JPS645907B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a blood-contacting medical device having highly antithrombotic properties in which the blood-contacting part is coated with a polydialkylsiloxane mixed system of polyurethane having no urea bond, and a method for manufacturing the same. Polydialkylsiloxane-polyurethane block copolymers are known as polydialkylsiloxane-polyurethane antithrombotic substances (Japanese Patent Publication No. 55-8177, Japanese Patent Publication No. 49-29350),
-29350 proposes a block copolymer in which a polydialkylsiloxane block and a polyurethane block are bonded through silicon-nitrogen bonds. On the other hand, in Japanese Patent Publication No. 55-8177, antithrombotic properties occur when the blood-contacting surface coated with polydimethylsiloxane-polyurethane block copolymer exhibits a micro-heterogeneous structure in which particles with a diameter of 0.1 to 3 μ are almost uniformly dispersed. It is disclosed that the polymer material is preferably a block copolymer in order to have such a micro-heterogeneous structure. It is also said that the above-mentioned block copolymer exhibits far superior antithrombotic properties than polydimethylsiloxane or polyurethane homopolymer. The present inventors are currently pursuing the cause and effect relationship of antithrombotic properties of polyurethane-polydimethylsiloxane. The present invention was completed based on the discovery that extremely excellent antithrombotic properties, which cannot be obtained with a simple mixture of siloxanes and which far exceed the antithrombotic properties exhibited by known block copolymers, can be obtained. The present invention provides a blood contact medical device having excellent antithrombotic properties and a method for manufacturing the same. An object of the present invention is to apply a solution of polydialkylsiloxane, polyurethane without urea bonds, and at least a crosslinking agent of polydialkylsiloxane dissolved in an ether-based solvent to the blood-contacting part of a blood-contacting medical device. This is achieved by drying and/or heat treatment. The first feature of the present invention is that at least the polydialkylsiloxane is crosslinked in the mixture film of polydialkylsiloxane and polyurethane without urea bond applied to the blood contact area,
It is an essential factor for excellent antithrombotic properties. Most preferably, the polydialkylsiloxane is crosslinked. Further, both the polyurethane and the polydialkylsiloxane may be crosslinked. The second feature of the present invention lies in the solvent constituting the solution, and it is important to use a solvent whose main component is ether. The present invention will be explained in detail below. Polydialkylsiloxanes used in the present invention include polydimethylsiloxane, polydiethylsiloxane, polymethylphenylsiloxane, dimethylsiloxane-diphenylsiloxane copolymer, polymethylvinylsiloxane, polymethylphenylvinylsiloxane, and the like. Polydimethylsiloxane having an active group that can be used with the room temperature vulcanization (RTV) agent described below is most suitable because it is easily available. Further, the molecular weight is preferably in the range of 10,000 to 160,000, and even more preferably in the range of 30,000 to 80,000. The polyurethanes without urea bonds used in the present invention (hereinafter simply referred to as polyurethanes) are polyester polyurethanes and polyether polyurethanes, and are produced by known methods such as those described in Japanese Patent Publication No. 48-24518. Contains things. Examples of polyester polyurethanes include those obtained by esterification between glycols such as ethylene glycol and diethylene glycol, or polyhydric alcohols such as trimethylolpropane and glycerin, and polyhydric carboxylic acids such as adipic acid and succinic acid, and ethylene diisocyanate. It is soluble in the below-mentioned solvent containing a condensation product of an isocyanate group-containing compound conventionally used in the production of polyurethane such as 4-tolylene diisocyanate. Polyether polyurethanes include polymers of alkylene oxide such as ethylene oxide and 1,2-propylene oxide, or polymers of alkylene oxide and propylene glycol, 1,2-propylene oxide, etc.
It is soluble in the below-mentioned solvent, which includes a condensation product of a polyhydric alcohol such as 6-hexanetriol and a condensation product of the above-mentioned isocyanate group-containing compound. The amount of polydialkylsiloxane in the polyurethane and polydialkylsiloxane mixture is from 0.1 to 50
% by weight, and it is desirable that at least half of the amount is polyurethane. Preferably 0.5-30% by weight,
More preferably, it is in the range of 1 to 20% by weight. The higher the amount of polyurethane, the more elastic the performance will be, so blood contact medical devices such as artificial hearts and auxiliary artificial hearts, as well as blood-contact medical devices that constantly bend and expand and contract, such as intra-aortic balloon pumps and other pulsatile pumps, will have more elastic performance. Suitable for forming blood contact parts of If the amount of polyurethane is less than the above-mentioned mixing ratio range, the elastic properties will deteriorate and it cannot be used for the above-mentioned purposes. Further, if the proportion of polydialkylsiloxane in the mixture is less than 0.1% by weight, antithrombotic properties cannot be obtained. The crosslinking agents used in the present invention are selected from the respective crosslinking agents of polydialkylsiloxanes and polyurethanes, as well as crosslinking agents common to the two aforementioned polymers. Polydialkylsiloxane is used as a crosslinking agent for ≡SiOH, ≡Si-CH
=CH ₂ , ≡SiH, ≡SiOR (R is CH ₃ , C ₂ H ₅ , etc.),
When it has an active group such as ≡SiOCOR (R is CH ₃ , C ₂ H ₅ or the like), a known crosslinking agent can be used as a room temperature crosslinking (RTV) agent. For example, the general formula RnSi
(OR') _4-o [In the formula, R represents an alkyl group, aryl group, etc., R' represents an alkoxy group, acyloxy group, etc., and n represents 0, 1 to 3] Dimethylcyacetoxysilane, methyl Compounds such as triacetoxysilane, trimethylacetoxysilane, phenyltriacetoxysilane, dimethyldimethoxysilane, trimethylethoxysilane, phenyltriethoxysilane, trimethyltrifluoroacetoxysilane; include vinyltriacetoxysilane, vinyltrimethoxysilane, etc. Examples include silane coupling agents, but are not limited thereto. Furthermore, the organic peroxides described below can be used regardless of the presence or absence of the above-mentioned active groups in the polydialkylsiloxane. As a crosslinking agent for polyurethane, when using a prepolymer having an isocyanate group at the end of the molecular chain as polyurethane, trimethylolpropane, glycerin, pentaerythritol, trimethylol-1,2,
Polyhydric alcohols such as 6-hexanetriol and sorbitol can be used. Examples of crosslinking agents for polydialkylsiloxanes and polyurethanes include organic peroxides such as benzoyl peroxide, bis-2,4-dichlorobenzoyl peroxide, di-tert-butyl peroxide, and tert-butyl cumyl peroxide. The crosslinking agent used in the present invention is not limited to the above-mentioned crosslinking agents. The amount of crosslinking agent used is preferably 2 to 10% by weight, more preferably 4 to 10% by weight based on the polymer.
It is 8% by weight. However, when using an organic peroxide, it is desirable to use it in an amount of 2% by weight or less. 2% by weight
If it exceeds this, the elasticity will be poor. The solvent used in the present invention is an ether, and from the viewpoint of application to medical equipment, it is necessary that the solvent can be easily removed from the coating film (evaporation, washing with water, etc.), and it is desirable that the boiling point is low. , the boiling point is 110℃
The following are desirable. In addition, water-soluble ethers are desirable because they can be easily removed by washing with water. Therefore, preferred ethers include ethers such as tetrahydrofuran and dioxane, and ethers with high boiling points such as anisole, cyclohexanone,
Ethyl ether, butyl ether, etc. which are insoluble in water are unsuitable. In the present invention, the solvents can be used alone or in combination. It is preferred to use a mixture of tetrahydrofuran and dioxane to provide excellent antithrombotic properties. The weight ratio of dioxane/tetrahydrofuran is preferably 1 or less,
More preferably 1/1 to 1/4, still more preferably 1/1.5 to 1/3.0. If it is larger than 1, the stability of the solution will deteriorate, and if it is smaller than 1/4, the antithrombotic property will be reduced. The ethers may also contain small amounts of other solvents, such as alcohol, as long as they do not significantly affect the practice of the present invention. In the method of the present invention, it is preferable that polydialkylsiloxane and polyurethane are dissolved in an ether as a solvent at a temperature ranging from room temperature to 50°C so as to have the above-mentioned mixing ratio. If it is difficult to dissolve at a temperature within this range, it is desirable to dissolve each polymer individually in a solvent heated to a higher temperature, cool it to room temperature, and then mix the respective polymer solutions. There are no restrictions on the concentration of the polymer in the solution, but it is usually a few percent to 20 percent by weight. The crosslinking agent is added to this polymer solution and thoroughly stirred and dissolved. Applying the thus prepared coating solution to the blood contacting part of the medical device by brushing, dipping, or spraying,
Evaporate the solvent and form a film. If heating is required for crosslinking, further heating may be performed. In carrying out the method of the present invention, a preferred embodiment uses room temperature crosslinking (RTV) as the polydialkylsiloxane.
Room-temperature crosslinking of said polydialkylsiloxanes using possible polydialkylsiloxanes, particularly preferably polydialkylsiloxanes containing ≡SiOCOR (R is methyl, ethyl, etc.) groups as active groups, in solution in a mixture with polyurethane as crosslinking agent. This is the case when a coating solution containing an agent is used. In this case, crosslinking also progresses due to moisture (in the air and in the solvent), so it is desirable to add the crosslinking agent just before coating, so that the crosslinking progresses to the extent that the coating solution does not gel. It is desirable to suppress it. For this purpose, water in the solvent used must be removed.
It is desirable to dehydrate to 1600ppm or less, preferably 1000ppm or less, more preferably 800ppm or less,
A concentration of 10 ppm or more is necessary for solution stability, and if it is less than this, macroscopic phase separation may occur. A blood-contacting medical device in which a film of a mixture of polydialkylsiloxane and polyurethane is formed by the method of the present invention and having a blood-contacting portion in which at least polydialkylsiloxane is crosslinked has not only excellent antithrombotic properties, but also Since the film has excellent elastic properties, it is suitable for forming a constantly pulsating blood contact part such as an artificial heart or an intra-aortic balloon pump. The present invention will be specifically explained below using Examples. Example 1 Polypropylene glycol (average molecular weight 1100)
and methylene bis(4-phenyl isocyanate)
A mixed solvent of dioxane/tetrahydrofuran (mixing ratio by weight of 1/2) in which 90 parts by weight of polyether polyurethane prepared using a known method and 10 parts by weight of polydimethylsiloxane (molecular weight 56,000) having terminal acetate groups were sufficiently dehydrated. at room temperature,
They were dissolved and mixed under stirring to prepare a uniform viscous solution (polymer concentration 13% by weight). To this solution, 6.8% by weight of methyltriacetoxysilane based on the polydimethylsiloxane was added and thoroughly mixed at room temperature (coating solution 1). Further, the above solution (with no addition of polydimethylsiloxane) was continuously stirred at 50°C for 10 hours to prepare a block copolymer of polydimethylsiloxane and polyurethane (coating liquid 2). The inside of a clean test tube with an inner diameter of 15 mm was coated with Coating Solution 1 and Coating Solution 2, respectively, and the solvent was evaporated (room temperature, 24 hours). For comparison, antithrombotic properties were compared using a modified Lee-White method (Kanai, ed., Clinical Testing Methods Summary, 86, Kanehara Publishing) using the same clean test tubes without the above-mentioned coating, and the results are shown in Table 1. The results were obtained.

