JPS622949A - Antithrombotic polyurethane elastomer and blood contact medical device using the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a new polyurethane-based elastomer antithrombotic composite and a blood contact medical device using the same.

[Summary of the invention]

The present invention provides an antithrombotic elastomer composition that includes three-dimensional chain extension of a prepolymer containing a hydrophilic polyether in the presence of a hydrophobic polyether polyurethane to produce an excellent polyurethane. An antithrombotic elastomer composition having both mechanical properties and excellent antithrombotic properties is obtained.

In addition, the present invention provides a blood contact medical device that uses the above-mentioned antithrombotic polyurethane elastomer as +4f'1, so that the mechanical properties are suitable for practical use and the blood contacting surface (I'C surface plugging property is excellent). Blood contact medical equipment will be provided.

[Conventional technology] l, and the problems that the invention seeks to solve]

Conventional antithrombotic elastomers include polyether-based segmented polycarethanes (e.g., Biomer manufactured by Ethicon, Inc., USA), Girinine resins, and polysiloxane → J
Block copolymers of elastomer and polyurethane (for example, Caldi No. 1 manufactured by Conn., USA), heparinized polyurethane (Japanese Patent Publication No. 13729/1983), and the like are known. Practical yt
However, antithrombotic properties are still insufficient. For example, known segmented polyurethanes are expected to have further improved antithrombotic properties.
7. Heparinized polyurethane exudes heparin in a short period of time, and the duration of its antithrombotic properties is extremely short. However, sterilization and sterilization are cumbersome), so the cost is still an issue.

Also, Borishi l-1 Kirin and Boriu I, Tan is nitrogen and (1
Polymers (U.S. #'r
a (3rd degree 562.352) tel A reactive substance having a crosslinking iq reactive group and having poor stability over time -1-
In addition, the expression of 1Δ thrombus F varies depending on the storage strip A'1 and molding conditions, and a white liquid contact surface with a certain excellent antithrombotic property is generated. (The main thing is strict process control, which is extremely important.)

In addition, the segmented polyurethane "ζ hydrophilic ↑] I poly・"l urethane has excellent antithrombotic properties, but this 71
Because L is aqueous, when it comes into contact with blood, it absorbs water from the blood and swells, causing a change in volume.2,7 Moreover, it may partially dissolve in water, and its mechanical M quality rapidly changes due to water absorption. It deteriorates and cannot be put to practical use at all.

In addition, despite the fact that the 5th mer, which has favorable mechanical qualities and excellent antithrombotic properties, is indispensable for the development of blood-contact medical devices, it is actually 7l- )
4. We strongly hope for its development41.

〇　Means to Solve the Problem〕 The present inventor has developed a polyether-based segment! Focusing on the mechanical properties of borylthane containing polytetramethylene oxyto' in its molecular chain, we developed the antithrombotic properties of hydrophilic polyurethane into this polyurethane without impairing its mechanical properties. Various studies were conducted on ways to achieve both.

A hydrophobic polyurethane in which the polyether part is polytetramethylene oxide, and a polyether part is polyalkylene oxide (the number of carbon atoms in each alkylene oxide constituting the width unit is either 2 or 8:I:3). If a method of simply mixing a hydrophilic polyurethane with a hydrophilic polyurethane, the mechanical properties will not improve no matter how the mixing ratio or /Ft combination method is changed.

The present inventor used a very special method to synthesize main chain 11 bow polytetramethylene oxide+CJIz-CJ-(:1h-
CT! □-〇) 7. Polyalkylene oxide-(-CI
IR-CH2-0)-.

(However, we have developed a method to efficiently utilize the excellent (nine-sided plug property) of segmented polyurethane (called hydrophilic polyurethane in unknown Ill. books) having R = I (or CHi) in its main chain. Also reaching the heading the present invention.

The polyether of the soft segment part of the segment 1 to polyurethane is boria-butylene oxide (the number of carbon atoms in each al-4-synoxy 1 constituting the m-position of the single qf structure is either 2 or 3), specifically Polyethylene oxide, polypropylene oxide, ethyleneoxy 1'-propylene oxide random copolymer, polyethylene oxide-polypropylene oxide;
-B type, A -BA type, B -A -B type, etc.), these boriu[/tans are highly hydrophilic and extremely absorb water and swell when they come into contact with water, and the - part is water-resistant. The present inventor has found that H1H has very poor mechanical properties, but its antithrombotic properties are dramatically improved.

The present inventors have developed a new 1.0-urethane that combines the advantages of hydrophobic polyurethane with excellent mechanical properties and hydrophilic polyurethane with superior antithrombotic properties. Polyurethane antithrombotic +A l
As a result of conducting various tests 8.I in order to develop it, we conducted a 4I acid reaction of the hydrophilic polyurethane in a solution prepared by dissolving the hydrophobic polyurethane described above, and at this time, a trifunctional group was used as a chain extender. By the presence of the chain extender described in 1- above, a three-dimensional structure is generated in some parts, and molecules of the hydrophobic polyurethane described in 1-1 are entangled in the network of the hydrophilic poly-1-urethane growth molecules. ) N (cross 1
This suppresses the drawback that the tetrahydrophilic polyurethane dissolves and flows out when it comes into contact with water, and the surface that comes into contact with water becomes substantially tIC-thrombotic. It has been found that compositions can be obtained which can be coated predominantly with a polyurethane that is more than 1 hydrophilic.

