrylate, dimethylaminomethyl (meth) Examples include acrylate, dimethylaminoethyl (meth)acrylate, etc., but the present invention is not limited only to such examples. These vinyl monomers may be used alone or in combination of two or more.

Alkoxypolyoxyalkylene glycols include, for example, polyethylene glycol, polypropylene glycol, methoxypolyethylene glycol, ethoxypolyethylene glycol, methoxypolypropylene glycol, ethoxypolypropylene glycol, and other alkoxy groups having 1 to 4 carbon atoms and oxyalkylene groups having 1 to 4 carbon atoms. and alkoxypolyoxyalkylene glycol having 2 to 30 moles of oxyalkylene groups, but the present invention is not limited to these examples. These alkoxypolyoxyalkylene glycols may be used alone or in combination of two or more.

Carboxybetaine monomers include, for example, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloylaminoethyl-N,N-dimethylammonium-α- Examples include N-methylcarboxybetaine, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, and the like, but the present invention is not limited to these examples. These carboxybetaine monomers may be used alone or in combination of two or more.

Sulfobetaine monomers include, for example, [3-(acryloylamino)propyl]dimethyl(3-sulfobutyl)ammonium hydroxide inner salt, [3-(methacryloylamino)propyl]dimethyl(3-sulfobutyl)ammonium hydroxide inner salt, N-(meth)acryloyloxyethyl-N,N-dimethylammoniummethyl-α-sulfobetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammoniumethyl-α-sulfobetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammoniumethyl-α-sulfobetaine ) acryloyloxyethyl-N,N-dimethylammoniumpropyl-α-sulfobetaine, etc., but the present invention is not limited to these examples. These sulfobetaine monomers may be used alone or in combination of two or more.

Examples of alkylene oxides include alkylene oxides having 2 to 4 carbon atoms such as ethylene oxide and propylene oxide, but the present invention is not limited to these examples. These alkylene oxides may be used alone or in combination of two or more.

Examples of the cyclic compound include lactides such as L-lactide, lactones such as ε-caprolactone, trimethyl carbonate, cyclic amino acids, morpholine-2,5-dione, etc., but the present invention is limited to such examples. is not limited to These cyclic compounds may be used alone or in combination of two or more.

Among the biocompatible monomers, (alkoxy) polyoxyalkylene group-containing unsaturated monomers, hydroxyalkyl (meth)acrylates in which the hydroxyalkyl group has 2 to 4 carbon atoms, and alkoxy groups in which the number of carbon atoms is 1 4 to 4 and the alkyl group has 1 to 4 carbon atoms, a vinyl monomer, an alkoxy group having 1 to 4 carbon atoms and an oxyalkylene group having 1 to 4 carbon atoms, and an addition of an oxyalkylene group Alkoxypolyoxyalkylene glycols, carboxybetaine monomers and sulfobetaine monomers having a number of moles of 2 to 30 are preferred, having an alkoxy group having 1 to 4 carbon atoms and an oxyalkylene group having 1 to 4 carbon atoms, and having an oxyalkylene group. Alkoxypolyalkylene glycol mono(meth)acrylate having an addition mole number of 2 to 30, 2-hydroxyethyl (meth)acrylate, glycerin (meth)acrylate, N-2-hydroxypropyl (meth)acrylamide, methoxyethyl (meth) acrylates, n-butyl (meth)acrylate, n-lauryl (meth)acrylate, 2-(meth)acryloyloxyethylphosphorylcholine, tetrahydrofurfuryl (meth)acrylate, N-vinylpyrrolidone, styrene, polyethylene glycol, carboxybetaine monomers and Sulfobetaine monomers are more preferred.

The biocompatible monomer can be used in combination with other monomers copolymerizable with the biocompatible monomer within a range that does not impede the object of the present invention. Other monomers copolymerizable with biocompatible monomers include, for example, aziridine compounds, (meth)acrylic acid, methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, n- Alkyl (meth)acrylates such as butyl (meth)acrylate, isobutyl (meth)acrylate, tert-butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, glycidyl (meth)acrylate, and the like. It is not limited only to such examples. Each of these other monomers may be used alone, or two or more of them may be used in combination.

Examples of methods for polymerizing biocompatible monomers include living radical polymerization methods such as radical polymerization, atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, ionic polymerization, ring-opening polymerization, and the like. method, coordination polymerization method, polycondensation method, etc., but the present invention is not limited only to such examples.

A solvent may be used when polymerizing the biocompatible monomers. Examples of the solvent include aromatic solvents such as water, benzene, toluene and xylene; alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol and tert-butyl alcohol; solvents containing halogen atoms such as dichloromethane and dichloroethane; Ether solvents such as diethylene glycol dimethyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether, ethyl cellosolve, butyl cellosolve; ester solvents such as ethyl acetate, butyl acetate, cellosolve acetate; acetone, methyl ethyl ketone, methyl isobutyl ketone, diacetone alcohol, etc. and organic solvents such as amide solvents such as dimethylformamide, but the present invention is not limited to these examples. These solvents may be used alone or in combination of two or more. The amount of the solvent may be appropriately determined in consideration of the polymerization conditions, the composition of the biocompatible monomers, the concentration of the resulting polymer, and the like.

A chain transfer agent can be used to adjust the molecular weight of the biocompatible polymer when polymerizing the biocompatible monomer. The chain transfer agents include those corresponding to compounds containing functional groups for introducing functional groups into biocompatible polymers (hereinafter simply referred to as "functional group-containing compounds"). A chain transfer agent corresponding to a compound can be used as one or both of a chain transfer agent and a functional group-containing compound.

Examples of chain transfer agents include alkali metal thioacetates such as sodium thioacetate and potassium thioacetate, cysteine, cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, -hydrophilic thiol-based chain transfer agents such as mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, their sodium salts, potassium salts; primary alcohols such as 2-aminopropan-1-ol, isopropyl Secondary alcohols such as alcohols, phosphorous acid, hypophosphorous acid and salts thereof (e.g., sodium hypophosphite, potassium hypophosphite, etc.), sulfurous acid, hydrogen sulfite, dithionous acid, metabisulfite and Non-thiol chains such as salts thereof (e.g., sodium sulfite, sodium bisulfite, sodium dithionite, sodium metabisulfite, potassium sulfite, potassium bisulfite, potassium dithionite, potassium metabisulfite, etc.) Transfer agent; butanethiol, octanethiol, decanethiol, dodecanethiol, hexadecanethiol, octadecanethiol, cyclohexylmercaptan, thiophenol, octyl thioglycolate, octyl 2-mercaptopropionate, octyl 3-mercaptopropionate, mercaptopropionate 2 -hydrophobic thiol-based chain transfer agents such as ethylhexyl ester, 2-mercaptoethyl octanoate, 1,8-dimercapto-3,6-dioxaoctane, decantrithiol, and dodecylmercaptan; 4-chloro-3,5- 2'-cyanobutane-2'-yl dimethylpyrazole-1-carbodithioate, 2'-cyanobutane-2'-yl 3,5-dimethylpyrazole-1-carbodithioate, cyanomethyl 3,5-dimethylpyrazole-1-carbodithioate , 2-cyanoprop-2-yl-dithiobenzoate, S-(2-cyanoprop-2-yl)-S-dodecyltrithiocarbonate, 4-[(2-carboxyethylsulfanylthiocarbonyl)sulfanyl]-4- Reversible addition-cleavage of cyanopentanoic acid, 4-cyano-4-(thiobenzoylthio)pentanoic acid, 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, bis(dodecylsulfanylthiocarbonyl)disulfide, etc. Examples include chain transfer agents for chain transfer polymerization methods. However, the invention is not limited to only such exemplifications. These chain transfer agents may be used alone or in combination of two or more.

The amount of the chain transfer agent may be appropriately set according to the type of biocompatible monomer, polymerization conditions such as polymerization temperature, and the target molecular weight of the biocompatible polymer. When obtaining a polymer having a molecular weight of 1000 to 90000, it is preferably 0.1 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, per 100 parts by mass of the biocompatible monomer. preferable.

A polymerization initiator can be used when polymerizing the biocompatible monomers. The polymerization initiator includes those corresponding to the functional group-containing compound, and the polymerization initiator corresponding to the functional group-containing compound can be used as one or both of the polymerization initiator and the functional group-containing compound. can.

Examples of polymerization initiators include azoisobutyronitrile, 4,4′-azobis(4-cyanopentanoic acid), 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide]. , 2,2′-azobis[2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide], 2,2′-azobis(2-methyl-2-propenylpropanamide ), 2,2′-azobis(2-methylpropionamidine) dihydrochloride, 2,2′-bis(2-imidazolin-2-yl)[2,2′-azobispropane] dihydrochloride, 2, 2′-azobis[N-(2-carboxyethyl)-2-methylpropionamidine], 2,2′-azobis[2-[1-(2-hydroxyethyl)-2-imidazolin-2-yl]propane di hydrochloride, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(2-methylbutyronitrile), tert-butylperoxy-2-ethylhexanoate, 2,2 '-azobisisobutyronitrile, benzoyl peroxide, di-tert-butyl peroxide, cyclohexanone peroxide, radical polymerization initiators such as acetylacetone peroxide; bromomethylbenzene, 1-(bromomethyl)-4-methylbenzene, 2 -ethyl bromoisobutyrate, 2-hydroxyethyl 2-bromoisobutyrate, bis[2-(2'-bromoisobutyryloxy)ethyl]disulfide, 10-undecenyl 2-bromoisobutyrate, 4-(1-bromoethyl)benzoic acid, etc. However, the present invention is not limited only to such examples. These polymerization initiators may be used alone or in combination of two or more.

The amount of the polymerization initiator may be appropriately set according to the desired physical properties of the polymer to be obtained. It is preferably 0.005 to 10 parts by mass.

Functional group-containing compounds can be used to obtain biocompatible polymers with functional groups. As the functional group, an anionic functional group, a cationic functional group, a nonionic functional group and an amphoteric functional group are preferable. The functional group is preferably a reactive functional group from the viewpoint of modifying a drug or the like. Suitable functional groups include, for example, a group represented by the formula: -COOM (M represents a hydrogen atom or an alkali metal atom; the same shall apply hereinafter), a hydroxyl group, an allyl group, an epoxy group, an aldehyde group, an amino group, and a CONH- group. , a thiol group, etc., but the present invention is not limited only to such examples. Examples of M include alkali metal atoms such as a sodium atom and a potassium atom. Although the number of functional groups in the biocompatible polymer having functional groups is not particularly limited, it is usually preferably from 1 to 6.