[Table] A clean glass plate was coated with Coating Solution 1 of the invention example, and the solvent was evaporated. As a result of observing the free surface (the surface not in contact with the glass plate) of the formed film with a scanning electron microscope, many protrusions with a diameter of several μm were observed on the film surface. Analysis using an X-ray microanalyzer revealed that this protrusion was a phase rich in polydimethylsiloxane. Example 2 Dioxane/tetrahydrofuran obtained by thoroughly dehydrating 70 parts by weight of polyurethane having terminal isocyanate groups prepared from 30 parts by weight of polydimethylsiloxane (molecular weight 36,000) having terminal acetate groups, polyethylene glycol (average molecular weight 500) and tolylene diisocyanate. (weight ratio 1/3) at room temperature with stirring to prepare a viscous solution with a polymer concentration of 9.0% by weight. 2.8 parts by weight of dimethyldiacetoxysilane was added to this solution, and after thorough mixing, the solution was divided into two parts. Further, 4 parts by weight of pentaerythritol was added to one side and mixed uniformly. Using these two solutions and a solution containing no crosslinking agent as a comparative example,
The inner surfaces of three clean 15 mm inner diameter glass tubes were each coated with each, and the solvent was allowed to evaporate (room temperature, 24 hours).
If it also contains pentaerythritol,
Further, heat treatment was performed at 120°C for 1 hour. Antithrombotic properties were tested in the same manner as in Example 1, and the results shown in Table 2 were obtained.

