JP3399986B2 - Manufacturing method of blood compatible material - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a material having excellent blood compatibility, which comprises coating a phospholipid-polymer complex on the surface of a substrate of a medical device such as a catheter or artificial organ.

[0002]

2. Description of the Related Art Generally, there is a problem that calcium in blood easily deposits on the surface of highly hydrophilic material, resulting in loss of material properties. In the animal experiment using phosphatidylcholine having a choline group, no calcium deposition was observed on the material surface even after about 1 month. From such a case, it is considered that the phospholipid having a choline group is particularly suitable for the surface which is brought into contact with blood for a long period of time. Although the reason for this is not clear, phospholipids having a choline group generate a cation of a choline group and an anion of a phosphate group at the pH of a living body, are electrically neutral as a molecule, and cause deposition of calcium ions. It is thought that this is because the effect is suppressed.

Phospholipids form the membrane surface of cells such as vascular endothelial cells, which is the contact surface with blood, keep the contact surface with blood superhydrophilic, and are extremely irritating to blood. It is known to form less surface.

However, there have been very few reports on blood-compatible materials using phospholipids, and Ishihara et al. (Biomaterial, V
o1.9, No6, 296 (1991)) and a method of incorporating phospholipids into a polymer as a plasticizer (Table 63-50).
No. 1298) is known.

However, the method of copolymerizing a phospholipid with methacrylic acid is complicated, and the method of incorporating a phospholipid in a polymer as a plasticizer requires a large amount of phospholipid, which is very costly and requires a large amount of surface. There is an issue that cannot be said to localize blood compatibility only.

[0006]

[Problems to be Solved by the Invention] In the method of polymerizing a phospholipid and a reactive monomer, the operation of reaction and purification is complicated, and in the method of incorporating phospholipid into a polymer as a plasticizer, this polymer is used. The problem is that a large amount of phospholipid in proportion to the size of the structure formed by the method is required, and when a medical device such as a catheter or an artificial organ is made, it becomes very expensive.

The present invention is intended to solve such problems of the prior art, and found out that the thin film surface of the phospholipid-polymer complex formed by coating has extremely good blood compatibility, and earnestly studied. The present invention has been completed by conducting research.

[0008]

Means for Solving the Problems That is, the present invention is as follows: 1) Styrene-based elastomer, styrene-butadiene copolymer, styrene-ethylene-butadiene terpolymer, hydrogenated product thereof, and diene-based synthetic rubber. Which is a mixed composition of at least one of isoprene polymer, butadiene-styrene copolymer, linear polybutadiene, 1,2-polybutadiene, butyl rubber (isoprene-isobutylene copolymer), chloroprene polymer and phospholipid, The styrene-based elastomer and / or diene-based synthetic rubber and phosphorus are mixed so that the concentration of the phospholipid in these mixed compositions is 5 to 80 wt% and the concentration of the mixed composition in the solvent is 1 to 30 wt%. N-hexane, diethyl ether, which is a common organic solvent with lipids,
Dissolve in one kind selected from petroleum ether, benzene, toluene and chloroform, or a mixture thereof to prepare a solution, apply the solution on the surface of the base material, and then dry the blood-compatible material. Production method, 2) Phospholipids are phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, lecithin,
And at least one selected from the group consisting of hydrogenated unsaturated fatty acids or derivatives thereof.
The method for producing a blood compatible material according to (1), which comprises a phospholipid of a species.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, as the styrene-based elastomer compounded with the phospholipid, a styrene-butadiene copolymer, a styrene-ethylene-butadiene terpolymer, or a hydrogenated product thereof can be used. Further, as the diene synthetic rubber, isoprene polymer, butadiene-styrene copolymer, linear polybutadiene, 1,2-polybutadiene, butyl rubber (isoprene-isobutylene copolymer) and chloroprene polymer can be used.

What is important here is that these styrene-based elastomers and diene-based synthetic rubbers are different from other polymers in that a common solvent for phospholipids can be found, and that after coating, the surface of the base material of the medical device is applied. That is, it is possible to form a thin film on the surface of the medical device while adhering well and maintaining the flexibility of the medical device.

The common organic solvent for the styrene elastomer and / or diene synthetic rubber and the phospholipid in the present invention is n-hexane, diethyl ether, petroleum ether, benzene, toluene, chloroform and the like. What is important here is the selection of a common solvent, a combination of a styrene elastomer and a diene synthetic rubber and a phospholipid, or the proper selection of these solvents depending on the compounding ratio. It is also possible to use a mixed solvent in which is mixed at an arbitrary ratio. In addition, a solvent having a relatively high volatility is suitable for forming a thin film on the surface by coating on a medical device and drying at a relatively low temperature.

The phospholipids used in the present invention are phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol,
It is at least one phospholipid selected from the group consisting of sphingomyelin, lecithin, hydrogenated unsaturated fatty acids thereof, and derivatives thereof.

In the present invention, the mixing ratio of the phospholipid and the styrene elastomer or the diene synthetic rubber, or the concentration of each component in the composite is extremely important. For cost and excellent blood compatibility, A suitable concentration of phospholipid in the complex is 5-80 wt%. If the phospholipid concentration in the complex is less than 5 wt%, even if it is applied to the surface of the substrate, the surface cannot have sufficient hydrophilicity, and good blood compatibility cannot be obtained. The reason for this is not clear, but at concentrations as low as less than 5 wt% phospholipids cannot cover the entire surface of the material and foreign body reactions of blood are initiated from the exposed matrix polymer site. It is supposed to be because of this. In addition, the phospholipid concentration in the complex was 8
When it exceeds 0 wt%, it cannot be adapted to a hydrophobic substrate and is repelled, so that a film of the composite cannot be formed well. In addition, there are drawbacks such that the composition easily swells. Practically, in terms of cost and performance,
More preferably, the ratio of phospholipid to the total composition is 20 to 60 wt%.

The degree of hydrophilicity of the blood-compatible surface coated with such a composition can be freely changed depending on the mixing ratio of the phospholipid and the matrix polymer, and the contact angle of water is from 100 °. It can be changed in the range of 0 °, but for excellent blood compatibility, the contact angle of water is 20
Hydrophilic surfaces below ° are suitable.

On the other hand, when the phospholipid-polymer complex is applied to the surface of the substrate, the concentration of the entire composition in the organic solvent is important for controlling the coating thickness at the time of application. Thirty
wt% is preferable, and more preferably 5 to 25 wt%. When the concentration exceeds 30 wt%, the solution viscosity is high, and the coating surface becomes rough due to dripping of the solution and bubbles generated when the solvent volatilizes during drying after coating the substrate, which is not preferable.

The effect is exhibited when the thickness of the coating layer is at least 1 μm, but it is preferable to apply the coating to an average thickness of 5 to 10 μm in consideration of variations during coating. In the method for producing a blood-compatible material of the present invention, among styrene-based elastomers and diene-based synthetic rubbers and phospholipids,
It is preferable to dissolve the one having the larger compounding ratio in the solvent first.
This is important in preparing a homogeneous composition solution.

[0017]

EXAMPLES The effects of the present invention will be described below with reference to examples and comparative examples. Examples 1 and 2 2 g of pellet-shaped styrene-ethylene-butadiene terpolymer butadiene hydrogenated elastomer (Taftec H1041 manufactured by Asahi Kasei Co., Ltd.) was mixed with diethyl ether (manufactured by Wako Pure Chemical Industries, Ltd., reagent). Special grade) 100 ml
Ultrasonic waves were applied to the sample to sufficiently dissolve it. Furthermore, 1 g and 2 g of powdered L-α-dipalmitoylphosphatidylcholine (manufactured by Wako Pure Chemical Industries, Ltd., for biochemistry) were added to this while thoroughly stirring to completely dissolve it, and the phospholipid concentration relative to the polymer Were adjusted to 33 wt% and 50 wt%, respectively, to prepare phospholipid-polymer complex solutions having two levels of phospholipid concentration. Next, this solution was treated with an inner diameter of 12.3 mm and a length of 75.
Pour it into a mm test tube, discharge it, and at 25 ° C for 1
After drying for an hour and further at 50 ° C. for 1 hour, a thin film of phospholipid-polymer complex was colored in a glass test tube.

At the same time, this phospholipid-polymer complex was applied to a slide glass and dried at 25 ° C. for 1 hour, and further 50
After drying at ℃ for 1 hour, the contact angle of water on the surface was measured (using a contact angle meter CA-S 150 type manufactured by Kyowa Interface Science Co., Ltd.). It was confirmed that the surface was sufficiently hydrophilic.

Comparative Example 1 The glass test tube used in the examples. Comparative Example 2 PVC (Sumitomo Beklite Co., Ltd., Sumicon 1170G55)
A solution prepared by dissolving 2 g of 100 g in tetrahydrofuran was prepared, poured into a test tube having an inner diameter of 12.3 mmφ and a length of 75 mm in the same manner as in the example, discharged, and dried at 50 ° C. for 1 hour to prepare a glass test tube. The thing which apply | coated PVC was created.

In the test tube thus obtained, 2 ml of blood collected from a mongrel dog was rapidly injected, and the blood coagulation time was measured by the Rewhite method in which the blood coagulation time was measured in a 37 ° C. constant temperature bath. The sex was evaluated. The evaluation results of the blood coagulation test are as shown in Table 1, and the blood compatible material according to the present invention exhibits a blood coagulation time delay of 4 times or more that of glass, and has a surface property excellent in blood compatibility. It was

[0021]

[Table 1]

[0022]

EFFECTS OF THE INVENTION By forming a phospholipid-polymer complex thin film of several μm to several tens of μm on the surface of a medical device by the manufacturing method according to the present invention, excellent blood can be obtained only on the surface requiring antithrombotic treatment. Since compatibility can be imparted, a small amount of phospholipid can be applied to the surface of a medical device having a complicated shape,
Can easily and inexpensively provide antithrombogenicity, and has excellent blood compatibility on the surface of various medical devices, including bypass tubes and blood circuits used during circulatory surgery, in contact with blood. It can be applied as a material.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-63-277064 (JP, A) JP-A-3-39309 (JP, A) Special table Sho-63-501298 (JP, A) Special table Sho-61- 500918 (JP, A) Special table 1-500440 (JP, A) Special table 6-502087 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61L 15/00-33 / 18 C08J 7/04

Claims (2)

(57) [Claims] 1. At least one selected from a styrene-butadiene copolymer which is a styrene-based elastomer, a styrene-ethylene-butadiene terpolymer and a hydrogenated product thereof, and an isoprene polymer which is a diene-based synthetic rubber. A mixed composition of at least one selected from a polymer, a butadiene-styrene copolymer, a linear polybutadiene, a 1,2-polybutadiene, a butyl rubber (isoprene-isobutylene copolymer) and a chloroprene polymer, and a phospholipid, The concentration of phospholipid in the mixed composition is 5 to 8
0 wt%, and the concentration of the mixed composition in the solvent is 1
Selected from n-hexane, diethyl ether, petroleum ether, benzene, toluene and chloroform, which are common organic solvents for styrene-based elastomers and / or diene-based synthetic rubbers and phospholipids so as to be 30 to 30 wt%.
A method for producing a blood-compatible material, which comprises dissolving a solution in one kind or a mixture thereof to prepare a solution, applying the solution to a surface of a substrate, and then drying. 2. The phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, lecithin, hydrogenated unsaturated fatty acids thereof, and derivatives thereof. The method for producing a blood compatible material according to claim 1, which comprises at least one phospholipid selected from the group consisting of: