JPH0135669B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to improved anti-thrombotic properties, and more particularly to a blood-contacting medical device with improved anti-thrombotic properties in blood contacting parts. It is a well-known fact that antithrombotic properties can be imparted to blood-contacting surfaces of medical devices by coating them with polysiloxane, but the antithrombotic properties are by no means satisfactory from a practical standpoint. is also generally well recognized. On the other hand, it has also been proposed to use a block copolymer consisting of a polysiloxane block such as polydimethylsiloxane and a polyurethane block as a coating material with improved antithrombotic properties. (Special Publication No. 49-29350 and Special Publication No. 55
-8177 Publication). According to Special Publication No. 55-8177,
The surface coated with the polysiloxane-polyurethane block copolymer has a heterogeneous structure, and antithrombotic properties are obtained only when the entire surface has a heterogeneous structure in which particles with a diameter of approximately 0.1 to 2 μ are almost uniformly dispersed. It is taught that this occurs. In addition, the special public service 1977-
Mr. Yoji Imai, one of the inventors of invention No. 8177, wrote in "Kobunshi" Vol. 12, No. 248, p. 569 (1971) that a heterogeneous structure in which particles of 0.1 to 2μ are uniformly dispersed is a resistive material. It explains that it is the essence that has an effect on blood clots. On the other hand, the above-mentioned Japanese Patent Publication No. 49-29350 does not describe at all the fine structure of the surface coated with the polysiloxane-polyurethane block copolymer. The present inventors have repeatedly investigated the relationship between the surface microstructure of coating layers made of various polydialkylsiloxane-polyurethane copolymers and the development of antithrombotic properties in order to provide coating surfaces with even better antithrombotic properties. Surprisingly, contrary to conventional knowledge, when a polydialkylsiloxane-polyurethane copolymer with a specific composition is used as a coating material and the coated surface condition exhibits a certain level of smoothness, conventional polyurethane copolymer It has been found that the siloxane-polyurethane block copolymer coated surface exhibits excellent antithrombotic properties that far exceed the values expected from the coated surface. The blood-contact medical device with excellent antithrombotic properties according to the present invention has at least a surface that comes into contact with blood with 70 to 98% by weight of polyether-based or polyester-based polyurethane blocks and 2 to 30% by weight of polydialkylsiloxane blocks. A solution containing a block copolymer consisting of
The average value of the surface roughness is determined by evaporating the solvent from the deposits in an atmosphere of ℃ or less and relative humidity of 50% or less.
The blood flow contacting medical device according to the present invention has a blood coagulation time of 85 minutes or more according to the Lee-White method and is formed with a coated surface having a particle diameter of 0.01μ or less. It not only exhibits thrombotic properties, but also has excellent long-lasting antithrombotic properties. Therefore, blood flow contact medical devices include not only those that are used for a relatively short period of time, such as extracorporeal circulation circuits used during treatment with an artificial kidney, but also those that are used for a long period of time, such as Examples include blood storage bags, artificial hearts, cardiac auxiliary ventricles, intra-aortic balloons, pulsatile blood pumps, sutureable skin grafts, artificial blood vessels, and cannulae. The blood contact surface forming material used in the present invention is a copolymer consisting of 2 to 30% by weight of polydialkylsiloxane blocks and 70 to 98% by weight of polyether or polyester polyurethane blocks. Even more preferably, the weight ratio of the polyurethane block to the polydialkylsiloxane block is
It was found to be 8.5:1.5 to 9.5:0.5. The structure of the urethane that makes up the polyurethane block is
In view of the achieved antithrombotic properties, polyether urethane is more desirable than polyester urethane. Moreover, polydimethylsiloxane is preferable as the polydialkylsiloxane. The blood contact surface formed from the above block copolymer must have an average surface roughness of 0.01 μm or less. The average value of this surface roughness is desirably 0.001μ or less. The smoothness of the blood contact surface with an average surface roughness of 0.01μ or less and the micro-heterogeneous phase structure with a size of 0.01μ or less are closely related to the composition of the coating material. A polyurethane-polydialkylsiloxane block copolymer having a composition in which the polyurethane block portion is 70 to 98% by weight and the polydialkylsiloxane block portion is 2 to 30% by weight has the above-mentioned smoothness and microheterogeneous phase structure. It is possible to easily form a blood contact surface having a The block copolymers used in the present invention are produced by a condensation-type reaction between the urethane-amide groups of a preformed polyurethane and the reactive end groups, preferably reactive acetate groups, of a preformed polydialkylsiloxane. . The block copolymers used in this invention are characterized by excellent mechanical stability at low temperatures and can be easily molded and cast into films and sheets. It is also possible to coat the surface of the article by any suitable method, for example by painting or dipping. The block copolymer used in the present invention is
It is manufactured using polydialkylsiloxane and polyurethane which have been previously manufactured according to the method described in Japanese Patent Publication No. 48-24518. Polydialkylsiloxanes basically consist of a backbone of repeating silicon and oxygen atoms and groups bonded to the silicon atoms, such as aryl, allyl, vinyl, such as alkyl, alkoxy, phenyl, and between the halogen atoms and the silicon atoms. and haloalkyl having at least 3 carbon atoms. The block copolymers used in this invention are made from linear to moderately branched polysiloxanes having from about 3 to 100 or more repeating units. Block copolymers exhibiting excellent blood compatibility include lower alkyl substituents,
Examples are polydialkylsiloxanes having repeating methyl, ethyl, propyl and butyl groups on the silicon atoms. Most preferred for producing the block copolymer used in the present invention is polydimethylsiloxane. The polyurethane is a polyether type or polyester type polyurethane manufactured by a known method as described in Japanese Patent Publication No. 48-24518. Examples of polyurethane-type polyurethanes include glycols such as ethylene glycol, diethylene glycol, etc., or trimethylolpropane;
Traditionally used to produce polyurethanes such as ethylene diisocyanate and 2,4-tolylene diisocyanate, which are esterified between polyhydric alcohols such as glycerin and polycarboxylic acids such as adipic acid and succinic acid. This includes those condensed with isocyanate group-containing compounds. Polyether type polyurethanes include polymers of alkylene oxides such as ethylene oxide and 1,2-propylene oxide, or polymers of alkylene oxide and propylene glycol, 1,2-propylene oxide, etc.
It includes those obtained by condensing a polyhydric alcohol such as 2,6-hexanetriol with the above-mentioned isocyanate group-containing compound. The block copolymers used in this invention are obtained by a process which is essentially a condensation type reaction between the urethane-amide groups of the polyurethane and the reactive end groups, preferably acetate or hydroxy groups, of the polysiloxane. Since only the urethane-amide of the polyurethane participates in this reaction, this reaction can be accomplished using either polyether or polyester urethanes. To aid in understanding, the reaction of a polyurethane with a polysiloxane having acetate end groups is shown as an example of the production of the most preferred block copolymer of the present invention. R ₁ −O−CO−N(R ₂ )H+CH ₃ COO−Si(X) ₂ −O−R ₃ →R ₁ −O−CO−N(R ₂ )−Si(X) ₂ −O−R ₃ ＋ _CH3CO
OH where R ₁ and R ₂ represent segments of the polyurethane chain, R ₃ is the remaining chain of the polysiloxane, and X represents a substituent bonded to the silicon atom. It should be noted that the bonds between the segments of the block copolymer are silicon-nitrogen bonds. As long as the block copolymer is made from preformed polyurethane, either polyether urethane or polyester urethane can be used, but the main purpose of the present invention is to provide a copolymer with high hydrolytic stability. Polyether urethane is preferred because it provides high antithrombotic properties. There are no particular restrictions on the selection of polyurethane, but
The final product naturally has different physical properties depending on the nature of the polyurethane chosen. The above condensation reaction is preferably carried out over a long period of time while raising the temperature of the reaction solution. A preferred solvent is dioxanetetrahydrofuran or mixtures thereof. The above reaction between the polyurethane and the acetate-terminated blocked polydialkylsiloxane is preferably carried out under anhydrous conditions. Otherwise, the hydrolysis reaction between water and acetate groups with the formation of silanol groups will proceed at a faster rate than the reaction between acetate groups and urethanamide groups. The above condensation type reaction can also be carried out using polydialkylsiloxanes having terminal hydroxyl groups. However, the terminal hydroxyl group is less reactive than its acetate counterpart, so