Examples of functional group-containing compounds used for introducing functional groups into the biocompatible polymer polymerized using the polymerization initiator or chain transfer agent include alkali metal thioacetates such as sodium thioacetate and potassium thioacetate. salts, cysteine, cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, sodium thereof salts, potassium salts such as 4-[(2-carboxyethylsulfanylthiocarbonyl)sulfanyl]-4-cyanopentanoic acid, 4-cyano-4-(thiobenzoylthio)pentanoic acid, 4-cyano-4-[(dodecyl Thiol-based chain transfer agents containing functional groups such as sulfanylthiocarbonyl)sulfanyl]pentanoic acid, bis(dodecylsulfanylthiocarbonyl)disulfide; 4,4′-azobis(4-cyanopentanoic acid), 2,2′-azobis [2-methyl-N-(2-hydroxyethyl)propionamide], 2,2′-azobis[2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide], 2,2'-azobis(2-methyl-2-propenylpropanamide), 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 2,2'-bis(2-imidazolin-2-yl) [2,2′-azobispropane] dihydrochloride, 2,2′-azobis[N-(2-carboxyethyl)-2-methylpropionamidine], 2,2′-azobis[2-[1-( 2-hydroxyethyl)-2-imidazolin-2-yl]propane dihydrochloride, cyclohexanone peroxide, acetylacetone peroxide, bis[2-(2′-bromoisobutyryloxy)ethyl]disulfide, etc. However, the present invention is not limited only to such examples. These functional group-containing compounds may be used alone or in combination of two or more.

When a living polymerization initiator is used as the polymerization initiator, the biocompatible polymer prepared using the living polymerization initiator is reacted with a functional group-containing compound at the end of the biocompatible polymer. Functional groups may be introduced into the biocompatible polymer. Examples of the functional group-containing compound that reacts with the halogen atom present at the end of the biocompatible polymer prepared using the living polymerization initiator include amine compounds such as ethanolamine, ethylenediamine and propyldiamine, glycolic acid, Alcohols such as hydroxypropionic acid, ethylene glycol, propanediol, butanediol and hydroquinone; carboxylic acids such as glycine, malonic acid, succinic acid, adipic acid and terephthalic acid; dithiols such as ethanedithiol, propanedithiol and hexadecanedithiol. cysteine, cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethane Thiol compounds such as sulfonic acids and their sodium salts and potassium salts are included, but the present invention is not limited only to such examples.

A method of introducing a functional group into a biocompatible polymer using the polymerization initiator or chain transfer agent, or a halogen atom present at the end of the biocompatible polymer prepared using the living polymerization initiator and the A functional group present at the end of a biocompatible polymer prepared by a method of introducing a functional group into the biocompatible polymer by reacting it with a functional group-containing compound that reacts with a halogen atom, and the functional group-containing compound Functional groups may be introduced into the biocompatible polymer by reacting with .

Examples of the functional group-containing compound that reacts with the functional group present at the end of the biocompatible polymer include amine compounds such as ethanolamine, ethylenediamine and propyldiamine, glycolic acid, hydroxypropionic acid, ethylene glycol, and propane. Alcohols such as diols, butanediol and hydroquinone; carboxylic acids such as glycine, malonic acid, succinic acid, adipic acid and terephthalic acid; dithiol compounds such as ethanedithiol, propanedithiol and hexadecanedithiol; Cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, their sodium salts, potassium salts Thiol compounds such as 2-hydroxyethyl disulfide, 3-hydroxypropyl disulfide, bis(6-hydroxyhexyl) disulfide, bis(8-hydroxyoctyl) disulfide, 6,6'-dihydroxy-2,2'-dinaphthyl Disulfide, 3,3'-dihydroxydiphenyl disulfide, 4,4'-dihydroxydiphenyl disulfide, bis(2-aminoethyl) disulfide dihydrochloride, 2,2'-diaminodiphenyl disulfide, 3-aminopropyl disulfide, bis(6 -aminohexyl) disulfide, bis(8-aminooctyl) disulfide, compounds having a disulfide group such as 4,4'-diaminodiphenyl disulfide, etc., but the present invention is not limited only to such examples. No.

The amount of the functional group-containing compound for introducing the functional group into the biocompatible polymer depends on the type of biocompatible monomer, polymerization conditions such as polymerization temperature, and the target molecular weight of the biocompatible polymer. Although it is not particularly limited, when obtaining a polymer having a weight average molecular weight of 1000 to 90000, it is preferably 0.1 to 20 parts by weight per 100 parts by weight of the biocompatible monomer. It is preferably from 0.5 to 15 parts by mass.

Polymerization conditions for polymerizing the biocompatible monomer may be appropriately set according to the polymerization method, and are not particularly limited. The polymerization temperature is preferably room temperature to 200°C, more preferably 40 to 140°C. Moreover, the atmosphere in which the biocompatible monomer is polymerized is preferably an inert gas such as nitrogen gas or argon gas. The reaction time may be appropriately set so that the polymerization reaction of the biocompatible monomers is completed.

Methods for introducing the functional group to at least one molecular terminal of the biocompatible polymer include, for example,
(1) a method of polymerizing a biocompatible monomer in the presence of a polymerization initiator containing the functional group as a polymerization initiator;
(2) a method of polymerizing a biocompatible monomer in the presence of a chain transfer agent containing the functional group as a chain transfer agent;
(3) When the biocompatible polymer has an allyl group at its terminal, the allyl group possessed by the biocompatible polymer is boronated, and then the boronated biocompatible polymer and the functional group-containing compound are combined. A method of introducing a functional group possessed by the functional group-containing compound by reacting it,
(4) When the biocompatible polymer has a terminal hydroxyl group, the hydroxyl group is reacted with a tolylating agent such as tosyl chloride, then thioacetylated, and the thioacetylated biocompatible polymer is hydrolyzed. A method of introducing a thiol group as a functional group by
(5) a method of reacting a halogen atom present at the end of a biocompatible polymer with a functional group-containing compound;
(6) A functional group present at the end of a biocompatible polymer prepared by the method of introducing the functional group according to any one of (1) to (5) into at least one molecular end of the biocompatible polymer. a method of introducing a functional group into the biocompatible polymer by reacting the group with a functional group-containing compound;
(7) A functional group present at the end of a biocompatible polymer prepared by the method of introducing the functional group according to any one of (1) to (5) into at least one molecular end of the biocompatible polymer. A method of introducing a thiol group as a functional group by reacting a group with a compound having a disulfide group, and then cleaving the disulfide bond using a reducing agent that cleaves the disulfide bond,
(8) polymerizing a biocompatible monomer in the presence of a polymerization initiator or a polymerization initiator having a disulfide group as a chain transfer agent, and then cleaving the disulfide bond using a reducing agent that cleaves the disulfide bond; A method of introducing a thiol group as a functional group by
(9) After polymerizing a biocompatible monomer in the presence of a chain transfer agent for reversible addition-fragmentation chain transfer polymerization, reacting an amine compound, sodium hydroxide, sodium borohydride, etc. Examples include a method of introducing a thiol group as a functional group, but the present invention is not limited only to such examples.

A biocompatible polymer can be obtained by polymerizing a biocompatible monomer as described above. The biocompatible polymer to be obtained has a functional group possessed by the functional group-containing compound for introducing a functional group into the biocompatible polymer at at least one molecular terminal. The functional group may be present only at one end of the biocompatible polymer, or may be present at both ends of the biocompatible polymer. Suitable functional groups possessed by the biocompatible polymer include, for example, groups represented by the formula: -COOM, hydroxyl groups, allyl groups, epoxy groups, aldehyde groups, amino groups, CONH- groups, thiol groups, and the like. , the invention is not limited to such examples only.

The weight-average molecular weight of the biocompatible polymer is 1000 or more, preferably 2000 or more, more preferably 3000 or more, from the viewpoint of improving drug sustained release properties, particle shape retention properties, hemolysis resistance, and external release properties. 90,000 or less, preferably 50,000 or less, more preferably 30,000 or less, even more preferably 25,000 or less, still more preferably 20,000 or less, and even more preferably 15,000 or less, from the viewpoint of improving in vitro release properties.

In addition, the weight average molecular weight of the biocompatible polymer means the value when measured based on the method described in the following examples.

From the viewpoint of improving hemolysis resistance, the molecular weight distribution (value of [polymerization average molecular weight/number average molecular weight]) of the biocompatible polymer is preferably 1 to 2, more preferably 1 to 1.5, and still more preferably 1 to 1.3.

In the present invention, a biocompatible polymer having an ester bond, an amide bond, or a disulfide bond between two or more biocompatible polymers has an ester bond, an amide bond, or a disulfide bond between two or more biocompatible polymers, respectively. means a polymer with bonds. One or two or more ester bonds, amide bonds or disulfide bonds may be contained between the polymers. When two or more ester bonds, amide bonds or disulfide bonds are contained between polymers, only the same type of bond or multiple types of bonds may be contained. In addition to the three types of bonds described above, other bonds may be included as long as they do not interfere with the object of the present invention.

A biocompatible polymer having an ester bond, an amide bond, or a disulfide bond between biocompatible polymers is, for example, an ester bond, an amide bond, or a disulfide bond between biocompatible polymers of the same type or different types. obtained by letting A biocompatible polymer used for forming an ester bond, an amide bond or a disulfide bond between biocompatible polymers may be a biocompatible polymer having a functional group only at one end. , a biocompatible polymer having functional groups at both ends.

As a method for forming an ester bond or an amide bond between biocompatible polymers, for example, as shown in the following production examples, the functional groups possessed by the biocompatible polymer are chemically reacted, followed by amidation. , esterification, condensation, and the like, but the present invention is not limited to such examples.

Bonding between biocompatible polymers by amidation, esterification, condensation or the like is performed by, for example, dissolving the biocompatible polymer in a solvent such as water or an organic solvent, adding a carbodiimide-based condensing agent, imidazole to the resulting solution. It can be carried out by adding a condensing agent such as a condensing agent, a triazine condensing agent, a phosphonium condensing agent, an uronium condensing agent, or a halonium condensing agent. Moreover, the bonding between the biocompatible polymers may be performed in the presence of the condensing agent and the condensation aid or the dehydration aid.

