JP2018178072A - Biocompatible medical material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a biocompatible medical material superior in sustained release of inclusion, retention of a shape of a formed particle, hemolysis-resistance and outside body-releasing.SOLUTION: A biocompatible medical material contains biocompatible polymer having ester bond, amide bond or disulfide bond between the biocompatible polymers having 1000-90000 weight-average molecular weight. And a biocompatible medical material that weight-average molecular weight is 1000-90000 contains biocompatible polymer having thiol group in at least one molecular end.SELECTED DRAWING: None

Description

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

  As a biocompatible material that does not cause a biodefense reaction when it enters a living body, it has a synthetic polymer compound having a repeating unit consisting of alkoxyalkyl (meth) acrylate on its surface, and is in contact with a living tissue or body fluid Biocompatible medical materials used for applications (see, for example, Patent Document 1), a polymer synthesized by anionic polymerization from alkoxyalkyl (meth) acrylate, and a ratio of weight average molecular weight to number average molecular weight (weight average molecular weight A biocompatible material (for example, see Patent Document 2) or the like in which the value of / number average molecular weight) is 1.0 to 1.5 and the weight average molecular weight is 40000 or more has been proposed. Although the above-mentioned biocompatible medical materials and biocompatible materials can both be used for medical devices or the like in contact with blood or living tissue, they retain drugs because their properties to retain drugs are insufficient. 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 an end group possessed by a polymer arm has been proposed (see, for example, Patent Document 3) . However, the above-mentioned conjugate has a disadvantage that it is inferior in extracorporeal excretion due to its large molecular weight.

Unexamined-Japanese-Patent No. 04-152952 Japanese Patent Application Publication No. 2003-012723 Japanese Patent Application Publication No. 2013-534931

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

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 1,000 to 9,000,
(2) a biocompatible medical material comprising a biocompatible polymer having a disulfide bond between biocompatible polymers having a weight average molecular weight of 1,000 to 9,000, and (3) a weight average molecular weight of The present invention relates to a biocompatible medical material, which is 1000 to 900000 and contains a biocompatible polymer having a thiol group at at least one molecular terminal.

  According to the present invention, a biocompatible medical material excellent in sustained release of a drug, retention of particle shape, hemolytic resistance and extracorporeal release is provided.

  The biocompatible medical material of the present invention is, as described above, a biocompatible polymer having an ester bond or an amide bond between biocompatible polymers having a weight average molecular weight of 1,000 to 9,000, 9,000 to 9,000. A biocompatible polymer having a disulfide bond between biocompatible polymers having a weight average molecular weight or a biocompatible weight having a weight average molecular weight of 1000 to 90000 and having a thiol group at at least one molecular terminal Contains coalescing.

  The biocompatible polymer having a weight average molecular weight of 1000 to 90,000 and the biocompatible polymer having a weight average molecular weight of 1000 to 90,000 and having a thiol group at at least one molecular terminal are all, for example, biological organisms. It can be obtained by polymerizing compatible monomers.

  As a biocompatible monomer, for example, (alkoxy) polyoxyalkylene group-containing unsaturated monomer, hydroxyl group-containing (meth) acrylate, alkoxyalkyl (meth) acrylate, vinyl monomer, alkoxypolyoxyalkylene glycol, carboxybetaine Although a monomer, a sulfobetaine monomer, an alkylene oxide, a cyclic compound, an amino acid, an aspartic acid, glutamic acid etc. are mentioned, this invention is not limited only to this illustration. 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. Also, "(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 alkoxy polyoxyalkylene group-containing unsaturated monomer, and the polyoxyalkylene group-containing unsaturated monomer The saturated monomer and the alkoxypolyoxyalkylene group-containing unsaturated monomer may be used alone or in combination.

  As the (alkoxy) polyoxyalkylene group-containing unsaturated monomer, for example, a compound of the formula (I):

(Wherein, R ¹ , R ² and R ³ are each independently a hydrogen atom or a methyl group, R ⁴ is an alkylene group having 2 to 18 carbon atoms, and R ⁵ is a hydrogen atom or 1 to 20 carbon atoms A hydrocarbon group, X is a direct bond when the alkylene group of 1 to 5 carbon atoms, -CO- group, or R ¹ R ³ C = CR ² -group is a vinyl group, m is-(R ⁴ O) -Average added mole number of group, and represents 1 to 300)
The (alkoxy) polyoxyalkylene group containing unsaturated monomer etc. which are represented by are mentioned.

Incidentally, two or more expression in one molecule: If the oxyalkylene group represented by -R ⁴ O-exist, the oxyalkylene group may be bonded at random, be bonded in block It may be well coupled alternately.

In formula (I), R ⁵ is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms. Among R ⁵ , a saturated hydrocarbon group having 1 to 20 carbon atoms and an unsaturated hydrocarbon group having 2 to 20 carbon atoms are preferable, an alkyl group having 1 to 20 carbon atoms is more preferable, and an alkyl having 1 to 10 carbon atoms The group is more preferable, the alkyl group having 1 to 3 carbon atoms is further preferable, and the alkyl group having 1 or 2 carbon atoms is further more preferable.

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 an oxyethylene group, an oxypropylene group, an oxybutylene group, an oxyisobutylene group, an oxy-1-butene group, an oxy-2-butene group and the like, but the present invention is not limited thereto. It 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, or an oxybutylene group is more preferable, and an oxyethylene group is more preferable. Is more preferred.

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

X is a direct bond when the C1-C5 alkylene group, -CO- group, or R < ¹ > R < ³ > C = CR < ² >-group is a vinyl group. Among these groups, -CO- is preferred.

  Examples of (alkoxy) polyoxyalkylene group-containing unsaturated monomers include (alkoxy) unsaturated alcohol polyalkylene glycol adducts, (alkoxy) polyalkylene glycol ester monomers, (alkoxy) polyalkylene glycol monomaleine Although an acid ester etc. are mentioned, this invention is not limited only to this illustration.

  "(Alkoxy) unsaturated alcohol polyalkylene glycol adduct" means unsaturated alcohol polyalkylene glycol adduct or alkoxy unsaturated alcohol polyalkylene glycol adduct, and unsaturated alcohol polyalkylene glycol adduct and alkoxy unsaturated alcohol The 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-) Thenyl) ethers, such as methoxypolyethylene glycol mono (3-methyl-3-butenyl) ether, present invention is not limited only to those exemplified.

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

  The (alkoxy) polyalkylene glycol ester monomer is a monomer in which an unsaturated group and a polyalkylene glycol chain are linked via an ester bond. As the (alkoxy) polyalkylene glycol ester-based monomer, for example, an esterified product 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 having an oxyethylene group as a main component are preferable. 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, Aliphatic alcohols having 1 to 30 carbon atoms such as 3-hexanol, octanol, 2-ethyl-1-hexanol, nonyl alcohol, lauryl alcohol, cetyl alcohol and stearyl alcohol, and C3 to C30 alicyclics such as cyclohexanol And C 3 -C 30 unsaturated alcohols such as alcohol, (meth) allyl alcohol, 3-buten-1-ol, 3-methyl-3-buten-1-ol, etc. Also, two or more kinds may be used in combination. Examples of the esterified compounds 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) acrylate etc. are mentioned, These (alkoxy) polyalkylene glycol ester type | system | group monomers may be used independently, respectively, and may use 2 or more types together.

  Among (alkoxy) polyalkylene glycol ester type monomers, it has an alkoxy group having 1 to 4 carbon atoms such as methoxypolyethylene glycol monomethacrylate and an oxyalkylene group having 1 to 4 carbon atoms, and the addition mole of the oxyalkylene group An alkoxypolyalkylene glycol mono (meth) acrylate having a number of 2 to 30 is preferred.

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

  As hydroxyl group-containing (meth) acrylate, for example, carbon number of hydroxyalkyl group such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, glycerin (meth) acrylate, N-2-hydroxypropyl (meth) acrylamide, etc. is 2 to 2 Examples include hydroxyalkyl (meth) acrylate which is 4 and the like, 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.

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

  The vinyl monomer is a compound having biocompatibility having a vinyl group other than (alkoxy) polyoxyalkylene group-containing unsaturated monomer, hydroxyl group-containing (meth) acrylate and alkoxyalkyl (meth) acrylate. Examples of the vinyl monomer include 2- (meth) acryloyloxymethyl phosphorylcholine, 2- (meth) acryloyloxyethyl phosphorylcholine, tetrahydrofurfuryl (meth) acrylate, isopropyl acrylamide, vinyl alcohol, vinyl formamide, vinyl isobutyl acrylamide, Meta) acrylamide, dimethyl acrylamide, vinyl acetamide, N-vinyl pyrrolidone, styrene, diaminomethyl (meth) acrylate, diaminoethyl (meth) acrylate, dimethylamino (meth) acrylate, diethylamino (meth) acrylate, dimethylaminomethyl (meth) Although acrylate, dimethylaminoethyl (meth) acrylate etc. are mentioned, the present invention is limited only to such an illustration. Not to. These vinyl monomers may be used alone or in combination of two or more.

  As the alkoxy polyoxy alkylene glycol, for example, alkoxy group having 1 to 4 carbon atoms such as polyethylene glycol, polypropylene glycol, methoxy polyethylene glycol, ethoxy polyethylene glycol, methoxy polypropylene glycol, ethoxy polypropylene glycol and the like, and oxy alkylene having 1 to 4 carbon atoms Although it has a group and the alkoxypolyoxyalkylene glycol etc. whose addition mole number of an oxyalkylene group is 2-30 are mentioned, this invention is not limited only to this illustration. These alkoxy polyoxyalkylene glycols may be used alone or in combination of two or more.

  Examples of carboxybetaine monomers include N- (meth) acryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine and N- (meth) acryloylaminoethyl-N, N-dimethylammonium-α- Although N-methyl carboxy betaine, 3-[[2- (methacryloyl oxy) ethyl] dimethyl ammonio] propionate, etc. are mentioned, this invention is not limited only to this illustration. These carboxybetaine monomers may be used alone or in combination of two or more.

  As the sulfobetaine monomer, for example, [3- (acryloylamino) propyl] dimethyl (3-sulfobutyl) ammonium hydroxide internal salt, [3- (methacryloylamino) propyl] dimethyl (3-sulfobutyl) ammonium hydroxide internal Salts, N- (meth) acryloyloxyethyl-N, N-dimethylammonium methyl-α-sulfobetaine, N- (meth) acryloyloxyethyl-N, N-dimethylammoniumethyl-α-sulfobetaine, N- (meth) Acryloyloxyethyl-N, N-dimethylammonium propyl-α-sulfobetaine and the like can be mentioned, but the present invention is not limited to such examples. These sulfobetaine monomers may be used alone or in combination of two or more.

  As an alkylene oxide, although C2-C4 alkylene oxides, such as ethylene oxide and a propylene oxide, etc. are mentioned, for example, this invention is not limited only to this illustration. These alkylene oxides may be used alone or in combination of two or more.

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

  Among biocompatible monomers, (alkoxy) polyoxyalkylene group-containing unsaturated monomer, hydroxyalkyl (meth) acrylate having 2 to 4 carbon atoms of hydroxyalkyl group, and 1 carbon atom of alkoxy groupア ル コ キ シ 4 having an alkoxyalkyl acrylate having an alkyl group having 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 adding an oxyalkylene group Alkoxy polyoxyalkylene glycol having a number of moles of 2 to 30, a carboxybetaine monomer and a sulfobetaine monomer are preferable, and having an alkoxy group having 1 to 4 carbon atoms and an oxyalkylene group having 1 to 4 carbon atoms, an oxyalkylene group Alkoxy polyalkylene glycol mono (M ) Acrylate, 2-hydroxyethyl (meth) acrylate, glycerin (meth) acrylate, N-2-hydroxypropyl (meth) acrylamide, methoxyethyl (meth) acrylate, n-butyl (meth) acrylate, n-lauryl (meth) Acrylate, 2- (meth) acryloyloxyethyl phosphoryl choline, tetrahydrofurfuryl (meth) acrylate, N-vinyl pyrrolidone, styrene, polyethylene glycol, carboxybetaine monomers and sulfobetaine monomers are more preferred.

  In addition, a biocompatible monomer can be used together with the other monomer which can be copolymerized with a biocompatible monomer in the range which does not inhibit the objective of this invention. Other monomers copolymerizable with the biocompatible monomer include, for example, an aziridine compound, (meth) acrylic acid, methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, n- Examples include 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, but the present invention It is not limited to only this example. These other monomers may be used alone or in combination of two or more.

  Examples of the method for polymerizing the biocompatible monomer include living radical polymerization method represented by radical polymerization method, atom transfer radical polymerization method, reversible addition fragmentation chain transfer polymerization method, ionic polymerization method, ring opening weight Although legal, coordination polymerization, polycondensation and the like can be mentioned, the present invention is not limited to such examples.

  In polymerizing the biocompatible monomer, a solvent may be used. As the solvent, for example, aromatic solvents such as water, benzene, toluene and xylene; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol and tert-butyl alcohol; halogen atom-containing solvents such as dichloromethane and dichloroethane; Ether solvents such as diethylene glycol dimethyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether, ethyl cellosolve and butyl cellosolve; ester solvents such as ethyl acetate, butyl acetate and cellosolve acetate; acetone, methyl ethyl ketone, methyl isobutyl ketone, diacetone alcohol etc Ketone solvents; and organic solvents such as amide solvents such as dimethylformamide, but the present invention is limited only to such examples. Not to. 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 monomer, the concentration of the obtained polymer, and the like.

  When polymerizing the biocompatible monomer, a chain transfer agent can be used to adjust the molecular weight of the biocompatible polymer. Among the chain transfer agents, those corresponding to compounds having a functional group for introducing a functional group into a biocompatible polymer (hereinafter simply referred to as "functional group-containing compound") are included, The chain transfer agent corresponding to the compound can be used as one or both of a chain transfer agent and a functional group-containing compound.

  As a chain transfer agent, for example, alkali metal salts of thioacetate such as sodium thioacetate, potassium thioacetate, cysteine, cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3 -Hydrophilic thiol chain transfer agents such as mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, sodium salts and potassium salts thereof; Primary alcohols such as 2-aminopropan-1-ol, isopropyl Secondary alcohols such as alcohols, phosphorous acid, hypophosphorous acid and their salts (eg sodium hypophosphite, potassium hypophosphite etc), sulfite, hydrogen sulfite, dithionite, metabisulfite and Their salts (eg sodium sulfite, sulfite Non-thiol chain transfer agents such as sodium hydrogen phosphite, sodium dithionite, sodium metabisulfite, potassium sulfite, potassium bisulfite, potassium dithionite, potassium metabisulfite, etc.); butanethiol, octanethiol, Decanethiol, dodecanethiol, hexadecanethiol, octadecanethiol, cyclohexylmercaptan, thiophenol, octyl thioglycollate, octyl 2-mercaptopropionate, octyl 3-mercaptopropionate, 2-ethylhexyl mercaptopropionic acid, 2-mercaptooctanoic acid Hydrophobic thiol chain transfer agents such as ethyl ester, 1,8-dimercapto-3,6-dioxaoctane, decanetrithiol, dodecyl mercaptan; 4-chloro-3, -Dimethylpyrazole-1-carbodithioate 2'-cyanobutane-2'-yl, 3,5-dimethylpyrazole-1-carbodithioate 2'-cyanobutane-2'-yl, 3,5-dimethylpyrazole-1-carbodithioate Cyanomethyl, 2-cyanoprop-2-yl-dithiobenzoate, S- (2-cyanoprop-2-yl) -S-dodecyl trithiocarbonate, 4-[(2-carboxyethylsulfanylthiocarbonyl) sulfanyl] -4 -Cyclopentanoic acid, 4-cyano-4- (thiobenzoylthio) pentanoic acid, 4-cyano-4-[(dodecylsulfanylthiocarbonyl) sulfanyl] pentanoic acid, reversible addition of bis (dodecylsulfanylthiocarbonyl) disulfide, etc. Chain transfer agents for cleavage chain transfer polymerization It is, the present invention is not limited only to those exemplified. 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 the biocompatible monomer, the polymerization conditions such as the polymerization temperature, the molecular weight of the target biocompatible polymer, etc., and is not particularly limited. When a polymer having a molecular weight of 1,000 to 9,000 is obtained, it is preferably 0.1 to 20 parts by mass, and more preferably 0.5 to 15 parts by mass, per 100 parts by mass of the biocompatible monomer. preferable.

  When polymerizing the biocompatible monomer, a polymerization initiator can be used. Among the polymerization initiators, those corresponding to functional group-containing compounds are included, and the polymerization initiators corresponding to functional group-containing compounds may be used as one or both of a polymerization initiator and a functional group-containing compound it can.

  As a polymerization initiator, for example, 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] ester Pan dihydrochloride, 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, acetylacetone peroxide, and other radical polymerization initiators; bromomethylbenzene, 1- (bromomethyl) -4-methylbenzene 2-bromoisobutyrate ethyl, 2-bromoisobutyrate 2-hydroxyethyl, bis [2- (2'-bromoisobutyryloxy) ethyl] disulfide, 2-bromoisobutyric acid 10-undecenyl, 4- (1-bromoethyl) benzoate Listed as living radical polymerization initiators such as acids It is, the present invention is not limited only to those exemplified. 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 obtained polymer, etc., but usually 0.001 to 20 parts by mass, preferably 100 parts by mass of the biocompatible monomer. Preferably, it is 0.005 to 10 parts by mass.

  In order to obtain a biocompatible polymer having a functional group, a functional group-containing compound can be used. As said 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. As a suitable functional group, for example, a group represented by a formula: -COOM (M represents a hydrogen atom or an alkali metal atom. The same applies to the following), a hydroxyl group, an allyl group, an epoxy group, an aldehyde group, an amino group, a CONH- group And thiol groups, but the present invention is not limited to such examples. As said M, alkali metal atoms, such as a sodium atom and a potassium atom, are mentioned, for example. The number of functional groups in the biocompatible polymer having a functional group is not particularly limited, but in general, preferably 1 to 6.

  As a functional group containing compound used in order to introduce a functional group into a biocompatible polymer polymerized using the above-mentioned polymerization initiator or chain transfer agent, for example, alkali metal thioacetate 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 and the like, 4-[(2-carboxyethylsulfanylthiocarbonyl) sulfanyl] -4-cyanopentanoic acid, 4-cyano-4- (thiobenzoylthio) pentanoic acid, 4-cyano-4-[(dodecyl) Sulfanylthiocarbonyl) sulfa Thiol-based chain transfer agents containing functional groups such as tetrachloropentanoate, 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. Although the polymerization initiator containing a functional group etc. are mentioned, this invention is not limited only to this illustration. These functional group-containing compounds may be used alone or in combination of two or more.

  In addition, when using a living polymerization initiator as a polymerization initiator, the said functional group containing compound is made to react with the halogen atom which exists in the terminal of the biocompatible polymer prepared using the said living polymerization initiator. Functional groups may be introduced into the biocompatible polymer. The functional group-containing compound to be reacted with the halogen atom present at the end of the biocompatible polymer prepared using the living polymerization initiator includes, for example, amine compounds such as ethanolamine, ethylene diamine and propyl diamine, 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 Compounds, allyl mercaptan, etc., cysteine, cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-merka Topuropion acid, thioacetic acid, thiomalic acid, 2-mercapto ethanesulfonic acid, their sodium salts, such as thiol compounds such as potassium salts, the present invention is not limited only to those exemplified.

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

  The functional group-containing compound to be reacted with the functional group present at the end of the biocompatible polymer includes, for example, amine compounds such as ethanolamine, ethylene diamine and propyl diamine, glycolic acid, hydroxypropionic acid, ethylene glycol, propane Alcohols such as diol, butanediol and hydroquinone, Carboxylic acids such as glycine, malonic acid, succinic acid, adipic acid and terephthalic acid, Dithiol compounds such as ethanedithiol, propanedithiol, hexadecanedithiol, allyl mercaptan etc., cysteine, Cysteamine, 2-mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, Mercaptoethanesulfonic acid, thiol compounds such as sodium salts and potassium salts thereof, 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'- Compounds having a disulfide group such as diaminodiphenyl disulfide, 3-aminopropyl disulfide, bis (6-aminohexyl) disulfide, bis (8-aminooctyl) disulfide, 4,4'-diaminodiphenyl disulfide Although the like, the present invention is not limited only to those exemplified.

  The amount of the functional group-containing compound for introducing the functional group into the biocompatible polymer depends on the type of the biocompatible monomer, the polymerization conditions such as the polymerization temperature, and the molecular weight of the targeted biocompatible polymer. No particular limitation is imposed, but when obtaining a polymer having a weight average molecular weight of 1,000 to 9,000, it is 0.1 to 20 parts by weight per 100 parts by weight of the biocompatible monomer. Preferably, it is more preferably 0.5 to 15 parts by mass.

  The 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 from room temperature to 200 ° C, more preferably from 40 to 140 ° C. Moreover, it is preferable that the atmosphere at the time of polymerizing a biocompatible monomer is inert gas, such as nitrogen gas and argon gas. The reaction time may be appropriately set so as to complete the polymerization reaction of the biocompatible monomer.

As a method of introducing the functional group into at least one molecular terminal of the biocompatible polymer, 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 the end, after the allyl group possessed by the biocompatible polymer is borated, the biocompatible polymer and the functional group-containing compound which are borated A method of introducing a functional group which the functional group-containing compound has by reacting
(4) When the biocompatible polymer has a hydroxyl group at the end, the hydroxyl group is reacted with a tolylizing agent such as tosyl chloride and then thioacetylated to hydrolyze the thioacetylated biocompatible polymer By introducing a thiol group as a functional group,
(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 the above (1) to (5) into at least one molecular terminal of the biocompatible polymer A method of introducing a functional group into the biocompatible polymer by reacting a 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 the above (1) to (5) into at least one molecular terminal 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 for cleaving the disulfide bond,
(8) After polymerizing a biocompatible monomer in the presence of a polymerization initiator having a disulfide group as a polymerization initiator or a chain transfer agent, cleaving the disulfide bond using a reducing agent for cleaving 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, an amine compound, sodium hydroxide, sodium borohydride or the like is reacted with Although the method etc. which introduce | transduce a thiol group as a functional group are mentioned, this invention is not limited only to this illustration.

  By polymerizing the biocompatible monomer as described above, a biocompatible polymer can be obtained. The obtained biocompatible polymer has a functional group possessed by a functional group-containing compound for introducing a functional group into the biocompatible polymer at at least one molecular terminal thereof. 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, etc. The present invention is not limited to only this example.

  The weight average molecular weight of the biocompatible polymer is at least 1,000, preferably at least 2,000, more preferably at least 3,000, from the viewpoint of improving sustained release of the drug, retention of particle shape, hemolytic resistance and extracorporeal release. From the viewpoint of improving extracorporeal release, it is 90000 or less, preferably 50000 or less, more preferably 30000 or less, still more preferably 25000 or less, still more preferably 20000 or less, still more preferably 15000 or less.

  In addition, the weight average molecular weight of a biocompatible polymer means the value when it measures based on the method as described in the following Example.

  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, from the viewpoint of improving hemolytic resistance. 1 to 1.3.

  In the present invention, a biocompatible polymer having an ester bond, an amide bond or a disulfide bond between biocompatible polymers is an ester bond, an amide bond or a disulfide between two or more biocompatible polymers, respectively. It means a polymer having a bond. In addition, between polymers, an ester bond, an amide bond, or a disulfide bond may be contained by 1 or 2 or more. When two or more ester bonds, amide bonds or disulfide bonds are contained between polymers, only one kind of bond may be contained, or plural kinds of bonds may be contained. In addition to the above three types of binding, other types of binding may be included as long as the object of the present invention is not inhibited.

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

  As a method of forming an ester bond or an amide bond between biocompatible polymers, for example, as shown in the following production example, after chemically reacting a functional group possessed by the biocompatible polymer, amidification is carried out Although the method etc. which couple | bond biocompatible polymers by esterification, condensation, etc. are mentioned, this invention is not limited only to this illustration.

  The binding of the biocompatible polymers to each other by the above amidation, esterification, condensation, etc. is carried out, for example, by dissolving the biocompatible polymer in a solvent such as water, an organic solvent, etc. It can be carried out by adding a condensing agent such as a condensing agent, a triazine condensing agent, a phosphonium condensing agent, a uronium condensing agent, a halonium condensing agent and the like. In addition, the bonding between the biocompatible polymers may be performed in the presence of the condensing agent and a condensation aid or a dehydration aid.

  As a method of forming an ester bond or an amide bond between biocompatible polymers, a commonly used method may be mentioned in addition to the method of forming an ester bond or an amide bond between the biocompatible polymers. As a commonly used method, for example, “The Chemical Society of Japan, 22 Organic Synthetic IV Acids, Amino Acids, and Peptides”, edited by The Chemical Society of Japan, 4th Edition, Maruzen Co., Ltd., November 30, 1992, 193 Although the method etc. which are described on -310 pages are mentioned, this invention is not limited only to this illustration.

