JP2890316B2 - Materials for biocompatible medical devices - Google Patents

Materials for biocompatible medical devices

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Publication number
JP2890316B2
JP2890316B2 JP1174133A JP17413389A JP2890316B2 JP 2890316 B2 JP2890316 B2 JP 2890316B2 JP 1174133 A JP1174133 A JP 1174133A JP 17413389 A JP17413389 A JP 17413389A JP 2890316 B2 JP2890316 B2 JP 2890316B2
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mpc
copolymer
polymer
methacrylate
materials
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JPH0339309A (en
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宣男 中林
昭彦 渡辺
一彦 石原
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科学技術振興事業団
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Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a biocompatible polymer comprising a copolymer obtained from 2-methacryloyloxyethyl phosphorylcholine and a hydrophobic monomer. The present invention relates to materials for medical devices.

[Conventional technology]

In recent years, synthetic polymer materials have been widely used for medical polymer materials including artificial organs.

Typical examples thereof include hydrophobic polymers such as polyvinyl chloride, polystyrene, silicone resin, polymethacrylate and fluorine-containing resin, polyvinyl alcohol, poly (2-hydroxyethyl methacrylate), and the like as medical polymer materials. It is a hydrophilic polymer such as polyacrylamide.

Phospholipids are widely present in living organisms, are a major component of biological membranes, are specifically present in the membrane-like structure of cells, and the role of phospholipids on the expression of membrane functions is being elucidated .

Some of the monomers having the same structure as the polar group of the phospholipid are already known. Some copolymers with 2-methacryloyloxyethyl phosphorylcholine (MPC) and methyl methacrylate (MMA) have also been reported [Kobunshi Ronbunsh
u), Vol. 35, No. 7, PP423-427 (July 1978)].

[Problems to be solved by the invention]

2. Description of the Related Art In recent years, with the advancement of medical technology, the chance of contact between a material and a living tissue or blood has increased. In this case, the biocompatibility of the material always becomes a problem. Absorbing and denaturing biological components such as proteins and blood cells on the material surface not only causes unusual adverse effects such as thrombus formation and inflammatory reaction on the living body, but also leads to deterioration of the material, This is a fundamental and urgent issue that must be solved for medical materials.

Conventional hydrophobic polymer materials such as polyvinyl chloride and polystyrene and hydrophilic polymer materials such as polyvinyl alcohol and poly (2-hydroxyethyl methacrylate) are not satisfactory in biocompatibility. Also, MPC monomers and polymers are water-soluble,
It cannot be used as a medical material. MPC and MMA
For copolymers of the above, if the MPC composition is to be increased and the characteristics of the MPC are to be developed, they will be dissolved in water or swell significantly and the mechanical strength will be reduced. Is extremely difficult.

[Means for solving the problem]

The present inventors have paid attention to the fact that the surface of a biological membrane constituting a tissue in a living body exhibits extremely good biocompatibility, in particular, non-adsorbing and non-activating properties of a biological component. As a result of studying polymers that can be applied to medical materials by improving the shortcomings of polymers,
A copolymer obtained from 2-methacryloyloxyethyl phosphorylcholine (MPC) and a hydrophobic monomer, that is, a copolymer having the same structure as a polar group of phospholipid (phosphatidylcholine), which is a main component of a biological membrane, that is, copolymerized with MPC In the methacrylic acid ester copolymer, by selecting the substituents of the methacrylic acid ester and controlling the composition, a copolymer having good mechanical strength and moldability can be obtained while maintaining the properties of the phospholipid polymer. The inventors have found that the above problems can be solved, and have reached the present invention.

That is, the present invention has a general formula [Where a is 0.03 to 0.70, b is 0.30 to 0.97, n is an integer of 2 or more, and R is H, OR '(R' is an aliphatic hydrocarbon group or an aromatic hydrocarbon group)] The present invention relates to a biocompatible medical device material comprising a copolymer of 2-methacryloyloxyethyl phosphorylcholine and methacrylic ester having a repeating unit and a molecular weight of 5000 or more.

In the copolymer of the present invention, 2-methacryloyloxyethyl phosphorylcholine (MPC) is a compound having the following chemical structural formula.

This MPC is obtained, for example, by reacting 2-bromoethyl phosphoryl dichloride with 2-hydroxyethyl methacrylate to obtain 2-methacryloyloxyethyl 2'-bromoethyl phosphoric acid (MBP), and reacting this MBP in a methanol solution of trimethylamine. Methacrylic acid ester, which is a copolymer component that can be obtained by [Where n is an integer of 2 or more, and R represents H or OR '(R': an aliphatic hydrocarbon group or an aromatic hydrocarbon group)], wherein the aliphatic hydrocarbon group is an alkyl group, an alkenyl group, or the like. And the aromatic group is a phenyl group or the like. When n is less than 2, when the composition of MPC is increased to express the effect of MPC because of its low hydrophobicity and low glass transition temperature when it is made into a copolymer with MPC, it dissolves in water or significantly. Swells and decreases in strength. Specific examples of the methacrylic acid ester include ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, tridecyl methacrylate, 2-ethoxyethyl methacrylate, and 2 methacrylic acid. -Ethoxypropyl, 2-phenoxyethyl methacrylate, 2-butoxyethyl methacrylate and the like.

The copolymer can be produced, for example, by reacting MPC and methacrylic acid ester in a solvent in the presence of an initiator.

The solvent only needs to dissolve the monomer, and specific examples include water, methanol, ethanol, propanol, t-butanol, benzene, toluene, dimethylformamide, tetrahydrofuran, chloroform, and mixtures thereof.

Any initiator may be used as long as it is a usual radical initiator, and aliphatic azo compounds such as 2,2'-azobisisobutyronitrile (AIBN) and azobismalenonitrile, benzoyl peroxide, Organic peroxides such as lauroyl peroxide, ammonium persulfate and potassium persulfate can be exemplified.

The ratio of the MPC component (a) to the methacrylate component (b) in the copolymer ranges from 0.03 to 2.33, and a / b is
If it is less than 0.03, the effect of MPC is not exhibited, which is not preferable. On the other hand, if a / b exceeds 2.33, the copolymer will excessively swell in water, resulting in a decrease in strength.

Although the molecular weight of the polymer of the present invention can be variously changed according to the purpose, the material of the obtained copolymer is 5,000 or more, preferably 10,000 or more from the viewpoint of strength.

[Action]

Since the phospholipid polymer of the present invention has a phospholipid polar group derived from MPC on the copolymer surface, it strongly interacts with a phospholipid molecule derived from a living body, and forms an oriented phospholipid adsorption layer similar to a biological membrane on the material surface. The molecular design is based on a completely new concept of obtaining excellent biocompatibility for stable formation. Therefore, adsorption of biological components such as proteins and blood cells is extremely small, and activation of platelets that induces thrombus formation can be suppressed. Therefore, as a field of application of the phospholipid polymer of the present invention,
It is a material for biocompatible medical devices, and is useful as a material mainly used in direct contact with a biological component such as a medical material, a clinical test material, a formulation material, and an optical material. It can be used for bags, hemodialysis membranes, catheters, encapsulating materials, enzyme electrodes, contact lenses and the like. When the phospholipid polymer of the present invention is used as such a material, not only the method of molding using the polymer itself as a material, but also dissolving the polymer in a solvent and applying this solution to the material surface to modify the surface It is also possible.

〔Example〕

Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples.

Production Example 1 Synthesis of MPC-n-butyl methacrylate (BMA) copolymer MPC / BMA = 10/90
0.562 g (1.9 mmol) of MPC and 2.44 g (17.1 mmol) of MPC so that the total monomer concentration becomes 1.0 mol / l and the initiator concentration becomes 10 mmol / l.
l) was weighed into a glass reaction tube for polymerization, and 2,2'-azoisobutyronitrile (AIBN) 0.0327 was used as a polymerization initiator.
g, 5 ml of methanol (MeOH) and 15 ml of tetrahydrofuran (THF) were added as polymerization solvents. After sufficiently replacing the inside of the reaction tube with argon, the reaction tube was sealed. This was heated to 60 ° C. for 16 hours to carry out a polymerization reaction. After cooling the reaction mixture on ice, 1000 ml of hexane-diethyl ether (3: 2)
The polymer was precipitated by dropping the mixture. This is separated by filtration and sufficiently hexane-diethyl ether (3: 2)
After washing with the mixed solution, the polymer was dried under reduced pressure to obtain a white powdery polymer. Yield 1.17 g, polymerization rate 37.2%.

IR (cm -1 ) 3200-2900 (CH 2 , CH 3 ), 1720 (C = 0), 11
00-1200 (COC), 1250 (P = 0) The molecular weight was measured by analyzing a THF solution of the polymer using GPC, and as a result, it was 37,000 in terms of polystyrene.

0.5 g of the polymer was dissolved in 5 ml of a MeOH-THF (1: 1) mixed solvent, and the solution was cast on a 25 cm 2 Teflon plate. After distilling off the solvent at room temperature, it was dried under reduced pressure to a thickness of 100
A μm polymer film was prepared. The surface of the film was analyzed by ESCA (X-ray photoelectron spectrometer), and the MPC molar composition in the polymer was calculated from the analysis values of phosphorus atoms and carbon atoms, resulting in 11.0%
Met.

Place the previously weighed polymer membrane in water at 30 ° C.
The weight of the film immersed in water for 10 days was measured. The weight of water contained in the membrane was calculated from the increase in weight, and the water content was determined by calculating the ratio to the weight of the water-containing membrane.
5.7%.

Production Example 2-7 An MPC-BMA copolymer was obtained in the same manner as in Production Example 1 except that the charged monomer composition ratios of MPC and BMA were variously changed. Table 1 shows the results.

Production Example 8-9 BMA was replaced with tridecyl methacrylate (TDMA), and MPC and
An MPC-TDMA copolymer was obtained in the same manner as in Production Example 1 except that the charged monomer composition ratio with TDMA was changed. Table 1 shows the results.

Production Example 10-11 An MPC-PEMA copolymer was obtained in the same manner as in Production Example 1, except that BMA was changed to 2-phenoxyethyl methacrylate (PEMA) and the charged monomer composition ratio of MPC and PEMA was changed. Table 1 shows the results.

Example 1 Measurement of Platelet Adhesion Percentage of platelets was 1x10 by centrifuging rabbit fresh blood.
Platelet rich plasma (PRP) containing 8 cells / ml was prepared. A 0.5% (MeOH-THF 1: 1) solution of a phospholipid polymer was prepared, and acrylic beads (200-600 μm in diameter) were immersed in the solution. Ten
After a minute, the beads were separated by filtration and the solvent was distilled off to prepare polymer-coated beads. 0.52g of these beads is 10c in length
m, a 3 mm inner diameter tube made of polyvinyl chloride was packed closest to form a column. PRP containing 119 μl of a 1 mol / l calcium chloride solution was passed through this column at a flow rate of 0.23 ml / min for 20 minutes. The number of platelets flowing out of the column was measured with a Coulter counter to obtain a platelet outflow curve. The results are shown in FIG. The platelet adhesion was calculated by the following equation.

Table 2 shows the results. Similarly, poly (BMA) and poly (MM
A), poly (2-hydroxyethyl methacrylate, HEM)
The results when the beads and glass beads coated with A) were used are shown as comparative examples.

Example 2 Effect of MPC Composition on Platelet Outflow Rate To see the effect of MPC composition on platelet outflow rate, acrylic beads coated with a polymer having a different MPC composition were filled in a column in the same manner as described above, and platelets were treated in the same manner as above. Passed through. The results are as shown in FIG. MPC
In the case of poly (BMA) -coated beads having a composition of 0, a decrease in the outflow rate was observed from 12 minutes after the passage of platelets, and no outflow was observed at 17 minutes. With an increase in the MPC composition, a decrease in the platelet outflow rate tends to be suppressed.
In the 20 copolymers, the outflow rate of platelets showed a value of almost 1.0.

Example 3 Measurement of Protein Adsorption Rate A 0.5% (MeOH-THF1: 1) solution of a phospholipid polymer was prepared, and a quartz plate (length 40 mm, width 9 mm, thickness 3 mm) was prepared.
Was immersed. After standing for 10 minutes, the quartz plate was taken out and left overnight at room temperature to evaporate the solvent and coat the polymer. This polymer-coated quartz plate was added to albumin (0.45
g / dl), γ-globulin (0.16 g / dl) and lysozyme (0.45 g / dl) in a phosphate buffer solution (pH 7.4) for 30 minutes to allow the proteins to adsorb, and then to a phosphate buffer solution. Rinsed thoroughly. The amount of protein adsorbed on the surface was quantified by measuring the absorbance of the quartz plate with a spectrophotometer. Table 3 shows the results. Similarly, the results when a quartz plate coated with poly (BMA), poly (MMA), and poly (HEMA) are used are shown as comparative examples.

Example 4 Drug release characteristics of MPC-BMA copolymer hydrogel membrane To a chloroform solution of the copolymer obtained in the same manner as in Production Example 1, 1,4-di (2-hydroxyethoxy) benzene (DHEB) was added. A film was formed by a casting method.

A 1 cm × 1 cm device was fabricated from this film, immersed in a pH buffer, and the amount of released DHEB was measured using UV. FIG. 2 shows the DHEB release characteristics from a device prepared by changing the copolymer composition. The DHEB release rate increased as the MPC composition increased. FIG. 3 shows the release amount of DHEB when the temperature is changed. It is apparent from this that the release rate reversibly changes by changing the temperature from 30 ° C. to 40 ° C. to 30 ° C. This is considered to be a result corresponding to the change in the degree of swelling of the device, and indicates that the MPC-BMA copolymer hydrogel film can be applied as a pharmaceutical carrier, a capsule material, a catheter material, and the like.

[Brief description of the drawings]

FIG. 1 is a graph showing platelet efflux curves with respect to the MPC composition in the MPC-BMA copolymer, and FIG. 2 is a graph showing MPC-BM of various MPC compositions.
FIG. 3 is a graph showing the release characteristics of DHBE from the A copolymer device, and FIG. 3 is a graph showing the release characteristics of DHBE from the MPC-BMA copolymer device according to the temperature change.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 identification code FI C08L 43/02 C08L 43/02 (58) Fields investigated (Int.Cl. 6 , DB name) C08F 230 / 02,220 / 10 C08L 43 / 02,33 / 04 A61L 27 / 00,31 / 00 REGISTRY (STN) CA (STN)

Claims (1)

    (57) [Claims]
  1. (1) General formula [Where a is 0.03 to 0.70, b is 0.30 to 0.97, n is an integer of 2 or more, R is H, OR '(R' represents an aliphatic hydrocarbon group or an aromatic hydrocarbon group)] A biocompatible medical device material comprising a copolymer of 2-methacryloyloxyethyl phosphorylcholine and methacrylic acid ester having a repeating unit and a molecular weight of 5,000 or more. ]
JP1174133A 1989-07-07 1989-07-07 Materials for biocompatible medical devices Expired - Lifetime JP2890316B2 (en)

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Cited By (3)

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US6769871B2 (en) 2001-08-13 2004-08-03 Sun Medical Technology Research Corporation Blood pump and ventricular assist device
CN102210890A (en) * 2011-05-26 2011-10-12 浙江大学 Endothelial cell selective composite coating material used for cardiovascular stent and preparation method thereof
WO2011132713A1 (en) 2010-04-21 2011-10-27 国立大学法人北海道大学 Lipid membrane structure with nuclear transferability

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GB9023498D0 (en) 1990-10-29 1990-12-12 Biocompatibles Ltd Soft contact lens material
US6090901A (en) * 1991-07-05 2000-07-18 Biocompatibles Limited Polymeric surface coatings
US6743878B2 (en) 1991-07-05 2004-06-01 Biocompatibles Uk Limited Polymeric surface coatings
US6087462A (en) * 1995-06-07 2000-07-11 Biocompatibles Limited Polymeric surface coatings
EP0593561B1 (en) * 1991-07-05 2000-03-22 Biocompatibles Limited Polymeric surface coatings
AT196303T (en) * 1991-08-08 2000-09-15 Biocompatibles Ltd Polymer surface coating composition
DE69212102T2 (en) * 1991-10-14 1996-11-21 Nof Corp Treatment lotion for contact lenses
US6258371B1 (en) 1998-04-03 2001-07-10 Medtronic Inc Method for making biocompatible medical article
AU756846B2 (en) * 1998-12-11 2003-01-23 Biocompatibles Uk Limited Crosslinked polymers and refractive devices formed therefrom
DE60004055T2 (en) 1999-05-27 2004-04-15 Biocompatibles Uk Ltd., Farnham Polymer solutions
KR100492652B1 (en) * 1999-11-09 2005-05-31 닛폰 유시 가부시키가이샤 Composition for hydrogel, hydrogel, and use thereof
AU7669201A (en) * 2000-07-27 2002-02-13 Asahi Medical Co Modified hollow-fiber membrane
EP1657302B1 (en) 2003-06-25 2013-01-16 Nof Corporation Method of forming embryoid bodies
US20100040666A1 (en) * 2005-06-24 2010-02-18 Hiroshi Azuma Method for Control of Drug Elution Rate and Composition for Coating of Drug-Eluting Stent
US7935000B2 (en) 2009-04-01 2011-05-03 Nike, Inc. Golf clubs and golf club heads
CN102333554A (en) * 2009-04-24 2012-01-25 21世纪国际新技术株式会社 Resin product for medical use and respiration-assisting tube
JPWO2011093416A1 (en) 2010-01-29 2013-06-06 富士フイルム株式会社 Pharmaceutical composition and oral preparation
JP6149682B2 (en) * 2013-10-17 2017-06-21 日油株式会社 Gastric ulcer prophylactic agent
JP2015214630A (en) * 2014-05-08 2015-12-03 国立大学法人山形大学 Antibacterial polymer, production method therefor, and usage thereof
JPWO2017204187A1 (en) * 2016-05-24 2019-03-22 公益財団法人がん研究会 Extracellular vesicle collection method and extracellular vesicle container
CN106632833B (en) * 2016-10-31 2018-12-07 四川大学 A kind of Injectable temperature sensitive hydrogel artificial crystalline lens material and preparation method thereof with cellular membrane biomimetic

Cited By (3)

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US6769871B2 (en) 2001-08-13 2004-08-03 Sun Medical Technology Research Corporation Blood pump and ventricular assist device
WO2011132713A1 (en) 2010-04-21 2011-10-27 国立大学法人北海道大学 Lipid membrane structure with nuclear transferability
CN102210890A (en) * 2011-05-26 2011-10-12 浙江大学 Endothelial cell selective composite coating material used for cardiovascular stent and preparation method thereof

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