Higher temperatures, ie, above 100°C, and the presence of a dehydrating agent are required. This dehydrating agent is preferably volatile, and acetic anhydride is recommended. The extent to which the reactive end groups of the polydialkylsiloxane react with the urethane groups can be controlled by the reaction conditions. The material thus obtained is essentially an elastomer. In order to obtain an elastomer having a higher modulus of elasticity, crosslinking between the polyurethane component and the polydialkylsiloxane component may be promoted. This can be achieved in at least two ways. In the first method, the block copolymer is heated in a solid state or in a molten state at a temperature of 100 DEG C. or higher, preferably in the range of 110 DEG to 120 DEG C., for an arbitrary period of time depending on the desired degree of curing. In this case, a time of up to 4 hours is preferred. The second method further generates randomly distributed crosslinks between polymer chains by the action of organic peroxide catalysts at elevated temperatures. Incorporation of the peroxide catalyst into the block copolymer is preferably carried out while the block copolymer is still in solution after it has been formed. After recovery by evaporation of the solvent, the block copolymer is heated to initiate the peroxide-induced crosslinking reaction. Preferably, the reaction is carried out at 110-120°C for a maximum of 2 hours. The peroxide used is at most 2% by weight of the total solids. To form a blood-contacting surface made of the polyurethane-polydialkylsilosane block copolymer described above, the article to be coated is immersed in a solution of the block copolymer dissolved in a solvent, or the blood-contacting surface of the article is coated. It may be applied more than once. When the part of the intended medical device having a blood contacting surface is in the form of a film or sheet, it can also be formed from a solvent solution of the block copolymer by a casting method. The solvent is removed after dipping or coating or casting, but in order to form a surface with the smoothness required by the present invention,
It is important to control the evaporation rate of this solvent. If the evaporation rate of the solvent is too high, the average value of the surface roughness of the resulting coated surface will exceed 0.01μ, resulting in a decrease in antithrombotic properties. The rate of evaporation of the solvent can be controlled by various means, the first of which is adjustment of temperature. Generally, to obtain a surface with good antithrombotic properties, it is sufficient to maintain the atmospheric temperature during solvent evaporation at 35°C or lower, more preferably at 25°C or lower. The second evaporation rate control means is the partial pressure of the solvent in the atmosphere. The partial pressure of the solvent vapor may be appropriately adjusted to below saturation.
The atmosphere is such that the vapor pressure of the solvent used at the operating temperature is
mmHg, when the saturated vapor pressure at that temperature is AmmHg, 0.9A≧X≧0.05A, more preferably 0.8A≧
It may be within the range of X≧0.1A. When X is larger than 0.9A, the evaporation rate is too low, resulting in poor productivity, which is not preferable. If it is smaller than 0.05A, the evaporation rate is too high and the smoothness of the coated surface becomes rougher than 0.1μ, making it impossible to achieve the object of the present invention. It is also possible to use mechanical means to slowly evaporate the solvent, for example by covering the coated object with a container of a certain size. Furthermore, the present inventors have discovered that the humidity of the atmosphere is extremely important during the evaporation of the solvent after the coating process. During solvent evaporation, if the humidity of the atmosphere exceeds a certain level, bubbles are generated in the coating, which causes the formation of non-uniform pores in the surface structure and reduces the antithrombotic properties. The humidity is at least 50% relative humidity or less, preferably 45% or less, even more preferably 30% or less. By satisfying the above-mentioned conditions, coating the blood-contacting part of the medical device with the special polyurethane-polydialkylsilosane copolymer described in the present invention, or immersing the mandrel in a solution of the above-mentioned block copolymer. A highly antithrombotic surface can be formed by forming a molded product such as a tube made only of the above block copolymer by a method or the like, and by controlling the surface smoothness of the blood contacting part to 0.01 μm or less. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, blood coagulation measurements in Examples were performed by the following method. The method is the so-called Lee White (Lee−
White). That is, the walls of a test tube with an inner diameter of 16 mm are coated with the copolymer solution and left to dry at room temperature for 24-48 hours. During this standing period, the solvent and acetic acid produced as a by-product during the reaction were all volatilized. The thickness of the film on the test tube wall is approximately 30μ.
