Amphiphilic compound, medical resin composition using same, and pharmaceutical additive

Abstract

To provide means for reducing adsorptivity to a plastic while suppressing decrease in take-in efficiency into a cell, in an amphiphilic compound which is applicable to liposome with long-term retentivity in blood as a medicine carrier.SOLUTION: An amphiphilic compound has a site (I) including a structural unit (A) derived from a monomer (a) which has two or more hydroxyl groups in the molecule and has 2 to 10 carbon atoms constituting a side chain among carbon atoms of the structural unit, and a hydrocarbon group having 8 or more carbon atoms.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to an amphiphilic compound, a medical resin composition using the same, and a pharmaceutical additive.

Background Art

[0002] In recent years, formulations based on drug delivery systems (i.e., drug delivery systems (DDS)) have been actively developed. In recent DDS formulations, there are formulations that make it easier for drugs to accumulate in target cells by molecular target therapeutic agents in active targeting therapy and by nanotechnology in passive targeting therapy. As substances used in this passive targeting therapy, polyethylene glycol (PEG) is widely used.

[0003]

[0004] For example, formulations such as PEGylated liposomes obtained by modifying liposomes or polymeric micelles with PEG and used as drug carriers for long-circulating liposomes, and doxorubicin encapsulated therein (Doxil (registered trademark)) are clinically used.

[0005] Since the backbone structure of PEG is simple, it has high flexibility. In addition, since it has the property of being able to hydrate many water molecules, modifying drug particles or carriers with PEG forms a thick hydration layer on the particle surface. It is known that this hydration layer suppresses the interaction with serum proteins and cells, and as a result, the residence time of the drug in the blood (in the body) is greatly extended (stealthization).

[0006] ​Thus, drugs modified with PEG are expected to continue to play an important role in novel formulation technologies in the future, and many are currently in clinical trials. However, in recent years, in liposomes and polymeric micelles surface-modified with PEG, a phenomenon has been reported in which the stealth property of the drug is lost due to repeated administration (frequent administration) (Accelerated Blood Clearance: ABC phenomenon) (Non-Patent Document 1).

[0007] This ABC phenomenon means that there is a possibility that the pharmacological effect may be reduced with repeated administration and unexpected side effects may be induced. Therefore, in the future, for such PEGylated drugs, it is also expected that restrictions will be imposed on the types of target diseases and the drug administration patterns (dose / frequency of administration / number of administrations), and overcoming this issue is strongly desired.

[0008] To date, attempts have been made to suppress the occurrence of the ABC phenomenon by preparing modified drugs using modifiers other than PEG. For example, as a PEG alternative polymer, a technique has been reported in which polyvinylpyrrolidone (PVP) is used as a modifier to impart stealth properties to protein drugs (Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0010] The present inventors have been developing amphiphilic compounds having a hydrophilic moiety and a hydrophobic moiety in the molecule, mainly for application to long-circulating liposomes as drug carriers. In the studies conducted at that time, the present inventors found that PVP exhibits high adsorptivity to plastics such as polypropylene (PP). Here, polypropylene (PP) is widely used as a constituent material of the syringe barrel of a syringe. For this reason, for example, when a polymer-modified liposome is used as a drug carrier to constitute an injection solution or a prefilled syringe, or when a protein modified with a polymer is used as an active ingredient to constitute an injection solution or a prefilled syringe, the liposome containing the active ingredient is adsorbed to the inner wall of the syringe via PVP, and there is a possibility that some of the active ingredient encapsulated in the liposome remains in the syringe without being administered. In addition, there is also a problem that the uptake efficiency into cells decreases in conventionally known PEG-modified liposomes.

[0011] Therefore, an object of the present invention is to provide a means capable of reducing the adsorptivity to plastics while suppressing a decrease in the uptake efficiency into cells in an amphiphilic compound applicable to long-circulating liposomes as drug carriers and the like.

Means for Solving the Problems

[0012] In view of the above problems, the present inventors conducted intensive studies. As a result, a site containing a structural unit derived from a monomer having two or more hydroxyl groups in the molecule and having 2 to 10 carbon atoms constituting the side chain among the carbon atoms of the structural unit (hereinafter simply referred to as "site (I)" in this specification) and a hydrocarbon group having 8 or more carbon atoms. By using an amphiphilic compound containing in the molecule, it was found that the above problems can be solved, and the present invention has been completed.

[0013] That is, according to one embodiment of the present invention, there is provided an amphiphilic compound having two or more hydroxyl groups in the molecule and having a moiety (I) containing a structural unit (A) derived from a monomer (a) in which the number of carbon atoms constituting the side chain among the carbon atoms of the structural unit is 2 to 10, and a hydrocarbon group having 8 or more carbon atoms.

Advantages of the Invention

[0014] According to the present invention, in an amphiphilic compound that can be applied to long-circulating liposomes as a drug carrier, etc., it is possible to reduce the adsorption to plastic while suppressing a decrease in the uptake efficiency into cells.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Figure 4

Embodiments for Carrying Out the Invention

[0016] One embodiment of the present invention is an amphiphilic compound having two or more hydroxyl groups in the molecule and a moiety (I) containing a structural unit (A) derived from a monomer (a) in which the number of carbon atoms constituting the side chain among the carbon atoms of the structural unit is 2 to 10, and a hydrocarbon group having 8 or more carbon atoms.

[0017] The moiety (I) of the amphiphilic compound having such a structure has a lower adsorptivity to plastics such as PP compared to PVP. Therefore, while the compound can be applied to long-circulating liposomes as a drug carrier, etc., it is possible to reduce the adsorptivity to plastics. As a result, for example, the risk that the active ingredient encapsulated therein remains in the syringe when a liposome modified with the compound is used as a drug carrier can be reduced. Also, it is possible to significantly suppress the decrease in the uptake efficiency into cells as seen in liposomes modified with PEG.

[0018] The mechanism by which the amphiphilic compound according to the present invention can exhibit excellent performance when used, for example, in the above-described applications is not completely clear, but a mechanism such as hydrophobic adsorption is presumed. Note that this mechanism is based on presumption, and the present invention is not limited to the mechanism at all.

[0019] Hereinafter, preferred embodiments of the present invention will be described. Note that the present invention is not limited only to the following embodiments. Furthermore, combinations of two or more of the individual preferred forms of the present invention described below are also preferred forms of the present invention.

[0020] In this specification, "X to Y" indicating a range means "X or more and Y or less", and "weight" and "mass" are treated as synonyms. Further, in this specification, "(meth)acrylate" means acrylate or methacrylate, "(meth)acrylic" means acrylic or methacrylic, and acrylate and methacrylate may be used alone or in combination. Furthermore, unless otherwise specified, measurements such as operations and physical properties are measured under the conditions of room temperature (20 to 25 °C) / relative humidity 40 to 50%.

[0021] <Amphiphilic compound> The amphiphilic compound according to this embodiment has a moiety (I) containing a structural unit (A) having a predetermined structure and a hydrocarbon group having 8 or more carbon atoms. Hereinafter, these components will be described in detail.

[0022] (Moiety (I)) The amphiphilic compound according to the present invention first has a moiety (I) containing a structural unit (A) derived from a monomer (a) having two or more hydroxyl groups in the molecule and having 2 to 10 carbon atoms in the carbon atoms of the structural unit that constitute the side chain. In a preferred embodiment, the moiety (I) is composed of a polymer having two or more hydroxyl groups in the molecule and having a structural unit (A) derived from a monomer (a) having 2 to 10 carbon atoms in the carbon atoms of the structural unit that constitute the side chain. Here, in the present specification, the “structural unit (Q) derived from monomer (P)” (P represents any appropriate symbol, and there may be no notation of (P)) typically means that one of the bonds of the polymerizable unsaturated double bond possessed by the “monomer (P)” (or simply “monomer”) is opened by polymerization and becomes a unit (Q) (Q represents any appropriate symbol, and there may be no notation of (Q)) that constitutes at least a part of the polymer. The above “structural unit derived from monomer (P)” may be a structural unit formed by another production method as long as it has the same structure as the structural unit formed by polymerizing monomer (P) (or simply “monomer”) as described above (the structural unit represented by the general formula (Q) in the specific examples shown below). For example, a deprotection treatment may be performed on the structural unit formed by polymerizing a monomer (a) in which the hydroxyl group is protected to form the structural unit (A). For example, after polymerizing (2-methyl-2-ethyl-1,3-dioxolan-4-yl)methyl (meth)acrylate or glycidyl ether (meth)acrylate, hydrolysis may be performed to form a structural unit derived from glycerin (meth)acrylate.

[0023] The monomer (a) having two or more hydroxyl groups in the molecule and having 2 to 10 carbon atoms in the carbon atoms of the structural unit that constitute the side chain is preferably a vinyl monomer, and more preferably a (meth)acrylic monomer. Further, the monomer (a) may be a monofunctional monomer or a polyfunctional monomer, but preferably contains a monofunctional monomer, and more preferably consists of a monofunctional monomer.

[0024] Here, as the monomer (a), (meth)acrylic monomers such as glycerin mono(meth)acrylate (also known as 2,3-dihydroxypropyl (meth)acrylate), 1,2-dihydroxyethyl (meth)acrylate, 2,2-dihydroxyethyl (meth)acrylate, dihydroxybutyl (meth)acrylate, trimethylolpropane mono(meth)acrylate, pentaerythritol mono(meth)acrylate, dipentaerythritol mono(meth)acrylate are preferably used. Among these, glycerin monoacrylate (GLMA) or glycerin monomethacrylate (GLMMA) is preferred due to easy industrial availability and high reactivity. By polymerizing these (meth)acrylic monomers (a), the ethylenic double bond contained in the monomer (a) is cleaved to form a structural unit (A). Note that only one type of monomer (a) may be used alone, or two or more types may be used in combination.

[0025] In addition, among the carbon atoms of the structural unit derived from the monomer (a), the number of carbon atoms constituting the side chain is 2 to 10. In this specification, the "side chain" refers to the part other than the main chain containing the structural unit. And the "main chain" means the chain of continuously bonded carbon atoms in the polymer formed by the consecutive connection of the structural units, in which the number of carbon atoms is the largest. However, exceptionally, when the monomer (a) is a methacrylic monomer, the methyl group bonded to the carbon atom constituting the unsaturated double bond in the monomer is considered not to constitute either the main chain or the side chain. As described above, among the carbon atoms of the structural unit derived from the monomer (a), the number of carbon atoms constituting the side chain is 2 to 10, and this number of carbon atoms is preferably 3 to 8, more preferably 4 to 6.

[0026] Here, the structural unit (A) preferably contains a structural unit represented by the following chemical formula (1).

[0027]

Chemical formula

[0028] In formula (1), R 1 represents a hydrogen atom or a methyl group, preferably a hydrogen atom. Further, X is -C(=O)-O-, -C(=O)-NH-, -O-, -CH 2 O- or -CH 2 CH 2 O-, preferably -C(=O)-O-.

[0029] Among the structural units represented by the above chemical formula (1), those in which R 1 is a hydrogen atom and X is -C(=O)-O- are derived from glycerin monoacrylate (GLMA) as the monomer (a). Further, among the structural units represented by the above chemical formula (1), those in which R 1 is a methyl group and X is -C(=O)-O- are derived from glycerin monomethacrylate (GLMMA) as the monomer (a).

[0030] The proportion of the structural unit (A) derived from the monomer (a) having two or more hydroxyl groups in the molecule and the number of carbon atoms constituting the side chain among the carbon atoms of the structural unit in the part (I) constituting the amphiphilic compound is, for example, 1 to 100% by mass, preferably 20 to 100% by mass, more preferably 50 to 100% by mass, still more preferably 60 to 100% by mass, even more preferably 80 to 100% by mass, particularly preferably 90 to 100% by mass, and most preferably 100% by mass. If the proportion of the structural unit (A) is within the above range, the effects of the present invention can be achieved.

[0031] When the moiety (I) constituting the amphiphilic compound contains a constitutional unit (hereinafter also simply referred to as "constitutional unit (B)") other than the constitutional unit (A), the constitutional unit (B) can be derived from any radically polymerizable monomer (hereinafter, the monomer that becomes the constitutional unit (B) by copolymerization is also referred to as "monomer (b)"). When the moiety (I) constituting the amphiphilic compound contains the constitutional unit (B), the proportion of the constitutional unit (B) in the moiety (I) is, for example, 99% by mass or less, preferably 80% by mass or less, more preferably 50% by mass or less, still more preferably 40% by mass or less, even more preferably 20% by mass or less, and particularly preferably 10% by mass or less.

[0032] Examples of the monomer (b) include, for example, hydroxyl group-containing (meth)acrylates other than the monomer (a), polyoxyalkylene group-containing monomers, alkoxyalkyl (meth)acrylates, vinyl monomers, alkylene oxides, alkoxypolyoxyalkylene glycols, cyclic compounds, amino acids (for example, aspartic acid, glutamic acid), and the like. These monomers (b) may also be used alone or in combination of two or more.

[0033] Examples of the hydroxyl group-containing (meth)acrylate include hydroxyalkyl (meth)acrylates having 2 to 4 carbon atoms in the hydroxyalkyl group such as 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate.

[0034] Examples of the polyoxyalkylene group-containing unsaturated monomer include, for example, the monomer represented by the following chemical formula (2).

[0035]

Chemical formula

[0036] In formula (2), R 2 , R 3 and R 4 each independently represent a hydrogen atom or a methyl group, and R 5represents an alkylene group having 2 to 18 carbon atoms, R 6 represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and X represents an alkylene group having 1 to 5 carbon atoms, a -CO- group, or R 2 R 4 C=CR 3 - when the group is a vinyl group, it represents a direct bond, and m is the average number of moles of added -(R 5 O)- groups and represents a number from 1 to 300. In formula (2), (R 5 O) m when composed of two or more R 5 O, the two or more R 5 O may have any bonding form, random, block, or alternating.

[0037] In formula (2), R 6 is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms. Among R 6 , a hydrogen atom and a hydrocarbon group having 1 to 20 carbon atoms are preferred, a hydrocarbon group having 1 to 10 carbon atoms is more preferred, a hydrocarbon group having 1 to 3 carbon atoms is even more preferred, and a hydrocarbon group having 1 or 2 carbon atoms is even more preferred. Among hydrocarbon groups, an alkyl group or an alkenyl group is preferred, an alkyl group having 1 to 20 carbon atoms is more preferred, an alkyl group having 1 to 10 carbon atoms is even more preferred, and an alkyl group having 1 to 3 carbon atoms is even more preferred.

[0038] In formula (2), the oxyalkylene group represented by the formula: -R 5 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, etc. Among these oxyalkylene groups, an oxyalkylene group having 2 to 8 carbon atoms is preferred, an oxyalkylene group having 2 to 4 carbon atoms such as an oxyethylene group, an oxypropylene group, and an oxybutylene group is more preferred, and an oxyethylene group is even more preferred.

[0039] In chemical formula (2), m is the formula: -R 5It is the average number of moles of oxyalkylene groups represented by O-. The average number of moles of addition means the average value of the number of moles of oxyalkylene groups in 1 mole of the polyoxyalkylene group-containing unsaturated monomer. The lower limit of m is preferably 2 or more, more preferably 4 or more, and still more preferably 8 or more. The upper limit of m is preferably 100 or less, more preferably 50 or less.

[0040] X is an alkylene group having 1 to 5 carbon atoms, a -CO- group, or R 2 R 4 C=CR 3 When the - group is a vinyl group, it represents a direct bond. Among these groups, the -CO- group is preferable.

[0041] Examples of the polyoxyalkylene group-containing unsaturated monomer include an unsaturated alcohol polyalkylene glycol adduct, a polyalkylene glycol ester monomer, and an (alkoxy) polyalkylene glycol monomaleic acid ester.

[0042] The 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 the unsaturated alcohol polyalkylene glycol adduct include polyethylene glycol monovinyl ether, polyethylene glycol monoallyl ether, polyethylene glycol mono(2-methyl-2-propenyl) ether, polyethylene glycol mono(2-butenyl) ether, polyethylene glycol mono(3-methyl-3-butenyl) ether, polyethylene glycol mono(3-methyl-2-butenyl) ether, polyethylene glycol mono(2-methyl-3-butenyl) ether, polyethylene glycol mono(2-methyl-2-butenyl) ether, polyethylene glycol mono(1,1-dimethyl-2-propenyl) ether, polyethylene polypropylene glycol mono(3-methyl-3-butenyl) ether, and methoxypolyethylene glycol mono(3-methyl-3-butenyl) ether.

[0043] The polyalkylene glycol ester monomer is a monomer in which an unsaturated group and a polyalkylene glycol chain are bonded via an ester bond.

[0044] As the polyalkylene glycol ester 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 alkoxypolyalkylene glycols, those mainly composed of an oxyethylene group are preferable. Examples of the alcohol include aliphatic alcohols having 1 to 30 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, octanol, 2-ethyl-1-hexanol, nonyl alcohol, lauryl alcohol, cetyl alcohol, stearyl alcohol, etc., alicyclic alcohols having 3 to 30 carbon atoms such as cyclohexanol, unsaturated alcohols having 3 to 30 carbon atoms such as (meth)allyl alcohol, 3-buten-1-ol, 3-methyl-3-buten-1-ol, etc. Examples of the esterified product include methoxypolyethylene glycol 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. Among polyalkylene glycol ester monomers, for example, (alkoxy)polyalkylene glycol mono(meth)acrylate such as methoxypolyethylene glycol monomethacrylate is preferable.

[0045] Examples of the alkoxyalkyl (meth)acrylate include alkoxyalkyl (meth)acrylates in which the alkoxy group has 1 to 4 carbon atoms and the alkyl group has 1 to 4 carbon atoms, such as methoxymethyl (meth)acrylate, methoxyethyl (meth)acrylate, methoxypropyl (meth)acrylate, ethoxymethyl (meth)acrylate, ethoxyethyl (meth)acrylate, and ethoxypropyl (meth)acrylate. These alkoxyalkyl (meth)acrylates may be used alone or in combination of two or more.

[0046] Examples of the vinyl monomer include (meth)acrylic acid, methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, tert-butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, n-lauryl (meth)acrylate, n-stearyl (meth)acrylate, diaminomethyl (meth)acrylate, diaminoethyl (meth)acrylate, dimethylamino (meth)acrylate, diethylamino (meth)acrylate, glycidyl (meth)acrylate, styrene, aziridines, 2-(meth)acryloyloxymethyl phosphorylcholine, 2-(meth)acryloyloxyethyl phosphorylcholine, tetrahydrofurfuryl (meth)acrylate, isopropylacrylamide, vinyl alcohol, vinyl formamide, vinylisobutylacrylamide, (meth)acrylamide, dimethylacrylamide, vinylacetamide, and N-vinylpyrrolidone.

[0047] Examples of the alkylene oxide include alkylene oxides having 2 to 4 carbon atoms, such as ethylene oxide and propylene oxide.

[0048] Examples of the alkoxypolyoxyalkylene glycol include alkoxypolyoxyalkylene glycols having an alkoxy group with 1 to 4 carbon atoms and an oxyalkylene group with 1 to 4 carbon atoms, such as polyethylene glycol, polypropylene glycol, methoxypolyethylene glycol, ethoxypolyethylene glycol, methoxypolypropylene glycol, and ethoxypolypropylene glycol, and having an addition molar number of oxyalkylene groups of 2 to 30.

[0049] Examples of the cyclic compound include lactides such as L-lactide, lactones such as ε-caprolactone, trimethyl carbonate, cyclic amino acids, morpholine-2,5-dione, and the like.