  By forming an ester bond or an amide bond between biocompatible polymers as described above, it is possible to obtain a biocompatible polymer having an ester bond or an amide bond between biocompatible polymers. it can.

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

  As a method of forming a disulfide bond between biocompatible polymers, for example, a disulfide compound having two or more functional groups having reactivity with a functional group possessed by the biocompatible polymer, and the biocompatibility A method of forming one or more disulfide bonds between biocompatible polymers by reacting with a hydrophobic polymer (hereinafter referred to as method A), in the presence of a polymerization initiator having a disulfide group There is a method of forming a disulfide bond between the biocompatible polymers by polymerizing the biocompatible monomer in step (hereinafter referred to as method B) and the like, but the present invention is not limited to such exemplification. It is not limited.

In the method A, for example, a biocompatible polymer having a functional group such as a carboxyl group;
To obtain a biocompatible polymer having a disulfide bond between biocompatible polymers by reacting with a disulfide compound having two or more functional groups such as a hydroxyl group having reactivity with the functional group. Can. 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, and 6,6 ′. -Dihydroxy-2,2'-dinaphthyl disulfide, 3,3'-dihydroxydiphenyl disulfide, 4,4'-dihydroxydiphenyl disulfide, bis (2-aminoethyl) disulfide dihydrochloride, 2,2'-diaminodiphenyl disulfide And compounds having a disulfide group such as 3-aminopropyl disulfide, bis (6-aminohexyl) disulfide, bis (8-aminooctyl) disulfide, 4,4'-diaminodiphenyl disulfide, etc. , It is not limited only to hunt illustration.

  The amount of the biocompatible polymer per equivalent of the functional group of the disulfide compound having two or more functional groups is preferably 1.5 to 5 from the viewpoint of efficiently forming a disulfide bond between the biocompatible polymers. 2.5 equivalents, more preferably 1.8 to 2.2 equivalents.

  When a biocompatible polymer having a functional group and a disulfide compound having two or more functional groups having reactivity to the functional group are reacted, water or an organic solvent can be used. Examples of the organic solvent 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-based organic solvents such as ethyl cellosolve, butyl cellosolve and diglyme; Ester-based organic solvents such as ethyl acetate, butyl acetate and cellosolve acetate; Ketone-based organic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and diacetone alcohol; Amide-based organic solvents; and aromatic organic solvents such as benzene, toluene, xylene and the like, but the present invention is limited to such examples only. Not. These solvents may be used alone or in combination of two or more. The amount of the solvent per 100 parts by mass of the biocompatible polymer is not particularly limited, but generally, it is preferably about 100 to 500 parts by mass.

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

  The biocompatible polymer having a disulfide bond between the biocompatible polymers obtained as described above may be dried by drying under reduced pressure, lyophilization, etc., if necessary.

  In the method B, a disulfide bond can be formed between the polymers of the biocompatible polymer by polymerizing the biocompatible monomer in the presence of a polymerization initiator having a disulfide group.

  As a biocompatible monomer used for the said method B, the biocompatible monomer which has the above-mentioned functional group can be mentioned, for example.

  Examples of the polymerization initiator having a disulfide group include bis [2- (2'-bromoisobutyryloxy) ethyl] disulfide and the like, but the present invention is not limited to such examples. The 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, etc., but usually 0.001 to 100 parts by mass of the biocompatible monomer is preferable. It is 20 parts by mass, more preferably 0.005 to 10 parts by mass.

  In addition, when polymerizing a biocompatible monomer in the presence of a polymerization initiator having a disulfide group, an organic solvent can be used. Examples of the organic solvent include ketone organic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and diacetone alcohol; alcohol organic solvents such as methanol, ethanol, isopropanol, n-butanol and tert-butyl alcohol; dichloroethane, dichloromethane, Solvents containing halogen atoms such as chloroform; ether-based organic solvents such as propylene glycol methyl ether, dipropylene glycol methyl ether, ethyl cellosolve, butyl cellosolve and diglyme; ester-based organic solvents such as ethyl acetate, butyl acetate and cellosolve acetate; Of organic solvents such as benzene, toluene, and xylene; and organic solvents such as benzene, toluene, and the like; The present invention is not limited only to. These solvents may be used alone or in combination of two or more. The amount of the solvent per 100 parts by mass of the biocompatible polymer is not particularly limited, but in general, the amount is preferably 500 parts by mass or less.

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

  As described above, by polymerizing the biocompatible monomer in the presence of the polymerization initiator having a disulfide group, a biocompatible polymer having a disulfide bond 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 is referred to as a “specific bond-containing biocompatible polymer” for convenience.

  The specific bond-containing biocompatible polymer may have a functional group at one end or both ends, or may have no functional group. As said functional group, the same functional group as the functional group which the biocompatible polymer couple | bonded has can be illustrated, for example.

  Further, 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, a thiol group is used as a functional group in the method (1). The polymerization initiator contained, the chain transfer agent containing a thiol group as a functional group in the method (2), and the thiol group as a functional group in the method (3), the method (5) and the method (6) By using the contained thiol group-containing compound, a biocompatible polymer having a thiol group at one end 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 the thiol group. As functional groups other than a thiol group, although a carboxyl group, a hydroxyl group, an allyl group, an epoxy group, an aldehyde group, an amino group etc. are mentioned, for example, this invention is not limited only to this illustration.

  The hemolysis degree 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 having excellent hemolytic resistance. The following content is more preferably 30% or less, still more preferably 20% or less. In addition, the hemolysis degree of a specific bond containing biocompatible polymer and a thiol group containing biocompatible polymer is a value when it measures based on the method as described in the following Example.

  The specific bond-containing biocompatible polymer and the thiol group-containing biocompatible polymer can be used as particles. The average particle diameter of the particles is preferably 10 nm or more, more preferably 20 nm or more from the viewpoint of preventing normal cells to act, and preferably 1000 nm or less, more preferably 500 nm or less from the viewpoint of causing diseased cells More preferably, it is 200 nm or less. In addition, the average particle diameter of particle | grains is a value when it measures based on the method as described in the following Example.

  The functional groups possessed by the specific bond-containing biocompatible polymer and the thiol group-containing biocompatible polymer are, if necessary, proteins, monosaccharides, polysaccharides, sugar chains, antibodies, nucleic acids, drug substances, amino acids, peptides, folic acid , Dextrin etc. may be modified. These proteins, monosaccharides, polysaccharides, sugar chains, antibodies, nucleic acids, drug substances, amino acids, peptides, folic acid, dextrin and the like are functional groups possessed by the specific bond-containing biocompatible polymer and the thiol group-containing biocompatible polymer. It may be attached directly 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. In addition, the biocompatible medical material of the present invention may contain an additive as long as the object of the present invention is not inhibited. Additives include, for example, water, physiological saline, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, carboxymethyl cellulose 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, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, Lactose, phosphate buffered saline, biodegradable polymer, serum free medium, pharmaceutically acceptable surfactant Although such a physiological pH buffer acceptable in a living body and the like, and the present invention is not limited only to those exemplified. 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 a drug or the like. As a method of 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 for a biocompatible medical material is used. A method of combining a carrier with a drug or the like by bonding a drug or the like to a functional group possessed by the method, a method of mixing biocompatible medical materials and a drug or the like so as to have a uniform composition, particles of a drug or the like Method of coating with a compatible medical material, particleizing a mixture of a lipid and a biocompatible medical material, and containing a drug or the like inside the obtained particle, or a particle containing a drug or the like encapsulated in a liposome A method of encapsulating the particles in the inside of the skin of a biocompatible medical material by coating with a compatible medical material, particles of a mixture of a drug or the like and a liposome for biocompatible medical use A method of encapsulating the particles in the inside of the skin of a biocompatible medical material by coating with a filler, and a method of encapsulating a pharmaceutical or the like by micelleting the pharmaceutical or the like with the biocompatible medical material However, the present invention is not limited to such examples.

  The liposome is prepared, for example, by dissolving the lipid in a solvent such as tert-butyl alcohol or chloroform, followed by lyophilization, or adding a solution in which the drug is dissolved to the lipid to swell the lipid and disperse it in ultrasound. After the reaction, the resulting dispersion can be prepared, for example, by the addition of polyethylene glycol-phosphatidyl ethanolamine or the like.

  The liposome may be cationized with a cationizing agent. Liposomes are obtained, for example, by dissolving hydrogenated soybean lecithin, cholesterol, 3,5-dipentadecyloxybenzamidine hydrochloride and the like in a solvent such as tert-butyl alcohol and freezing the obtained lipid mixed solution be able to. The lipids that make up the 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. Examples of the phospholipid include phospholipids such as phosphatidyl choline (lecithin), phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl inositol, sphingomyelin, cardiolybin and the like, and those obtained by adding hydrogen to the phospholipid.

  In addition, although the liposome was mentioned in said example, an emulsion, a nanoparticle, a micro particle, a high molecular compound etc. can be used instead of a liposome, for example.

  Biologically or pharmacologically active agents can be used as agents. As the drug, for example, antitumor agent, anticancer agent, antibiotic, antiviral agent, anticancer effect enhancer, immune enhancer, immunomodulator, immunostimulant, radiosensitizer, radioprotectant, antihistamine, anti-inflammatory Agent, decongestant, antifungal, antiarthritic, antiasthmatic, angiogenesis inhibitor, enzyme, antioxidant, hormone, angiotensin converting enzyme inhibitor, smooth muscle cell proliferation agent, smooth muscle cell migration Inhibitor, platelet aggregation inhibitor, chemical mediator release inhibitor, vascular endothelial cell proliferation promoter, vascular endothelial cell proliferation inhibitor, interferon, interleukin, colony stimulating factor, cytokine, tumor necrosis factor, granulocyte macrophage colony Stimulatory factor, granulocyte colony stimulating factor, macrophage colony stimulating factor, stem cell factor, beta type transforming growth factor, liver Cell growth factor, vascular endothelial cell growth factor, erythropoietin, vaccine, protein, mucoprotein, peptide, polysaccharide, lipopolysaccharide, sugar chain, antisense, ribozyme, decoy, nucleic acid, antibody, etc. The invention is not limited to such examples. These agents may be used alone or in combination of two or more.

  Although the biocompatible medical material is obtained as described above, the specific bond-containing biocompatible polymer or the thiol group-containing biocompatible polymer used for the biocompatible medical material may be crosslinked. Examples of the method of crosslinking the polymer include a chemical crosslinking method, a physical crosslinking method and the like. As a chemical crosslinking method, for example, epoxy compound, oxidized starch, glutaraldehyde, formaldehyde, dimethyl sverimino acid, carbodiimide, succinimidyl compound, diisocyanate compound, acyl azide, reuterin, tris (hydroxymethyl) phosphine, copper ascorbate, glucose A method of crosslinking the polymer using a chemical crosslinking agent such as lysine or a photooxidant, a method of chemically crosslinking the polymer by thermal dehydration treatment, irradiation of ultraviolet rays, irradiation of electron beam, irradiation of gamma rays, etc. It can be mentioned. Further, as a physical crosslinking method, for example, a method of crosslinking a polymer with a salt, a method of crosslinking a polymer by electrostatic interaction, a method of crosslinking a polymer by hydrogen bond, a polymer of hydrophobic interaction And the like. In the case of crosslinking, only one type of crosslinking method may be used, or two or more types of crosslinking methods may be used in combination.

  Although subjects to which the agent is administered include mammals such as humans, monkeys, rats, dogs, cats, and domestic animals, the present invention is not limited to such examples.

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

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

  As described above, since the biocompatible medical material of the present invention is excellent in sustained release of the drug, retention of particle shape, hemolytic resistance and extracorporeal release, the drug is retained, orally or orally. It is expected to be used as a pharmaceutical carrier used when introduced into the body via blood, for example, a carrier for injection, a carrier for oral administration, and the like.

  The present invention will next be described in more detail by way of examples, which should not be construed as limiting the invention thereto.

Production Example 1
200 g of diethylene glycol dimethyl ether (made by Tokyo Kasei Kogyo Co., Ltd., the same in the following) was added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe and a reflux condenser (condenser). The inner space of the reaction vessel was replaced with nitrogen gas by raising the temperature of the diethylene glycol dimethyl ether inside to 80 ° C. and introducing nitrogen gas into the reaction vessel at a flow rate of 20 mL / min for 30 minutes.

  Next, a mixture of 110 g of methoxyethyl acrylate, 440 mg of 4,4'-azobis (4-cyanopentanoic acid) [Wako Pure Chemical Industries, Ltd., product number: V-501, the same in the following] and 20 g of diethylene glycol dimethyl ether is used. It was continuously dropped into the reaction vessel maintained at 80 ° C. over time. After adding 110 mg of 4,4'-azobis (4-cyanopentanoic acid) to the reaction vessel after 3 hours and 4 hours from the start of dropwise addition 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 a carboxyl group at its end (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 the polymer (1) was 5,500.

In addition, 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.
[Conditions for measuring weight average molecular weight of polymer]
-Measuring equipment: Tosoh Co., Ltd. product number: HLC-8320GPC
・ Molecular weight column: Tosoh Co., Ltd. product number: TSK gel G4000HHR connected in series in series ・ Eluent: Dimethylformamide ・ Standard substance for calibration curve: Polyethylene glycol ・ Preparation of solution for measurement: Heavy in eluent (dimethylformamide) The coalescing was dissolved to prepare a solution having a polymer concentration of 0.3% by mass, and the solution was used after being filtered through a filter.

Production Example 2
300 g of a mixed solvent consisting of 50% by mass of diethylene glycol dimethyl ether and 50% by mass of ethanol is added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe and a reflux condenser (condenser) The mixed solvent in the 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.

  Next, 120 g of methoxyethyl acrylate, 2,2'-azobis [2-methyl-N- (2-hydroxyethyl) propionamide] [manufactured by Wako Pure Chemical Industries, Ltd., part number: VA-086, the same applies hereinafter] 500 mg And a mixture of 60 g of the mixed solvent was continuously dropped into a reaction vessel maintained at 80 ° C. for 2 hours. After 2 hours and 4 hours from the start of dropwise addition of the mixture while maintaining the temperature of the contents of the reaction vessel at 80 ° C., 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) propionamide] After 125 mg is added to the reaction vessel, the temperature of the contents of the reaction vessel is maintained at 80 ° C. for 2 hours to contain polymethoxyethyl acrylate [hereinafter referred to as polymer (2)] having a hydroxyl group at the end. The resulting polymer solution was obtained. The solid content in the polymer solution was 25% by mass, and the weight average molecular weight of the polymer (2) was 5,200.

Production Example 3
A mixed solution of 220 mg of 4- (1-bromoethyl) benzoic acid, 5.4 g of methoxyethyl acrylate and 5.4 g of diethylene glycol dimethyl ether was added to a 50 mL eggplant flask, and then the internal space of the eggplant flask was purged with nitrogen gas. A reaction solution was obtained by adding 440 mg of a bipyridine ligand and 160 mg of copper bromide in an eggplant flask and stirring for 3 hours while maintaining the temperature of the contents of the eggplant flask at 80 ° C. The resulting reaction solution was purified by passing through a silica column.

  Next, 160 mg of sodium hydroxide and 330 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 to have a carboxyl group at one end and the other end. 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 the polymer (3) was 5,000.

Production Example 4
A mixed solution of 220 mg of 4- (1-bromoethyl) benzoic acid, 6.9 g of methoxyethyl acrylate and 6.9 g of diethylene glycol dimethyl ether was added to a 50 mL eggplant flask, and then the inner space of the eggplant flask was purged with nitrogen gas. A reaction solution was obtained by adding 440 mg of a bipyridine ligand and 160 mg of copper bromide in an eggplant flask and stirring for 3 hours while maintaining the temperature of the contents of the eggplant flask at 80 ° C. The resulting reaction solution was purified by passing through a silica column.

  Next, 200 mg of sodium hydroxide and 420 mg of cysteamine are added to the purified reaction solution, and the reaction solution is stirred at a temperature of 80 ° C. for 4 hours to have a carboxyl group at one end and a thiol 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 the polymer (4) was 6,300.

Production Example 5
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 was added to a 50 mL eggplant flask, and then the inner space of the eggplant flask was purged with nitrogen gas. A reaction solution was obtained by adding 440 mg of a bipyridine ligand and 160 mg of copper bromide in an eggplant flask and stirring for 3 hours while maintaining the temperature of the contents of the eggplant flask at 80 ° C. The resulting reaction solution was purified by passing through a silica column.

  Next, 190 mg of sodium hydroxide and 330 mg of ethylenediamine are added to the purified reaction solution, and the reaction solution is stirred at a temperature of 80 ° C. for 4 hours to have a carboxyl group at one end and an amino 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 the polymer (5) was 5,800.

Production Example 6
A mixed solution of 220 mg of 2-bromoisobutyric acid 2-hydroxyethyl (manufactured by Sigma Aldrich), 5.8 g of methoxyethyl acrylate and 5.8 g of diethylene glycol dimethyl ether is added to a 50 mL eggplant flask, and then the internal space of the eggplant flask is It was replaced by gas. A reaction solution was obtained by adding 440 mg of a bipyridine ligand and 160 mg of copper bromide in an eggplant flask and stirring for 3 hours while maintaining the temperature of the contents of the eggplant flask at 80 ° C. The resulting reaction solution was purified by passing through a silica column.

  Next, 180 mg of sodium hydroxide and 400 mg of cysteamine are added to the purified reaction solution, and the reaction solution is stirred at a temperature of 80 ° C. for 4 hours to have 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)] is obtained. The solid content in the polymer solution was 46% by mass, and the weight average molecular weight of the polymer (6) was 5,600.

Production Example 7
In a 100 mL Schlenk tube, 2 g (solid amount) of the polymer (1) obtained above, 1.9 g (solid amount) of the polymer (2) obtained above and 2 g of dichloromethane are added, and the mixture obtained Was cooled to -5.degree. 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 is added to a Schlenk tube under stirring and stirred for 1 hour at -5 ° C under stirring. Maintain and then at room temperature for 1 hour. The mixture was filtered and the precipitate was removed to obtain a biocompatible copolymer of polymethoxyethyl acrylate having an ester bond in its main chain [hereinafter referred to as polymer (7)]. 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 the polymer (3) obtained above and 2 g of dichloromethane were added into 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 are added into a Schlenk tube, and after stirring for 8 hours, the resulting mixture is purified and lyophilized. The polymer A in which the carboxyl group of the polymer (3) was protected was obtained.

(2) Preparation of polymer B 2 g (solid content) of the polymer (3) obtained above in a 100 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a gas inlet pipe 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 cooling on an ice bath.

  Next, while maintaining the temperature of the mixture at 0 ° C., isobutylene was blown into the reaction vessel to an increase of 20 mL, sealed, and stirred for 72 hours. Thereafter, the mixture was neutralized with triethylamine, and then the obtained mixture was purified and freeze-dried to obtain a polymer B in which the hydroxyl group of the polymer (3) was protected.

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

  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 is added into a Schlenk tube under stirring and stirred for 1 hour at -5 ° C under stirring. Maintain and then at room temperature for 1 hour. The mixture was filtered to remove precipitates, and the obtained filtrate was cooled with an ice bath, and 5 mL of trifluoroacetic acid was added to the filtrate under 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)] is obtained. The weight average molecular weight of the obtained polymer (8) was 11,000.

Production Example 9
Into a 100 mL Schlenk tube, 1.6 g (solid amount) of the polymer A obtained above, 2 g (solid amount) of the polymer (4) obtained above and 4 g of dichloromethane are added, and the obtained mixture is It cooled to ° C.

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

  Next, the mixed solution obtained above is stirred at 20 ° C. for 1 hour and lyophilized 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)] is obtained. 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 the polymer (5) obtained above and 2 g of dichloromethane were added into 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 are added to a Schlenk tube, and after stirring for 8 hours, the resulting mixture is purified and lyophilized to protect the amino group of the polymer (5). Polymer C was obtained.

(2) Preparation of Biocompatible Copolymer 2 g (solid content) of the polymer C obtained above in a 100 mL Schlenk tube, 1.9 g (solid content) of the polymer (6) obtained above, and 4 g of dichloromethane Was added and the resulting mixture was cooled to -5.degree.

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

  Next, the mixed solution obtained above is stirred at 20 ° C. for 1 hour and lyophilized 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)] is obtained. 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 in a 100 mL Schlenk tube, the internal space of the Schlenk tube is flushed 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 for 3 hours while maintaining the temperature of the contents of the Schlenk tube at 80 ° C. 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, the reaction solution is stirred at a temperature of 80 ° C. for 4 hours, and the resulting reaction solution is purified to obtain carboxyl at one end. A polymer solution having a group and containing polymethoxyethyl acrylate having a hydroxyl group at the other end was obtained.

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

  Next, while maintaining the temperature of the mixture at 0 ° C., isobutylene was blown into a Schlenk tube to a 20 mL increase, sealed, and stirred for 72 hours. Thereafter, the mixture was neutralized with triethylamine, and the obtained mixture was purified and lyophilized to obtain a polymer D protected with 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 the polymer D obtained above in a 100 mL Schlenk tube, 0.7 g (solid content) of the polymer (6) obtained above, and 4 g of dichloromethane Was added and the resulting mixture was cooled to -5.degree.

  A mixture of 70 mg of diisopropylcarbodiimide, 1 g of dichloromethane and 5 mg of 4-dimethylaminopyridine is added into a Schlenk tube under stirring, maintaining the temperature of the mixture at -5 ° C., under stirring for 1 hour at -5 ° C. Maintain and then at room temperature for 1 hour. The mixture was filtered to remove precipitates, and the obtained filtrate was cooled with an ice bath, and 5 mL of trifluoroacetic acid was added to the filtrate under 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)] is 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 are added to a 30 mL eggplant flask, and the resulting mixture is cooled with an ice bath It 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 dropped 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 stirred at room temperature for 24 hours. Thereafter, the obtained reaction solution is concentrated through a silica column to obtain a thiol group-containing biocompatible polymer [hereinafter referred to as polymer (12)] of polymethoxyethyl acrylate having a thiol group at one end. The The weight average molecular weight of the obtained polymer (12) was 5500.

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 are added to a 30 mL eggplant flask, and the resulting mixture is cooled with an ice bath It stirred.

  Next, the eggplant flask is ice-cooled, and while confirming that the temperature in the reaction system is 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 After dropping the mixed solution of in the eggplant flask, the eggplant flask was removed from the ice bath and stirred at room temperature for 24 hours. Thereafter, 320 mg of dithiothreitol was added to the mixed solution, and the disulfide bond was cleaved by stirring at room temperature for 24 hours. The obtained reaction solution was concentrated through a silica column to obtain a thiol group-containing biocompatible polymer (hereinafter referred to as a polymer (13)) of polymethoxyethyl acrylate having a thiol group at one end. The weight average molecular weight of the obtained polymer (13) was 4100.

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, the Schlenk tube The internal space of was replaced with nitrogen gas. In a Schlenk tube, 50 mg of N, N, N ′, N ′ ′, N ′ ′-pentamethyldiethylene triamine (Sigma Aldrich) and 40 mg of copper bromide are added, and the temperature of the contents of the Schlenk tube is maintained at 80 ° C. The reaction solution was obtained by stirring for a time. After adding 2.5 g of methyl ethyl ketone to the obtained reaction solution, purification was carried out by passing through an alumina column. The reaction solution after column purification was reprecipitated with 10 g of hexane to obtain polymethoxyethyl acrylate having a disulfide group. The weight average molecular weight of the obtained polymethoxyethyl acrylate having a disulfide group was 8800.

  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, and then filtered through a filter and purified. Thus, a polymer solution containing polymethoxyethyl acrylate [hereinafter referred to as polymer (14)] having a thiol group at one end was obtained. The solid content in the polymer solution was 25% by mass, and the weight average molecular weight of the obtained polymer (14) was 4400.

Production Example 15
In a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe and a reflux condenser (condenser), 180 g of diethylene glycol dimethyl ether is added, and the temperature of diethylene glycol dimethyl ether in the reaction vessel is raised to 80.degree. The inner 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 20 mL / min.

  Next, a mixture 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 is maintained at 80 ° C for 2 hours. The solution was continuously dropped into the reaction vessel. After adding 100 mg of 4,4'-azobis (4-cyanopentanoic acid) to the reaction vessel after 3 hours and 4 hours from the start of dropwise addition 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 polyhydroxypropyl methacrylamide [hereinafter referred to as polymer (15)] having a carboxyl group at an end 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
In a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe 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 is added The mixed solvent in the 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.

  Next, N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine [Osaka Organic Chemical Industry Co., Ltd. product, trade name: GLBT] 100 g, 2,2′-azobis [2-methyl A mixed solution of 400 mg of -N- (2-hydroxyethyl) propionamide] and 100 g of the mixed solvent was continuously added dropwise over 2 hours into a reaction vessel maintained at 80 ° C. After 2 hours and 4 hours from the start of dropwise addition of the mixture while maintaining the temperature of the contents of the reaction vessel at 80 ° C., 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) propionamide] After 100 mg is added to the reaction vessel, the temperature of the contents of the reaction vessel is maintained at 80 ° C. for 2 hours to contain polycarboxybetaine having hydroxyl groups at its terminal [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 the 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 pipe 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 is added The mixed solvent in the 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.

  Next, a reaction vessel in which 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. It dripped continuously inside. After 2 hours and 4 hours from the start of dropwise addition of the mixture while maintaining the temperature of the contents of the reaction vessel at 80 ° C., 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) propionamide] A polymer containing polystyrene having a hydroxyl group at its terminal [hereinafter referred to as polymer (17)] by adding 100 mg to the reaction vessel and maintaining the temperature of the contents of the reaction vessel at 80 ° C. for 2 hours A solution was obtained. The solid content in the polymer solution was 25% by mass, and the weight average molecular weight of the polymer (17) was 6,500.

Production Example 18
In a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe 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 is added The mixed solvent in the 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.

  Next, a mixture of 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, the same applies hereinafter) and 40 g of the mixed solvent The solution was continuously dropped into a reaction vessel maintained at 80 ° C. for 2 hours. In a reaction vessel, 125 mg of 2,2'-azobis (2-methylpropionamidine) dihydrochloride was added 3 hours and 4 hours after the start of dropwise addition of the mixture while maintaining the temperature of the contents of the reaction vessel at 80 ° C. After the addition, the temperature of the contents of the reaction vessel is maintained at 80 ° C. for 2 hours to obtain a polymer solution containing an amino group-containing polylauryl methacrylate [hereinafter referred to as polymer (18)]. The The solid content in the polymer solution was 20% by mass, and the weight average molecular weight of the polymer (18) was 5900.

Production Example 19
In a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe 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 is added The mixed solvent in the 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.

  Next, a mixture of 90 g of n-butyl methacrylate, 450 mg of 2,2'-azobis (2-methylpropionamidine) dihydrochloride and 30 g of the mixed solvent is continuously added to a reaction vessel maintained at 80 ° C for 2 hours. It 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 after 3 hours and 4 hours from the start of dropwise addition of the mixture, respectively. A polymer solution containing poly n-butyl methacrylate [hereinafter referred to as polymer (19)] having an amino group at the end by maintaining the temperature of the contents of the reaction vessel at 80 ° C. for 2 hours after addition. I got The solid content in the polymer solution was 20% by mass, and the weight average molecular weight of the polymer (19) was 5,300.

Production Example 20
In a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe and a reflux condenser (condenser), 180 g of diethylene glycol dimethyl ether is added, and the temperature of diethylene glycol dimethyl ether in the reaction vessel is raised to 80.degree. The inner 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 20 mL / min.

  Next, a mixture 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 to a reaction vessel maintained at 80 ° C over 2 hours. After adding 100 mg of 4,4'-azobis (4-cyanopentanoic acid) to the reaction vessel after 3 hours and 4 hours from the start of dropwise addition 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 polyhydroxyethyl methacrylate having a carboxyl group at its end (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 the polymer (20) was 5,700.

Production Example 21
(1) Preparation of Polymer E 180 g of diethylene glycol dimethyl ether is added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe 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 methoxypolyethylene glycol methacrylate (average added mole number of ethylene oxide: 9), 400 mg of 4,4'-azobis (4-cyanopentanoic acid) and 20 g of diethylene glycol dimethyl ether is 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) in the reaction vessel after 3 hours and 4 hours from the start of dropwise addition of the mixture, respectively. By adding and maintaining at 80 ° C. for 2 hours, a polymer solution containing polymethoxy polyethylene glycol methacrylate having a carboxyl group at an end (hereinafter referred to as “polymer E”) was obtained. The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of the polymer E was 5,000.

(2) Preparation of Biocompatible Copolymer 2 g (solid content) of the polymer E obtained above in a 100 mL Schlenk tube, 2.1 g (solid content) of the polymer (2) obtained above, and 4 g of dichloromethane Was added and the resulting mixture was cooled to -5.degree.

  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 is added into a Schlenk tube under stirring and stirred for 1 hour at -5 ° C under stirring. Maintain and then at room temperature for 1 hour. A biocompatible copolymer of polymethoxyethyl acrylate and polymethoxypolyethylene glycol methacrylate having an ester bond in its main chain by filtering the mixture and removing precipitates [hereinafter referred to as polymer (21)] I got The weight average molecular weight of the obtained polymer (21) was 11,600.

Production Example 22
In a 100 mL Schlenk tube, 1.2 g of methoxypolyethylene glycol (weight average molecular weight: 5000, manufactured by Sigma Aldrich Co.), 2 g (solid content) of the polymer (1) obtained above and 4 g of dimethylformamide are obtained. The mixture is cooled to -5.degree.

  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 is added into a Schlenk tube under stirring, and 1 at -5 ° C under stirring. The time was maintained and then at room temperature for 1 hour. The mixture is filtered to remove precipitates to obtain a biocompatible copolymer of polyethylene glycol and polymethoxyethyl acrylate [hereinafter referred to as polymer (22)] having an ester bond in the main chain. The The weight average molecular weight of the obtained polymer (22) was 9000.

Production Example 23
(1) Preparation of Polymer F 180 g of diethylene glycol dimethyl ether is added to a 500 mL reaction vessel equipped with a thermometer, a stirrer, a dropping funnel, a nitrogen gas inlet pipe 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 mixed solution of 100 g of 2-methacryloyloxyethyl phosphorylcholine, 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.

  Next, 100 mg of 4,4'-azobis (4-cyanopentanoic acid) is added after 3 hours and 4 hours from the start of dropwise addition of the mixture while maintaining the temperature of the contents of the reaction vessel at 80.degree. By maintaining at 2 ° C. for 2 hours, a polymer solution containing poly 2-methacryloyloxyethyl phosphorylcholine having a carboxyl group at an end (hereinafter referred to as polymer F) was obtained. The solid content in the polymer solution was 33% by mass, and the weight average molecular weight of the polymer F was 5,000.

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

  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 is added into a Schlenk tube under stirring and stirred for 1 hour at -5 ° C under stirring. Maintain and then at room temperature for 1 hour. A biocompatible copolymer of polymethoxyethyl acrylate and poly 2-methacryloyloxyethyl phosphorylcholine having an ester bond in the main chain by filtering the mixture and removing precipitates [Polymer (23) To get The weight average molecular weight of the obtained polymer (23) was 12000.

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

  Next, 10 mg of azobisisobutyronitrile is added after 3 hours and 4 hours after the start of dropwise addition of the mixture while maintaining the temperature of the contents in the reaction vessel at 90 ° C., and maintained at 90 ° C. for 2 hours As a result, 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 the polymer (24) was 71,000.

Production Example 25
A mixed solution of 200 mg of 4- (1-bromoethyl) benzoic acid, 6.0 g of glycerol methacrylate and 6.0 g of isopropyl alcohol was added to a 50 mL eggplant flask, and then the internal space of the eggplant flask was replaced with nitrogen gas. A reaction solution was obtained by adding 320 mg of a bipyridine ligand and 130 mg of copper bromide into an eggplant flask and stirring for 3 hours while maintaining the temperature of the contents of the eggplant flask at 80 ° C. The resulting reaction solution was purified by passing through a silica column.

  Next, 190 mg of sodium hydroxide and 280 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 to have a carboxyl group at one end and the other end. A polymer solution containing polyglycerin methacrylate having a hydroxyl group [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 the polymer (25) was 6,500.

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

  Next, 180 mg of sodium hydroxide and 330 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 to have a carboxyl group at one end and the other end. 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 the polymer (26) was 5,600.

Production Example 27
(1) Preparation of Polymer G 4 g (solid content) of the 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 are added into a Schlenk tube, and after stirring for 8 hours, the resulting mixture is purified and lyophilized. The polymer G in which the carboxyl group of the polymer (25) was protected was obtained.

(2) Preparation of Biocompatible Copolymer 2 g (solid content) of the polymer (1) obtained above in a 100 mL Schlenk tube, 2.4 g (solid content) of the polymer G obtained above, and dimethylformamide 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 is added into a Schlenk tube under stirring, and 1 at -5 ° C under stirring. The time was maintained and then at room temperature for 1 hour. The mixture was filtered to remove precipitates, and the obtained filtrate was cooled with an ice bath, and 5 mL of trifluoroacetic acid was added to the filtrate under 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 an ester bond in the main chain and a polyglycerin methacrylate having terminal carboxyl group and polymethoxyethyl acrylate. A compatible copolymer [hereinafter referred to as polymer (27)] was obtained. The weight average molecular weight of the obtained polymer (27) was 13100.