[Table] From observation using an electron microscope (scanning type) of the free surface of the coating on the glass plate obtained in the same manner as Experiment No. 2,
As in Example 1, protrusions with a diameter of several microns to 10 microns were observed. This portion was again rich in polydimethylsiloxane. Example 3 Commercially available polyether polyurethane (BF
Goodrich Chemical product, ESTANE5714) 95
Polydimethylsiloxane (molecular weight 80,000) having a terminal hydroxyl group is obtained by heating the weight part, dissolving it in tetrahydrofuran while stirring, and cooling it to room temperature.
5 parts by weight were added and dissolved to obtain a solution with a polymer concentration of 12% by weight. 0.1 part by weight of methyltriacetoxysilane was added to this and mixed uniformly. The above solution was applied to the inside of a glass test tube and dried at room temperature for 24 hours. Then wash thoroughly with water
It was dried at 40°C for 24 hours. As a comparative example, a glass test tube coated with only the polydimethylsiloxane was used. Blood clotting time was measured by a modified Lee-White method. The results are shown in Table 3.

[Table] Example 4 Same as Example 1 except that 20 parts by weight of polydimethylsiloxane, 80 parts by weight of commercially available polyurethane (Paraprene P300, manufactured by Nippon Elastolan Co., Ltd.), and sufficiently dehydrated dioxane were used as the solvent. A coating solution was prepared in exactly the same manner, coated on the inner wall of a glass test tube, and the blood coagulation time was measured using a modified Lee-White method and found to be 70 minutes. Blood coagulated in 14 minutes in glass test tubes that were not coated with the above solution. When the same experiment was conducted using the above polymers at a mixing ratio of 1/1 (weight ratio), the blood coagulation time was 72 minutes. Example 5 An experiment was conducted under the same conditions as in Example 1 except that the dioxane/tetrahydrofuran mixing ratio (weight) was 1/3.5 and 0.7 parts by weight of methyltriacetoxysilane was used. Blood clotting time using the modified Lee-White method was 82 minutes, and 45 minutes when no cross-linking agent was used. Example 6 A coating solution was prepared under the same conditions as in Example 1 except that 0.5 parts by weight of benzoyl peroxide was used as a crosslinking agent based on 100 parts by weight of the total amount of polymer. This solution was applied to the inner surface of a glass test tube, dried at room temperature for 24 hours, and then heated at 100° C. for 45 minutes in a nitrogen stream to effect crosslinking. Blood clotting time according to the modified Lee-White method was 73 minutes. Example 7 The same polydimethylsiloxane and polyurethane as in Example 1 were used, the total amount of polymer was the same, the mixing ratio of polydimethylsiloxane and polyurethane was changed, methyltriacetoxysilane was used as the crosslinking agent, and 10% of polydimethylsiloxane was used. hand,
A mixture was prepared in the same manner as in Example 1, and its antithrombotic properties were measured by a modified Lee-White method. The results are shown in FIG. Further, after forming a film on a flat glass plate, the film was peeled off from the glass plate, and the tensile strength and elongation were measured, and the results are shown in FIG. It can be seen that the antithrombotic property decreases when the polydimethylsiloxane content is 0.5% or less, and conversely, the mechanical strength decreases when the polydimethylsiloxane content exceeds 50%.

[Brief explanation of drawings]

FIG. 1 shows the blood coagulability of Example 7, and FIG. 2 shows the strength characteristics of the film of Example 7.

Claims (1)

[Scope of Claims] 1. An antithrombotic medical device whose blood contact portion is coated with a mixture of polydialkylsiloxane and polyurethane having no urea bond, characterized in that at least the polydialkylsiloxane is crosslinked. A blood-contact medical device with sexual characteristics. 2. A solution prepared by dissolving polydialkylsiloxane, polyurethane without urea bonds, and at least a crosslinking agent of polydialkylsiloxane in a solvent containing ether as a main component is applied to the blood-contacting part of the blood-contacting medical device, followed by drying and/or heat treatment. A method for manufacturing a blood contact medical device according to claim 1, characterized in that: