JP6226357B2 - Biocompatible polymers as antithrombotic materials - Google Patents

Description

  The present invention mainly relates to a biocompatible polymer as an antithrombogenic material. More specifically, when it is placed in a living body or comes into contact with a substance derived from a living body, blood compatibility such as an anti-coagulant action and a target biological substance can be selectively adsorbed. A polymer for use as a medical material having a function and capable of being chemically decomposed in vivo or in vitro, a novel compound for synthesizing the polymer, and a polymer using the compound And a composition containing the polymer and a medical device using the composition.

  In general, when a biological component such as blood comes into contact with the surface of a medical material, the surface of the material is recognized as a foreign substance, and nonspecific adsorption, denaturation, multilayer adsorption, etc. of proteins in the biological tissue occur on the material surface. As a result, activation of the coagulation system, complement system, platelet system, etc. occurs. For this reason, in order to prevent the medical device surface which is a contact interface with the living body from being recognized as a foreign substance, it is desired to impart biocompatibility to the medical device surface. Specifically, in medical devices such as artificial lung devices, dialysis devices, blood storage bags, platelet storage bags, blood circuits, artificial hearts, indwelling needles, catheters, guide wires, stents, artificial blood vessels, endoscopes, blood It is desired that a portion that contacts a biological material such as has excellent biocompatibility.

  As a means of imparting biocompatibility to the surface of medical devices, conventional materials have been artificially synthesized and applied to the surface of various medical devices to reduce the burden on the living body. Attempts have been made. Examples of such biocompatible materials include 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, polyethylene glycol (PEG), poly (2-methoxyethyl acrylate) (PMEA), polyalkoxyalkyl (meth) acrylamide, etc. Is known and has been put to practical use in various applications. By using these biocompatible materials at sites where blood or other biological components such as the surface of medical materials come into contact, the surface of medical devices is prevented from being recognized as a foreign substance, and the coagulation system, complement system, platelets Activation of the system and the like is suppressed.

The MPC polymer is a kind of betaine that maintains electrical neutrality in a living environment, and binds a phospholipid polar group covering a living cell membrane to a polymerizable group such as a vinyl group via an ester bond. And a polymer produced by polymerizing the polymerizable group, and has a structure in which a phospholipid polar group is provided as a side chain with respect to the alkyl chain (main chain).
Polyethylene glycol (PEG) has a structure in which (C ₂ H ₄ —O), which is an ether structure, is a repeating unit, and is known to exhibit very excellent biocompatibility. However, since PEG itself is water-soluble, it needs to be used as a block copolymer or graft copolymer with another polymer for the purpose of imparting water resistance when used as a medical material. is there. On the other hand, poly (2-methoxyethyl acrylate) (PMEA) and the like are obtained by polymerizing a monomer in which a group mainly composed of an ether structure, which is a structural unit of PEG, is bonded to a vinyl group or the like to form an alkyl chain (main chain) On the other hand, it has a structure provided as a side chain having an ether structure as a main component. It has been clarified that by adopting such a structure, water resistance can be imparted by an alkyl chain while maintaining the biocompatibility exhibited by PEG.
Polyalkoxyalkyl (meth) acrylamide has an ether structure at the end of the side chain and has a structure with (meth) acrylamide as a repeating unit, and due to its moderate hydrophilicity, the activity of coagulation system, complement system and platelet system It has been found that it is possible to suppress oxidization and to express excellent blood affinity.

  Including MPC polymer having side chain containing phospholipid polar group on main chain, PEG composed of ether structure, PMEA which is polymer having side chain composed mainly of ether structure, and ether structure and amide bond Even though polymer materials having hydrophilic groups such as ether structures and amide bonds, such as polyalkoxyalkyl (meth) acrylamide having a high molecular weight, have a high biocompatibility despite having a completely different structure from substances constituting the living body. The reason for showing is not necessarily clear. On the other hand, recent research has revealed that these polymers can contain water molecules in a state called “intermediate water” observed in biological materials (see, for example, Non-Patent Document 1). I want to be) That is, as described in the above document, a substance exhibiting biocompatibility can contain “intermediate water” regardless of whether it is a biologically derived substance or an artificial synthetic product. It has been experimentally shown that non-specific adsorption of proteins in living tissue is prevented by the presence of water molecules in a state called as being on the surface of the substance, and as a result, bioaffinity is expressed. In order for a given substance to contain “intermediate water”, it is not always necessary for the substance to have a structure suitable for containing “intermediate water” like PEG. It has been revealed that “intermediate water” can also be contained by providing a structure suitable for containing “water” as a side chain.

  The intermediate water contained in the biocompatible substance is typically characterized by the release and absorption of unique latent heat seen in the temperature rising process after supercooling. That is, for substances containing intermediate water, in the process of gradually heating to near room temperature after cooling to about −100 ° C., the release of latent heat is observed near −40 ° C., or the latent heat is below freezing above −10 ° C. Absorption and absorption of specific latent heat is observed, such as the absorption of. Various verifications have revealed that the release and absorption of these latent heats is caused by the fact that a certain proportion of water molecules contained in the substance cause ordering and disordering. A molecule is defined as intermediate water. Intermediate water is presumed to be weakly constrained by specific effects from the molecules that make up the substance, but it has been shown that it is also contained in biological materials such as phospholipids in biological tissues. It is thought to be related to prevention of non-specific adsorption of proteins. In addition to the PMC polymer provided with a phospholipid polar group contained in the living body as a side chain, the substance such as PEG, PMEA, polyalkoxyalkyl (meth) alkylamide, etc. can contain intermediate water. It is thought to be related to the expression of affinity.

On the other hand, the existence of biodegradable polymers having biodegradability that has been decomposed and disappeared by the action of hydrolysis, enzymatic degradation or the like has been known so far. Biodegradable polymers are generally used for the purpose of reducing the burden on the natural environment by being destroyed by action from the natural world after being discarded. On the other hand, in recent years, the use of biodegradable polymers for medical devices such as surgical sutures, stents, and catheters that are indwelled in the body makes it unnecessary to remove the thread after treatment is completed, It has become common to add a function to release the release.
In biodegradable polymers used for medical devices placed in the body, in addition to the property of degrading in a predetermined period, substances generated by degradation are not toxic to the living body and are discharged outside the body by metabolism. It is common to be designed. As an example of a medical device in which such a biodegradable polymer is used, for example, in Patent Document 1, a biodegradable polymer-drug mixed layer having a predetermined structure is provided on the surface of an in-vivo indwelling object. Thus, a technique is described in which a drug is gradually released as the biodegradable polymer is decomposed. Patent Document 2 discloses a biodegradable polymer used for catheters and the like, and does not generate carboxylic acid when decomposed in vivo, thereby reducing the risk of inflammation due to local pH reduction. And polymers that are considered biocompatible are described.
However, in the biodegradable polymer used in the medical device as described above, there are limited prior examples in consideration of the affinity (biological affinity) to the living body when it exists as a polymer. That is, while being used in a medical device, it is a polymer showing biocompatibility that does not cause a foreign body reaction to blood or tissue in the living body, and is biodegraded and metabolized within a predetermined period. Few polymers have been provided so far. For example, Patent Document 3 describes a polymer in which a phospholipid component exhibiting blood affinity, non-thrombogenicity, and the like is introduced to a biodegradable polymer by covalent bonding, and both biodegradability and blood affinity are compatible. Attempts have been made, but no manifestation of this property has been confirmed.

Tanaka, M. et al., J. Biomat. Sci. Polym. Ed., 2010, 21, 1849-1863

JP 2009-61021 A JP 2012-232909 A JP 2012-46761 A

As described above, the possibility of a material having biocompatibility that does not cause a foreign body reaction to blood or tissue in the living body when the polymer is present in the living body is not necessarily a biodegradable polymer. It has not been revealed so far. For this reason, for example, in a stent placed in a blood vessel, it is also common to prevent restenosis by mixing an antithrombotic drug such as heparin with a biodegradable polymer provided on the stent surface. It has become.
In order to solve the above problems, an object of the present invention is to provide a polymer that exhibits biocompatibility and exhibits good biodegradability. It is another object of the present invention to provide a novel compound used as a monomer in the production of the polymer, a method for producing the compound, and a method for producing a polymer using the compound. It is another object of the present invention to provide a medical device using the polymer.

In order to solve the above problems, the present invention has the following features.
(1) A biocompatible polymer composition comprising a structure containing at least one ether group in the side chain and a main chain comprising a biodegradable polymer skeleton.
(2) The biodegradable polymer skeleton has the formula: (I)
-C _B -A- (I)
(Where
C _B is selected from unit structures having a carbonate bond, an ester bond, an amide bond, a urethane bond or a urea bond;
A is a C _1-8 alkylene group in which a hydrogen atom is replaced by at least one group —Y;
Y is represented by the formula: -LZ (wherein Z is a structure having at least one chain ether, cyclic ether or acetal structure, L is a linker between the main chain and Z, an alkylene group, Selected from unit structures having an ether bond, a thioether bond, an ester bond, an amide bond, a urethane bond or a urea bond, or a combination thereof))
The biocompatible polymer composition according to the above (1), comprising a repeating unit represented by:
(3) said A is, C _1-8 or at least one carbon atom other than a carbon atom adjacent to C _B in the alkylene group is replaced by a heteroatom selected from N, O or S, and / or The biocompatible polymer composition according to (2) above, wherein the hydrogen atom in the C _1-8 alkylene group is a group substituted with a lower alkyl group.
(4) The linker L is a group shown below:

Or a bioaffinity according to (2) or (3) above, wherein the bioaffinity is selected from the group having a 1,2,3-triazole group at the binding part of Z and Z Polymer composition.
(5) Z is the following formula (II):

[Wherein, l is an integer of 1 to 30 and U is a hydrogen atom or a linear or branched alkyl group having 5 or less carbon atoms, or the following formula (III):

(Wherein l ′ is an integer of 1 to 5)]
Or Z is a group represented by the following formula (IV):

(Wherein l ″ is an integer of 1 to 5), or Z is the following formula (V):

(In the formula, M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, and E and E ′ are each independently —O— or —CH ₂ —. However, at least one is —O—, and Q ′ and Q ″ each independently represent a hydrogen atom, a linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C _3-8. Represents alicyclic alkyl or benzyl, or Q ′ and Q ″ together form an alkylene group having 2 to 5 carbon atoms, and k and k ′ are each independently an integer of 0 to 2 Is)
The biocompatible polymer composition according to any one of (2) to (4) above, which is a group represented by:
(6) The biocompatible polymer composition according to any one of (1) to (5), wherein the main chain is a copolymer of a biodegradable polymer and a non-biodegradable polymer.
(7) The following general formula (VII):

(Where
X and X ′ are independently of each other —O—, —NH— or —CH ₂ —, but at least one is not —CH ₂ —;
Y is a structural moiety represented by the group -LZ (wherein L and Z are as defined in claim 2);
M is a hydrogen atom, a linear or branched alkyl group having 3 or less carbon atoms, or a group -LZ;
m and m ′ are each independently an integer of 0 to 5, provided that when X and X ′ are both —O—, at least one of m and m ′ is not 0, and m and m The sum of 'is 7 or less;
Each of these may be different in each repeating unit,
The monomer compound represented by these.
(8) A method for producing a biocompatible polymer composition, comprising a step of ring-opening polymerization of the monomer compound represented by the general formula (VII) described in (7) above.
(9) A biocompatible polymer composition produced by ring-opening polymerization of the monomer compound described in (7) above.
(10) Any one of the above (1) to (6) for suppressing a foreign body reaction to blood or tissue until it is decomposed when used in contact with tissue or blood in a living body The biocompatible polymer composition described in 1.
(11) A medical device comprising the biocompatible polymer composition according to any one of (1) to (6), (9) and (10).

  According to the present invention, it is possible to provide a polymer material that exhibits biocompatibility such as antithrombogenicity to a living body and exhibits good biodegradability.

1 is a ¹ H-NMR spectrum of MPA-ME shown in Example 1. 2 is a ¹ H-NMR spectrum of MTC-ME shown in Example 2. 2 is a ¹ H-NMR spectrum of P (TMC-ME) shown in Example 3. 2 is a ¹ H-NMR spectrum of PTMC shown in Comparative Example 1. It is a graph which shows the result of DSC measurement in Example 4. 10 is a graph showing the platelet adhesion number in Example 7.

Definition of Terms In the present invention, the following terms are used to indicate the contents described for each, whether they appear alone or in combination.

  In this specification, the term “alkyl group” refers to a monovalent saturated hydrocarbon group including a straight or branched carbon chain having a skeleton of carbon atoms. The term “alkylene group” refers to a divalent hydrocarbon group composed of a linear carbon chain. The term “alkylene oxide chain” refers to a structure in which a carbon atom other than the end of the alkylene group is replaced with an ether bond.

  The term “alkenyl” refers to a monovalent saturated hydrocarbon group comprising a straight or branched carbon chain having one or more carbon-carbon double bonds in the skeleton of carbon atoms. The number of carbon atoms in the alkenyl is not particularly limited, but preferably 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and most preferably 2 to 6 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl (vinyl), propenyl, butenyl, 2-methylpropenyl, pentenyl, hexenyl, and the like. The term “alkynyl” refers to a monovalent saturated hydrocarbon group containing a straight or branched carbon chain having one or more carbon-carbon triple bonds in the skeleton of carbon atoms. The number of carbon atoms in the alkynyl is not particularly limited, but preferably 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and most preferably 2 to 6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, 2-methylpropynyl, pentynyl, hexynyl and the like.

  In this specification, the term “alkoxy” refers to a monovalent saturated hydrocarbon group in which the above alkyl group is bonded to an oxygen atom and is bonded to another molecular structure through the oxygen atom. The number of carbon atoms in alkoxy is not particularly limited, but preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and most preferably 1 to 6 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy, pentoxy, hexoxy and the like.

The term “alicyclic alkyl” refers to a monovalent aliphatic cyclic hydrocarbon group in which a carbon skeleton forms a ring. The alicyclic alkyl is represented by the number of carbon atoms that form a ring. For example, when “C _3-8 alicyclic alkyl” is referred to, the number of carbon atoms that form a ring is 3 to 8. Show. Examples of alicyclic alkyl are cyclopropyl (C ₃ H ₅ ), cyclobutyl (C ₄ H ₇ ), cyclopentyl (C ₅ H ₉ ), cyclohexyl (C ₆ H ₁₁ ), cycloheptyl (C ₇ H ₁₃ ), Including, but not limited to, cyclooctyl (C ₈ H ₁₅ ) and the like.

The term “chain ether” refers to a structure in which one —CH ₂ — moiety other than the terminal in the alkyl group is replaced with an ether bond (—O—). The term “cyclic ether” indicates a structure in which one —CH ₂ — moiety of the alicyclic alkyl is replaced with an ether bond.

  The term “monomer” or “monomer” refers to a low molecular weight molecule that can be used interchangeably and can be a component of the basic structure of a polymer. The monomer usually has a functional group that becomes a reaction point of the polymerization reaction, such as a carbon-carbon double bond or an ester bond.

  The term “polymer” or “polymer” refers to a molecule having a structure composed of repeating monomer units, which can be used interchangeably and can be obtained from a monomer having a low molecular weight. The term “polymer” refers to a macromolecule formed by covalently bonding a large number of atoms, such as a protein, a nucleic acid and the like, in addition to a polymer.

  In the polymer, the term “average degree of polymerization” refers to the average number of monomer units contained in one polymer molecule. That is, in the polymer composition, polymer molecules having different lengths are dispersed within a certain range.

  Regarding the degree of polymerization of the polymer, the “number average molecular weight” means the average molecular weight per molecule in the polymer composition, and the “weight average molecular weight” means the molecular weight calculated by weighting the weight. Further, the ratio between the number average molecular weight and the weight average molecular weight is referred to as the degree of dispersion, which is a measure of the molecular weight distribution of the polymer composition. The closer the degree of dispersion is to 1, the closer the average degree of polymerization in the polymer composition and the more polymer chains of the same length.

  In the present invention, the term “biocompatible material” refers to a material that is difficult to be recognized as a foreign substance when it comes into contact with a biological substance because it can contain intermediate water. Biocompatible materials exhibit activity that induces or does not induce specific protein adsorption or cell adhesion, for example, if the material does not have biological activity such as complement activity, thrombus activity, tissue invasiveness, etc. Contains materials. In the present invention, the term “blood compatible material” refers to a material that does not cause blood coagulation mainly due to adhesion or activation of platelets.

  In the present invention, “biodegradable polymer” refers to a polymer that can be chemically degraded by the action of hydrolysis, enzymatic degradation, microbial degradation and the like. Examples of biodegradable polymers include chemically synthesized polymers such as polylactic acid, polyesters such as polycaprolactone, polycarbonates, and the like, polymers derived from living organisms such as polypeptides, polysaccharides, celluloses, and combinations thereof. Can be mentioned.

  In the present invention, the “side chain” refers to a branched structure bonded to the polymer main chain.

  Accordingly, one embodiment of the present invention is a biocompatible polymer composition comprising a structure containing at least one ether group in the side chain and a main chain comprising a biodegradable polymer skeleton. In the present specification, the “biocompatible polymer composition” refers to a polymer composition having a structure particularly suitable for suppressing blood coagulation and preventing the formation of thrombus, such as medical materials in such applications. Can be used for

One embodiment of the present invention is a biocompatible polymer composition having a repeating unit represented by the following formula (I).
-C _B -A- (I)
In the above formula (I), C _B is an ether bond, a thioether bond, an ester bond, an amide bond, selected from a unit structure having a urethane bond or a urea bond, or a combination thereof, as a non-limiting example, the following Examples of unit structures listed in Scheme 1 include:

In the above formula (I), A is a C _1-8 alkylene group in which a hydrogen atom is substituted by at least one group -Y. A is optionally substituted at least one carbon atom other than the carbon atom adjacent to C _B in the C _1-8 alkylene group with a heteroatom selected from N, O or S, and / or C _A group in which a hydrogen atom in a _1-8 alkylene group is substituted with a lower alkyl group may be used. The group Y is a group represented by the formula: -LZ, and L is a linker between the main chain and Z, and is an alkylene group, an ether bond, a thioether bond, an ester bond, an amide bond, or a urethane bond. Alternatively, it is selected from unit structures having a urea bond or a combination thereof. Z is not particularly limited as long as it is a molecular chain having at least one chain ether such as polyethylene glycol, cyclic ether, or acetal structure, that is, at least one ether group. Each of these may be different in each repeating unit.

That is, the polymer according to the present invention, among the biodegradable polymers known conventionally, as shown similar to that of the aliphatic polyester-based or polyamide-based, the alkylene group represented by A or the like as a main chain in the C _B It includes a repeating unit bonded by a carbonate bond, an ester bond, a urethane bond, a urea bond, an amide bond, or the like. In addition, a side chain containing an ether structure is introduced to a carbon atom contained in the alkylene group or the like by a predetermined bonding mode.
It has been conventionally known that when a side chain containing an ether structure is introduced into a polymer having an alkyl chain as a main chain, the polymer exhibits biocompatibility. On the other hand, in the present invention, by introducing a side chain containing the ether structure into a main chain that is expected to be biodegradable having an alkylene group or the like bonded thereto by a carbonate bond or the like, biodegradability is achieved. This is based on the finding that biocompatibility can be imparted without loss.

The degree of polymerization of the polymer according to the present invention is not particularly limited, but the average molecular weight of the polymer also changes depending on the degree of polymerization, and the operability when used as a material changes depending on the molecular weight. From such points, the average molecular weight of the polymer according to the present invention is preferably in the range of 2000 to 1000000, more preferably in the range of 5000 to 800000, and most preferably in the range of 8000 to 500000. The molecular weight distribution of the polymer according to the present invention is not particularly limited, but is preferably in the range of 1.0 to 10, more preferably in the range of 1.0 to 8, and 1.05 to 5.0. The range is most preferable. In the polymer according to the present invention, the structure of each of C _B and A of formula (I) may be different in each repeating unit. Such a polymer can be synthesized by performing a polymerization reaction using two or more kinds of monomer molecules as a raw material of the polymer.

In the above formula (I), the structural portion Z is not particularly limited as long as it is a molecular chain having at least one chain ether such as polyethylene glycol, a cyclic ether or an acetal structure, that is, at least one ether group.
In one embodiment of the present invention, the structural moiety Z can be represented by the following formula (II).

In the formula (II), the repeating number (l) is an integer of 1 to 30, and U is a hydrogen atom or a linear or branched alkyl group having 5 or less carbon atoms. The repetition represented by the formula (II) corresponds to a chain ether, and when the number of repetitions (l) is large, there is a tendency that the solubility of the side chain in water tends to be high. Will have. For this reason, although the structure represented by the formula (II) depends on the density or the like introduced into the polymer, typically, l is 20 or less, and preferably 10 or less. In particular, when the structure represented by the formula (II) is introduced into the polymer at a high density, even if l is 5 or less in order to ensure the water resistance of the polymer, the polymer contains intermediate water in a sufficient ratio. can do. Further, by setting l to 1, 2, 3 or so, a polymer capable of adsorbing predetermined cells while suppressing platelet adhesion while ensuring sufficient water resistance and reducing the content of intermediate water. can do. In addition, the repetition represented by the formula (II) corresponds to ethylene glycol (—C ₂ H ₄ —O—), but is not limited to this in the present invention, and propylene is used to improve the water resistance of the polymer. A structure corresponding to glycol (—C ₃ H ₆ —O—) can also be used.
In the structure U provided at the end of the chain ether, the water resistance of the polymer is improved by using the alkyl group having a large carbon number, while the intermediate water contained by the decrease in the carbon number is increased. Typically, methyl (carbon number 1) is preferred as U.
U may be a group that can be represented by the following formula (III).

In the formula (III), l ′ can be an integer of 1 to 5, but when l ′ is 1 (that is, when it is a 3-membered ring), the ring opens in water and becomes unstable. , L ′ is preferably 2, 3, 4 or 5.
In another specific embodiment of the present invention, the structural portion Z can be represented by the following formula (IV).

The structure represented by the formula (IV) corresponds to a cyclic ether, and by introducing such a structure into the side chain, it becomes possible to contain intermediate water. In formula (IV), l ″ can be an integer of 1 to 5, but when l ″ is 1 (that is, when it is a three-membered ring), the ring opens in water and becomes unstable. , L ″ are preferably 2, 3, 4 or 5.
In another aspect of the present invention, the structural portion Z can be represented by the following formula (V).

In the formula (V), M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, preferably methyl. E and E ′ are each independently —O— or —CH ₂ —, and at least one of them may be —O—, but preferably has an acetal structure in which both are —O—. Q ′ and Q ″ each independently represent a hydrogen atom, linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C _3-8 alicyclic alkyl or benzyl, or Q 'And Q "together form an alkylene group having 2 to 5 carbon atoms, and are preferably a hydrogen atom or an alkyl having 6 or less carbon atoms in order to keep the proportion of the intermediate water that can be contained to a desirable level. Most preferably, Q and Q ′ are both a hydrogen atom or methyl. k and k ′ are each independently an integer of 0 to 2, but from the viewpoint of availability of raw materials, it is preferable that k = 1 and k ′ = 0.
The structural part Z as described above has at least one ether group (—O—), and thus can exhibit high molecular mobility as seen in, for example, polyethylene glycol. It is considered that intermediate water can be contained as a polymer by having such a structure in the side chain. And by adjusting the number of ether groups contained in the structural part Z, the bulkiness of the structural part Z itself, etc., the amount of intermediate water that can be contained in the resulting polymer is adjusted to adjust the degree of antithrombogenicity. be able to.

In the above formula (I), the linker L is a part that plays a role of linking the main chain and the structural part Z, and is typically an ether group, an ester group, an amide group, an amino group, a urethane group, a urea group, an alkylene group. Divalent functional groups such as groups can be used. It is known that the structural part Z can generally have a high molecular mobility by having an ether structure as described above, and by having such a structure in the side chain part, It is considered that intermediate water can be contained as a polymer. For this reason, as the linker L that connects the main chain and the structural portion Z, it is desirable to select and use various types of structures that do not inhibit the molecular mobility according to the individual structure of the structural portion Z. In addition, in order to satisfactorily contain intermediate water as a polymer and exhibit biocompatibility, it is desirable that each part of the polymer does not become hydrophobic, and in particular, it is desirable that adsorption of biological substances such as proteins hardly occurs. . For this reason, as a structure of the linker L, it is desirable that the hydrophobic structure is not excessively large and does not include a functional group having a strong polarity. Moreover, it is desirable to use a linker having a structure that can easily carry out the reaction of introducing the structural moiety Z when the monomer molecule is synthesized.
The specific structure of the linker L that is desirably used depends on the structure of the structural part Z to be used, but in general, the ether group, ester group, amide group, amino group, urethane group, urea group, alkylene group are generally used. In addition to the above, unit structures as exemplified in the above-mentioned scheme 1 can be mentioned. In forming a bond between the linker L and the structural part Z, for example, a reaction called a click reaction (see, for example, Angew. Chem. Int. Ed., 2001, 40, 2004-2021) can be used. A linker having a 1,2,3-triazole structure derived from azide and alkylene can also be introduced. As an exemplary synthesis method, a linker such as an ethenyl group (—C≡C—) introduced at the end of the linker L exemplified above is reacted with an azide to thereby form the linker L and the structural moiety exemplified above. A structure in which Z is bonded to each other through a 1,2,3-triazole ring can be obtained. These structures can be used as the linker L as well.