Production Example 28
(1) Preparation of Polymer H 4 g (solid content) of the polymer (26) obtained above and 4 g of dimethylformamide were added into 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 are added into a Schlenk tube, and after stirring for 8 hours, the resulting mixture is purified and lyophilized. The polymer H in which the carboxyl group of the polymer (26) was protected was obtained.

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

  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 is added into a Schlenk tube under stirring, and 1 at -5 ° C under stirring. The time was maintained and then at room temperature for 1 hour. The mixture was filtered to remove precipitates, and the obtained filtrate was cooled with an ice bath, and 5 mL of trifluoroacetic acid was added to the filtrate under 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 an ester bond in the main chain and a polyglycerin methacrylate having terminal carboxyl group and polymethoxyethyl acrylate. 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 are added to a 30 mL eggplant flask, and the resulting mixture is cooled with an ice bath It stirred.

  Next, the eggplant flask is ice-cooled, and while confirming that the temperature in the reaction system is 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 After dropping the mixed solution of in the eggplant flask, the eggplant flask was removed from the ice bath and stirred at room temperature for 24 hours. The obtained reaction solution was concentrated through a silica column to obtain a polymethoxyethyl acrylate having a disulfide bond [hereinafter referred to as polymer (29)]. The obtained polymer (29) has a disulfide bond, and its weight average molecular weight is 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, the Schlenk tube The internal space of was replaced with nitrogen gas. In a Schlenk tube, 50 mg of N, N, N ′, N ′ ′, N ′ ′-pentamethyldiethylene triamine (Sigma Aldrich) and 40 mg of copper bromide are added, and the temperature of the contents of the Schlenk tube is maintained at 80 ° C. The reaction solution was obtained by stirring for a time.

  Next, 2.5 g of methyl ethyl ketone was added to the reaction solution obtained above and then purified by passing through an alumina column. The column-purified reaction solution was reprecipitated with 10 g of hexane to obtain a polymethoxyethyl acrylate [hereinafter referred to as polymer (30)] having a disulfide bond. The obtained polymer (30) had a disulfide bond and had an average molecular weight of 8800.

  5 g of dichloromethane and 650 mg of dithiothreitol are added to 2 g of the polymer (30) obtained above, and the obtained mixture is stirred at room temperature for 72 hours, and then filtered through a filter and purified to obtain thiol at one end A polymer solution containing polymethoxyethyl acrylate having a group was obtained. The weight average molecular weight of the polymethoxyethyl acrylate having a thiol group at one end obtained as described above was 4400. From this, it was confirmed that the polymer (30) obtained above has a disulfide bond between the polymers of polymethoxyethyl acrylate having a weight average molecular weight of 4400.

Example 1
The polymer (1) obtained above is used as a biocompatible medical material, and after freeze-drying for 8 hours, the polymer (1) 0.05 mmol, hydrogenated soybean lecithin 0.5 mmol, cholesterol 0.37 mmol Of a liposome by freezing a lipid mixture solution prepared by dissolving 0.08 mmol of 3,5-dipentadecyloxybenzamidine hydrochloride in 30 mL of tert-butyl alcohol in an ice bath and freeze-drying for about 8 hours A lipid mixture (1) was obtained as a raw material of lipid membrane.

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

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

  Next, as the physical properties of the biocompatible medical material, using the liposome or liposome dispersion obtained above, sustained release of the inclusion, retention of particle shape, hemolytic resistance and extracorporeal release are described below. It investigated based on. The results are shown in Table 1.

(1) Sustained release of drug A mixed solution of 1 mL of liposome dispersion and 200 μL of defibrinated blood (manufactured by Koji Bio Inc.) and 1 mL of PBS is placed in a thermostat bath at 37 ° C. and incubated for 30 minutes or 24 hours. The fluorescence intensity is measured at an excitation wavelength of 494 nm and a fluorescence wavelength of 521 nm using a product of Electric Co., Ltd., part number: SH-9000, and the drug release rate is expressed by the formula:
[Delivery rate of drug (%)] = [(F ₂ −F ₁ ) / (F ₃ −F ₁ )] × 100
[Wherein, F ₁ is the fluorescence intensity before incubation, F ₂ is the fluorescence intensity after incubation at 37 ° C., F ₃ is 2% polyoxyethylene (10) octyl phenyl ether instead of PBS added to the mixture] [Wako Pure Chemical Industries, Ltd., trade name: Triton-X] shows the fluorescence intensity (100% leakage) after adding and mixing the PBS solution.
The sustained release of the drug was evaluated based on the following evaluation criteria.

[Evaluation criteria for sustained release of inclusions]
A. When the incubation time is 30 minutes ◎: The release rate of the drug is less than 10% ○: the release rate of the drug is 10% to less than 30% Δ: the release rate of the drug is 30% to less than 90% ×: the release of the drug 90% or more

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

(2) Retention of particle shape In a sample holder in which a parallel plate of 7.9 mm in diameter of a visco-elasticity measuring apparatus (manufactured by Rheometric Scientific F Co., Ltd.) was set to have a gap of 10 μm. After 1 mL of the liposome dispersion was added and sheared at a frequency of 1 Hz was applied for 5 minutes, the liposome dispersion was recovered, the average particle size was measured, and the retention ratio of the particle size was calculated using the formula:
[Particle maintenance factor (%)] = [average particle size after test / average particle size before test] × 100
The particle shape retention was evaluated based on the following evaluation criteria.

[Evaluation criteria for retention of particle shape]
:: retention rate of particle size is 70% to 100%, :: retention rate of particle size is 20% to less than 70%, ×: retention rate of particle size is less than 20%

(3) Hemolysis resistance The liposome was dissolved in PBS to prepare a 1% by mass PBS solution.

  After 48 mL of PBS solution was added to 2 mL of rabbit defibrillated blood [Corgin Bio Inc.] and mixed by inversion, the mixture was centrifuged at 2000 rpm for 10 minutes at 4 ° C. 48 mL of PBS was added to the mixture from which the supernatant was removed, and mixed by inversion to obtain a blood solution.

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

  2 mL of 2% polyoxyethylene (10) octyl phenyl ether (manufactured by Wako Pure Chemical Industries, Ltd., trade name: Triton-X) PBS solution was added to 2 mL of the blood solution obtained above, and the solution was mixed by inversion The absorbance at a wavelength of 545 nm was measured as described above. The absorbance at this time was regarded as hemolytic 100%.

Then, the hemolysis degree formula:
[Degree of hemolysis (%)] = [absorbance of incubation supernatant / absorbance when using Triton-X] x 100
Hemolysis resistance was evaluated based on the following evaluation criteria.

Evaluation criteria for hemolytic resistance
:: hemolysis degree less than 30% ○: hemolysis degree 30% or more and less than 50% Δ: hemolysis degree 50% or more and less than 70% ×: hemolysis degree 70% or more

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

  Next, a mixed solution was prepared by adding 1 g of hemolyzed defibrillated blood (manufactured by Kojin Bio Co., Ltd.) and 3 g of PBS to the mixture obtained above. The resulting mixture was mixed by inversion, and incubation was performed at 37 ° C. for 24 hours.

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

[Evaluation criteria for extracorporeal release]
◎: weight average molecular weight of the polymer is 8000 or less ○: weight average molecular weight of the polymer is greater than 8000, 30000 or less Δ: weight average molecular weight of the polymer is greater than 30000, 60000 or less x: weight average molecular weight of the polymer is Over 60000

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

  Next, as the physical properties of the biocompatible medical material, using the liposome or liposome dispersion obtained above, sustained release of the inclusion, retention of particle shape, hemolytic resistance and extracorporeal release are described below. It investigated based on. The results are shown in Table 1. In Table 1, "-" means that evaluation is not performed.

  From the results shown in Table 1, the biocompatible medical material obtained in each example is excellent in sustained release of the inclusion, retention of the shape of formed particles, hemolytic resistance and extracorporeal release. Know that Therefore, the biocompatible medical material of the present invention is, for example, a carrier, a medical device, a device for holding a drug and used for introduction into the body orally or through blood, nasal, transdermal, eye drops and the like. It is expected that it will be used as a coating agent such as a medical coating agent for a substrate to be used for the like.

Claims (3)

  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 1,000 to 9,000.   A biocompatible medical material comprising a biocompatible polymer having a disulfide bond between biocompatible polymers having a weight average molecular weight of 1,000 to 9,000.   A biocompatible medical material comprising a biocompatible polymer having a weight average molecular weight of 1,000 to 9,000 and having a thiol group at at least one molecular terminal.