It was hot. Approximately 3-5 ml of freshly drawn blood was placed into coated test tubes and the clotting time was measured at 37°C. This clotting time was used as a measure of antithrombotic properties. For comparison, freshly drawn blood from the same donor was placed into uncoated test tubes and into test tubes coated with polyether-based urethane homopolymer or polydimethylsiloxane homopolymer. Furthermore, the roughness (smoothness) of the coating film surface refers to the height of surface protrusions determined from photographs taken by directly observing the coating film surface with a scanning electron microscope. Reference Example 1 [Preparation of block copolymers] A series of seven types of block copolymers were prepared from polydimethylsiloxane and polyether urethane. The compositions of these block copolymers had different ratios of the monopolymer components. This polyether urethane was prepared from polypropylene glycol having an average molecular weight of 1200 and methylene bis(4-phenyl isocyanate) using a known method. This polyether urethane had a total nitrogen content of about 2.1% and an intrinsic viscosity of 0.58 dl/g, measured at 25°C in dioxane. The polydimethylsiloxane was block-terminated with acetate groups and had 8 end groups per molecule. Its intrinsic viscosity is 0.27 measured at 25°C in anhydrous toluene.
It was dl/g. Each block copolymer was prepared in the same manner. A mixed anhydrous solvent system consisting of 70 parts by weight of tetrahydrofuran and 90 parts by weight of dioxane was prepared, and the polyether-based urethane was dissolved in this solvent mixture with stirring. After the reaction system was purged with nitrogen, a solution of polydimethylsiloxane having an acetate group at the end of the block dissolved in 15 parts by weight of purified tetrahydrofuran was gradually added to the polyether urethane solution. The mixture thus obtained is heated to a range of 40-50°C and maintained at this temperature for 6-10 hours with continuous stirring to form a dissolved copolymer consisting of blocks of polydimethylene siloxane and blocks of polyether-based urethane. A solution with coalescence was obtained. Table 1 shows the compositions of the seven types of block copolymers thus prepared.

[Table] Example 1 A coating layer was formed from the solution of each block copolymer prepared in Reference Example 1, and its coagulation time was measured by the first method. Note that the temperature during evaporation was varied in order to change the rate of solvent evaporation. The relative humidity of the evaporation atmosphere was 50%. The coagulation time of each coating film and the surface roughness determined from scanning electron micrographs are shown in Table 2.

【table】

[Table] From the results in Table 2, it can be seen that the lower the evaporation atmosphere temperature, the longer the coagulation time and the better the antithrombotic properties, and that the roughness of the coating surface is closely related to the antithrombotic properties; It can be seen that the more antithrombotic properties the better. Furthermore, it can be seen that the block copolymer used in the present invention is significantly superior to silicone membranes, which are considered to have the best anticoagulant properties among those conventionally used in practical use. Among the above, scanning electron micrographs of the surfaces of the samples of Experiment No. 6 and Experiment No. 15 (both comparative examples), which are examples of rough surfaces and poor antithrombotic properties, are shown in Fig. 1 1 and Fig. 1 2, respectively. . Further, similar photographs of the surfaces of samples of Experiment No. 2 and Experiment No. 10 (both examples of the invention) as examples of smooth surfaces and excellent antithrombotic properties are shown in FIG. 1 3 and FIG. 1 4, respectively. Reference Example 2 A block copolymer was prepared from polyether urethane and polydimethylsiloxane by the following method. The polyether urethane used was 0.25 dl/g.
has an intrinsic viscosity (measured at 25°C in dioxane) of
Analysis revealed that it contained 2.7% nitrogen. This polyether polyurethane was prepared from polypropylene glycol having an average molecular weight of 450 and 2,4-toluene diisocyanate by a known method. The polydimethylsiloxane was block terminated with acetate and had an intrinsic viscosity of 0.24 dl/g as measured at 25°C in anhydrous toluene. The method for synthesizing the block copolymer is as follows. A solvent system was prepared consisting of 100 parts by weight of tetrahydrofuran and 1200 parts by weight of dioxane. Both solvents were purified and rendered anhydrous. Approximately 405 parts by weight of the polyether urethane was dissolved in this solvent with gentle stirring. Thereafter, a solution of the block dissolved in 300 parts by weight of freshly distilled anhydrous tetrahydrofuran and 45 parts by weight of polydimethylsiloxane having an acetate group at the end was added to the polyether-based urethane solution for about 60 minutes with constant strong stirring. Added gradually. The mixture was kept at 35-40°C for 10 hours with continued high speed stirring. The resulting block copolymer can be formed into a film or sheet or applied to a surface using known dipping, casting or spraying techniques. Example 2 Stainless steel mandrel (diameter 170mm,
125 mm in length) was immersed in the solution of the block copolymer prepared in Reference Example 2, the film formed on the mandrel was cured, and the block copolymer was dried for 48 hours in an air atmosphere from which dust was removed. A tube (wall thickness 500μ) consisting of the union was prepared. The drying temperature was 30°C (sample A) and 60°C (test B). Note that the relative humidity in the dry atmosphere was 46%. Thereafter, the obtained tube was wrapped in a sterile bag and sterilized with ethylene oxide in a conventional manner. Scanning electron micrographs of Sample A and Sample B are shown in FIG. 21 and FIG. 2, respectively. Sample A
The surface roughness of sample B was less than 0.01μ, while that of sample B was greater than 0.1μ. Both samples were placed inside a sheep artery. Three months after implantation, the experimental sheep remained normal. At this point, we took out the embedded tube and observed its surface, and found that the appearance of sample A was completely the same as when it was installed in the tube, but sample B
A slight thrombus was observed. Example 3 A tetrahydrofuran/dioxane mixed solvent solution of the polyether-based polyurethane-polydimethylsiloxane block copolymer prepared in Reference Example 2 was kept at room temperature, and approximately 5 to 10 parts by weight of purified fresh anhydrous cyclohexanone was added to the solution to about 10 parts by weight. 8 parts by weight were added. The resulting solution was transferred to a previously cleaned pressure can and sprayed a small amount at a time through a nozzle onto a spiral rhodium plated mandrel with a highly polished surface. Each time a small amount of spraying was completed, it was allowed to stand at a predetermined temperature (shown in Table 4 below). The storage temperature is sample A: 20℃, sample B: 25℃,
Sample C: The temperature was 55°C. The relative humidity in the atmosphere in which it was left was 42%. This spray-and-leave operation produces a thickness of approx.
This was continued until a 0.06 cm film of block copolymer was formed on the mandrel. The film was cured and dried at 60° C. for a minimum of 72 hours in a dedusted air atmosphere with forced air circulation. The helical tube was then removed from the mandrel. The tube had an inner diameter of 2.57 cm and a wall thickness of 0.06 cm. The surfaces of samples A and B were smooth, and both had surface roughness of 0.01 μm or less. Scanning electron micrographs of the surfaces of both samples are shown in FIGS. 31 and 2, respectively. Moreover, the surface roughness of sample C was large. A similar photograph of the surface of sample C is shown in FIG. The tube made according to the above method was sterilized with ethylene oxide gas and then connected to the lower part of the descending aorta of an experimental pig. The pig was allowed to function normally for 210 days before the tube was removed and tested. For samples A and B, there were no detectable pathological effects in the animals, and no deterioration of the tubes due to transplantation into pigs was detected. However, some blood clots were observed in sample C. Reference Example 3 A series of 6 polydimethylsiloxanes and polyester urethanes with different proportions of their respective homopolymer components whose block ends end with acetate groups.
A block copolymer of seeds was created. This polyester urethane has an intrinsic viscosity of 0.45 dl/g (measured at 25°C in dioxane) and a nitrogen content of approximately 1.1%.
It was hot. This polyester urethane is poly(ethylene glycol) with hydroxyl terminals.
It was prepared from terephthalate and 1,5-naphthalene diisocyanate by known methods using a 1:1 combination of ethylene glycol and glycerol as chain extenders. Polysiloxane is 0.24 dl/g measured at 25°C in anhydrous toluene.
It was a block-terminated acetate-terminated polydimethylsiloxane having an intrinsic viscosity of about 90% and a content of about 9 terminal silanol groups per molecule. Each of the block copolymers was prepared in the following manner. Approximately 50% dioxane is added to this polyester urethane.
parts by weight and 100 parts by weight of tetrahydrofuran. Both solvents were purified and rendered anhydrous. A polydimethylsiloxane whose block end ends with an acetate group was dissolved in purified anhydrous tetrahydrofuran and added to the polyester-based urethane solution. Stir the resulting mixture for 4-5 hours.
The temperature was kept in the range 50-60°C and then cooled. In this way, a polyester polyurethane-polydimethylsiloxane block copolymer having the composition shown in Table 3 was obtained.

[Table] Example 4 The following experiment was conducted using the block copolymer solution prepared in Reference Example 3. Blood compatibility was measured by coating the inner wall of a test tube with a solution of the above block copolymer and drying it in the same manner as in Example 1. The drying temperature was changed as shown in Table 4 below to control the solvent evaporation rate. Relative humidity was maintained at 45%. Fresh, collected whole blood approx.
~5 ml was added to the block copolymer coated test tube and the clotting time at 37°C was measured. For comparison, an uncoated glass test tube, a tube coated with polyester-based urethane homopolymer, and a tube coated with polydimethylsiloxane homopolymer in an amount of 3 to 5 ml of freshly collected whole blood from the same donor. added to. The clotting time and surface smoothness of each sample were as shown in Table 4.

【table】

[Table] *1 Reference example 3, sample No. in Table 3.
*2 The * mark in the experiment number indicates a comparative example. The results in Table 4 also show that the lower the evaporation atmosphere temperature, the longer the coagulation time and the better the antithrombotic properties, and the roughness of the copolymer surface and the antithrombotic properties It can be seen that there is a close relationship between the two, and that the smoother the surface, the better the antithrombotic properties. Among the samples shown in Table 4, scanning electron micrographs of the surfaces of the samples of experiment numbers 30 and 36 (both comparative examples), which are examples of rough surfaces and poor antithrombotic properties, are shown in Figures 1 and 4, respectively. Shown in 2. Further, a similar photograph of the surface of the sample of Experiment No. 27 (invention example) is shown in FIG. 4 as an example of a smooth surface and excellent antithrombotic properties.

[Brief explanation of drawings]

Figures 1 to 4 are scanning electron micrographs of the surface of a polyurethane-polydialkylsiloxane block copolymer;
3 and 4, FIG. 2 1, FIG. 3 1 and 2, and 4 FIG. 3
3 and 4, FIGS. 1 and 2 represent rough surfaces corresponding to comparative examples.

Claims (1)

[Claims] 1. A solution containing a block copolymer consisting of 70 to 98% by weight of polyether-based or polyester-based polyurethane blocks and 2 to 30% by weight of polydialkylsiloxane blocks is applied to the blood contact area, Blood coagulation time is 85 minutes or more according to the Lee-White method, which is obtained by evaporating the solvent from the deposits in an atmosphere with a humidity of 50% or less to form a coated surface with an average surface roughness of 0.01μ or less. A blood-contacting medical device having a blood-contacting surface of .