Examples of the method for forming an ester bond or an amide bond between biocompatible polymers include a method for forming an ester bond or an amide bond between the biocompatible polymers, as well as other commonly used methods. Examples of commonly used methods include, for example, The Chemical Society of Japan, "Experimental Chemistry Course 22 Organic Synthesis IV Acids, Amino Acids, and Peptides", 4th Edition, Maruzen Co., Ltd., November 30, 1992, 193. - 310, but the present invention is not limited to such examples.

By forming an ester bond or an amide bond between biocompatible polymers as described above, a biocompatible polymer having an ester bond or an amide bond between biocompatible polymers can be obtained. can.

A biocompatible polymer having disulfide bonds between biocompatible polymers is obtained by forming disulfide bonds between biocompatible polymers. The biocompatible polymers may be of the same type or of different types.

As a method for forming disulfide bonds between biocompatible polymers, for example, a disulfide compound having two or more functional groups reactive with the functional groups of the biocompatible polymer and the biocompatible A method of forming one or more disulfide bonds between biocompatible polymers by reacting with a biocompatible polymer (hereinafter referred to as method A) in the presence of a polymerization initiator having a disulfide group A method of forming a disulfide bond between the biocompatible polymers by polymerizing the biocompatible monomers (hereinafter referred to as method B). It is not limited.

In method A, for example, a biocompatible polymer having a functional group such as a carboxyl group;
Obtaining a biocompatible polymer having a disulfide bond between the biocompatible polymers by reacting it with a disulfide compound having two or more functional groups such as hydroxyl groups reactive with the functional group. can be done. Examples of the disulfide compound having two or more functional groups include 2-hydroxyethyl disulfide, 3-hydroxypropyl disulfide, bis(6-hydroxyhexyl) disulfide, bis(8-hydroxyoctyl) disulfide, 6,6'-dihydroxy-2,2'-dinaphthyl disulfide, 3,3'-dihydroxydiphenyl disulfide, 4,4'-dihydroxydiphenyl disulfide, bis(2-aminoethyl) disulfide dihydrochloride, 2,2'-diaminodiphenyl disulfide , 3-aminopropyl disulfide, bis(6-aminohexyl) disulfide, bis(8-aminooctyl) disulfide, compounds having a disulfide group such as 4,4'-diaminodiphenyl disulfide. , is not limited to such examples.

The amount of the biocompatible polymer per functional group equivalent of the disulfide compound having two or more functional groups is preferably 1.5 to 1.5 from the viewpoint of efficiently forming disulfide bonds between the biocompatible polymers. 2.5 equivalents, more preferably 1.8 to 2.2 equivalents.

Water or an organic solvent can be used when reacting a biocompatible polymer having a functional group with a disulfide compound having two or more functional groups reactive with the functional group. Examples of organic solvents include halogen atom-containing solvents such as dichloromethane, dichloroethane, and chloroform; alcohol-based organic solvents such as methanol, ethanol, isopropanol, n-butanol, and tert-butyl alcohol; propylene glycol methyl ether, dipropylene glycol methyl ether. Ether organic solvents such as , ethyl cellosolve, butyl cellosolve, and diglyme; Ester organic solvents such as ethyl acetate, butyl acetate, and cellosolve acetate; Ketone organic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diacetone alcohol; Dimethylformamide, etc. and aromatic organic solvents such as benzene, toluene and xylene, but the present invention is not limited to these examples. These solvents may be used alone or in combination of two or more. Although the amount of the solvent per 100 parts by mass of the biocompatible polymer is not particularly limited, it is usually preferably about 100 to 500 parts by mass.

The temperature at which the biocompatible polymer having a functional group and the disulfide compound having two or more reactive functional groups with respect to the functional group are reacted is not particularly limited, and is usually room temperature. , may be heated or cooled as necessary.

If necessary, the biocompatible polymer having disulfide bonds between the biocompatible polymers thus obtained may be dried by vacuum drying, freeze drying, or the like.

In method B, disulfide bonds can be formed between polymers of the biocompatible polymer by polymerizing biocompatible monomers in the presence of a polymerization initiator having disulfide groups.

Examples of biocompatible monomers used in Method B include biocompatible monomers having the above-described functional groups.

Polymerization initiators having a disulfide group include, for example, bis[2-(2'-bromoisobutyryloxy)ethyl]disulfide, but the present invention is not limited to such examples. A polymerization initiator having a disulfide group may have a bromine atom or the like as a functional group other than the disulfide group.

The amount of the polymerization initiator having a disulfide group may be appropriately set according to the desired physical properties of the biocompatible polymer. 20 parts by mass, more preferably 0.005 to 10 parts by mass.

An organic solvent can be used when the biocompatible monomer is polymerized in the presence of a polymerization initiator having a disulfide group. Examples of the organic solvent include ketone organic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and diacetone alcohol; alcoholic organic solvents such as methanol, ethanol, isopropanol, n-butanol and tert-butyl alcohol; dichloroethane, dichloromethane, halogen atom-containing solvents such as chloroform; ether organic solvents such as propylene glycol methyl ether, dipropylene glycol methyl ether, ethyl cellosolve, butyl cellosolve and diglyme; ester organic solvents such as ethyl acetate, butyl acetate and cellosolve acetate; amide organic solvents; aromatic organic solvents such as benzene, toluene and xylene; organic solvents such as organic solvents such as benzene, toluene, and xylene; These solvents may be used alone or in combination of two or more. Although the amount of the solvent per 100 parts by mass of the biocompatible polymer is not particularly limited, it is usually preferably 500 parts by mass or less.

The temperature at which the biocompatible monomer is polymerized in the presence of a polymerization initiator having a disulfide group is preferably room temperature to 150°C. Moreover, the atmosphere in which the biocompatible monomer is polymerized in the presence of the polymerization initiator having a disulfide group is preferably an inert gas such as nitrogen gas or argon gas. The time required to polymerize the biocompatible monomers in the presence of the polymerization initiator having disulfide groups is appropriately set so that the reaction for forming disulfide bonds between the polymers of the biocompatible polymer is completed. Although it is not particularly limited, it is usually about 30 minutes to 24 hours.

By polymerizing biocompatible monomers in the presence of a polymerization initiator having disulfide groups as described above, a biocompatible polymer having disulfide bonds between the biocompatible polymers can be obtained. .

Hereinafter, a biocompatible polymer having an ester bond, an amide bond or a disulfide bond between biocompatible polymers will be referred to as a "specific bond-containing biocompatible polymer" for convenience.

The specific bond-containing biocompatible polymer may have a functional group at one or both ends, or may have no functional group. Examples of the functional group include functional groups similar to those possessed by the biocompatible polymer to be bound.

In addition to the method (4) and the methods (7) to (9) in which the functional group is introduced into at least one molecular terminal of the biocompatible polymer, the method (1) in which a thiol group is used as the functional group. containing a polymerization initiator, a chain transfer agent containing a thiol group as a functional group in the method (2), and a thiol group as a functional group in the methods (3), (5) and (6). By using the contained thiol group-containing compound, a biocompatible polymer having thiol groups at one or both ends (hereinafter referred to as "thiol group-containing biocompatible polymer") can be obtained. When a thiol group is present only at one end of the thiol group-containing biocompatible polymer, the other molecular end may have a functional group other than a thiol group. Functional groups other than thiol groups include, for example, carboxyl groups, hydroxyl groups, allyl groups, epoxy groups, aldehyde groups, and amino groups, but the present invention is not limited to these examples.

The degree of hemolysis of the specific bond-containing biocompatible polymer and the thiol group-containing biocompatible polymer is preferably 70% or less, more preferably 50%, from the viewpoint of obtaining a biocompatible medical material with excellent hemolysis resistance. Below, more preferably 30% or less, still more preferably 20% or less. The degree of hemolysis of the specific bond-containing biocompatible polymer and the thiol group-containing biocompatible polymer is a value measured according to the method described in Examples below.

Specific bond-containing biocompatible polymers and thiol group-containing biocompatible polymers can be used as particles. The average particle size of the particles is preferably 10 nm or more, more preferably 20 nm or more, from the viewpoint of not acting on normal cells, and preferably 1000 nm or less, more preferably 500 nm or less from the viewpoint of acting on diseased cells. , and more preferably 200 nm or less. In addition, the average particle diameter of the particles is a value when measured based on the method described in the following examples.

The functional groups possessed by the specific bond-containing biocompatible polymer and the thiol group-containing biocompatible polymer may include proteins, monosaccharides, polysaccharides, sugar chains, antibodies, nucleic acids, active pharmaceutical ingredients, amino acids, peptides, folic acid, as required. , dextrin, etc. may be modified. These proteins, monosaccharides, polysaccharides, sugar chains, antibodies, nucleic acids, active pharmaceutical ingredients, amino acids, peptides, folic acid, dextrin, etc. are functionalized by specific bond-containing biocompatible polymers and thiol group-containing biocompatible polymers. It may be directly attached to the group or may be attached via a linker.

The biocompatible medical material of the present invention contains a specific bond-containing biocompatible polymer or a thiol group-containing biocompatible polymer. The biocompatible medical material of the present invention may contain additives as long as they do not impair the purpose of the present invention. Examples of additives include water, physiological saline, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, carboxymethylcellulose sodium salt, sodium polyacrylate, sodium alginate, water-soluble dextran. , sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, gelatin, agar, diglycerin, propylene glycol, polyethylene glycol, petroleum jelly, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, Examples include lactose, phosphate buffered saline, biodegradable polymers, serum-free media, surfactants acceptable as pharmaceutical additives, and physiological pH buffers acceptable in vivo. , is not limited to such examples. These additives may be used alone or in combination of two or more.

The biocompatible medical material of the present invention can be used, for example, as a carrier for holding pharmaceuticals and the like. As a method for holding a drug or the like in the biocompatible medical material of the present invention, for example, a specific bond-containing biocompatible polymer or a thiol group-containing biocompatible polymer used in the biocompatible medical material is used. A method of combining a carrier and a drug by binding a drug to a functional group possessed by the carrier, a method of mixing a biocompatible medical material and a drug so as to form a uniform composition, a method of mixing particles such as a drug into a living body. A method of coating with a compatible medical material, a method of granulating a mixture of a lipid and a biocompatible medical material and encapsulating a drug or the like in the resulting particles, a method of encapsulating a drug or the like in liposomes, and applying the drug to a living body A method of encapsulating the particles in the skin of a biocompatible medical material by coating with a compatible medical material, and a method of coating particles of a mixture of a drug or the like and liposomes with a biocompatible medical material , a method of encapsulating the particles inside the skin of a biocompatible medical material, and a method of encapsulating a drug by forming micelles with a biocompatible medical material. , is not limited to such examples.

The liposomes can be prepared, for example, by dissolving the lipid in a solvent such as tert-butyl alcohol or chloroform and then freeze-drying it, or by adding a drug-dissolved solution to the lipid to swell the lipid and disperse it with ultrasonic waves. It can be prepared by, for example, adding polyethylene glycol-phosphatidylethanolamine or the like to the resulting dispersion.

Liposomes may be cationized with a cationizing agent. Liposomes are obtained by, for example, dissolving hydrogenated soybean lecithin, cholesterol, 3,5-dipentadecyloxybenzamidine hydrochloride, etc. in a solvent such as tert-butyl alcohol, and freezing the obtained lipid mixed solution. be able to. Lipids that constitute liposomes are stable in vivo. Examples of the lipids include lipids derived from biomaterials, phospholipids or derivatives thereof, lipids other than phospholipids or derivatives thereof, and the like. Phospholipids include, for example, phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolibin, and hydrogenated phospholipids.

Although liposomes are used in the above examples, emulsions, nanoparticles, microparticles, polymer compounds, and the like, for example, can be used instead of liposomes.

Biologically or pharmacologically active agents can be used as agents. Examples of drugs include antitumor agents, anticancer agents, antibiotics, antiviral agents, anticancer effect enhancers, immunopotentiators, immunomodulators, immunorestorers, radiosensitizers, radioprotectors, antihistamines, and anti-inflammatory agents. decongestants, antifungals, antiarthritics, antiasthmatics, angiogenesis inhibitors, enzymatic agents, antioxidants, hormones, angiotensin-converting enzyme inhibitors, smooth muscle cell proliferation agents, smooth muscle cell migration inhibitors, platelet aggregation inhibitors, chemical mediator release inhibitors, vascular endothelial cell growth promoters, vascular endothelial cell growth inhibitors, interferons, interleukins, colony-stimulating factors, cytokines, tumor necrosis factors, granulocyte macrophage colonies stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, stem cell factor, β-type transforming growth factor, hepatocyte growth factor, vascular endothelial cell growth factor, erythropoietin, vaccine, protein, mucoprotein, peptide, polysaccharide, liposome Examples include polysaccharides, sugar chains, antisense, ribozymes, decoys, nucleic acids, antibodies, etc., but the present invention is not limited to these examples. These agents may be used alone or in combination of two or more.

A biocompatible medical material is obtained as described above, and the specific bond-containing biocompatible polymer or thiol group-containing biocompatible polymer used in the biocompatible medical material may be crosslinked. Examples of the method for cross-linking the polymer include a chemical cross-linking method and a physical cross-linking method. Examples of chemical cross-linking methods include epoxy compounds, oxidized starch, glutaraldehyde, formaldehyde, dimethyl suberiminate, carbodiimide, succinimidyl compounds, diisocyanate compounds, acyl azide, reuterin, tris(hydroxymethyl)phosphine, copper ascorbate, glucose. A method of cross-linking a polymer using a chemical cross-linking agent such as lysine or a photo-oxidizing agent, a method of chemically cross-linking a polymer by thermal dehydration, ultraviolet irradiation, electron beam irradiation, gamma ray irradiation, etc. mentioned. Examples of physical cross-linking methods include a method of cross-linking a polymer with a salt, a method of cross-linking a polymer by electrostatic interaction, a method of cross-linking a polymer by hydrogen bonding, and a method of cross-linking a polymer by hydrophobic interaction. and the like. At the time of crosslinking, only one type of crosslinking method may be used, or two or more types of crosslinking methods may be used in combination.

Subjects to which the drug is administered include mammals such as humans, monkeys, rats, dogs, cats, and domestic animals, but the present invention is not limited to these examples.

When administering a drug by injection, the drug can be injected into the body by, for example, intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intradermal injection, intratumoral injection, and the like.

The amount of the drug to be held in the biocompatible medical material of the present invention varies depending on the subject to which the drug is administered, the type of drug, etc., and cannot be generally determined. It is preferably about 1 μg to 50 g per 100 g of polymer (solid content) contained in the material.

As described above, the biocompatible medical material of the present invention is excellent in drug sustained release, particle shape retention, hemolysis resistance, and in vitro release properties. It is expected to be used as a pharmaceutical carrier for introduction into the body via blood, for example, a pharmaceutical carrier for injection, a pharmaceutical carrier for oral administration, and the like.

EXAMPLES Next, the present invention will be described in more detail based on examples, but the present invention is not limited only to these examples.

Production example 1
200 g of diethylene glycol dimethyl ether [manufactured by Tokyo Kasei Kogyo Co., Ltd.; The diethylene glycol dimethyl ether inside was heated to 80° C., and nitrogen gas was introduced into the reaction vessel at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction vessel with nitrogen gas.

Next, a mixture of 110 g of methoxyethyl acrylate, 440 mg of 4,4'-azobis(4-cyanopentanoic acid) [manufactured by Wako Pure Chemical Industries, Ltd., product number: V-501, the same applies hereinafter] and 20 g of diethylene glycol dimethyl ether was It was continuously added dropwise into a reaction vessel maintained at 80° C. over time. After adding 110 mg of 4,4'-azobis(4-cyanopentanoic acid) into the reaction vessel 3 hours and 4 hours after the start of dropping of the mixture while maintaining the temperature of the contents of the reaction vessel at 80 ° C. By maintaining the temperature of the contents of the reaction vessel at 80° C. for 2 hours, a polymer solution containing polymethoxyethyl acrylate having terminal carboxyl groups (hereinafter referred to as polymer (1)) was obtained. The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of polymer (1) was 5,500.

In each example and each comparative example, the weight average molecular weight of the polymer was measured by gel permeation chromatography under the following measurement conditions.
[Measurement conditions for weight average molecular weight of polymer]
・ Measuring equipment: manufactured by Tosoh Corporation, product number: HLC-8320GPC
・Molecular weight column: manufactured by Tosoh Corporation, product number: Two TSKgel G4000HHR are connected in series ・Eluent: dimethylformamide ・Standard material for calibration curve: polyethylene glycol ・Preparation of solution for measurement: The coalescence was dissolved to prepare a solution having a polymer concentration of 0.3% by mass, and the solution was filtered with a filter before use.

Production example 2
Into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), 300 g of a mixed solvent consisting of 50% by mass of diethylene glycol dimethyl ether and 50% by mass of ethanol was added to react. The mixed solvent in the container was heated to 80° C., and nitrogen gas was introduced into the reaction container at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction container with nitrogen gas.

Next, 120 g of methoxyethyl acrylate, 500 mg of 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide] [manufactured by Wako Pure Chemical Industries, Ltd., product number: VA-086, same below] and 60 g of the mixed solvent was continuously added dropwise over 2 hours into a reaction vessel maintained at 80°C. While maintaining the temperature of the contents of the reaction vessel at 80° C., 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide] was After adding 125 mg into the reaction vessel, the temperature of the contents of the reaction vessel was maintained at 80° C. for 2 hours to contain polymethoxyethyl acrylate having a terminal hydroxyl group [hereinafter referred to as polymer (2)]. A polymer solution was obtained. The solid content in the polymer solution was 25% by mass, and the weight average molecular weight of polymer (2) was 5,200.

Production example 3
After adding a mixture of 220 mg of 4-(1-bromoethyl)benzoic acid, 5.4 g of methoxyethyl acrylate and 5.4 g of diethylene glycol dimethyl ether into a 50 mL eggplant flask, the inner space of the eggplant flask was replaced with nitrogen gas. A reaction solution was obtained by adding 440 mg of bipyridine ligand and 160 mg of copper bromide into an eggplant flask and stirring the content of the eggplant flask at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 160 mg of sodium hydroxide and 330 mg of ethanolamine were added to the purified reaction solution, and the reaction solution was stirred at a temperature of 80° C. for 4 hours to obtain a carboxyl group at one end and a A polymer solution containing polymethoxyethyl acrylate having a hydroxyl group [hereinafter referred to as polymer (3)] was obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of polymer (3) was 5,000.

Production example 4
After adding a mixture of 220 mg of 4-(1-bromoethyl)benzoic acid, 6.9 g of methoxyethyl acrylate and 6.9 g of diethylene glycol dimethyl ether into a 50 mL eggplant flask, the inner space of the eggplant flask was replaced with nitrogen gas. A reaction solution was obtained by adding 440 mg of bipyridine ligand and 160 mg of copper bromide into an eggplant flask and stirring the content of the eggplant flask at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 200 mg of sodium hydroxide and 420 mg of cysteamine were added to the purified reaction solution, and the reaction solution was stirred at a temperature of 80° C. for 4 hours to obtain a carboxyl group at one end and a thiol group at the other end. A polymer solution containing polymethoxyethyl acrylate having a group [hereinafter referred to as polymer (4)] was obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of polymer (4) was 6,300.

Production example 5
After adding a mixed solution of 220 mg of 4-(1-bromoethyl)benzoic acid, 6.5 g of methoxyethyl acrylate and 6.5 g of diethylene glycol dimethyl ether into a 50 mL eggplant flask, the inner space of the eggplant flask was replaced with nitrogen gas. A reaction solution was obtained by adding 440 mg of bipyridine ligand and 160 mg of copper bromide into an eggplant flask and stirring the content of the eggplant flask at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 190 mg of sodium hydroxide and 330 mg of ethylenediamine were added to the purified reaction solution, and the reaction solution was stirred at a temperature of 80° C. for 4 hours to obtain a carboxyl group at one end and an amino group at the other end. A polymer solution containing polymethoxyethyl acrylate having a group [hereinafter referred to as polymer (5)] was obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of polymer (5) was 5,800.

Production example 6
After adding a mixture of 220 mg of 2-hydroxyethyl 2-bromoisobutyrate (manufactured by Sigma-Aldrich), 5.8 g of methoxyethyl acrylate and 5.8 g of diethylene glycol dimethyl ether into a 50 mL eggplant flask, the inner space of the eggplant flask was purged with nitrogen. replaced with gas. A reaction solution was obtained by adding 440 mg of bipyridine ligand and 160 mg of copper bromide into an eggplant flask and stirring the content of the eggplant flask at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 180 mg of sodium hydroxide and 400 mg of cysteamine were added to the purified reaction solution, and the reaction solution was stirred at a temperature of 80° C. for 4 hours to obtain a hydroxyl group at one end and a thiol group at the other end. A polymer solution containing polymethoxyethyl acrylate [hereinafter referred to as polymer (6)] was obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of polymer (6) was 5,600.

Production example 7
2 g (solid content) of polymer (1) obtained above, 1.9 g (solid content) of polymer (2) obtained above and 2 g of dichloromethane were added into a 100 mL Schlenk tube, and the resulting mixture was cooled to -5°C. While maintaining the temperature of the mixture at −5° C., a mixture of 180 mg of diisopropylcarbodiimide, 10 mg of 4-dimethylaminopyridine and 1 g of dichloromethane was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. By filtering the mixture and removing the precipitate, a biocompatible copolymer of polymethoxyethyl acrylate having an ester bond in the main chain [hereinafter referred to as polymer (7)] was obtained. The weight average molecular weight of the obtained polymer (7) was 10,200.

Production example 8
(1) Preparation of polymer A 2 g (solid content) of polymer (3) obtained above and 2 g of dichloromethane were added to a 100 mL Schlenk tube, and the resulting mixture was heated to 80°C.

Next, 170 mg of tert-butyl pyrocarbonate and 50 mg of N,N-dimethyl-4-aminopyridine as a catalyst were added into a Schlenk tube, stirred for 8 hours, and the resulting mixture was purified and freeze-dried. , to obtain a polymer A in which the carboxyl group of the polymer (3) was protected.

(2) Preparation of polymer B 2 g (solid content) of the polymer (3) obtained above was placed in a 100 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a gas inlet tube and a reflux condenser (condenser). and 2 mL of dichloromethane and 20 μL of concentrated sulfuric acid were added and the resulting mixture was refluxed with ice bath cooling.

Next, while maintaining the temperature of the mixture at 0° C., isobutylene was blown into the reaction vessel until the volume increased by 20 mL, and the vessel was sealed and stirred for 72 hours. Then, after neutralizing the mixture with triethylamine, the obtained mixture was purified and freeze-dried to obtain polymer B in which the hydroxyl group of polymer (3) was protected.

(3) Preparation of biocompatible copolymer 2 g (solid content) of polymer A obtained above, 2 g (solid content) of polymer B obtained above and 4 g of dichloromethane were added to a 100 mL Schlenk tube to obtain The resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 200 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 10 mg of 4-dimethylaminopyridine was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. The mixture was filtered to remove the precipitate, and while the obtained filtrate was cooled in an ice bath, 5 mL of trifluoroacetic acid was added to the filtrate with stirring to obtain a mixed solution.

Next, the mixed solution obtained above is stirred at 20° C. for 1 hour and freeze-dried to have an ester bond in the main chain, a carboxyl group at one end, and a hydroxyl group at the other end. A biocompatible copolymer of polymethoxyethyl acrylate [hereinafter referred to as polymer (8)] was obtained. The weight average molecular weight of the obtained polymer (8) was 11,000.

Production example 9
1.6 g (solid content) of the polymer A obtained above, 2 g (solid content) of the polymer (4) obtained above and 4 g of dichloromethane were added into a 100 mL Schlenk tube, and the resulting mixture was reduced to -5. Cooled to °C.

While maintaining the temperature of the mixture at −5° C., a mixture of 160 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 8 mg of 4-dimethylaminopyridine was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. The mixture was filtered to remove the precipitate, and while the obtained filtrate was cooled in an ice bath, 5 mL of trifluoroacetic acid was added to the filtrate with stirring to obtain a mixed solution.

Next, the mixed solution obtained above is stirred at 20 ° C. for 1 hour and freeze-dried to have an ester bond in the main chain, a carboxyl group at one end, and a thiol group at the other end. A biocompatible copolymer of polymethoxyethyl acrylate [hereinafter referred to as polymer (9)] having The weight average molecular weight of the obtained polymer (9) was 12,500.

Production example 10
(1) Preparation of polymer C 2 g (solid content) of polymer (5) obtained above and 2 g of dichloromethane were added to a 100 mL Schlenk tube, and the resulting mixture was heated to 80°C.

Next, 170 mg of tert-butyl pyrocarbonate and 100 mg of triethylamine were added to the Schlenk tube, and after stirring for 8 hours, the resulting mixture was purified and freeze-dried to protect the amino group of polymer (5). Polymer C was obtained.

(2) Preparation of biocompatible copolymer 2 g (solid content) of polymer C obtained above, 1.9 g (solid content) of polymer (6) obtained above and 4 g of dichloromethane were placed in a 100 mL Schlenk tube. was added and the resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 170 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 8 mg of 4-dimethylaminopyridine was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. The mixture was filtered to remove the precipitate, and while the obtained filtrate was cooled in an ice bath, 5 mL of trifluoroacetic acid was added to the filtrate with stirring to obtain a mixed solution.

Next, the mixed solution obtained above is stirred at 20 ° C. for 1 hour and freeze-dried to have an ester bond in the main chain, an amino group at one end, and a thiol group at the other end. A biocompatible copolymer of polymethoxyethyl acrylate [hereinafter referred to as polymer (10)] having The weight average molecular weight of the obtained polymer (10) was 13,000.

Production Example 11
(1) Preparation of Polymer D After adding a mixture of 20 mg of 4-(1-bromoethyl)benzoic acid, 3 g of methoxyethyl acrylate and 3 g of diethylene glycol dimethyl ether into a 100 mL Schlenk tube, the inner space of the Schlenk tube was filled with nitrogen gas. replaced. A reaction solution was obtained by adding 40 mg of a bipyridine ligand and 15 mg of copper bromide into a Schlenk tube and stirring the content of the Schlenk tube at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 15 mg of sodium hydroxide and 60 mg of ethanolamine are added to the purified reaction solution, and the reaction solution is stirred at a temperature of 80° C. for 4 hours. A polymer solution containing polymethoxyethyl acrylate having a group and a hydroxyl group at the other end was obtained.

2 mL of dichloromethane and 20 μL of concentrated sulfuric acid were added to 2 g of the polymer solution obtained above, and the resulting mixture was refluxed while cooling in an ice bath.

Next, while maintaining the temperature of the mixture at 0° C., isobutylene was blown into the Schlenk tube until the volume increased by 20 mL, and the mixture was sealed and stirred for 72 hours. Thereafter, the mixture was neutralized with triethylamine, and the resulting mixture was purified and freeze-dried to obtain polymer D with protected hydroxyl groups. The weight average molecular weight of the obtained polymer D was 15,000.

(2) Preparation of biocompatible copolymer 2 g (solid content) of polymer D obtained above, 0.7 g (solid content) of polymer (6) obtained above and 4 g of dichloromethane were placed in a 100 mL Schlenk tube. was added and the resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 70 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 5 mg of 4-dimethylaminopyridine was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. The mixture was filtered to remove the precipitate, and while the obtained filtrate was cooled in an ice bath, 5 mL of trifluoroacetic acid was added to the filtrate with stirring to obtain a mixed solution.

Next, the mixed solution obtained above is stirred at 20 ° C. for 1 hour and freeze-dried to have an ester bond in the main chain, a hydroxyl group at one end, and a thiol group at the other end. A biocompatible copolymer of polymethoxyethyl acrylate [hereinafter referred to as polymer (11)] was obtained. The weight average molecular weight of the obtained polymer (11) was 20,000.

Production example 12
2 g (solid content) of the polymer (1) obtained above, 4 g of dichloromethane and 15 mg of N-(4-pyridyl)dimethylamine were added to a 30 mL eggplant flask, and the resulting mixture was cooled in an ice bath. Stirred.

Next, the eggplant flask was ice-cooled, and a mixed solution of 30 mg of 2-mercaptoethanol, 60 mg of diisopropylcarbodiimide, and 4 g of dichloromethane was added dropwise into the eggplant flask while confirming that the temperature in the reaction system was 10°C or less. After that, the eggplant flask was removed from the ice bath, and the mixture was stirred at room temperature for 24 hours. Thereafter, the resulting reaction solution is passed through a silica column and concentrated to obtain a thiol group-containing biocompatible polymer of polymethoxyethyl acrylate having a thiol group at one end [hereinafter referred to as polymer (12)]. rice field. The weight average molecular weight of the obtained polymer (12) was 5,500.

Production example 13
2 g (solid content) of the polymer (1) obtained above, 4 g of dichloromethane and 16 mg of N-(4-pyridyl)dimethylamine were added to a 30 mL eggplant flask, and the resulting mixture was cooled in an ice bath. Stirred.

Next, the eggplant flask was ice-cooled, and while confirming that the temperature in the reaction system was 10° C. or less, 48 mg of 2-hydroxyethyl disulfide [manufactured by Tokyo Chemical Industry Co., Ltd.], 78 mg of diisopropylcarbodiimide, and 4 g of dichloromethane were added. was added dropwise into the eggplant flask, the eggplant flask was removed from the ice bath, and the mixture was stirred at room temperature for 24 hours. After that, 320 mg of dithiothreitol was added to the mixed solution, and the mixture was stirred at room temperature for 24 hours to break disulfide bonds. The resulting reaction solution was passed through a silica column and concentrated to obtain a thiol group-containing biocompatible polymer of polymethoxyethyl acrylate having a thiol group at one end [hereinafter referred to as polymer (13)]. The weight average molecular weight of the obtained polymer (13) was 4,100.

Production example 14
After adding a mixture of 100 mg of bis[2-(2′-bromoisobutyryloxy)ethyl]disulfide (manufactured by Sigma-Aldrich), 2.5 g of methoxyethyl acrylate and 1 g of methyl ethyl ketone into a 100 mL Schlenk tube, was replaced with nitrogen gas. 50 mg of N,N,N′,N″,N″-pentamethyldiethylenetriamine (manufactured by Sigma-Aldrich) and 40 mg of copper bromide were added to the Schlenk tube, and the temperature of the contents of the Schlenk tube was maintained at 80° C. for 5 minutes. After stirring for hours, a reaction solution was obtained. After adding 2.5 g of methyl ethyl ketone to the resulting reaction solution, purification was performed by passing through an alumina column. Polymethoxyethyl acrylate having disulfide groups was obtained by reprecipitating the reaction solution after column purification with 10 g of hexane. The weight average molecular weight of the resulting polymethoxyethyl acrylate having disulfide groups was 8,800.

Next, 5 g of dichloromethane and 650 mg of dithiothreitol are added to 2 g of the polymethoxyethyl acrylate having a disulfide group obtained above, and the reaction solution is stirred at room temperature for 72 hours, filtered through a filter, and purified. , to obtain a polymer solution containing polymethoxyethyl acrylate having a thiol group at one end [hereinafter referred to as polymer (14)]. The solid content in the polymer solution was 25% by mass, and the weight average molecular weight of the obtained polymer (14) was 4,400.

Production example 15
180 g of diethylene glycol dimethyl ether was added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), and the diethylene glycol dimethyl ether in the reaction vessel was heated to 80°C, The internal space of the reaction vessel was replaced with nitrogen gas by introducing nitrogen gas into the reaction vessel at a flow rate of 20 mL/min for 30 minutes.

Next, a mixed solution of 100 g of N-2-hydroxypropyl methacrylamide (manufactured by Sigma-Aldrich), 400 mg of 4,4′-azobis(4-cyanopentanoic acid) and 20 g of diethylene glycol dimethyl ether was kept at 80° C. for 2 hours. It was continuously added dropwise into the reaction vessel. After adding 100 mg of 4,4'-azobis(4-cyanopentanoic acid) into the reaction vessel 3 hours and 4 hours after the start of dropping the mixed liquid while maintaining the temperature of the contents of the reaction vessel at 80 ° C. By maintaining the temperature of the contents of the reaction vessel at 80° C. for 2 hours, a polymer solution containing polyhydroxypropyl methacrylamide having terminal carboxyl groups [hereinafter referred to as polymer (15)] was obtained. . The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of the obtained polymer (15) was 6,000.

Production example 16
Into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), 400 g of a mixed solvent consisting of 50% by mass of diethylene glycol dimethyl ether and 50% by mass of ethanol was added to react. The mixed solvent in the container was heated to 80° C., and nitrogen gas was introduced into the reaction container at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction container with nitrogen gas.

Next, N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine [manufactured by Osaka Organic Chemical Industry Co., Ltd., trade name: GLBT] 100 g, 2,2′-azobis[2-methyl —N-(2-hydroxyethyl)propionamide] and 100 g of the mixed solvent were continuously added dropwise over 2 hours into a reaction vessel maintained at 80°C. While maintaining the temperature of the contents of the reaction vessel at 80° C., 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide] was After adding 100 mg into the reaction vessel, the temperature of the contents of the reaction vessel was maintained at 80° C. for 2 hours to contain polycarboxybetaine having a terminal hydroxyl group [hereinafter referred to as polymer (16)]. A polymer solution was obtained. The solid content in the polymer solution was 20% by mass, and the weight average molecular weight of polymer (16) was 7,300.

Production Example 17
Into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), 260 g of a mixed solvent consisting of 50% by mass of diethylene glycol dimethyl ether and 50% by mass of ethanol was added to react. The mixed solvent in the container was heated to 80° C., and nitrogen gas was introduced into the reaction container at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction container with nitrogen gas.

Next, a mixture of 80 g of styrene, 400 mg of 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide] and 65 g of the mixed solvent was kept at 80° C. for 2 hours in a reaction vessel. It was continuously dripped inside. While maintaining the temperature of the contents of the reaction vessel at 80° C., 2,2′-azobis[2-methyl-N-(2-hydroxyethyl)propionamide] was After adding 100 mg into the reaction vessel, the temperature of the contents of the reaction vessel was maintained at 80° C. for 2 hours to obtain a polymer containing polystyrene having a terminal hydroxyl group [hereinafter referred to as polymer (17)]. A solution was obtained. The solid content in the polymer solution was 25% by mass, and the weight average molecular weight of polymer (17) was 6,500.

Production example 18
Into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), 400 g of a mixed solvent consisting of 50% by mass of diethylene glycol dimethyl ether and 50% by mass of ethanol was added to react. The mixed solvent in the container was heated to 80° C., and nitrogen gas was introduced into the reaction container at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction container with nitrogen gas.

Next, 110 g of lauryl methacrylate, 500 mg of 2,2′-azobis(2-methylpropionamidine) dihydrochloride [manufactured by Wako Pure Chemical Industries, Ltd., product number: V-50, hereinafter the same] and 40 g of the mixed solvent were mixed. The liquid was continuously added dropwise over 2 hours into a reaction vessel maintained at 80°C. While maintaining the temperature of the contents of the reaction vessel at 80° C., 125 mg of 2,2′-azobis(2-methylpropionamidine) dihydrochloride was added to the reaction vessel 3 hours and 4 hours after the start of dropping the mixture. After the addition, the temperature of the contents of the reaction vessel was maintained at 80° C. for 2 hours to obtain a polymer solution containing polylauryl methacrylate having an amino group at its terminal [hereinafter referred to as polymer (18)]. rice field. The solid content in the polymer solution was 20% by mass, and the weight average molecular weight of polymer (18) was 5,900.

Production Example 19
Into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), 330 g of a mixed solvent consisting of 50% by mass of diethylene glycol dimethyl ether and 50% by mass of ethanol was added to react. The mixed solvent in the container was heated to 80° C., and nitrogen gas was introduced into the reaction container at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction container with nitrogen gas.

Next, a mixed solution of 90 g of n-butyl methacrylate, 450 mg of 2,2′-azobis(2-methylpropionamidine) dihydrochloride and 30 g of the mixed solvent was continuously placed in a reaction vessel maintained at 80° C. over 2 hours. Dripped. While maintaining the temperature of the contents of the reaction vessel at 80° C., 110 mg of 2,2′-azobis(2-methylpropionamidine) dihydrochloride was added to the reaction vessel 3 hours and 4 hours after the start of dropping the mixture. After the addition, the temperature of the contents of the reaction vessel was maintained at 80° C. for 2 hours to obtain a polymer solution containing poly n-butyl methacrylate having an amino group at its terminal [hereinafter referred to as polymer (19)]. got The solid content in the polymer solution was 20% by mass, and the weight average molecular weight of polymer (19) was 5,300.

Production example 20
180 g of diethylene glycol dimethyl ether was added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), and the diethylene glycol dimethyl ether in the reaction vessel was heated to 80°C, The internal space of the reaction vessel was replaced with nitrogen gas by introducing nitrogen gas into the reaction vessel at a flow rate of 20 mL/min for 30 minutes.

Next, a mixed solution of 100 g of 2-hydroxyethyl methacrylate, 400 mg of 4,4'-azobis(4-cyanopentanoic acid) and 20 g of diethylene glycol dimethyl ether was continuously added dropwise over 2 hours into the reaction vessel maintained at 80°C. After adding 100 mg of 4,4'-azobis(4-cyanopentanoic acid) into the reaction vessel 3 hours and 4 hours after the start of dropping the mixed liquid while maintaining the temperature of the contents of the reaction vessel at 80 ° C. By maintaining the temperature of the contents of the reaction vessel at 80° C. for 2 hours, a polymer solution containing polyhydroxyethyl methacrylate having terminal carboxyl groups (hereinafter referred to as polymer (20)) was obtained. The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of polymer (20) was 5,700.

Production example 21
(1) Preparation of Polymer E Add 180 g of diethylene glycol dimethyl ether into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), and diethylene glycol dimethyl ether in the reaction vessel. was heated to 80° C., and nitrogen gas was introduced into the reaction vessel at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction vessel with nitrogen gas. After that, a mixed solution of 100 g of methoxypolyethylene glycol methacrylate (average number of added moles of ethylene oxide: 9), 400 mg of 4,4'-azobis(4-cyanopentanoic acid) and 20 g of diethylene glycol dimethyl ether was continuously dropped into the reaction vessel over 2 hours. did.

Next, while maintaining the temperature of the contents of the reaction vessel at 80° C., 100 mg of 4,4′-azobis(4-cyanopentanoic acid) was added to the reaction vessel 3 hours and 4 hours after the start of dropping the mixture. By adding and maintaining at 80° C. for 2 hours, a polymer solution containing polymethoxypolyethylene glycol methacrylate (hereinafter referred to as polymer E) having terminal carboxyl groups was obtained. The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of polymer E was 5,000.

(2) Preparation of biocompatible copolymer 2 g (solid content) of polymer E obtained above, 2.1 g (solid content) of polymer (2) obtained above and 4 g of dichloromethane were placed in a 100 mL Schlenk tube. was added and the resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 200 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 10 mg of 4-dimethylaminopyridine was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. By filtering the mixture and removing the precipitate, a biocompatible copolymer of polymethoxyethyl acrylate and polymethoxypolyethylene glycol methacrylate having an ester bond in the main chain [hereinafter referred to as polymer (21)] got The weight average molecular weight of the obtained polymer (21) was 11,600.

Production example 22
Into a 100 mL Schlenk tube were added 1.2 g of methoxypolyethylene glycol [weight average molecular weight: 5000, manufactured by Sigma-Aldrich], 2 g of the polymer (1) obtained above (solid content) and 4 g of dimethylformamide. The mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 180 mg of diisopropylcarbodiimide, 1 g of dimethylformamide and 9 mg of 4-dimethylaminopyridine was added into the Schlenk tube under stirring, and maintained for 1 hour and then at room temperature for 1 hour. The mixed solution is filtered to remove precipitates, thereby obtaining a biocompatible copolymer of polyethylene glycol and polymethoxyethyl acrylate having an ester bond in the main chain [hereinafter referred to as polymer (22)]. rice field. The weight average molecular weight of the obtained polymer (22) was 9,000.

Production example 23
(1) Preparation of Polymer F Add 180 g of diethylene glycol dimethyl ether into a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), and diethylene glycol dimethyl ether in the reaction vessel. was heated to 80° C., and nitrogen gas was introduced into the reaction vessel at a flow rate of 20 mL/min for 30 minutes to replace the internal space of the reaction vessel with nitrogen gas. Thereafter, a mixture of 100 g of 2-methacryloyloxyethylphosphorylcholine, 400 mg of 4,4'-azobis(4-cyanopentanoic acid) and 20 g of diethylene glycol dimethyl ether was continuously added dropwise into the reaction vessel over 2 hours.

Next, while maintaining the temperature of the contents of the reaction vessel at 80° C., 100 mg of 4,4′-azobis(4-cyanopentanoic acid) was added 3 hours and 4 hours after the start of dropping of the mixed solution. C. for 2 hours to obtain a polymer solution containing poly 2-methacryloyloxyethylphosphorylcholine having a terminal carboxyl group (hereinafter referred to as polymer F). The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of polymer F was 5,000.

(2) Preparation of biocompatible copolymer 2 g (solid content) of polymer F obtained above, 2.1 g (solid content) of polymer (2) obtained above and 4 g of dichloromethane were placed in a 100 mL Schlenk tube. was added and the resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 200 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 10 mg of 4-dimethylaminopyridine was added into a Schlenk tube under stirring, and the mixture was stirred at −5° C. for 1 hour. maintained and then at room temperature for 1 hour. By filtering the mixture and removing the precipitate, a biocompatible copolymer of polymethoxyethyl acrylate and poly 2-methacryloyloxyethylphosphorylcholine having an ester bond in the main chain [hereinafter referred to as polymer (23) ] was obtained. The weight average molecular weight of the obtained polymer (23) was 12,000.

Production example 24
180 g of toluene was added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet tube and a reflux condenser (condenser), and the temperature of toluene in the reaction vessel was raised to 90° C. at 20 mL/min. The internal space of the reaction vessel was replaced with nitrogen gas by introducing nitrogen gas into the reaction vessel for 30 minutes at a flow rate of . After that, a mixture of 100 g of methyl methacrylate, 50 mg of azobisisobutyronitrile and 20 g of toluene was continuously added dropwise into the reactor over 2 hours.

Next, while maintaining the temperature of the content in the reaction vessel at 90°C, 10 mg of azobisisobutyronitrile is added 3 hours and 4 hours after the start of dropping of the mixture, and the temperature is maintained at 90°C for 2 hours. Thus, a polymer solution containing polymethyl methacrylate [hereinafter referred to as polymer (24)] was obtained. The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of polymer (24) was 71,000.

Production example 25
After adding a mixture of 200 mg of 4-(1-bromoethyl)benzoic acid, 6.0 g of glycerin methacrylate and 6.0 g of isopropyl alcohol into a 50 mL eggplant flask, the inner space of the eggplant flask was replaced with nitrogen gas. A reaction solution was obtained by adding 320 mg of bipyridine ligand and 130 mg of copper bromide into an eggplant flask and stirring the content of the eggplant flask at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 190 mg of sodium hydroxide and 280 mg of ethanolamine were added to the purified reaction solution, and the reaction solution was stirred at a temperature of 80° C. for 4 hours to obtain a carboxyl group at one end and a A polymer solution containing polyglycerol methacrylate having hydroxyl groups (hereinafter referred to as polymer (25)) was obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of polymer (25) was 6,500.

Production example 26
After adding a mixed solution of 200 mg of 4-(1-bromoethyl)benzoic acid, 6.0 g of glycerin acrylate and 6.0 g of isopropyl alcohol into a 50 mL eggplant flask, the inner space of the eggplant flask was replaced with nitrogen gas. A reaction solution was obtained by adding 320 mg of bipyridine ligand and 130 mg of copper bromide into an eggplant flask and stirring the content of the eggplant flask at 80° C. for 3 hours. The resulting reaction solution was purified by passing through a silica column.

Next, 180 mg of sodium hydroxide and 330 mg of ethanolamine were added to the purified reaction solution, and the reaction solution was stirred at a temperature of 80° C. for 4 hours to obtain a carboxyl group at one end and a A polymer solution containing a polyglycerin acrylate having a hydroxyl group [hereinafter referred to as polymer (26)] was obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of polymer (26) was 5,600.

Production Example 27
(1) Preparation of polymer G 4 g (solid content) of polymer (25) obtained above and 4 g of dimethylformamide were added to a 100 mL Schlenk tube, and the resulting mixture was heated to 80°C.

Next, 340 mg of tert-butyl pyrocarbonate and 100 mg of N,N-dimethyl-4-aminopyridine as a catalyst were added into a Schlenk tube, stirred for 8 hours, and the resulting mixture was purified and freeze-dried. , to obtain polymer G in which the carboxyl group of polymer (25) was protected.

(2) Preparation of biocompatible copolymer 2 g (solid content) of polymer (1) obtained above, 2.4 g (solid content) of polymer G obtained above and dimethylformamide were placed in a 100 mL Schlenk tube. 4 g was added and the resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 180 mg of diisopropylcarbodiimide, 1 g of dimethylformamide and 9 mg of 4-dimethylaminopyridine was added into the Schlenk tube under stirring, and maintained for 1 hour and then at room temperature for 1 hour. The mixture was filtered to remove the precipitate, and while the obtained filtrate was cooled in an ice bath, 5 mL of trifluoroacetic acid was added to the filtrate with stirring to obtain a mixed solution.

Next, the mixed solution obtained above is stirred at 20° C. for 1 hour, and freeze-dried to obtain a living body of polyglycerin methacrylate and polymethoxyethyl acrylate having an ester bond in the main chain and a carboxyl group at the end. A compatible copolymer [hereinafter referred to as polymer (27)] was obtained. The weight average molecular weight of the obtained polymer (27) was 13,100.

Production example 28
(1) Preparation of polymer H 4 g (solid content) of polymer (26) obtained above and 4 g of dimethylformamide were added to a 100 mL Schlenk tube, and the resulting mixture was heated to 80°C.

Next, 340 mg of tert-butyl pyrocarbonate and 100 mg of N,N-dimethyl-4-aminopyridine as a catalyst were added into a Schlenk tube, stirred for 8 hours, and the resulting mixture was purified and freeze-dried. , to obtain polymer H in which the carboxyl group of polymer (26) was protected.

(2) Preparation of biocompatible copolymer 2 g (solid content) of polymer (1) obtained above, 2 g (solid content) of polymer H obtained above and 4 g of dimethylformamide were placed in a 100 mL Schlenk tube. was added and the resulting mixture was cooled to -5°C.

While maintaining the temperature of the mixture at −5° C., a mixture of 180 mg of diisopropylcarbodiimide, 1 g of dimethylformamide and 9 mg of 4-dimethylaminopyridine was added into the Schlenk tube under stirring, and maintained for 1 hour and then at room temperature for 1 hour. The mixture was filtered to remove the precipitate, and while the obtained filtrate was cooled in an ice bath, 5 mL of trifluoroacetic acid was added to the filtrate with stirring to obtain a mixed solution.

Next, the mixed solution obtained above is stirred at 20° C. for 1 hour, and freeze-dried to obtain a living body of polyglycerin methacrylate and polymethoxyethyl acrylate having an ester bond in the main chain and a carboxyl group at the end. A compatible copolymer [hereinafter referred to as polymer (28)] was obtained. The weight average molecular weight of the obtained polymer (28) was 11,800.

Production example 29
2 g (solid content) of the polymer (1) obtained above, 4 g of dichloromethane and 16 mg of N-(4-pyridyl)dimethylamine were added to a 30 mL eggplant flask, and the resulting mixture was cooled in an ice bath. Stirred.

Next, the eggplant flask was ice-cooled, and while confirming that the temperature in the reaction system was 10° C. or less, 48 mg of 2-hydroxyethyl disulfide [manufactured by Tokyo Chemical Industry Co., Ltd.], 78 mg of diisopropylcarbodiimide, and 4 g of dichloromethane were added. was added dropwise into the eggplant flask, the eggplant flask was removed from the ice bath, and the mixture was stirred at room temperature for 24 hours. The resulting reaction solution was passed through a silica column and concentrated to obtain polymethoxyethyl acrylate having disulfide bonds [hereinafter referred to as polymer (29)]. The resulting polymer (29) had disulfide bonds and a weight average molecular weight of 7,000.

Production example 30
After adding a mixture of 100 mg of bis[2-(2′-bromoisobutyryloxy)ethyl]disulfide (manufactured by Sigma-Aldrich), 2.5 g of methoxyethyl acrylate and 1 g of methyl ethyl ketone into a 100 mL Schlenk tube, was replaced with nitrogen gas. 50 mg of N,N,N′,N″,N″-pentamethyldiethylenetriamine (manufactured by Sigma-Aldrich) and 40 mg of copper bromide were added to the Schlenk tube, and the temperature of the contents of the Schlenk tube was maintained at 80° C. for 5 minutes. After stirring for hours, a reaction solution was obtained.

Next, after adding 2.5 g of methyl ethyl ketone to the reaction solution obtained above, purification was performed by passing through an alumina column. The reaction solution after column purification was reprecipitated with 10 g of hexane to obtain polymethoxyethyl acrylate having disulfide bonds [hereinafter referred to as polymer (30)]. The resulting polymer (30) had disulfide bonds and an average molecular weight of 8,800.

5 g of dichloromethane and 650 mg of dithiothreitol were added to 2 g of the polymer (30) obtained above, and the resulting mixture was stirred at room temperature for 72 hours, filtered through a filter, and purified to obtain a thiol at one end. A polymer solution containing polymethoxyethyl acrylate having groups was obtained. The weight average molecular weight of the obtained polymethoxyethyl acrylate having a thiol group at one end was 4,400. From this, it was confirmed that the polymer (30) obtained above had a disulfide bond between polymethoxyethyl acrylate polymers having a weight average molecular weight of 4,400.

Example 1
The polymer (1) obtained above was used as a biocompatible medical material and freeze-dried for 8 hours. and 0.08 mmol of 3,5-dipentadecyloxybenzamidine hydrochloride in 30 mL of tert-butyl alcohol. A lipid mixture (1) was obtained as a raw material for lipid membranes.

By dissolving 0.2 mmol of the fluorescent dye carboxyfluorescein in 10 mL of 0.01 mol/L phosphate-buffered saline [manufactured by Wako Pure Chemical Industries, Ltd.] (hereinafter referred to as PBS), the inner aqueous layer of the liposome (2 ).

Next, the inner water layer (2) is added to the mixture (1) obtained above, the mixture is heated at 65°C for 10 minutes, and then the mixture is subjected to ultrasonic treatment for 5 minutes. , to obtain a liposome dispersion. The liposome dispersion obtained above was pumped to a polycarbonate film having a pore size of 0.2 μm, and further pumped to a polycarbonate film having a pore size of 0.1 μm for particle size regulation. The average particle size of the liposomes obtained above was measured using a concentrated particle size analyzer [manufactured by Otsuka Electronics Co., Ltd., product number: FPAR-1000]. Table 1 shows the results.

Next, using the liposomes or liposome dispersions obtained above, the physical properties of the biocompatible medical material were evaluated by the following methods: investigated on the basis of Table 1 shows the results.

(1) Sustained Release of Drug A mixture of 1 mL of liposome dispersion, 200 μL of defiberized rabbit blood [manufactured by KojiBio Co., Ltd.] and 1 mL of PBS was placed in a constant temperature bath at 37° C. and incubated for 30 minutes or 24 hours. Using SH-9000 manufactured by Denki Co., Ltd., fluorescence intensity was measured at an excitation wavelength of 494 nm and a fluorescence wavelength of 521 nm, and the release rate of the drug was calculated by the formula:
[Drug release rate (%)]=[(F ₂ −F ₁ )/(F ₃ −F ₁ )]×100
[In the formula, F ₁ is the fluorescence intensity before incubation, F ₂ is the fluorescence intensity after incubation at 37° C., F ₃ is added to the mixed solution instead of PBS, and 2% polyoxyethylene (10) octylphenyl ether [Manufactured by Wako Pure Chemical Industries, Ltd., trade name: Triton-X] Fluorescence intensity (100% leakage) after adding and mixing with PBS solution]
and the sustained release properties of the drug were evaluated based on the following evaluation criteria.

[Evaluation Criteria for Sustained Release of Inclusions]
A. When the incubation time is 30 minutes ◎: drug release rate is less than 10% ○: drug release rate is 10% or more and less than 30% △: drug release rate is 30% or more and less than 90% ×: drug release 90% or more

B. When the incubation time is 24 hours ◎: drug release rate is less than 60% ○: drug release rate is 30% or more and less than 60% △: drug release rate is 10% or more and less than 30% ×: drug release 10% or more

(2) Retainability of Particle Shape A parallel plate with a diameter of 7.9 mm of a viscoelasticity measuring device [manufactured by Rheometric Scientific F.E. After adding 1 mL of the liposome dispersion and applying shear strain at a frequency of 1 Hz for 5 minutes, the liposome dispersion was collected and the average particle size was measured, and the particle size retention rate was calculated by the formula:
[Particle size maintenance rate (%)] = [Average particle size after test/Average particle size before test] × 100
and the retention of the particle shape was evaluated based on the following evaluation criteria.

[Evaluation criteria for retention of particle shape]
○: Particle size retention rate is 70% or more and 100% or less △: Particle size retention rate is 20% or more and less than 70% ×: Particle size retention rate is less than 20%

(3) Hemolysis resistance Liposomes were dissolved in PBS to prepare a 1% by mass PBS solution.

48 mL of the PBS solution was added to 2 mL of defiberized rabbit blood [manufactured by Kohjin Bio Co., Ltd.], mixed by inversion to prepare a mixed solution, and then centrifuged at 4° C. and 2000 rpm for 10 minutes. A blood solution was obtained by adding 48 mL of PBS to the mixture from which the supernatant was removed and mixing by inversion.

2 mL of the liposome solution obtained above was added to 2 mL of the blood solution obtained above, mixed by inversion, incubated at 37° C. for 1 hour, and further centrifuged at 4° C. and 2000 rpm for 10 minutes. The absorbance of the supernatant at a wavelength of 545 nm was measured with a spectrophotometer [manufactured by Shimadzu Corporation, product number: UV-3600].

To 2 mL of the blood solution obtained above, 2 mL of 2% polyoxyethylene (10) octylphenyl ether [manufactured by Wako Pure Chemical Industries, Ltd., trade name: Triton-X] PBS solution was added and mixed by inversion. Absorbance at a wavelength of 545 nm was measured in the same manner as described above. The absorbance at this time was defined as 100% hemolytic.

Then the degree of hemolysis is given by the formula:
[Hemolysis (%)]=[Absorbance of incubation supernatant/Absorbance when using Triton-X]×100
and the hemolysis resistance was evaluated based on the following evaluation criteria.

[Evaluation criteria for resistance to hemolysis]
◎: hemolysis less than 30% ○: hemolysis 30% or more and less than 50% △: hemolysis 50% or more and less than 70% ×: hemolysis 70% or more

(4) In vitro release property A mixture was obtained by mixing 0.1 g of the polymer freeze-dried for 8 hours and 0.5 g of dimethylformamide.

Next, 1 g of defibrinated rabbit blood [manufactured by Kohjin Bio Co., Ltd.] and 3 g of PBS were added to the above-obtained mixture to prepare a mixed solution. After the obtained mixture was mixed by inversion, it was incubated at 37° C. for 24 hours.

Next, the above-incubated mixture was centrifuged at 2000 rpm for 10 minutes at 4°C, and the supernatant was diluted 10-fold with dimethylformamide and subjected to gel permeation chromatography in the same manner as above. The weight average molecular weight of the polymer was measured by , and the extracorporeal release property was evaluated using the weight average molecular weight of the polymer as an index. The evaluation criteria are shown below. It should be noted that the lower the weight average molecular weight of the polymer, the easier the release of the polymer to the outside of the body.

[External release evaluation criteria]
◎: The weight average molecular weight of the polymer is 8000 or less ○: The weight average molecular weight of the polymer is more than 8000 and is 30000 or less △: The weight average molecular weight of the polymer is more than 30000 and is 60000 or less ×: The weight average molecular weight of the polymer is over 60000

Examples 2-29 and Comparative Example 1
A liposome and a liposome dispersion were prepared in the same manner as in Example 1, except that the polymer shown in Table 1 was used as a biocompatible medical material instead of polymer (1). The average particle size of the liposomes obtained above was measured using a concentrated particle size analyzer [manufactured by Otsuka Electronics Co., Ltd., product number: FPAR-1000]. Table 1 shows the results.

Next, using the liposomes or liposome dispersions obtained above, the physical properties of the biocompatible medical material were evaluated by the following methods: investigated on the basis of Table 1 shows the results. In Table 1, "-" means that evaluation was not performed.

From the results shown in Table 1, the biocompatible medical materials obtained in each example are excellent in sustained release of inclusions, shape retention of formed particles, resistance to hemolysis, and release from the body. It can be seen that Therefore, the biocompatible medical material of the present invention is, for example, a carrier, a medical device, or an instrument used for holding a drug and introducing it into the body through the oral route, blood, nasal route, transdermal route, eye drop, or the like. It is expected to be used as a coating agent such as a medical coating agent for substrates used in such as.

Claims (11)

A group having a weight average molecular weight of 1,000 to 90,000 and having at least one molecular end represented by the formula: -COOM (M represents a hydrogen atom or an alkali metal atom), a hydroxyl group, an allyl group, an epoxy group, an aldehyde group, or an amino group A biocompatible medical material comprising a biocompatible polymer in which a biocompatible monomer is polymerized and glycerin (meth)acrylate is used as the biocompatible monomer . A biocompatible medical material comprising a biocompatible polymer having a weight average molecular weight of 1000 to 90000 and having a thiol group at at least one molecular terminal, wherein the biocompatible polymer is biocompatible. Polymers obtained by polymerizing monomers are used, and the biocompatible monomers include (alkoxy)polyoxyalkylene group-containing unsaturated monomers, hydroxyl group-containing (meth)acrylates, polyethylene glycol, polypropylene glycol, methoxy At least one monomer selected from the group consisting of polyethylene glycol, ethoxypolyethylene glycol, methoxypolypropylene glycol, ethoxypolypropylene glycol, carboxybetaine monomer, sulfobetaine monomer, alkylene oxide, cyclic compound and amino acid is used, and the hydroxyl group is A biocompatible medical material, characterized in that glycerin (meth)acrylate is used as the contained (meth)acrylate. An alkoxy polyalkylene glycol mono (meth) having an alkoxy group having 1 to 4 carbon atoms and an oxyalkylene group having 1 to 4 carbon atoms as the biocompatible monomer, and having 2 to 30 moles of the oxyalkylene group. 3.) The biocompatible medical material according to claim 2, wherein at least one monomer selected from the group consisting of acrylate, glycerin (meth)acrylate, polyethylene glycol, carboxybetaine monomer and sulfobetaine monomer is used. . A biocompatible medical material comprising a biocompatible polymer having a disulfide bond between the biocompatible polymers having a weight average molecular weight of 1000 to 90000, wherein the biocompatible polymer is a biocompatible material Polymers obtained by polymerizing compatible monomers are used, and the biocompatible monomers include (alkoxy)polyoxyalkylene group-containing unsaturated monomers, hydroxyl group-containing (meth)acrylates, polyethylene glycol, and polypropylene glycol. , methoxypolyethylene glycol, ethoxypolyethylene glycol, methoxypolypropylene glycol, ethoxypolypropylene glycol, carboxybetaine monomer, sulfobetaine monomer, alkylene oxide, at least one monomer selected from the group consisting of cyclic compounds and amino acids is used, A biocompatible medical material, wherein glycerin (meth)acrylate is used as the hydroxyl group-containing (meth)acrylate. An alkoxy polyalkylene glycol mono (meth) having an alkoxy group having 1 to 4 carbon atoms and an oxyalkylene group having 1 to 4 carbon atoms as the biocompatible monomer, and having 2 to 30 moles of the oxyalkylene group. 5.) The biocompatible medical material according to claim 4, wherein at least one monomer selected from the group consisting of acrylate, glycerin (meth)acrylate, polyethylene glycol, carboxybetaine monomer and sulfobetaine monomer is used. . The biocompatible medical material according to any one of claims 1 to 5, wherein the biocompatible polymer has a molecular weight distribution (polymerization average molecular weight/number average molecular weight) of 1 to 2. The biocompatible medical material according to any one of claims 1 to 5, wherein the biocompatible polymer is used as particles having an average particle size of 10 to 1000 nm. The biocompatible polymer has functional groups at one or both ends, and the functional groups are proteins, monosaccharides, polysaccharides, sugar chains, antibodies, nucleic acids, active pharmaceutical ingredients, amino acids, peptides, folic acid, or dextrin. The biocompatible medical material according to any one of claims 1 to 5, which is bound to A composite obtained by combining the biocompatible medical material according to any one of claims 1 to 5 with a drug. A drug-encapsulating liposome, in which a drug-encapsulated liposome particle is coated with the biocompatible medical material according to any one of claims 1 to 5. A drug-encapsulating micelle, wherein a drug is micelle-formed with the biocompatible medical material according to any one of claims 1 to 5.