  Among the divalent functional groups used as the linker shown above, when a functional group containing an N—H bond such as an amide group, an amino group, a urethane group, or a urea group is used as the linker L, this Although the linker portion is preferable in that it exhibits hydrophilicity, there is a tendency that proteins existing in the living body are easily adsorbed to the polymer, and therefore, a biological substance in the body may be attached depending on the use. In addition, when an alkylene group such as methylene or ethylene is used, hydrophobicity is exhibited, and the proportion of intermediate water that can be contained in the polymer tends to decrease. On the other hand, when an ether group is used as a linker, the starting material for synthesis generally has an alcohol on both the main chain side and the side chain side, so that an additional by-product is generated in the reaction of introducing a protective group, making separation difficult. And the yield is expected to decrease. For this reason, it is particularly preferable to use an ester group as the linker L from the viewpoint of ease of production and biocompatibility.

In the polymer according to the present invention, the side chain having the above-described structure is not necessarily present for all the repeating units of the main chain. On the other hand, from the viewpoint of ease of synthesis and easy prediction of the degree of antithrombogenicity from the structure of the polymer, generally, a compound in which a structural portion Z is introduced in advance as a monomer compound used in the polymerization is mainly used. It is preferable that side chains including the structural portion Z exist for all the repeating units of the chain polymer.
It is also possible to introduce two structural parts Z via a linker into one carbon atom constituting the main chain contained in the part A in the above formula (I). Further, in the monomer used in the polymerization, in the polymer obtained by polymerization by introducing one or a plurality of carbonyl bonds or the like (C _B ) and one or more structural portions Z, It is also possible to arbitrarily adjust the number of structural portions Z existing between carbonyl bonds or the like (C _B ).
In the above formula (I), the portion represented by “C _B ” is a carbonate bond, an ester bond, a urethane bond, a urea bond, an amide bond, etc., all of which are oxygen atoms at at least one of carbonyl carbon and adjacent positions. It is comprised by the group in which an atom or a nitrogen atom exists. By introducing such a structure into the main chain of the polymer at a relatively high density, as in the case of conventionally known aliphatic polyester and polyamide biodegradable polymers, this part undergoes hydrolysis in vivo. It is thought that biodegradability is expressed.
In the polymer according to the present invention, binding mode, which is used as a binding moiety C _B can be appropriately determined based applications polymers are used, such as in particular the period required for biodegradation. If the binding moiety C _B using a urethane bond or an amide bond can be obtained with low polymer of biodegradation rate of a relatively body. On the other hand, when these bonding modes are used, it is expected that amine (NH ₂ ) or carboxylic acid is generated as a product during biodegradation, thereby limiting the application. In addition, the ester bond is expected to exhibit a relatively high biodegradation rate, but it is expected that a carboxylic acid is generated as a product during biodegradation in the same manner as the amide bond. On the other hand, when a carbonate bond is used as the binding portion C _B , it is expected to show a higher biodegradation rate than a urethane bond or an amide bond, and carbon dioxide and alcohol are obtained by biodegradation. It can be preferably used because it is expected.

In the above formula (I), the alkylene group “A” is a C _1-8 alkylene group in which a hydrogen atom is substituted with at least one group —Y and optionally a lower alkyl group, optionally adjacent to C _B. At least one carbon other than the carbon to be substituted may be replaced with a heteroatom selected from N, O or S. In connection with the selection of the linking moiety C _B , the alkylene group A can have at least one carbon atom and can be biodegradable with up to about 8 carbon chains. From the viewpoint of sex. Further, in an alkylene group having 3 or more carbon atoms, an alkylene oxide chain corresponding to a structure in which at least one of carbon atoms other than those located at both ends is substituted with an ether group can be used. Thus, by including an alkylene oxide chain having an ether group introduced in the main chain, the mechanical strength such as impact resistance as a polymer can be improved as compared with the case of using an alkyl chain, and the main chain. It also becomes possible to impart hydrophilicity to the chain.
In addition, as described above, an ether related to the inclusion of intermediate water in any carbon atom contained in the alkylene group or the like with respect to the main chain composed of an alkylene group or the like bonded to each other by the bonding portion C _B by the side chain by introducing a structure or the like, while maintaining biodegradability due to the binding moiety C _B, it may be a polymer that can contain intermediate water.

One preferred specific embodiment of the present invention, in the formula (I), is _{C B,} is an ester bond (-C (= O) O-), or carbonate bond (-OC (= O) O-) A biocompatible polymer composition comprising repeating units. More specifically, the biodegradable polymer skeleton has the following formula (VI):

(Where
X and X ′ are independently of each other —O—, —NH— or —CH ₂ —, but at least one is not —CH ₂ —;
M is a hydrogen atom, a linear or branched alkyl group having 3 or less carbon atoms, or a group -LZ;
m and m ′ are each independently an integer of 0 to 5, provided that when X and X ′ are both —O—, at least one of m and m ′ is not 0, and m and m The sum of 'is 7 or less;
Y is a structural moiety represented by the group -LZ (wherein L and Z are as defined above);
Each of these may be different in each repeating unit,
n represents the degree of polymerization, and is preferably a biocompatible polymer composition in the range of 2 to 2000.

M is preferably an alkyl group, and most preferably a methyl group.
The values of m and m ′ are determined by the selection of monomer raw material compounds. From the viewpoint of monomer preparation, the sum of m and m ′ is preferably in the range of 1 to 4, and m and m ′. Are most preferably 1.

  As one aspect of the present invention, the main chain can be a copolymer of a biodegradable polymer and a non-biodegradable polymer. As the non-biodegradable polymer, a polymer known to those skilled in the art can be appropriately used according to the required physical properties. Examples thereof include polymethyl methacrylate (PMMA), polyethyl methacrylate (PEMA), and polyvinyl. Examples include, but are not limited to, pyrrolidone (PVP), polyurethane, polyester, polyolefin, polystyrene, polyvinyl chloride, polyvinyl ether, polyvinylidene fluoride, polyfluoroalkene, nylon, and silicone. The non-biodegradable polymer skeleton may form a block copolymer with the biodegradable polymer skeleton, or may randomly copolymerize with a monomer unit that forms the biodegradable polymer. Moreover, in order to obtain desired physical properties, a copolymer with a plurality of non-biodegradable polymers may be formed.

The biocompatible polymer according to the present invention can be produced, for example, by ring-opening polymerization of a monomer having a cyclic structure into which a portion to be a side chain of a polymer obtained by polymerization is introduced in advance as follows.

For example, the general formula (VII), X adjacent the carbonyl carbon, as X ', by selecting from CH 2, _O, N, as the binding moiety C _B contained in the main chain of the polymer after polymerization, carbonate Any of a bond (O / O), an ester bond (CH ₂ / O), a urethane bond (O / N), an amide bond (CH ₂ / N), and a urea bond (N / N) is selected.
Further, the alkylene m, as m ', an integer including zero independently of one another (carbonate bond, in the case of the urea bond, either is not 0) by selecting, bound by a binding moiety C _B The length of the base A is determined. And as "Y" of the said general formula (VII), the structural part Z is combined with the carbon atom through the suitable linker L, and the side chain part which has an ether structure is provided in the side chain part of the polymer after superposition | polymerization be able to. As “M” in the above general formula (VII), a structural part Z can be bonded through a linker L in the same manner as hydrogen, an alkyl group, or “Y”.
The biocompatible polymer according to the present invention can be produced by ring-opening the cyclic monomer obtained as described above at any of the bonds adjacent to the carbonyl carbon and polymerizing each other. .
In the above description, the cyclic monomer including one portion Y including the structural portion Z has been described. However, the present invention is not limited to this, and one or two structural portions Z are also provided for appropriate carbon atoms contained in m and m ′. It is also possible to provide a portion Y including Further, by substituting appropriate carbon atoms contained in m and m ′ (when O and N are selected as X and X ′, excluding carbon atoms adjacent to O and N) with oxygen, An ether structure can be introduced into the main chain portion of the polymer after polymerization. It is also possible to substitute the carbon atom of the alkylene group A with a heteroatom such as N or S.

For example, in general formula (VII):
X and X 'are both oxygen atoms to form a cyclic carbonate, m and m' are both 1, M is a methyl group,
When Y having a predetermined ether structure bonded by an ester bond is used, ring-opening polymerization of the cyclic carbonate has a main chain in which a C = 3 alkylene group is bonded by a carbonate bond. A polymer in which the ether structure and a methyl group are provided as side chains with respect to the central carbon atom of the group can be obtained.