[0050] When the site (I) is composed of a polymer containing the structural unit (A), the polymer constituting the site may have a structure of a block copolymer obtained by bonding the same type or different types of polymers to each other.

[0051] From the viewpoint of adsorption to the inner wall of the syringe and the like, the number average molecular weight (Mn) of the above polymer is preferably 1000 or more, more preferably 2000 or more, and still more preferably 3000 or more. Further, from the viewpoint of in vitro excretion and the like, the number average molecular weight (Mn) of the above polymer is preferably 90000 or less, more preferably 30000 or less, and still more preferably 15000 or less. The value of the number average molecular weight (Mn) of the above polymer means the value measured based on the measurement method of Mn for the polymers obtained in Production Examples 1 to 7 in the Examples described later. Here, in the Examples described later, since the number average molecular weight (Mn) of the amphiphilic compound is measured, the value of Mn of the site (I) (polymer) can be calculated by subtracting the molecular weight of the site other than the site (I) (polymer) from this measured value. If an accurate value can be calculated, the value of Mn may be obtained by the same method using only the site (I) (polymer).

[0052] The molecular weight distribution of the above polymer (value of [weight average molecular weight (Mw) / number average molecular weight (Mn)]) is preferably from 1 to 5, more preferably from 1 to 3, still more preferably from 1 to 2, still more preferably from 1 to 1.5, and still more preferably from 1 to 1.3, from the viewpoint of the modifiability of the amphiphilic compound (polymer) to the liposome and the like.

[0053] The polymer constituting the moiety (I) can be obtained by polymerizing a monomer composition containing the monomer (a) and, if necessary, the monomer (b). Examples of the method for polymerizing the monomer composition include living radical polymerization methods typified by radical polymerization methods, atom transfer radical polymerization methods, reversible addition-fragmentation chain transfer (RAFT) polymerization methods, ion polymerization methods, ring-opening polymerization methods, coordination polymerization methods, polycondensation methods, etc. However, the present invention is not limited to such examples only.

[0054] When polymerizing the monomer composition, a solvent may be used. Examples of the solvent include aromatic solvents such as benzene, toluene, and xylene; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, and tert-butanol; halogen atom-containing solvents such as dichloroethane and dichloromethane; ether solvents such as diethyl 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; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diacetone alcohol; amide solvents such as dimethylformamide; and water. 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 monomer composition, the concentration of the resulting polymer, and the like.

[0055] When polymerizing the monomer composition, a chain transfer agent can be used to adjust the molecular weight of the polymer or introduce a hydrocarbon group.

[0056] Examples of the chain transfer agent include hydrophilic thiol-based chain transfer agents such as alkali metal thioacetates such as sodium thioacetate and potassium thioacetate, cysteine, cysteamine, mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, and their sodium salts and potassium salts; primary alcohols such as 2-aminopropan-1-ol, secondary alcohols such as isopropanol, phosphorous acid, hypophosphorous acid and their salts (e.g., sodium hypophosphite, potassium hypophosphite, etc.), sulfurous acid, bisulfite, dithionous acid, metabisulfite and their salts (e.g., sodium sulfite, sodium bisulfite, sodium dithionite, sodium metabisulfite, potassium sulfite, potassium bisulfite, potassium dithionite, potassium metabisulfite, etc.), and other non-thiol-based chain transfer agents; hydrophobic thiol-based chain transfer agents such as butanethiol, octanethiol, decanethiol, dodecanethiol, hexadecanethiol, octadecanethiol, thiocolesterol, cyclohexyl mercaptan, thiophenol, octyl thioglycolate, octyl 2-mercaptopropionate, octyl 3-mercaptopropionate, 2-ethylhexyl mercaptopropionate, 2-mercaptoethyl octanoate, 1,8-dimercapto-3,6-dioxaoctane, decanetrithiol, dodecyl mercaptan, etc. When performing reversible addition-fragmentation chain transfer (RAFT) polymerization, it is necessary to use a reversible addition-fragmentation chain transfer (RAFT) agent as the chain transfer agent. Examples of such RAFT agents include 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid, 2-cyano-2-propyl benzoate, 2-cyano-2-propyl dodecyltrithiocarbonate, 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, 2-(dodecylthiocarbonothioylthio)-2-methylpropanoic acid, cyanomethyl dodecylthiocarbonate, cyanomethyl methyl(phenyl)carbamothioate, bis(thiobenzoyl)disulfide, bis(dodecylsulfanylthiocarbonyl)disulfide, etc.These chain transfer agents may each be used alone or in combination of two or more.

[0057] The amount of the chain transfer agent may be appropriately set according to the kind of monomer contained in the monomer composition, polymerization conditions such as polymerization temperature, the molecular weight of the target polymer, etc., and is not particularly limited. However, when obtaining a polymer having a number average molecular weight of several thousands to several tens of thousands, it is preferably 0.1 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, of the chain transfer agent per 100 parts by mass of the monomer.

[0058] When polymerizing the monomer composition, a polymerization initiator can be used.

[0059] Examples of the polymerization initiator include radical polymerization initiators such as azoisobutyronitrile, 2,2’-azobis(4-dimethoxy-2,4-dimethylvaleronitrile), 4,4’-azobis(4-cyanopentanoic acid), 2,2’-azobis[2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide], 2,2’-azobis[N-(2-hydroxyethyl)-2-methoxypropanamide], 2,2’-azobis(2-methyl-2-propenylpropanamide), 2,2’-bis(2-imidazolin-2-yl)[2,2’-azobispropane] dihydrochloride, 2,2’-azobis(propane-2-carboxamidine) dihydrochloride, 2,2’-azobis[N-(2-carboxyethyl)-2-methylpropionamidine], 2,2’-azobis[2-[1-(2-hydroxyethyl)-2-imidazolin-2-yl]propane dihydrochloride, 2,2’-azobis(2,4-dimethylvaleronitrile), 2,2’-azobis(2-methylbutyronitrile), tert-butyl peroxy-2-ethylhexanoate, 2,2’-azobis(isobutyronitrile), benzoyl peroxide, di-tert-butyl peroxide, cyclohexanone peroxide, acetylacetone peroxide; living radical polymerization initiators such as bromomethylbenzene, 1-(bromomethyl)-4-methylbenzene, ethyl 2-bromoisobutyrate, 2-bromoisobutyric acid hydroxyethyl, bis[2-(2’-bromoisobutyryloxy)ethyl] disulfide, 10-undecenyl 2-bromoisobutyrate, 4-(1-bromoethyl)benzoic acid, etc. These polymerization initiators may be used alone or in combination of two or more kinds.

[0060] The amount of the polymerization initiator may be appropriately set according to the desired physical properties of the resulting polymer, etc. Usually, per 100 parts by mass of the monomer, the amount of the polymerization initiator is preferably 0.001 to 20 parts by mass, more preferably 0.005 to 10 parts by mass.

[0061] The polymerization conditions for polymerizing the monomer composition 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. Also, the atmosphere for polymerizing the monomer composition is preferably an inert gas such as nitrogen gas or argon gas. The reaction time may be appropriately set so that the polymerization reaction of the monomer is completed.

[0062] By polymerizing the monomer composition as described above, preferably, a polymer constituting part (I) can be obtained. Here, the obtained polymer may have a functional group at its terminal. When the polymer constituting part (I) has a functional group at its terminal, it is possible to easily modify a medicine or the like via the functional group or link it to a predetermined hydrocarbon group described later via the functional group. However, the polymer constituting part (I) may not have a functional group at its terminal. The amphiphilic compound according to the present invention has a hydrocarbon group having 8 or more carbon atoms and part (I) (including the polymer) in the molecule. When the polymer constituting part (I) has a functional group at its terminal, the functional group may be present only at one end of the polymer or may be present at both ends. Further, the functional group present at the terminal of the polymer may be located on the side where part (I) is bonded to a predetermined hydrocarbon group described later or may be located on the side opposite thereto.

[0063] Preferred functional groups that the polymer constituting part (I) may have include an anionic functional group, a cationic functional group, a nonionic functional group, and an amphoteric functional group. The functional group is preferably a reactive functional group. Suitable reactive functional groups include a -SH group, a group represented by the formula: -COOM (where M represents a hydrogen atom or an alkali metal atom), a hydroxyl group, an allyl group, an epoxy group, an aldehyde group, a -NH 2 group, a CONH- group, and the like. Examples of M include alkali metal atoms such as a sodium atom and a potassium atom. When the polymer has a functional group at its terminal, the number of the functional groups is not particularly limited, but is preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 to 2.

[0064] In order to introduce a functional group to the terminal of the polymer constituting part (I), a functional group-containing compound for introducing a functional group to the polymer can be used. Examples of the functional group-containing compound for introducing a functional group to the terminal of the polymer include alkali metal thioacetates such as sodium thioacetate and potassium thioacetate; thiol-based chain transfer agents such as cysteine, cysteamine, mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, and their sodium salts and potassium salts; polymerization initiators with introduced functional groups such as 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis[2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide], 2,2'-azobis[N-(2-hydroxyethyl)-2-methoxypropanamide], 2,2'-azobis(2-methyl-2-propenylpropanamide), 2,2'-bis(2-imidazolin-2-yl)[2,2'-azobispropane] dihydrochloride, 2,2'-azobis(propane-2-carboxamidine) 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. These functional group-containing compounds may be used alone or in combination of two or more. Among the above-mentioned functional group-containing compounds, there are those corresponding to the above-mentioned chain transfer agents and polymerization initiators. However, the functional group-containing compounds corresponding to the chain transfer agents or polymerization initiators may be used for only one of the purposes of the chain transfer agent or polymerization initiator, or for both purposes.

[0065] When a living polymerization initiator is used as the polymerization initiator, a functional group may be introduced to the terminal of the polymer prepared using the living polymerization initiator by reacting a functional group-containing compound with the halogen atom present at the terminal of the polymer. Examples of the functional group-containing compound capable of reacting with such a halogen atom to introduce a functional group to the terminal of the polymer include amine compounds such as ethylenediamine and propyldiamine, dithiol compounds such as ethanedithiol, propanedithiol, and hexadecanedithiol, allyl mercaptan, and thiol compounds such as cysteine, cysteamine, mercaptoethanol, thioglycerol, thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, thioacetic acid, thiomalic acid, 2-mercaptoethanesulfonic acid, and their sodium salts and potassium salts.

[0066] The amount of the functional group-containing compound for introducing a functional group to the terminal of the polymer may be appropriately set according to the type of the monomer (constituent unit) constituting the polymer, polymerization conditions such as the polymerization temperature, and the molecular weight of the target polymer, and is not particularly limited. When obtaining a polymer having a number-average molecular weight of several thousand to several tens of thousands, the amount of the chain transfer agent is preferably 0.1 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, per 100 parts by mass of the monomer.

[0067] As a method for introducing a functional group to the terminal of the polymer constituting the site (I), for example, (1) A method of polymerizing a monomer composition in the presence of a polymerization initiator having the functional group introduced thereto as the polymerization initiator to obtain a polymer. (2) A method of polymerizing a monomer composition in the presence of a chain transfer agent having the functional group introduced thereto as the chain transfer agent to obtain a polymer. (3) A method of reacting a halogen atom present at the terminal of the polymer with a functional group-containing compound. Although the above are examples, the present invention is not limited to such examples only.

[0068] (Hydrocarbon group) The amphiphilic compound according to the present invention is characterized in that, in addition to the "site (I) containing a structural unit (A) derived from a monomer (a) having two or more hydroxyl groups in the molecule" described above, it also has a hydrocarbon group having 8 or more carbon atoms. The specific structure of the hydrocarbon group is not particularly limited.

[0069] As an example, it is preferable that the hydrocarbon group is a group contained in an organic compound having the performance of forming an aggregate of molecules with each other by hydrophobic interaction in an aqueous solution. Examples of such organic compounds include hydrocarbons, hydrophobic polymers, lipids, and other organic molecules.

[0070] Examples of the hydrocarbon include aliphatic hydrocarbons having 8 to 50 carbon atoms or aromatic hydrocarbons having 8 to 50 carbon atoms. That is, in a preferred embodiment of the present invention, the hydrocarbon group has 8 to 50 carbon atoms, more preferably 8 to 40 carbon atoms, still more preferably 8 to 30 carbon atoms, and particularly preferably 8 to 20 carbon atoms.

[0071] Examples of the aliphatic hydrocarbon having 8 to 50 carbon atoms include, for example, linear alkanes such as octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, branched alkanes thereof, cyclic alkanes thereof, etc., and preferably linear alkanes.

[0072] Examples of the aromatic hydrocarbon having 8 to 50 carbon atoms include, for example, 2-phenylethane, 1,3,5-trimethylbenzene, naphthalene, anthracene, fluorescein, and their position isomers.

[0073] Examples of the hydrophobic polymer include polymers obtained by polymerizing, as a main component, those among vinyl monomers that can be constituent units of the above-described site (I) and have a hydrocarbon group having 8 or more carbon atoms in the side chain.

[0074] "Lipid" means an organic compound having a long-chain fatty acid or hydrocarbon chain, being poorly soluble in water and readily soluble in organic solvents. "Lipids" can be further broadly classified into phospholipids, glycolipids, sphingolipids, sterols, neutral lipids, saturated or unsaturated fatty acids, etc.

[0075] Phospholipids are broadly classified into glycerophospholipids and sphingophospholipids. Representative examples of glycerophospholipids include phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidic acid (PA). On the other hand, a representative example of sphingophospholipids is sphingomyelin. Specific examples of phospholipids include the lipids described in the following (a) to (i).

[0076] (a) Phosphatidylcholines Specific examples of phosphatidylcholines include dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), dilauroylphosphatidylcholine (DLPC), didecanoylphosphatidylcholine (DDPC), dioctanoylphosphatidylcholine (DOPC), dihexanoylphosphatidylcholine (DHPC), dibutyrylphosphatidylcholine (DBPC), dielaidoylphosphatidylcholine, dilinoleoylphosphatidylcholine, diarachidonoylphosphatidylcholine, diicosanoylphosphatidylcholine (DEPC), diheptanoylphosphatidylcholine, didecanoylphosphatidylcholine, diheptadecanoylphosphatidylcholine, dibehenoylphosphatidylcholine, elaeostearoylphosphatidylcholine, hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-arachidonoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1-palmitoyl-2-linoleoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, 1-palmitoyl-2-stearoylphosphatidylcholine, 1-stearoyl-2-palmitoylphosphatidylcholine, 1,2-dimyristoyl amido-1,2-deoxyphosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, 1-myristoyl-2-stearoylphosphatidylcholine, di-O-hexadecylphosphatidylcholine, trans-dielaidoylphosphatidylcholine, dipalmitelaidoyl-phosphatidylcholine, n-octadecyl-2-methylphosphatidylcholine, n-octadecylphosphatidylcholine, 1-laurylpropanediol-3-phosphocholine, erythro-N-lignoceroyl sphingophosphatidylcholine and palmitoyl-(9-cis-octadecenoil)-3-sn-phosphatidylcholine and the like.

[0077] (b) Phosphatidylserines Specific examples of phosphatidylserines include distearoyl phosphatidylserine (DSPS), dimyristoyl phosphatidylserine (DMPS), dilauroyl phosphatidylserine (DLPS), dipalmitoyl phosphatidylserine (DPPS), dioleoyl phosphatidylserine (DOPS), lysophosphatidylserine, elaeostearoyl phosphatidylserine, 1,2 - di-(9-cis-octadecenoyl)-3-sn-phosphatidylserine, and the like.

[0078] (c) Phosphatidylinositols Specific examples of phosphatidylinositols include dipalmitoyl phosphatidylinositol (DPPI), distearoyl phosphatidylinositol (DSPI), and dilauroyl phosphatidylinositol (DLPI), and the like.

[0079] (d) Phosphatidylglycerols Specific examples of phosphatidylglycerols include dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylglycerol (DSPG), dioleoyl phosphatidylglycerol (DOPG), dilauroyl phosphatidylglycerol (DLPG), dimyristoyl phosphatidylglycerol (DMPG), lysophosphatidylglycerol, hydrogenated soybean phosphatidylglycerol (HSPG), hydrogenated egg phosphatidylglycerol (HEPG), and cardiolipin (diphosphatidylglycerol), and the like.

[0080] (e) Phosphatidylethanolamine (cephalin) Specific examples of phosphatidylethanolamines (cephalin) include dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine (DOPE), dilauroylphosphatidylethanolamine (DLPE), dimyristoylphosphatidylethanolamine (DMPE), didecanoylphosphatidylethanolamine (DDPE), N-glutarylphosphatidylethanolamine (NGPE), lysophosphatidylethanolamine, N-(7-nitro-2,1,3-benzoxadiazol-4-yl)-1,2-dioleoyl-sn-phosphatidylethanolamine, elaeostearoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine, and 1-hexadecyl-2-palmitoylglycerophosphatidylethanolamine. In Production Example 7 described later, distearoyl N-(3-maleimid-1-oxopropyl)-L-α-phosphatidylethanolamine (manufactured by NOF Corporation, COATSOME (registered trademark) FE-8080MA3), a derivative of distearoylphosphatidylethanolamine (DSPE) having a maleimide group, is used as a raw material for the lipid. Thus, phosphatidylethanolamines (and other lipid derivatives) having functional groups such as maleimide groups and succinimide groups for linking to site (I) together with hydrocarbon groups having various carbon atom numbers of 8 or more can also be used in the same manner.

[0081] (f) Phosphatidic acids Specific examples of phosphatidic acids include dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSP A), dimyristoylphosphatidic acid (DMPA), and dioleoylphosphatidic acid (DOPA).

[0082] (g) Sphingomyelin lipids Specific examples of sphingolipids include, for example, sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, ceramide ciliate, ceramide phosphorylethanolamine, and ceramide phosphorylglycerol, among others.

[0083] Glycolipids are broadly classified into glyceroglycolipids and sphingoglycolipids. Examples of glycolipids include the lipids described in the following (a) to (c).

[0084] (a) Glyceroglycolipids Specific examples of glyceroglycolipids include diglycosyldiglyceride, glycosyldiglyceride, digalactosyldiglyceride, galactosyldiglyceride, sulfoxyribosyldiglyceride, (1,3)-D-mannosyl(1,3)diglyceride, digalactosylglyceride, digalactosyldilauroylglyceride, digalactosyldimyristoylglyceride, digalactosyldipalmitoylglyceride, digalactosyldistearoylglyceride, galactosylglyceride, galactosyldilauroylglyceride, galactosyldimyristoylglyceride, galactosyldipalmitoylglyceride, galactosyldistearoylglyceride, and digalactosyldiacylglycerol, among others.

[0085] (b) Sphingoglycolipids Specific examples of sphingoglycolipids include ceramide (cerebroside), galactosylceramide, lactosylceramide, digalactosylceramide, ganglioside GM1, ganglioside GM2, ganglioside GM3, sulfatide, ceramide oligohexoside, and globoside.

[0086] (c) Other glycolipids Other glycolipids include ceramide oligohexoside, palmitoyl glucoside, stearyl glucoside, myristyl glucoside, alkyl glucoside, aminophenyl glucoside, cholesteryl maltoside, cholesteryl glucoside, 3-cholesteryl-6'-(glycosylthio)hexyl ether glycolipid, glucamides, and the like.

[0087] The most representative of the sterols is cholesterol. In addition to cholesterol, sterols include, for example, cholesterol succinate, dihydrocholesterol, lanosterol, dihydrolanosterol, desmosterol, stigmasterol, sitosterol, campesterol, brassicasterol, thymosterol, ergosterol, campesterol, fucosterol, 22-ketosterol, 20-hydroxysterol, 7-hydroxycholesterol, 19-hydroxycholesterol, 22-hydroxycholesterol, 25-hydroxycholesterol, 7-dehydrocholesterol, 5α-cholest-7-en-3β-ol, epicholesterol, dehydroergosterol, cholesterol sulfate, cholesteryl hemisuccinate, cholesteryl phthalate, cholesteryl phosphate, cholesteryl valerate, cholesteryl hemisuccinate, 3βN-(N’,N’-dimethylaminoethane)-carbamoyl cholesterol, cholesteryl acetate, cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, cholesteryl arachidate, coprostanol, cholesteryl ester, cholesteryl phosphorylcholine, and 3,6,9-trioxaoctan-1-ol-cholesteryl-3e-ol, and the like.

[0088] Examples of neutral lipids include diglycerides (such as diolein, dipalmitolein) and mixed caprylin-caprin diglycerides, triacylglycerols (triolein, tripalmitolein, trimyristolein, trilaurin, tricaprin, tricaprylin, tricaproin, etc.), squalene, tocopherol, and cholesterol, and the like.

[0089] Examples of saturated fatty acids and unsaturated fatty acids include saturated or unsaturated fatty acids having 5 to 30 carbon atoms such as caprylic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, tridecylenic acid, myristic acid, pentadecylenic acid, palmitic acid, margaric acid, stearic acid, nonadecylenic acid, arachidic acid, dodecenoic acid, tetradecenoic acid, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, docosapentaenoic acid, and the like.

[0090] Regarding other organic molecules (regardless of natural compounds or chemically synthesized compounds), when they have a hydrocarbon group with 8 or more carbon atoms, they can be used as a source of the hydrocarbon group with 8 or more carbon atoms in the amphiphilic compound according to the present invention. For example, there are fat-soluble vitamins such as vitamin A (retinol), vitamin D (calciferol), vitamin E (tocopherol), vitamin K, and their derivatives. In addition, organic molecules composed of one or more long-chain alkyl chains (with 8 or more carbon atoms) (such as dialkyl glycerol, etc.) and carbon molecules such as fullerene C60 can also be used as a source of the hydrocarbon group with 8 or more carbon atoms.

[0091] Here, in a preferred embodiment of the present invention, the hydrocarbon group having 8 or more carbon atoms (preferably having 8 to 50 carbon atoms) is preferably bonded to the site (I) containing the structural unit (A) directly or via a divalent bonding group, or exists as a part of a lipid (such as a phospholipid) that is bonded to the site (I) containing the structural unit (A) directly or via a divalent bonding group.

[0092] A hydrocarbon group having 8 or more carbon atoms may also have a functional group at its terminal, similar to the polymer constituting moiety (I). When a hydrocarbon group having 8 or more carbon atoms has a functional group at its terminal, it becomes possible to modify a medicine or the like via the functional group. However, a hydrocarbon group having 8 or more carbon atoms may not have a functional group at its terminal. When a hydrocarbon group having 8 or more carbon atoms has a functional group at its terminal, the functional group may be present only at one terminal of the hydrocarbon group having 8 or more carbon atoms, or may be present at both terminals. Further, the functional group present at the terminal of the hydrocarbon group having 8 or more carbon atoms may be located on the side where the hydrocarbon group having 8 or more carbon atoms is bonded to moiety (I), or may be located on the opposite side.

[0093] From the viewpoint of in vitro excretion properties and the like, the molecular weight of the hydrocarbon group having 8 or more carbon atoms is preferably 5000 or less, preferably 2000 or less, and more preferably 1000 or less. Preferably it is 100 or more, and more preferably 150 or more. Here, the ratio of the molecular weight of the "hydrocarbon group having 8 or more carbon atoms" to the molecular weight of the amphiphilic compound is preferably 0.2 to 20%, more preferably 0.5 to 15%, and still more preferably 1 to 10%.

[0094] Further, in the present invention, when a hydrocarbon group having 8 or more carbon atoms is present in the amphiphilic compound as part of a lipid, the molecular weight of the lipid is preferably 2000 or less, and more preferably 1000 or less. Here, when a hydrocarbon group having 8 or more carbon atoms is present in the amphiphilic compound as part of a lipid, the ratio of the molecular weight of the lipid to the molecular weight of the amphiphilic compound is preferably 2 to 50%, more preferably 5 to 35%, and still more preferably 10 to 20%.

[0095] The above divalent linking group is a group that links moiety (I) and the hydrocarbon group having 8 or more carbon atoms, and its structure is not particularly limited, and it may be included in a part of the structure of moiety (I). As such a divalent linking group, specifically, -S-, -S-C(=S)-, -S-C(=S)-S-, -S-C(=S)-N(-Ra )-, -S-C(=S)-O-, -S-R b -C(=O)-O-, -S-R b -C(=O)-N(-R a )-, -S-R b -O-, -S-R b -O-C(=O)-, -O-, -O-C(=O)-, -N(-R a )-C(=O)- and divalent linking groups containing these are exemplified. Here, the above R a is a hydrogen atom or a hydrocarbon group having 1 to 30 carbon atoms. The above R b is a hydrocarbon group having 1 to 30 carbon atoms. Incidentally, a residue obtained by removing one hydrogen atom and one hydrocarbon group having 8 or more carbon atoms from a lipid (including a modified lipid) is also one of the preferred forms of the above divalent linking group. The above divalent linking group preferably has a molecular weight of 5000 or less, more preferably 2000 or less, and even more preferably 1000 or less.

[0096] Here, as a method for linking a hydrocarbon group having 8 or more carbon atoms and site (I) via a divalent linking group, when polymerizing a monomer composition in the presence of a chain transfer agent and / or a polymerization initiator to obtain a polymer constituting site (I), as the above chain transfer agent and / or polymerization initiator, a method using a chain transfer agent or a polymerization initiator having a structure that can form a site containing a hydrocarbon group having 8 or more carbon atoms in the molecule can be mentioned. In particular, by polymerizing a monomer composition using a chain transfer agent having a thiol group (-SH group) bonded to a hydrocarbon group having 8 or more carbon atoms, an amphiphilic compound in which the hydrocarbon group having 8 or more carbon atoms is bonded to site (I) via a thioether bond (-S-) can be obtained (see Production Examples 1 to 6 described later).

[0097] Also, as another method of linking a hydrocarbon group having 8 or more carbon atoms and moiety (I) via a divalent linking group, first, when polymerizing a monomer composition in the presence of a chain transfer agent to obtain a polymer constituting moiety (I), RAFT polymerization is carried out using a reversible addition-fragmentation chain transfer (RAFT) agent as the above chain transfer agent, whereby a thiol group (-SH group) is introduced to the terminal of the polymer constituting moiety (I). Subsequently, a compound having a functional group (for example, a maleimide group) capable of reacting with the thiol group (-SH group) is reacted with the thiol group (-SH group) together with a hydrocarbon group having 8 or more carbon atoms. Thereby, a hydrocarbon group having 8 or more carbon atoms and moiety (I) can be linked via a thioether bond (-S-) (see Production Example 7 described later). This method is particularly useful when a hydrocarbon group having 8 or more carbon atoms is present in an amphiphilic compound as a part of a lipid or other organic molecule.

[0098] In the amphiphilic compound according to the present invention, the polymer constituting moiety (I) or the polymer when a hydrocarbon group having 8 or more carbon atoms is present in the compound as a part of the polymer may have a cross-linked structure. Examples of the method of cross-linking the polymer include a chemical cross-linking method and a physical cross-linking method. Examples of the chemical cross-linking method include a method of cross-linking a polymer using a chemical cross-linking agent such as an epoxy compound, oxidized starch, glutaraldehyde, formaldehyde, suberimidic acid dimethyl, carbodiimide, succinimidyl compound, diisocyanate compound, acyl azide, lotherine, tris(hydroxymethyl)phosphine, copper ascorbate, glucose lysine, and a photooxidizing agent, and a method of chemically cross-linking a polymer by heat dehydration treatment, irradiation with ultraviolet rays, irradiation with electron beams, irradiation with gamma rays, etc. Examples of the physical cross-linking method include a method of cross-linking a polymer with a salt, a method of cross-linking a polymer by electrostatic interaction, a method of cross-linking a polymer by hydrogen bonding, and a method of cross-linking a polymer by hydrophobic interaction. The above cross-linking methods may be used alone or in combination of two or more. The number average molecular weight (Mn) of the amphiphilic compound according to the present invention is preferably 1000 or more, more preferably 2000 or more, preferably 100,000 or less, and more preferably 50,000 or less.

[0099] <Use of amphiphilic compound> Since the amphiphilic compound according to the present invention has high biocompatibility, it can be suitably used for medical applications. That is, according to another aspect of the present invention, a medical resin composition containing the amphiphilic compound according to the present invention is provided. This medical resin composition may consist of the amphiphilic compound according to the present invention, or may further contain other components. Examples of other components include water, physiological saline, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methyl cellulose, ethyl cellulose, 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 polymers, serum-free medium, surfactants acceptable as pharmaceutical additives, physiologically acceptable pH buffers in vivo, and the like. These additives may be used alone or in combination of two or more.

[0100] The amphiphilic compound or medical resin composition according to the present invention can be suitably used as a pharmaceutical additive. Examples of the pharmaceutical additive include a carrier for holding a medicine or the like. As a method of holding a medicine or the like with the amphiphilic compound or medical resin composition according to the present invention, for example, a method of complexing a carrier and a medicine or the like by bonding a medicine or the like to a site (I) constituting the amphiphilic compound or a functional group of a hydrocarbon group having 8 or more carbon atoms, a method of mixing the amphiphilic compound or medical resin composition and a medicine or the like so as to have a uniform composition, a method of coating particles of a medicine or the like with the amphiphilic compound or medical resin composition, a method of atomizing a mixture of a lipid and the amphiphilic compound or medical resin composition and encapsulating a medicine or the like inside the obtained particles, a method of coating particles encapsulating a medicine or the like with a liposome with the amphiphilic compound or medical resin composition so as to encapsulate the particles inside the outer skin of the amphiphilic compound or medical resin composition, a method of coating particles of a mixture of a medicine or the like and a liposome with the amphiphilic compound or medical resin composition so as to encapsulate the particles inside the outer skin of the amphiphilic compound or medical resin composition, a method of micellizing a medicine or the like with the amphiphilic compound or medical resin composition so as to encapsulate the medicine or the like, a method of liposomizing a medicine or the like with the amphiphilic compound and a lipid constituting a liposome so as to encapsulate the medicine or the like, and the like can be mentioned, but the present invention is not limited to such examples only.

[0101] The above liposome can be prepared, for example, by a method of dissolving a lipid in a solvent such as tert-butyl alcohol and then freeze-drying, a method of adding a solution in which a drug is dissolved to a lipid to swell the lipid and dispersing it by ultrasonic waves, and then adding polyethylene glycol-phosphatidylethanolamine or the like to the obtained dispersion.

[0102] The liposome is preferably cationized with a cationizing agent. As the cationizing agent, conventionally known ones can be appropriately selected and used. The liposome can be obtained, for example, by dissolving hydrogenated soy lecithin, cholesterol, 3,5-dipentadecyloxybenzimidine hydrochloride, etc. in a solvent such as tert-butyl alcohol and freezing the resulting lipid mixed solution. The lipid constituting the liposome is stable in vivo. As the lipid, those exemplified above as the source of hydrocarbon groups having 8 or more carbon atoms can be similarly used.

[0103] In the above example, liposomes were mentioned. Instead of liposomes, for example, emulsions, nanoparticles, microparticles, high molecular compounds, etc. can be used.

[0104] As the medicine, biologically or pharmacologically active medicines can be used. Examples of the medicine include antitumor agents, anticancer agents, antibiotics, antiviral agents, anticancer effect enhancers, immunostimulants, immunomodulators, immune restorers, radiation sensitizers, radiation protectors, antihistamines, anti-inflammatory agents, blood stasis removing agents, antifungal agents, anti-arthritis agents, anti-asthma agents, angiogenesis inhibitors, enzyme agents, antioxidants, hormones, angiotensin converting enzyme inhibitors, smooth muscle cell proliferators, smooth muscle cell migration inhibitors, platelet aggregation inhibitors, chemical mediator release inhibitors, vascular endothelial cell growth promoters, vascular endothelial cell growth inhibitors, interferons, interleukins, colony stimulating factors, cytokines, tumor necrosis factors, granulocyte macrophage colony stimulating factors, granulocyte colony stimulating factors, macrophage colony stimulating factors, stem cell factors, beta transforming growth factors, hepatocyte growth factors, vascular endothelial cell growth factors, erythropoietin, vaccines, proteins, mucoproteins, peptides, polysaccharides, lipopolysaccharides, sugar chains, antisense, ribozymes, decoys, nucleic acids, antibodies, etc. These medicines may be used alone or in combination of two or more.

[0105] Examples of the subject to which the medicine is administered include mammals such as humans, monkeys, mice, and domestic animals, but the present invention is not limited to such examples only.

[0106] When the medicine is administered by injection, for example, by intravenous injection such as drip infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intradermal injection, intratumoral injection, etc., the medicine can be injected into the body. Here, as described above, the hydrophilic part of the amphiphilic compound according to the present invention has a lower adsorptivity to plastics such as PP compared to PVP. For this reason, although the compound can be applied to long-term blood-retaining liposomes etc. as a drug carrier, it is possible to reduce the adsorptivity to plastics. As a result, for example, it is possible to reduce the risk that the active ingredient encapsulated in the liposome modified with the compound remains in the syringe. Therefore, one of the suitable uses of the amphiphilic compound or the medical resin composition according to the present invention is a pharmaceutical additive used as a carrier for holding a medicine etc. in the form of liposomes etc. And it is preferable that the pharmaceutical additive is added to a medicine administered in the form of an injection.

[0107] The amount of the medicine to be held in the amphiphilic compound or the medical resin composition according to the present invention varies depending on the subject to which the medicine is administered, the type of the medicine, etc., and thus cannot be determined unconditionally. Usually, it is preferable that the amount of the medicine is about 1 μg to 50 g per 100 g of the solid content contained in the amphiphilic compound or the medical resin composition according to the present invention.

Examples

[0108] Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

[0109] [Measurement of the average molecular weight of the polymer] The number average molecular weight of the polymers produced in Production Examples 1 to 7 and Comparative Production Example 1 described later was measured by gel permeation chromatography (GPC). At this time, the measurement conditions were as follows.

[0110] [Measurement conditions for the number-average molecular weight of the polymer (polymers obtained in Production Examples 1 to 7)] · Measuring instrument: HLC-8320GPC manufactured by Tosoh Corporation · Molecular weight column: Two TSKgel SuperAWM-H and SuperAW2500 manufactured by Tosoh Corporation are connected in series · Eluent: Dimethylformamide added with 10 mmol / L lithium bromide · Standard substance for calibration curve: Polystyrene · Preparation of measurement solution: Dissolve the polymer in dimethylformamide to prepare a solution with a polymer concentration of 0.2% by mass, and use the filtrate after filtering the solution with a filter

[0111] [Measurement conditions for the number-average molecular weight of the polymer (polymer obtained in Comparative Production Example 1)] · Measuring instrument: HLC-8320GPC manufactured by Tosoh Corporation · Molecular weight column: Two TSKgel α-M and α-2500 manufactured by Tosoh Corporation are connected in series · Eluent: A mixed solution of 80 vol% 0.2M aqueous sodium nitrate solution and 20 vol% acetonitrile · Standard substance for calibration curve: Polyethylene glycol · Preparation of measurement solution: Dissolve the polymer in the eluent to prepare a solution with a polymer concentration of 0.2% by mass, and use the filtrate after filtering the solution with a filter

[0112] [Production Examples of Amphiphilic Compounds (Polymers)] An amphiphilic compound having a polymer form was produced by the following method

[0113] (Production Example 1) A Schlenk tube equipped with a three-way cock was charged with 1.0 g of glycerin monoacrylate, 0.071 g of 4-cyano-4-(dodecylsulfanylthiocarbonyl)sulfanyl pentanoate, 0.022 g of 2,2'-azobis(isobutyronitrile), 1.8 g of ethanol, and 0.2 g of water. Next, the inside of the tube was purged with nitrogen and stirred at 70 °C for 1 hour. The resulting reaction solution was dropped into diethyl ether and purified to obtain polyglycerin monoacrylate containing an alkyl group (n-dodecyl group) at the end. The number average molecular weight of the obtained amphiphilic compound (polymer) was 2200. Among them, the molecular weight of the hydrocarbon group (n-dodecyl group) having 8 or more carbon atoms was 169.3.

[0114] (Production Example 2) A Schlenk tube equipped with a three-way cock was charged with 1.0 g of glycerin monoacrylate, 0.043 g of 4-cyano-4-(dodecylsulfanylthiocarbonyl)sulfanyl pentanoate, 0.013 g of 2,2'-azobis(isobutyronitrile), 1.8 g of ethanol, and 0.2 g of water. Next, the inside of the tube was purged with nitrogen and stirred at 70 °C for 1 hour. The resulting reaction solution was dropped into diethyl ether and purified to obtain polyglycerin monoacrylate containing an alkyl group (n-dodecyl group) at the end. The number average molecular weight of the obtained amphiphilic compound (polymer) was 10900. Among them, the molecular weight of the site containing a hydrocarbon group having 8 or more carbon atoms (n-dodecyl group) was 169.3.

[0115] (Production Example 3) A Schlenk tube equipped with a three-way cock was charged with 1.0 g of glycerin monoacrylate, 0.098 g of 1-octadecanethiol, 0.021 g of 2,2'-azobis(isobutyronitrile), 2.25 g of ethanol, and 0.25 g of water. Next, the inside of the tube was purged with nitrogen and stirred at 80 °C for 3 hours. The resulting reaction solution was dropped into diethyl ether and purified to obtain polyglycerin monoacrylate containing an alkyl group (n-octadecyl group) at the end. The number average molecular weight of the obtained amphiphilic compound (polymer) was 4100. Among them, the molecular weight of the hydrocarbon group (n-octadecyl group) having 8 or more carbon atoms was 253.5.

[0116] (Production Example 4) A Schlenk tube equipped with a three-way cock was charged with 1.0 g of glycerin monoacrylate, 0.049 g of 1-octadecanethiol, 0.014 g of 2,2'-azobis(isobutyronitrile), 1.8 g of ethanol, and 0.2 g of water. Next, the inside of the tube was purged with nitrogen and stirred at 80 °C for 3 hours. The resulting reaction solution was dropped into diethyl ether and purified to obtain polyglycerin monoacrylate containing an alkyl group (n-octadecyl group) at the end. The number average molecular weight of the obtained amphiphilic compound (polymer) was 8600. Among them, the molecular weight of the hydrocarbon group (n-octadecyl group) having 8 or more carbon atoms was 253.5.

[0117] (Production Example 5) A Schlenk tube equipped with a three-way cock was charged with 1.0 g of glycerin monomethacrylate, 0.045 g of 1-octadecanethiol, 0.013 g of 2,2'-azobis(isobutyronitrile), 1.6 g of ethanol, and 0.4 g of n-butanol. Next, the inside of the tube was purged with nitrogen and stirred at 80 °C for 3 hours. The solution part of the resulting reaction solution was dropped into diethyl ether and purified to obtain polyglycerin monomethacrylate containing an alkyl group (n-octadecyl group) at the end. The number average molecular weight of the obtained amphiphilic compound (polymer) was 4100. Among them, the molecular weight of the hydrocarbon group (n-octadecyl group) having 8 or more carbon atoms was 253.5.

