JPH06313009A - Terminal-functional polymer containing phosphoryl choline group - Google Patents

Abstract

PURPOSE:To produce a polymer containing a specific terminal-functional phosphoryl-choline group, capable of chemically modifying other polymer material and biopolymer, excellent in bioadaptability and useful as a medical material. CONSTITUTION:The polymer of formula [X1, X2 and Y1 are H or methyl; Y2 is COOR, carboxylic acid, amide, amide derivative, pyrrolidone, phenyl or halogen-substituted phenyl; R is alkyl or alkoxy-substituted alkyl; Z is carboxyl, hydroxyl, amino or mercapto; (n1)=1-10,000; n2=1-1,000; n3=0-10,000], having molecular weight of 500-1,000,000 and containing a terminal-functional phosphoryl-choline group. This polymer is produced by polymerizing (meth) acrylate containing phosphoryl choline group with other copolymerizable monomer using a radical polymerization initiator in the presence of chain transfer agent containing sulfur.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a terminal functional phosphorylcholine group-containing polymer which is excellent in biocompatibility and is useful as a medical material and is also useful as a chemical modifier using a terminal functional group.

[0002]

2. Description of the Related Art Hydrophobic polymers such as polyvinyl chloride, polyethylene, silicone resin, fluororesin, polymethylmethacrylate, polyvinyl alcohol, polyvinylpyrrolidone, poly-2-hydroxyethylmethacrylate,
Polymer materials such as hydrophilic polymers such as polyacrylic acid have been conventionally used in various medical fields. In particular, recently, it has been desired to use the polymer material for a longer period of time in an environment in which the polymer material comes into contact with living tissue or blood.

Excellent biocompatibility is required for using the polymeric material for a longer period of time, but the polymeric material is liable to cause protein adsorption or thrombus formation due to contact with biological components. Due to the above problem, biocompatibility is not sufficient, and control of adsorption of protein and blood on the surface of the polymer material has been a problem.

In order to improve the biocompatibility of the above-mentioned polymer material, a method of introducing a phospholipid structure which is a constituent of a biomembrane into the material is known.
ol. 35 No. 7 p. 423 July 197
8, JP-A-3-39309 and the like report a 2-methacryloyloxyethylphosphorylcholine polymer as a methacrylic acid ester having a phosphorylcholine group which is a polar group of a phospholipid molecule. However, when these polymers are used as they are, there is a problem of solubility in water, and when the polymer is coated on the surface of the material, there is a problem of adhesiveness. Is difficult to do.

[0005]

The object of the present invention is to have an excellent biocompatibility and, at the same time, to provide a terminal functional group capable of chemically modifying other polymer materials and biopolymers by a terminal reactive functional group. The purpose of the present invention is to provide a polymer containing a phosphorylcholine group.

[0006]

According to the present invention, the molecular weight represented by the following general formula 2 is 500 to 1,000,000.
An end-functional phosphorylcholine group-containing polymer (hereinafter referred to as polymer A) is provided.

[0007]

[Chemical 2]

The present invention will be described in more detail below.

The terminal functional phosphorylcholine group-containing polymer of the present invention is the polymer A represented by the above general formula 2. In the polymer A, n ₁ is an integer of 1 to 10000, n ₂ is an integer of 1 to 1000, and n ₃ is 0 to 10000.
Indicates an integer. At this time, n ₁ and n ₃ are 10000, n ₂
If the value exceeds 1000, the production is difficult.

Examples of the polymer A include compounds represented by the following general formulas 3-8.

[0011]

[Chemical 3]

[0012]

[Chemical 4]

[0013]

[Chemical 5]

[0014]

[Chemical 6]

[0015]

[Chemical 7]

[0016]

[Chemical 8]

The method for synthesizing the polymer A of the present invention is not particularly limited. For example, in the presence of a specific sulfur-containing chain transfer agent, a phosphorylcholine group-containing (meth) acrylate represented by the following general formula 9 is used. (Hereinafter referred to as MAPC), alone or with another copolymerizable monomer,
It can be obtained by a method of polymerizing with a specific radical polymerization initiator.

[0018]

[Chemical 9]

Examples of the MAPC include 2- (meth) acryloyloxyethylphosphorylcholine and 2- (meth) acryloyloxyethylphosphorylcholine.
(Meth) acryloyloxy-1-methylethylphosphorylcholine, 2- (meth) acryloyloxypropylphosphorylcholine, 2- (meth) acryloyloxyethoxyethylphosphorylcholine, β- (2 ′-(meth)
Acryloyloxy-1'-methylethoxy) -propylphosphorylcholine, 2- (meth) acryloyloxydiethoxyethylphosphorylcholine and the like can be mentioned.

Examples of vinyl monomers copolymerizable with MAPC include monomers represented by the following general formula 10.

[0021]

[Chemical 10]

As the vinyl monomer represented by the general formula 4, for example, methyl (meth) acrylate, (meth)
Ethyl acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, tridecyl (meth) acrylate, 2-ethoxyethyl (meth) acrylate, (meth) acrylic acid, ( (Meth) acrylic acid-2-hydroxyethyl, (meth) acrylic acid amide, (meth) acrylic acid-N, N-dimethylamide, N-vinylpyrrolidone, styrene, chlorostyrene, chloromethylstyrene, α-methylstyrene, etc. One kind or a mixture of two or more kinds can be used.

Examples of the sulfur-containing chain transfer agent used in the present invention include thioglycolic acid, thioglycol, aminoethanethiol and ethanedithiol. At this time, a solvent may be used in order to carry out the polymerization reaction more smoothly, and as the solvent, those soluble in the monomer, for example, water, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane are used. , Dimethylformamide,
Acetonitrile, chloroform, methylene chloride, benzene, ethyl acetate and mixtures thereof can be mentioned.

The initiator for initiating the polymerization reaction is not particularly limited as long as it is an ordinary radical initiator. For example, 2,2'-azobisisobutyronitrile and azobismalenonitrile are used. , Benzoyl peroxide, lauroyl peroxide, diisopropyl peroxycarbonate, ammonium persulfate, potassium persulfate and the like.

The molecular weight of the polymer A of the present invention is 500 to 1,00 in view of biocompatibility and strength as a polymer material.
It is synthesized so as to be 10,000, particularly 2000 to 500000. If the molecular weight is less than 500, the strength will decrease,
If it exceeds 1,000,000, it cannot be used because the synthesis is difficult.

The monomer concentration of the polymer A of the present invention is 0.1 mol / liter to 10 so that the above-mentioned molecular weight is obtained.
mol / l is preferred, especially 0.2-1 mol / l
L is preferred. The concentration ratio of chain transfer agent [S] /
[M] is 0.005 to 2 with respect to the monomer concentration.
Is preferable, and 0.01 to 1 is particularly preferable. Furthermore, the concentration ratio [S] / [I] of the radical initiator is such that the chain transfer agent concentration is 1.0 to 5 with respect to the radical initiator concentration.
It is desirable to add it in the range of 00, particularly 1.0 to 200. The polymerization temperature is preferably 20 to 100 ° C,
30-90 degreeC is especially desirable. The polymerization time is about 1 to 72 hours. Furthermore, when the MAPC is copolymerized with another copolymerizable vinyl monomer, the vinyl monomer content is preferably in the range of 95 to 0 mol% based on the total amount. If it exceeds 95 mol%, the biocompatibility effect of MAPC is not exhibited, which is not preferable.

[0027]

INDUSTRIAL APPLICABILITY The terminal functional phosphorylcholine group-containing polymer of the present invention has a phosphorylcholine group, which is a phospholipid-like polar group, in the side chain of the polymer, and thus forms a biological membrane-like structure, which is excellent. Shows biocompatibility. In addition, because it has little adsorption to biological components such as proteins and blood cells, artificial blood vessels, hemodialysis membranes, catheters, contact lenses,
It can be used for medical materials and the like that come into contact with biological components such as blood filters. Furthermore, utilizing the terminal reactivity,
Modification can also be performed as a chemical modifier for other synthetic polymers or biopolymers.

[0028]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto.

[0029]

Example 1 Ethanol, 2-methacryloyloxyethylphosphorylcholine (MPC) 0.45 mol / liter, and 3-mercaptopropionic acid 0.09 mol
/ Liter and azobisisobutyronitrile 9 × 10 ~ ⁴
Mol / l was used to freeze and degas by the sealed tube method. After polymerizing at 60 ° C. for 6 hours after sealing the tube in vacuum, the reaction solution was dropped into ether and the precipitate was collected. The obtained precipitate was washed and dried under reduced pressure to obtain a polymer represented by the following general formula 11. However, in the formula, n ₁ represents an integer of ₁ to 10000. The number average molecular weight of the obtained polymer was measured by gel permeation chromatography, and further the yield, molecular weight, terminal group, IR and NMR spectra were measured. At this time, the IR wavelength of choline was 970 cm- ¹ . The results of NMR spectrum analysis are shown in FIG. 1, and the results are shown in Table 1.

[0030]

[Chemical 11]

[0031]

Examples 2 to 7 2-aminoethanethiol (Example 2) or 2-hydroxyethanethiol (Example 3) instead of 3-mercaptopropionic acid as a chain transfer agent
In place of 0.45 mol / liter of 2-methacryloyloxyethylphosphorylcholine, 0.15 mol of 2-methacryloyloxyethylphosphorylcholine
/ Liter and n-butyl methacrylate (BMA) 0.
30 mol / liter (Example 4), 2-methacryloyloxyethylphosphorylcholine 0.15 mol / liter and styrene (St) 0.30 mol / liter (Example 5), 2-methacryloyloxypropylphosphorylcholine (MPPC) 0.45 mol / liter (Example 6) or 2-methacryloyloxyethoxyethylphosphorylcholine (MDPC) 0.45 mol / liter (Example 7) was carried out according to Example 1 except that the polymer represented by the following general formulas 12 to 17 was used. Got However, in the formula, n ₁ represents an integer of ₁ to 10000, and n ₃
Represents an integer of 0 to 10000. Table 1 shows each measurement result.

[0032]

[Chemical 12]

[0033]

[Chemical 13]

[0034]

[Chemical 14]

[0035]

[Chemical 15]

[0036]

[Chemical 16]

[0037]

[Chemical 17]

[0038]

[Table 1]

[Brief description of drawings]

FIG. 1 is the N of the inventive polymer obtained according to Example 1.
It is a chart which shows MR spectrum.

Claims (1)

[Claims] 1. A molecular weight of 500 represented by the following general formula 1.
~ 1,000,000 end-functionalized phosphorylcholine group-containing polymer. [Chemical 1]