In the present invention, as the monomer compound used as described above, for example,
5-methyl-5- (2-methoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
5-methyl-5- (2-ethoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
5-methyl-5- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxan-2-one,
5-methyl-5- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxan-2-one,
5-methyl-5- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxan-2-one 5-methyl-5- [2- (2-methoxyethoxy) ethyl] oxycarbonyl-1,3- Dioxan-2-one,
5-methyl-5- (2-epoxyoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
4-methyl-4- (2-methoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
4-methyl-4- (2-ethoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
4-methyl-4- (2-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxan-2-one,
4-methyl-4- (3-tetrahydrofuranylmethyl) oxycarbonyl-1,3-dioxan-2-one,
4-methyl-4- (3-tetrahydropyranylmethyl) oxycarbonyl-1,3-dioxan-2-one 4-methyl-4- [2- (2-methoxyethoxy) ethyl] oxycarbonyl-1,3- Dioxan-2-one,
4-methyl-4- (2-epoxyoxyethyl) oxycarbonyl-1,3-dioxan-2-one,
γ-methyl-γ- (2-methoxyethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (2-ethoxyethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (2-tetrahydrofuranylmethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (3-tetrahydrofuranylmethyl) oxycarbonyl-δ-valerolactone,
γ-methyl-γ- (3-tetrahydropyranylmethyl) oxycarbonyl-δ-valerolactone,
However, the present invention is not limited thereto, and a monomer to be used can be appropriately selected depending on the structure of the target polymer.

In the above description, a method for producing a biocompatible polymer according to the present invention by polymerizing a bond in which biodegradability such as a carbonate bond is expected and a monomer having a structure including a predetermined ether group is introduced, The present invention is not limited to this, and a polymer having a bond expected to be biodegradable is introduced into the present invention by introducing a structure containing a predetermined ether group with respect to a predetermined carbon atom forming the main chain. Such a biocompatible polymer may be produced. In the biocompatible polymer composition of the present invention, it is not always necessary that a structure containing an ether group is bonded as a side chain over all repeating units of the main chain polymer. However, the ease of synthesis and the characteristics of the polymer can be easily predicted. From this viewpoint, it is also preferable to polymerize a single type of monomer having a structure containing an ether group introduced therein to form a polymer.
In addition, for example, by using a monomer in which a plurality of carbonyl carbons forming a carbonate bond or the like in a polymer are introduced into a cyclic part of a cyclic monomer to be used, and a structure containing an ether group is introduced into an appropriate carbon forming a cyclic part. It is also possible to produce a polymer in which the distribution of side chains having a structure containing an ether group introduced between bonds that are expected to be biodegradable, such as carbonate bonds, is not the same in adjacent repeating units.

  In one embodiment of the present invention, the biodegradable polymer and the non-biodegradable polymer can be included in the main chain portion. A polymer having such a structure can be obtained, for example, by copolymerization of a biodegradable polymer and a non-biodegradable polymer.

In the compound represented by the general formula (VII), for example, when X and X ′ are both —O—, that is, a cyclic carbonate, such a compound is synthesized by a method known to those skilled in the art. can do. For example, as shown in the following scheme, starting from a derivative of a diol, (a) a reaction to introduce a structure containing an ether group, and (b) phosgene, diphenyl carbonate or carbon monoxide in the presence of a catalyst, etc. It can be synthesized by a process including a reaction in which a carbonic acid source is allowed to act to form a cyclic carbonate.

(Wherein M, m, m ′, Y, and Z are as defined above, P and P ′ represent a leaving group, and R is —O-phenyl or a chlorine atom. Yes or no)

  As yet another example, a compound of the general formula (VII) in which the linker moiety L is an ester bond is first prepared as a carboxylic acid having a diol structure, such as 2,2-bis (methylol) propionic acid, as step (a). It can be obtained by reacting an alcohol having a structure containing an ether group, for example, 2-methoxyethanol to form a bis (hydroxy) ester, and then reacting with triphosgene as step (b).

  The step of synthesizing the bis (hydroxy) ester is performed by heating in a solvent, for example, in the presence of an ion exchange resin. In the case of using a solvent, the type of the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material, but the alcohol having the structural part Z as the raw material is liquid and sufficiently dissolves the diol Can also be used as a solvent. The reaction temperature can range from room temperature to the boiling point of the solvent, but is preferably from room temperature to 100 ° C, and most preferably from 50 to 90 ° C in order to improve the yield. Although reaction time changes with a raw material compound and heating temperature, it is 1 to 100 hours, Preferably it is the range of 10 to 50 hours.

  When the linker portion L has a structure other than an ester, selection of the raw material compound, for example, when L is an amide, the alcohol having the structural portion Z is an amine, and when L is an ether group (—O—) The diol derivative is synthesized by appropriately changing the carboxylic acid having a diol structure to a halide. The reaction conditions used in this case are known to those skilled in the art.

  The step of forming the cyclic carbonate is carried out, for example, by reacting the obtained diol derivative with triphosgene in a suitable solvent in the presence of a base. The solvent to be used is not particularly limited, and examples thereof include halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, aromatic solvents such as benzene and toluene, or ethyl acetate. However, it is not limited to these. The base is used to decompose triphosgene to generate phosgene in the reaction system. Examples of the base used include, but are not limited to, triethylamine, diisopropylethylamine, pyridine and the like.

  In the compound represented by the general formula (VII), when one of X and X ′ is —O—, that is, a lactone, such a compound should be synthesized using methods known to those skilled in the art. Can do.

The lactone represented by the general formula (VII) is synthesized by a method including (a) a reaction for introducing a structure containing an ether group and (b) a lactonization reaction. The reaction for introducing a structure containing an ether group is as described above in the synthesis of carbonate. The lactonization reaction may be, for example, an intramolecular condensation of hydroxycarboxylic acid, a condensation reaction such as iodolactone formation or Staudinger ketene cycloaddition reaction, an oxidation reaction using a peracid such as Baeyer-Villiger oxidation of a cyclic ketone, or The reaction can be performed using a reaction known to those skilled in the art, such as oxidation of cyclized lactol. An oxidation reaction using a peracid is preferred because of its versatility for the synthesis of various monomer compounds. For example, the lactone represented by the general formula (VII) can be synthesized according to the following scheme. The starting compound is commercially available or can be obtained by synthetic methods known to those skilled in the art.

(Wherein M, m, m ′ and Z are as defined above)

  One embodiment of the present invention is a method for producing an antithrombotic polymer, comprising the step of ring-opening polymerization of a compound represented by the general formula (VII).

  The ring-opening polymerization of the compound represented by the general formula (VII) is performed by a method known to those skilled in the art. As the ring-opening polymerization method, a cationic polymerization reaction, an anionic polymerization reaction, or the like can be used. The cationic polymerization reaction is carried out using a Lewis acid such as boron trifluoride ether complex, titanium tetrachloride or aluminum chloride, a protonic acid such as hydrochloric acid or methanesulfonic acid, or an alkyl cation generator such as methyl iodide as an initiator. be able to. Anionic ring-opening polymerization can be performed using an alkali metal, a metal hydride, a metal alkoxide, an organometallic compound, or the like as an initiator.

  When the compound represented by the general formula (VII) is a cyclic carbonate, both cationic polymerization and anionic polymerization can be used when the compound is a lactone. When the cyclic carbonate is cationically polymerized, it is preferable to use an initiator that generates a counter anion having a large nucleophilicity such as an alkyl halide in order to suppress the by-production of the polyether accompanying decarboxylation. . In addition, tin octylate, which is believed to proceed through a coordinated insertion mechanism and is approved for use by the US Food and Drug Administration (FDA), is currently the most commonly used ring-opening polymerization of cyclic monomers. It is also possible to carry out the ring-opening polymerization reaction by using alcohol as an initiator. Furthermore, in recent years, organic molecular catalysts that have been attracting attention both moderately activate monomers and alcohol initiators by hydrogen bonds to advance the polymerization reaction, and thus suppress chain transfer reactions such as transesterification as well as decarboxylation. It is easy to obtain a polymer with a relatively uniform molecular weight distribution, using a thiourea structure or a Lewis acid containing an aromatic fluoroalcohol as a monomer activation catalyst, and a tertiary amine as an initiator activation catalyst. A polymerization reaction can also be performed.

  The ring-opening polymerization of the compound represented by the general formula (VII) is, for example, a polymerization initiator such as 1-pyrenebutanol, lauryl alcohol, decanol or stearyl alcohol in a solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran or toluene. Optionally in the presence of a cyclic amine polymerization initiator such as 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), dimethylaminopyridine (DMAP) or triethylenediamine (DABCO) It is carried out by reacting at room temperature under a nitrogen atmosphere using an organic molecular catalyst such as a thiourea compound such as 1- (3,5-bis (trifluoromethyl) phenyl) -3-cyclohexyl-2-thiourea.

In the polymerization method of the present invention, the reaction system is preferably performed in a nitrogen atmosphere from which oxygen and water are removed from the viewpoint of suppressing side reactions. The reaction temperature can be selected in the range of room temperature to the boiling point of the solvent. From the viewpoint of reaction control and the like, the temperature is preferably in the range of room temperature to 50 ° C., most preferably at room temperature. The reaction time varies depending on the compound of the general formula (VII) as a raw material, the reaction temperature, and the presence or absence of a catalyst. For example, when the reaction is performed at room temperature using a catalyst, the reaction time is 1 minute to 12 hours, preferably 30. Min to 6 hours, more preferably 1 to 3 hours. The completion of the reaction can be judged by whether or not the compound of the general formula (VII) as a monomer is present in the reaction system, and can be confirmed by a method such as ¹ H-NMR, TLC or the like. When the polymerization reaction has proceeded sufficiently, the polymerization reaction can be terminated by adding a reaction terminator. Examples of the reaction terminator include acetic acid, hydrochloric acid, sulfuric acid, benzoic acid and the like, but the type is not particularly limited.

  A biocompatible polymer composition produced by ring-opening polymerization of the monomer compound represented by the general formula (VII) is also an object of the present invention.

  The biocompatible polymer composition produced according to the present invention may contain, for example, a radical scavenger, a peroxide decomposer, an antioxidant, and an ultraviolet absorber as long as it does not depart from the spirit of the present invention. In addition, additives such as a heat stabilizer, a plasticizer, a flame retardant, and an antistatic agent can be added and used. Moreover, it can be used by mixing with polymers other than the polymer of this invention. Such a composition comprising the biocompatible polymer composition of the present invention is also an object of the present invention.

  The various biocompatible polymer compositions produced according to the present invention can be used alone by being dissolved in an appropriate organic solvent, or used by mixing with other polymer compounds depending on the purpose of use. Etc., and can be used as various compositions. Moreover, the medical device of this invention should just have the bioaffinity polymer composition of this invention in at least one part of the surface used in contact with the structure | tissue or blood in a living body. That is, a composition containing the biocompatible polymer composition of the present invention can be used as a surface treatment agent on the surface of a base material constituting a medical device. Moreover, you may comprise at least one part member of a medical device with the bioaffinity polymer composition of this invention, or its composition.

  One aspect of the present invention is a biocompatible polymer of the present invention for suppressing a foreign body reaction to blood or tissue until it is decomposed when used in contact with tissue or blood in vivo. It is a composition.

  The biocompatible polymer composition of the present invention can be preferably used for medical applications. When the biocompatible polymer composition of the present invention is mixed with another polymer compound and used as a composition, it can be used in an appropriate mixing ratio depending on the intended use. In particular, by setting the ratio of the biocompatible polymer composition of the present invention to 90% by weight or more, a composition having the characteristics of the present invention can be obtained. In addition, depending on the intended use, by setting the ratio of the biocompatible polymer composition of the present invention to 50 to 70% by weight, it is possible to obtain a composition having various characteristics while utilizing the features of the present invention. .

One aspect of the present invention is a medical device comprising the biocompatible polymer composition of the present invention. Here, the “medical device” includes an in-vivo implantable device such as a prosthesis and a device such as a catheter that may temporarily come into contact with a living tissue, and is not limited to those handled in vivo. The medical device of the present invention is a device used for medical applications having the polymer composition of the present invention on at least a part of its surface. The surface of the medical device referred to in the present invention refers to, for example, the surface of the material constituting the medical device that contacts blood when the medical device is used, the surface portion of the hole in the material, and the like.
In this specification, “used in contact with tissue or blood in a living body” is used, for example, in contact with the tissue or blood in a state where it is placed in the living body or in a state where the tissue in the living body is exposed. Naturally, the form and the form used in contact with blood which is an in vivo component taken out of the body in the extracorporeal circulation medical material are included. In addition, “used for medical use” includes the above-mentioned “used in contact with in vivo tissues and blood” or intended use.

  In the present invention, the material and shape of the base material constituting the medical device are not particularly limited, and may be any of, for example, a porous body, fiber, nonwoven fabric, particle, film, sheet, tube, hollow fiber, and powder. . The materials include natural polymers such as Kinishiki and hemp, nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polycarbonate, polysulfone, polyethersulfone, poly (meth) acrylate, and ethylene-vinyl alcohol. Examples thereof include synthetic polymers such as polymers and butadiene-acrylonitrile copolymers, and mixtures thereof. Further, metals, ceramics, composite materials thereof, and the like can be exemplified, and they may be composed of a plurality of base materials. The present invention is applied to at least a part of the surface in contact with blood, preferably almost the entire surface in contact with blood. Desirably, a biocompatible polymer composition is provided.

  The biocompatible polymer composition of the present invention can be used as a material constituting a whole medical device used in contact with a tissue or blood in a living body or a material constituting a surface portion thereof, and can be used as an implantable prosthesis. And therapeutic instruments, extracorporeal circulation type artificial organs, surgical sutures, and catheters (circulatory catheters such as angiographic catheters, guide wires, PTCA catheters, gastrointestinal catheters, gastrointestinal catheters, esophageal tubes, etc.) A biocompatible polymer according to the present invention, wherein at least a part of the surface in contact with blood of a medical device such as a catheter, tube, urinary catheter, urinary catheter, etc. It is desirable to be composed of a composition. In addition, the biodegradability of the biocompatible polymer composition according to the present invention can be used particularly preferably for a medical device placed in the body during treatment.

  The biocompatible polymer composition of the present invention comprises a hemostatic agent, a biological tissue adhesive, a tissue regeneration repair material, a drug sustained release carrier, a hybrid artificial organ such as an artificial pancreas and an artificial liver, an artificial blood vessel, and an embolization material. It may also be used as a matrix material for a scaffold for cell engineering.

  In these medical devices, surface lubricity may be further imparted because the tissue can be easily inserted into a blood vessel or tissue without damaging the tissue. As a method for imparting surface lubricity, a method in which a water-soluble polymer is insolubilized to form a water-absorbing gel layer on the material surface is excellent. According to this method, a material surface having both biocompatibility and surface lubricity can be provided.

The biocompatible polymer composition of the present invention itself is a material excellent in biocompatibility, but since it can further carry various physiologically active substances, not only blood filters but also blood storage containers and blood circuits It can be used for various medical devices such as indwelling needles, catheters, guide wires, stents, oxygenators, dialysis machines, and endoscopes.
Specifically, the biocompatible polymer composition of the present invention may be coated on at least a part of the substrate surface constituting the blood filter. Further, the polymer compound of the present invention may be coated on at least a part of the blood bag and the surface of the tube communicating with the blood bag in contact with the blood. In addition, blood in an extracorporeal circulation blood circuit composed of an instrument side blood circuit unit composed of a tube, an arterial filter, a centrifugal pump, a hemoconcentrator, a cardio pregear, etc., and an operative field side blood circuit unit composed of a tube, catheter, soccer, etc. At least a part of the surface in contact with the surface may be coated with the biocompatible polymer composition of the present invention.
Further, an inner needle having a sharp needle tip at a distal end, an inner needle hub installed on the proximal end side of the inner needle, a hollow outer needle into which the inner needle can be inserted, and a proximal end side of the outer needle An indwelling needle assembly comprising: an outer needle hub installed on the inner needle; a protector mounted on the inner needle and movable in the axial direction of the inner needle; and a connecting means for connecting the outer needle hub and the protector. At least a portion of the three-dimensional, blood-contacting surface may be coated with the biocompatible polymer composition of the present invention. Moreover, at least a part of the surface of the long tube that contacts the blood of the catheter composed of the adapter connected to the proximal end (hand side) may be coated with the biocompatible polymer composition of the present invention.
Further, at least a part of the surface of the guide wire that comes into contact with blood may be coated with the biocompatible polymer composition of the present invention. In addition, stents of various shapes, such as hollow tubular bodies made of metal materials or polymer materials with pores on the side, metal material wires or polymer material fibers knitted into a cylindrical shape, etc. At least a portion of the surface in contact with blood may be coated with the biocompatible polymer composition of the present invention.
Also, a large number of porous hollow fiber membranes for gas exchange are housed in a housing, blood flows on the outer surface side of the hollow fiber membrane, and oxygen-containing gas flows inside the hollow fiber membrane. The lung may be an artificial lung in which the outer surface or outer layer of the hollow fiber membrane is coated with the biocompatible polymer composition of the present invention.
Further, a dialysate circuit including at least one dialysate container filled with dialysate and at least one drainage container for collecting dialysate, and starting from the dialysate container, or The end point may be a dialyzer having a liquid feeding means for feeding dialysate, and at least a part of the surface in contact with the blood may be coated with the biocompatible polymer composition of the present invention.

  As a method for holding the composition containing the biocompatible polymer composition of the present invention on the surface of a medical device or the like, a coating method, a graft polymerization by radiation, electron beam or ultraviolet ray, a chemical reaction with a functional group of a base material is used. Well-known methods, such as a method of introducing by using, may be mentioned. Among these, the coating method is particularly preferable in practical use because the manufacturing operation is easy. Furthermore, there are coating methods, spraying methods, dipping methods and the like as coating methods, and any of them can be applied without any particular limitation. The film thickness is preferably 0.1 μm to 1 mm. For example, in the coating treatment by the application method of the composition containing the biocompatible polymer composition of the present invention, the coating solution is prepared by dissolving the composition containing the biocompatible polymer composition of the present invention in an appropriate solvent. After dipping the member, it can be carried out by a simple operation such as removing excess solution and then air-drying. In addition, in order to more firmly immobilize the biocompatible polymer composition of the present invention on the member to be coated, heat may be applied after coating to further improve the adhesion with the biocompatible polymer composition of the present invention. it can. Moreover, you may fix | immobilize by bridge | crosslinking the surface. As a method for crosslinking, a crosslinkable monomer may be introduced as a comonomer component. Moreover, you may bridge | crosslink by an electron beam, a gamma ray, and light irradiation.

  In addition to compounds having a plurality of vinyl groups or allyl groups in one molecule such as methylene bisacrylamide, trimethylolpropane diacrylate, triallyl isocyanate, trimethylolpropane triacrylate, tetramethylolmethane tetraacrylate, etc. And polyethylene glycol diacrylate. Among these, when various functional groups are introduced using polyethylene glycol diacrylate, the introduction rate of the compound having a functional group is high, and further, by introducing a polyethylene glycol chain to make it hydrophilic, as described above This is preferable because nonspecific adsorption of cells and proteins other than the intended purpose is suppressed. In this case, the molecular weight of the polyethylene glycol chain is preferably 100 to 10,000, and more preferably 500 to 6,000.

  As described above, when the composition containing the biocompatible polymer composition of the present invention is introduced into at least part of the surface of the medical device that comes into contact with blood, activation of the coagulation system, complement system, platelet system, etc. is suppressed. The biocompatibility can be imparted, and the biodegradability can be imparted. Therefore, the burden on the living body and the environment can be reduced.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these Examples. In addition, as long as there was no notice in particular, the chemical | medical agent used in the following examples used the commercial item as it was. In the following examples, confirmation of the structure of the products (intermediate compounds, final compounds) obtained in Examples 1 to 3 and Comparative Example 1, the degree of polymerization, and the number average molecular weight of the polymers obtained in each Example Measurement of molecular weight distribution and confirmation of the presence of intermediate water were performed as follows.

(1) Number average molecular weight ([Mn], unit: g / mol)
Gel permeation chromatography (GPC) calibrated with standard polystyrene having a known peak molecular weight ("HLC-8220" manufactured by Tosoh Corporation, column configuration: Tosoh TSK-gels super AW5000, super AW4000, super AW3000) Used to measure the number average molecular weight (Mn) and weight average molecular weight (Mw) of the polymer. (Solvent: tetrahydrofuran, temperature: 40 ° C., flow rate: 1.0 mL / min).

(2) Molecular weight distribution ([Mw / Mn])
It calculated | required as the ratio (Mw / Mn) using the value of the weight average molecular weight (Mw) and the number average molecular weight (Mn) calculated | required by the method of said (1).

(3) NMR measurement About structural analysis of a monomer and a polymer, ¹ H-NMR measurement and ¹³ C-NMR measurement were performed using an NMR measurement apparatus (JEOL 500 MHz JNM-ECX, manufactured by JEOL Ltd.). The chemical shift was based on CDCl ₃ ( ¹ H: 7.26 ppm, ¹³ C: 77.1 ppm).

[Example 1] Synthesis of 2-methoxyethyl 2,2-bis (methylol) propionate (MPA-ME)

2,2-bis (methylol) propionic acid (bis-MPA; 30.0 g, 0.224 mol), ion exchange resin Ameryst-15 (6.00 g) was added to 2-methoxyethanol (150 mL, 1.91 mol). ) And heated and stirred at 90 ° C. for 45 hours. Thereafter, the ion exchange resin was filtered off from the reaction solution, and the obtained filtrate was concentrated and dried under reduced pressure to give 2-methoxyethyl 2,2-bis (methylol) propionate (MPA-) as a pale yellow oily substance. ME) was obtained (25.1 g, yield 58.5%). ¹ H-NMR (500 MHz, CDCl ₃ ): δ 4.35 (quin, 2H, CH ₂ CH ₂ OCH ₃ ), 3.85 (d, 2H, CH _a H _b OH), 3.73 (d, 2H, CH ₂ H _b OH), 4.35 (quin, 2H, CH ₂ OCH ₃ ), 3.39 (s, 3H, OCH ₃ ), 1.11 (s, 3H, CH ₃ ).

Example 2 Synthesis of 5-methyl-5- (2-methoxyethyl) oxycarbonyl-1,3-dioxan-2-one (MTC-ME)

MPA-ME (25.1 g, 0.131 mol) and pyridine (63.5 mL, 0.787 mol) were added to dichloromethane (DCM; 150 mL) and cooled to −75 ° C. in a dry ice-acetone bath. Next, a DCM solution (200 mL) of triphosgene (19.5 g, 0.0655 mol) was added dropwise, and the mixture was stirred at −75 ° C. for 2 hours and then at room temperature for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (200 mL) was added and stirred for 45 minutes, and then the organic phase was washed twice with 1N aqueous hydrochloric acid solution (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), saturated brine (200 mL), and Washed with ion-exchanged water (200 mL). The obtained organic phase was dried over magnesium sulfate and then concentrated and dried under reduced pressure. Then, it refine | purifies with column chromatography (ethyl acetate), 5-methyl-5- (2-methoxyethyl) oxycarbonyl- 1, 3- dioxan-2-one (MTC-ME) is obtained as a colorless viscous liquid. Obtained (11.0 g, yield 43.8%). ¹ H-NMR (500MHz, CDCl ₃ ): δ 4.68 (d, 2H, CH _a H _b OCOO), 4.32 (quin, 2H, CH ₂ CH ₂ OCH ₃ ), 4.20 (d, 2H, CH _a H _b OCOO .), 3.57 (quin, 2H , CH 2 OCH 3), 3.33 (s, 3H, OCH 3), 1.31 (s, 3H, CH 3) 13 C-NMR (125MHz, CDCl 3): δ 171.2, 147.6, 73.0, 70.1, 65.0, 59.0, 40.3, 17.6.

[Example 3] Ring-opening polymerization of MTC-ME: Preparation of P (MTC-ME)

In a glove box under a nitrogen atmosphere, MTC-ME (0.441 g, 2.02 mmol) was added to 1-pyrenebutanol (PB; 5.2 mg, 0.019 mmol), 1,8-diazabicyclo [5.4.0]. Undec-7-ene (DBU; 6.1 mg, 0.040 mmol) and 1- (3,5-bis (trifluoromethyl) phenyl) -3-cyclohexyl-2-thiourea (TU; 15.0 mg, 0.041 mmol) ) In the presence of) in DCM (1 mL) at room temperature. After stirring for 90 minutes, consumption of the monomer was confirmed by ¹ H-NMR, and then several drops of acetic anhydride was added as a terminator and stirred overnight. Thereafter, the reaction solution was reprecipitated in diethyl ether: hexane (1: 3, 40 mL) and dried under vacuum to obtain a colorless and viscous polymer, P (MTC-ME) (0.350 g, yield). (Rate 79.3%). GPC: Mn 9556 g / mol, Mw / Mn 1.27. ¹ H-NMR (500MHz, CDCl ₃ ) δ 4.30 (m, 6H, COOCH ₂ ), 3.58 (t, 2H, CH ₂ OCH ₃ ), 3.36 (s, 3H, OCH ₃ ), 1.27 (s, 3H, CH ₃ ).

[Comparative Example 1] Synthesis of PTMC

In a glove box under nitrogen atmosphere, trimethylene carbonate (TMC: 408 mg, 4.0 mmol), PB (11.3 mg, 0.041 mmol), DBU (33.5 mg, 0.22 mmol), TU (75.3 mg). , 0.20 mmol) in the presence of DCM (1 mL) at room temperature. After stirring for 90 minutes, consumption of the monomer was confirmed by ¹ H-NMR, and then several drops of acetic anhydride was added as a terminator and stirred overnight. The reaction solution was then reprecipitated in methanol (40 mL) and dried under vacuum to give a colorless and viscous polymer PTMC (292.9 mg, 71.8%). GPC: Mn 12000 g / mol, Mw / Mn 1.1. ¹ H-NMR (500MHz, CDCl ₃ ) δ 4.25 (t, 4H, CH ₂ CH ₂ CH ₂ ), 2.05 (quin, 2H, CH ₂ CH ₂ CH ₂ ).

[Example 4] DSC measurement of P (TMC-ME) DSC measurement was performed on P (TMC-ME) in a dry state and a state containing 5% water. Measurement was performed using a DSC apparatus (SII Nano Technologies, Inc., “EXSTAR X-DSC7000”) under conditions of a nitrogen flow rate of 50 mL / min and 5.0 ° C./min. The temperature program was (i) cooling from 30 ° C to -100 ° C, (ii) holding at -100 ° C for 5 minutes, and (iii) heating from -100 ° C to 30 ° C. In (iii) above, the presence or absence of intermediate water was confirmed by the presence or absence of an exothermic peak due to low-temperature crystallization of water and an endothermic peak due to low-temperature melting of water. FIG. 5 shows the results of DSC measurement of P (TMC-ME) in a dry state and a state containing 5% water. From the figure of (b) showing the result of DSC measurement of P (TMC-ME) containing 5% water, the behavior accompanying low temperature melting of water around -5 ° C, low temperature crystallization of water around -15 ° C It was revealed that the antithrombotic polymer of the present invention retains intermediate water, that is, has biocompatibility and can function as a biocompatible polymer.

[Example 5] Measurement of static contact angle of water (droplet method)
PET (MTC-ME) and PTMC adjusted to concentrations of 1.0, 0.5, 0.2, and 0.1 w / v% on a PET substrate (diameter 14 mm, thickness 125 μm) pre-cleaned with methanol An acetone solution (40 μL) was applied by spin coating (spin conditions: 500 rpm 5 s, 2000 rpm 10 s, SLOPE 5 s, 4000 rpm 5 s, SLOPE 4 s, 25 ° C.). The second application was performed 10 minutes after the first spin coating. After vacuum drying for 24 hours, the contact angle with water was measured at each of the three points of the center, left end, and right end of each polymer-coated substrate. 2 μL of water droplet was used for each measurement.

[Example 6] Water static contact angle measurement (underwater bubble method)
The same polymer-coated substrate as in Example 5 was immersed in a water tank containing Milli-Q water with the coated surface facing downward. Using a micropipettor, the polymer-coated substrate on which bubbles (2 μL) were immersed was adhered to the center, the left end, and the right end, and the contact angle between the coating surface and the bubbles was measured using the θ / 2 method. The results of contact angle measurement of Examples 5 and 6 are shown in Table 1. The contact angle of the polymer obtained in Example 3 showed a small value compared to the case where PET was used as a control, indicating that the surface of the polymer obtained in Example 3 was more hydrophilic. . Moreover, the contact angle of the polymer obtained in Comparative Example 1 showed a larger value than when PET was used, indicating that the polymer surface was more hydrophobic.

[Example 7] Platelet adhesion test A spin-coated substrate coated with a 0.2 w / v% acetone solution of P (MTC-ME) was cut into 8 mm squares and fixed on a sample table for a scanning electron microscope (SEM). Human blood was centrifuged at 1500 rpm for 5 minutes, and the supernatant was collected as platelet rich plasma (PRP). The remaining blood was further centrifuged at 4000 rpm for 10 minutes, and the supernatant was collected as platelet poor plasma (PPP). Platelet solution with a platelet concentration of 4 × 10 ⁷ cells / mL while diluting PPP 800-fold with phosphate buffered saline (PBS) solution, further diluting PRP, and checking the platelet count with a microscope Was prepared. 200 μL of this platelet solution was dropped on each substrate and allowed to stand at 37 ° C. for 1 hour. Thereafter, each substrate was washed twice with a PBS solution, immersed in a 1% glutaraldehyde solution, and fixed at 37 ° C. for 2 hours. The immobilized sample was washed by immersing in PBS solution for 10 minutes, PBS: water = 1: 1 for 8 minutes, water for 8 minutes, and water for another 8 minutes. Each sample was air-dried at room temperature, and the platelet adhesion number was measured by SEM. The measurement results are three types of adhesion forms of platelets adhering to the surface of each substrate, that is, type I: small degree of activation, circular adhesion form similar to that in blood, type II: medium degree of activation The adhesive form in which pseudo-leg formation was observed, type III: classified into the extended adhesive form with a high degree of activation, and PET was evaluated as a control.

  The measurement result of the platelet adhesion number is shown in FIG. From this result, it became clear that the antithrombotic polymer of the present invention can suppress the number of adhesion of platelets to be small and exhibits good biocompatibility and antithrombogenicity as compared with PTMC of the comparative example.

[Example 8] Enzymatic degradation test Two types of polymers, P (MTC-ME) and PTMC, were used. 30 mg of polymer and 1 mL of lipase solution were added to a 1.5 mL tube and allowed to stand at 37 ° C. The lipase solution was changed every 2 days. After 9 days, the lipase solution was withdrawn from the tube and the remaining polymer sample was rinsed 3 times with milliQ water. Thereafter, the weight loss was determined from the polymer weight after 24 hours of vacuum drying at room temperature.
The weight loss rate after 9 days of the enzyme treatment was P (MTC-ME): 6.4% and PTMC: 1.7%, respectively. From this result, it was revealed that the antithrombotic polymer of the present invention has excellent biodegradability by an enzyme as compared with the PTMC of the comparative example.

According to the present invention, the polymer composition of the present invention can be used as an antithrombotic material to which substances that cause blood coagulation and the like hardly adhere. The polymer composition of the present invention can be used, for example, as a surface treatment agent for medical devices such as artificial blood vessels or medical devices that may come into contact with or be placed in the living body, such as stents. . Furthermore, since the medical device using the polymer composition of the present invention also has biodegradability, it can be decomposed as a highly functional medical material or smart biomaterial that does not give a load to the living body and the environment, for example, after tissue regeneration. -It can be used as an artificial substitute to be absorbed or as an implantable cell culture scaffold material.

Claims (9)

A structure containing at least one ether structure in its side chain, looking contains a main chain comprising a biodegradable polymer backbone, the biodegradable polymer backbone has the formula: (I)
-C _B -A- (I)
(Where
C _B represents a carbonate bond;
A is a C _1-8 alkylene group in which a hydrogen atom is replaced by at least one group —Y ;
Y is a formula: -LZ (wherein Z is a structure having at least one chain ether or cyclic ether, L is a linker between the main chain and Z, an alkylene group, an ether bond , A thioether bond, an ester bond, an amide bond, a urethane bond or a urea bond, or a group having a combination thereof, And a polymer containing a quaternary amine group) . In the above C _1-8 alkylene group, at least one carbon atom other than the carbon atom adjacent to C _B is replaced with a hetero atom selected from N, O or S, and / or C _{1- The} composition comprising the biocompatible polymer according to claim 1, wherein the hydrogen atom in the ₈ alkylene group is a group substituted with a lower alkyl group. The linker L is a group shown below:

The biocompatible polymer according to claim 1 , wherein the biocompatible polymer is selected from the group having a 1,2,3-triazole group at the bonding portion between the group and Z. Composition. Z represents the following formula (II):

[Wherein, l is an integer of 1 to 30, and U is a hydrogen atom or a linear or branched alkyl group having 5 or less carbon atoms,
Or the following formula (III):

(Wherein l ′ is a group represented by 1 to 5), or a group represented by
Alternatively, Z represents the following formula (IV):

[ Wherein l ″ is an integer of 1 to 5 ] ,
Alternatively, Z represents the following formula (V):

[ Wherein, M ′ is a hydrogen atom or a linear or branched alkyl group having 3 or less carbon atoms, and E and E ′ are each independently —O— or —CH ₂ —. However, at least one is —O—, and Q ′ and Q ″ each independently represent a hydrogen atom, a linear or branched alkyl having 6 or less carbon atoms, alkenyl or alkynyl, C _3-8. Represents alicyclic alkyl or benzyl, or Q ′ and Q ″ together form an alkylene group having 2 to 5 carbon atoms, and k and k ′ are each independently an integer of 0 to 2 a group represented by the is, compositions comprising a biocompatible polymer according to any one of claims 1 to 3. The biocompatibility according to any one of claims 1 to 4 , for suppressing a foreign body reaction to blood or tissue until it is decomposed when used in contact with tissue or blood in vivo. A composition comprising a functional polymer. The composition containing the biocompatible polymer as described in any one of Claims 1-4 used for the use which comprises at least one part of the whole medical device or the surface. The medical device corresponds to any one of a device used by being placed in a living body, a device used in contact with a living tissue, or a device used in contact with an in-vivo component taken out of the body. Item 7. A composition comprising the biocompatible polymer according to Item 6 . The medical device containing the composition containing the biocompatible polymer as described in any one of Claims 1-5 . The medical device according to claim 8 , which corresponds to any one of a device used by being placed in a living body, a device used in contact with a living tissue, or a device used in contact with an in-vivo component taken out of the body. Equipment.