[0118] (Production Example 6) 1.0 g of glycerin monomethacrylate, 0.045 g of 1-octadecanethiol, 0.013 g of 2,2'-azobis(isobutyronitrile), 1.6 g of ethanol, and 0.4 g of n-butanol were charged into a Schlenk tube equipped with a three-way cock. Next, the inside of the tube was purged with nitrogen and stirred at 80°C for 3 hours. The precipitated portion of the obtained reaction solution was dissolved in 1.0 g of ethanol and further dropped into diethyl ether for purification to obtain polyglycerin monomethacrylate containing an alkyl group (n-octadecyl group) at the terminal. The number average molecular weight of the obtained amphiphilic compound (polymer) was 14000. Among them, the molecular weight of the hydrocarbon group (n-octadecyl group) having 8 or more carbon atoms was 253.5.

[0119] (Production Example 7) 1.0 g of glycerin monomethacrylate, 0.022 g of 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid, 0.016 g of 2,2'-azobis(2,4-dimethylvaleronitrile), 0.8 g of ethanol, and 0.2 g of n-butanol were charged into a Schlenk tube equipped with a three-way cock. Next, the inside of the tube was purged with nitrogen and stirred at 50°C for 30 minutes. The obtained reaction solution was dropped into diethyl ether for purification. 0.2 g of the obtained polymer, 0.25 g of propylamine, and 1.0 g of water were charged and stirred overnight at room temperature and freeze-dried to obtain polyglycerin monomethacrylate having a thiol group introduced at the terminal. The number average molecular weight of the obtained polymer was 5200.

[0120] Subsequently, 0.0165 g of the polymer obtained above, 0.0276 g of distearoyl N-(3-maleimido-1-oxopropyl)-L-α-phosphatidylethanolamine (manufactured by NOF CORPORATION, COATSOME (registered trademark) FE-8080MA3), 75 μL of triethylamine, 0.06 g of chloroform, and 0.4 g of methanol were charged into a 10 mL screw tube. Then, after reacting overnight at room temperature, it was dropped into diethyl ether and purified to obtain polyglycerol monomethacrylate containing a lipid at the terminal. The number average molecular weight of the obtained amphiphilic compound (polymer) was 6000. Among these, the molecular weight of the lipid moiety, which is a source of hydrocarbon groups having 8 or more carbon atoms, was approximately 954.

[0121] (Comparative Production Example 1) 1.0 g of N-vinyl-2-pyrrolidone, 0.064 g of octadecanethiol, 0.018 g of 2,2'-azobis(isobutyronitrile), 1.6 g of ethanol, and 0.4 g of n-butanol were charged into a Schlenk tube equipped with a three-way cock. Then, the inside of the tube was purged with nitrogen and stirred at 80 °C for 3 hours. The obtained reaction solution was dropped into diethyl ether and purified to obtain polyvinylpyrrolidone containing an alkyl group (n-octadecyl group) at the terminal. The number average molecular weight of the obtained amphiphilic compound (polymer) was 12000. Among these, the molecular weight of the hydrocarbon group (n-octadecyl group) having 8 or more carbon atoms was 253.5.

[0122] [Preparation of Liposomes] 17.6 mg of hydrogenated soybean-derived phosphatidylcholine (Avanti Polar Lipids) and 4.7 mg of cholesterol (Tokyo Chemical Industry Co., Ltd.) were dissolved in 20 mL of methanol, then placed in a 200 mL eggplant flask and evaporated in a water bath at 65 °C to form a lipid membrane. 3 mL of PBS containing 20 w / v% glucose was added thereto, sealed, and incubated at 65 °C for 30 minutes to hydrate and obtain a lipid suspension. This lipid suspension was transferred to a micro test tube, 4 times the amount of PBS was added, and then centrifuged at 15,000×G for 20 minutes to precipitate the formed liposomes. After centrifugation, the supernatant was discarded, 1 mL of fresh PBS was added and resuspended, and the resuspended solution was sized with an extruder (pore size 0.1 μm) warmed to 65 °C to obtain a liposome suspension with a lipid equivalent of 12.9 mg / mL. The concentration of the liposome suspension was measured using LabAssay (trademark) phospholipid (FUJIFILM Wako Pure Chemical Corporation), and the measurement protocol conformed to the attached manual.

[0123] [Modification of Amphiphilic Compounds (Polymers) to Liposomes] The amphiphilic compound (polymer) prepared in Production Example 4 above, polyglycerin monoacrylate (number average molecular weight: 8,600) containing an alkyl group (n-octadecyl group) at its terminal, was dissolved in PBS to a concentration of 2 w / v% or 4 w / v% to prepare polymer solutions with different concentrations. Each of these polymer solutions was mixed with the liposome suspension prepared above in an equal volume and allowed to stand at 10°C for 60 minutes to modify the liposomes with the amphiphilic compound. Here, it is presumed that a structure was obtained in which the alkyl group portion of the polymer containing a terminal alkyl group was inserted into the lipid bilayer constituting the liposome, and the surface of the liposome was modified (coated) with the hydrophilic site of the polymer. On the other hand, a control group was prepared by mixing and reacting the same volume of PBS instead of the polymer solution. Thereafter, centrifugation was performed at 15,000 × G for 20 minutes, the supernatant was removed to remove the unreacted amphiphilic compound, and the formed precipitate was resuspended in PBS. The particle size of each liposome was measured using a Zetasizer Nano ZS (Malvern Panalytical). As a result, as shown in Fig. 1, the particle size of the liposomes in the control group was 160.6 ± 5.2 nm. In contrast, the particle sizes of the liposomes modified with the 2 w / v% and 4 w / v% polymer solutions were 174.8 ± 6.5 nm and 174.6 ± 5.5 nm, respectively, and an increase in the particle size due to the modification with the amphiphilic compound was confirmed.

[0124] [Cytotoxicity Test of Amphiphilic Compound (Polymer) Using Cultured Cells] L929 cells (DS Pharma Biomedical), which are mouse-derived fibroblasts, were cultured using DMEM medium (Nacalai Tesque) supplemented with fetal bovine serum (FBS) (DS Pharma Biomedical) at a final concentration of 10 w / v%. They were seeded in a 100-mm cell culture dish (BD Falcon) at a density of 5.0 × 10 3 cells / cm 2 and incubated at 37°C in 5% CO 2They were cultured under the following conditions. L929 cells cultured in a 100-mm cell culture dish until 70% confluent were treated with a 0.25 w / v% trypsin / 50 mM EDTA solution, and the above-described serum-supplemented DMEM medium was added to stop the trypsin reaction, obtaining an L929 cell suspension. The cell count in the L929 cell suspension was measured using a 0.4 w / v% trypan blue solution (FUJIFILM Wako Pure Chemical Corporation). The cell suspension was seeded into a 96-well plate (Thermo Fisher Scientific) so that the number of cells per well was 2.5×10 3 cells, and cultured at 37°C under 5% CO 2 for 24 hours. After 24 hours, 50 μL of the medium was removed from each well, and then 50 μL of a polymer solution prepared by dissolving the amphiphilic compounds (polymers) prepared in Production Examples 1 to 7 and Comparative Production Example 1 in PBS so as to be 2 w / v% was added to each well, and incubated at 37°C under 5% CO 2 for 24 hours. After incubation, 51 μL of a cell proliferation kit II (XTT) (Sigma-Aldrich) reagent was added to each well, and incubated at 37°C under 5% CO 2 for 3 hours. Thereafter, the absorbance was measured using a plate reader SH-9000 (Corona Electric Co., Ltd.). The measurement protocol conformed to the manual attached to the kit. Based on the measured values of the wells tested with PBS added instead of the polymer solution and the measured values of the wells to which each sample was added, the survival rate of L929 cells was calculated from the following formula.

[0125] (Survival rate) [%] = (Measured value of the well to which each sample was added) ÷ (Measured value of the well to which PBS was added) × 100 As a result, as shown in Figure 2, none of the polymer solutions gave a significant difference in the survival rate of L929 cells, and no significant cytotoxicity was observed.

[0126] [Cytotoxicity Test of Amphiphilic Compound (Polymer)-Modified Liposomes Using Cultured Cells] L929 cells (DS Pharma Biomedical), a mouse-derived fibroblast cell line, were cultured using DMEM medium (Nacalai Tesque) supplemented with fetal bovine serum (FBS) (DS Pharma Biomedical) at a final concentration of 10 w / v%. The cells were seeded at a density of 5.0×10 3 cells / cm 2 in 100 mm cell culture dishes (BD Falcon) and cultured at 37°C under 5% CO 2 2. When the L929 cells cultured in 100 mm cell culture dishes reached 70% confluence, they were treated with 0.25 w / v% trypsin / 50 mM EDTA solution, and the above-described serum-supplemented DMEM medium was added to stop the trypsin reaction, obtaining an L929 cell suspension. The number of cells in the L929 cell suspension was measured using a 0.4 w / v% trypan blue solution (FUJIFILM Wako Pure Chemical Corporation). The cell suspension was seeded in 96-well plates (Thermo Fisher Scientific) at a density of 2.5×10 3 cells per well and cultured at 37°C under 5% CO 2 2 for 24 hours. After 24 hours, 50 μL of the medium was removed from each well. Subsequently, according to the description in the section of "Modification of Amphiphilic Compounds (Polymers) to Liposomes" above, 50 μL of the modified liposome suspension or unmodified liposome suspension (both 5 mg-lipid / mL) obtained using a 2 w / v% solution of the amphiphilic compound (polymer) prepared in Production Examples 1 to 7 and Comparative Production Example 1 was added, and the mixture was incubated at 37°C under 5% CO 2 2 for 24 hours. After incubation, 51 μL of the Cell Proliferation Kit II (XTT) (Sigma-Aldrich) reagent was added to each well, and the mixture was incubated at 37°C under 5% CO 2 2 for 3 hours. Then, the absorbance was measured using a plate reader SH-9000 (Corona Electric Co., Ltd.). The measurement protocol conformed to the manual attached to the kit. Based on the measured values of the wells tested by adding PBS instead of the modified liposome suspension and the measured values of the wells to which each sample was added, the survival rate of L929 cells was calculated using the following formula.

[0127] (Survival rate)[%] = (Measurement value of the well with each sample added) ÷ (Measurement value of the well with PBS added) × 100 As a result, as shown in Fig. 3, liposomes modified with any of the amphiphilic compounds (polymers) did not give a significant difference in the survival rate of L929 cells, and no significant cytotoxicity was observed.

[0128] [Adsorption test of amphiphilic compound (polymer) on plastic surface] Each of the amphiphilic compounds (polymers) prepared in Production Example 4, Production Example 6, and Comparative Production Example 1 was dissolved in PBS to a concentration of 1 w / v% to prepare a polymer solution. 4.5 mL of this polymer solution and 1.5 g of polypropylene (PP) fine powder (average particle size 5 micrometers) were placed in a screw-cap bottle and stirred with a stirrer for 30 minutes. After stirring, the polymer concentration of each polymer solution was quantified from the peak area of GPC. From the initial polymer concentration (C 0 ) and the polymer concentration after the test (C t ), the amount of polymer adsorbed per 1 g of the fine powder was calculated using the following formula. The results are shown in Table 1 below.

[0129] (Adsorption amount on fine powder)[mg / g] = (C t - C 0 ) ÷ (Fine powder [g])

[0130]

Table 1

[0131] As can be seen from the results shown in Table 1, the adsorption on polypropylene (PP) fine powder was significantly less for the amphiphilic compounds (polymers) in which Site (I) consisted of GLMMA or GLMA compared to the amphiphilic compound (polymer) in which Site (I) consisted of PVP.

[0132] [Preparation of liposomes encapsulating fluorescent substance] 17.6 mg of hydrogenated soybean-derived phosphatidylcholine (Avanti Polar Lipids) and 4.7 mg of cholesterol (Tokyo Chemical Industry Co., Ltd.) were dissolved in 20 mL of methanol, then placed in a 200 mL eggplant flask and evaporated in a water bath at 65 °C to form a lipid membrane. 3 mL of PBS containing 20 w / v% glucose and 0.02% w / v fluorescein isothiocyanate (FITC) was added thereto, sealed, and incubated at 65 °C for 30 minutes for hydration to obtain a lipid suspension. This lipid suspension was transferred to a microtest tube, 4 volumes of PBS was added, and then centrifuged at 15,000×G for 20 minutes to precipitate the formed liposomes. After centrifugation, the supernatant was discarded, and 1 mL of fresh PBS was added and resuspended, and then sized with an extruder (pore size 0.1 μm) warmed to 65 °C to obtain a liposome suspension with a lipid equivalent of 13.7 mg / mL. The concentration of the liposome suspension was measured using LabAssay (trademark) phospholipid (FUJIFILM Wako Pure Chemical Corporation), and the measurement protocol was in accordance with the attached manual.

[0133] [Preparation of PEG-Modified Liposomes] 12.9 mg of hydrogenated soy-derived phosphatidylcholine (Avanti Polar Lipids), 3.4 mg of cholesterol (Tokyo Chemical Industry Co., Ltd.), and 3.76 mg of PEG-lipid (manufactured by NOF Corporation, SUNBRIGHT (registered trademark) DSPE-020CN) were dissolved in 20 mL of methanol, then placed in a 200 mL eggplant flask and evaporated in a water bath at 65 °C to form a lipid membrane. 3 mL of PBS containing 20 w / v% glucose and 0.02% w / v FITC was added thereto, sealed, and incubated at 65 °C for 30 minutes to hydrate and obtain a lipid suspension. This lipid suspension was transferred to a microtest tube, 4 volumes of PBS was added, and then centrifuged at 15,000 × G for 20 minutes to precipitate the formed liposomes. After centrifugation, the supernatant was discarded, 1 mL of fresh PBS was added and resuspended, and the resuspended solution was sized using an extruder (pore size 0.1 μm) warmed to 65 °C to obtain a liposome suspension at a lipid equivalent of 9.7 mg / mL. The concentration of the liposome suspension was measured using LabAssay (trademark) phospholipid (FUJIFILM Wako Pure Chemical Corporation), and the measurement protocol was based on the attached manual.

[0134] [Cell Uptake Test of Amphiphilic Compound (Polymer)-Modified Liposomes Using Cultured Cells] HepG2 cells (DS Pharma Biomedical Co., Ltd.), a human hepatocellular carcinoma-derived cell line, were cultured using MEM medium (Nacalai Tesque, Inc.) supplemented with fetal bovine serum (FBS) (DS Pharma Biomedical Co., Ltd.) at a final concentration of 10 w / v%. 5.0×10 3 cells / cm 2 were seeded in a 100 mm cell culture dish (BD Falcon) so as to achieve this, and cultured at 37 °C, 5% CO 2Cells were cultured under the conditions described below. HePG2 cells cultured to 70% confluence in a 100 mm cell culture dish were treated with a 0.25 w / v% trypsin / 50 mM EDTA solution, and the aforementioned serum-supplemented MEM medium was added to stop the trypsin reaction, obtaining a HepG2 cell suspension. The cell count in the HepG2 cell suspension was measured using a 0.4 w / v% trypan blue solution (FUJIFILM Wako Pure Chemical Corporation). The cell suspension was seeded in a 24-well plate (Thermo Fisher Scientific) such that the number of cells per well was 4×10 4 cells, and cultured at 37 °C and 5% CO 2 for 48 hours under the conditions described below. After 48 hours, the medium was removed from each well, and 500 μL of MEM medium without added serum was added. Next, in accordance with the description in the section "Modification of Amphiphilic Compounds (Polymers) in Liposomes" above, a fluorescent substance-encapsulated modified liposome suspension obtained using a 2 w / v% solution of the amphiphilic compound (polymer) prepared in Production Example 4 above, or a PEG-modified liposome prepared in accordance with the description in the section "[Preparation of PEG-Modified Liposomes]", or an unmodified liposome suspension (both at 5 mg-lipid / mL) was added in 50 μL portions each, and incubated at 37 °C or 4 °C and 5% CO 2 for 3 hours under the conditions described below. After incubation, the medium in each well was removed, washed twice with PBS, and then 350 μL of a 0.2 mol / L aqueous sodium hydroxide solution containing 0.02 w / v of Triton X-100 was added to lyse the cells, and the fluorescence intensity of the lysate was measured using a plate reader SH-9000 (Corona Electric Co., Ltd.). Based on the measured values of the wells incubated at 4 °C and the wells incubated at 37 °C, the amount of liposome uptake by HepG2 cells was calculated from the following formula.

[0135] (Uptake amount)[-]=(Measured value of the well incubated at 37 °C)-(Measured value of the well incubated at 4 °C) Next, the ratio of the uptake amount to that of the unmodified liposome was calculated from the following formula.

[0136] (Uptake amount ratio)[%]=(Uptake amount of each modified liposome)÷(Uptake amount of the unmodified liposome)×100 As a result, as shown in Fig. 4, the amount of uptake into cells by the PEG-modified liposomes was significantly decreased as compared with that by the unmodified liposomes, while no significant difference in the uptake amount was observed between the liposomes modified with the amphiphilic compound (polymer) and the unmodified liposomes.

[0137] This application is based on Japanese Patent Application No. 2019-067826 filed on Mar. 29, 2019, the disclosure of which is incorporated herein by reference in its entirety.

Claims

1. A site (I) containing a structural unit (A) derived from a monomer (a) having two or more hydroxyl groups in the molecule and having 2 to 10 carbon atoms in the side chain-constituting carbon atoms of the structural unit, a hydrocarbon group having 8 or more carbon atoms, and having, wherein the structural unit (A) contains a structural unit represented by the following chemical formula (1): 【Chemical 1】 In formula (1), R １ represents a hydrogen atom or a methyl group, X is -C(=O)-O-, -C(=O)-NH-, -O-, -CH ２ O - or -CH ２ CH ２ O - and represents and the proportion of the structural unit (A) in the site (I) is 80 to 100% by mass, the number average molecular weight (Mn) of the site (I) containing the structural unit (A) is 1000 to 15000, the hydrocarbon group is bonded to the site (I) via a divalent linking group selected from the group consisting of -S-, -S-C(=S)-, -S-C(=S)-S-, -S-C(=S)-N(-R a)-, -S-C(=S)-O-, -S-R b-C(=O)-O-, -S-R b-C(=O)-N(-R a)-, -S-R b-O-, -S-R b-O-C(=O)-, -N(-R a)-C(=O)- and a divalent group containing these (wherein R a is a hydrogen atom or a hydrocarbon group having 1 to 30 carbon atoms, and R b is a hydrocarbon group having 1 to 30 carbon atoms), an amphiphilic compound (however, excluding the following compounds PGMA-CDPA and PGMA-PHPMA).

2. [Chemical 2] The amphiphilic compound according to claim 1, wherein the site (I) is composed of a polymer having a structural unit (A) derived from the monomer (a).

3. The amphiphilic compound according to claim 1 or 2, wherein the hydrocarbon group has 8 to 50 carbon atoms.

4. The amphiphilic compound according to any one of claims 1 to 3, wherein the hydrocarbon group is contained in a long-chain fatty acid or hydrocarbon chain constituting a lipid and exists as a part of the lipid.

5. The amphiphilic compound according to any one of claims 1 to 4, wherein the monomer (a) contains a monofunctional monomer.

6. The amphiphilic compound according to any one of claims 1 to 5, wherein the hydrocarbon group is contained in a long-chain fatty acid or hydrocarbon chain constituting a lipid, exists as a part of the lipid, and the molecular weight of the lipid is 2000 or less.

7. A medical resin composition containing the amphiphilic compound according to any one of claims 1 to 6.

8. An emulsion, nanoparticles, microparticles or polymer compound containing the amphiphilic compound according to any one of claims 1 to 7. ​

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