In this composition, hydrophobic polyurethane molecules are entangled in the crosslinked network of hydrophilic poly-1-lyrethane molecules, so the hydrophilic polyurethane does not dissolve into water, but upon contact with water, the hydrophilic poly-1-lyrethane swells with water. The hydrated and swollen polyalkylene oxide chains expand their volume and cover the interface with blood, and the polyalkylene oxide chains that hydrate and swell rapidly adsorb albumin from the blood, promoting biotransformation and exhibiting antithrombotic properties. In addition to exerting
Solvate ions to prevent deposition phenomena 11. do. In this way, the present inventors have discovered that it is possible to prevent the phenomenon of calcification that occurs during long-term use of blood contact medical devices, which is currently attracting attention as a major problem.

The polyurethane used in the composition of the present invention is produced by synthesizing a hydrophilic polyurethane through a three-dimensional reaction with a hydrophobic polyurethane, which is a polyurethane having tetramethylene oxide in its main chain. be done. In this case, the hydrophilic parts used to synthesize hydrophilic polyurethane are hydroxyl at both ends! 1 (polyalkylene glycol (each alkylene oxy 1 constituting the monomer unit has either 2 or 3 carbon atoms) is prepared as a starting material. Specifically, polyethylene glycol with both terminal hydroxyl groups - Prepolymer (1) obtained by reacting a diisocyanate with at least one selected from the group consisting of polypropylene glycol, polypropylene glycol, ethylene glycol-loop 1-copylene gelicol random copolymer, and polypropylene glycol-polyethylene glycol block copolymer. using
Chain extension is carried out with diol, diamine, water, etc. in a solution containing hydrophobic polyurethane, and at this time, a trifunctional or F- chain extender is present to carry out the polyurethane production reaction. The present invention relates to the antithrombotic elastomer composition thus obtained and a blood contacting medical device with excellent antithrombotic properties, which is formed by using the antithrombotic elastomer composition to form a blood contacting surface of the blood contacting medical device.

When the polyurethane used in the present invention uses diamine or water as a chain extender, urea bonds are formed to form polyurethane urea, and this polyurethane urea is also included in the urethane referred to in the present invention.

The blood contact surface of the blood contact medical device of the present invention is composed of hydrophobic polyurethane and hydrophilic polyurethane, and the hydrophilic polyurethane molecules include a three-dimensional molecular structure. Hydrophobic polyurethane is entangled.

The hydrophilic polyether poly(1) of the present invention (containing the above-mentioned polyalkyleneoxy [S] in the main chain) and the hydrophobic polyether poly(1-ramethyleneoxy) of the present invention (containing the above-mentioned polyalkyleneoxy [S] in the main chain) The composition ratio of the hydrophilic polyether polyurethane (methane content is 0) is important in order to exhibit the mechanical properties and antithrombotic properties of the present invention. .5-50 double star%, preferably 1-50%
It is 30% by weight.

If the total amount of hydrophilic polyether polyurethane exceeds 50% by weight, swelling due to water absorption will be large and the mechanical properties will not be practical. In this case, the expression of anti-thrombotic t4t+ is insufficient. Interestingly, even when the total amount of hydrophilic polyether polyurethane is relatively small, hydrophilic polyurethane tends to spontaneously gather on the surface as the solvent evaporates, leading to thermodynamically stable phase separation. It is understood that this is a transition to water, especially when it comes into contact with water during film formation, and it oozes out onto the surface, but since it is entangled with the hydrophobic polyurethane in the crosslinked network, it does not flow out. The molecular weight of the hydrophilic polyether used in the synthesis of the antithrombotic elastomer composition of the present invention is 100 or more, preferably 200 to 3
,000, more preferably 300 to 2,000.

The molecular weight of the hydrophobic polyether (polytetramethylene oxide) used in the present invention is between 200 and 3.000, more preferably between 300 and 2.000.

The chain extender having three or more functional groups used in the present invention is one in which - there are 371 or more hydroxyl groups or amino groups in the molecule;
Examples include glycerin, pentaerythritol, triaminoethane, and triaminopropane. These 3
The proportion of chain extenders with a functional group of -1- in the total chain extenders is 1.
-30% is preferred; if it is less than 1%, there is a risk that the hydrophilic polyurethane will come into contact with water and flow out; if it is more than 30%, the degree of crosslinking will be too high and the composition may gel.

The characteristics of Polyurethane/L in the compositions of the present invention include three-dimensional chain extension of Polyurethane/Polymer containing a hydrophilic polyether in the presence of a hydrophobic polyether polyurethane. Sa1! This is where it is obtained. However, the polymer is pre-treated with a two-dimensional chain extender.
Part and reaction, Sa1! Then, add a trifunctional chain extender (7>7) to chain the polyether moiety. In addition, the chain may be further extended.

Preparation of the botanical +, -tan silk compositions of the present invention (11) must also be carried out in the presence of a solvent; without a solvent, the desired preferred entangled polymer cannot be obtained.

Preferred solvents and j) include dimethylform J8am[, dimethylacetamide, dimethylsulfoxy l-, tetrahyl-'+:+furan, sioquine, N-methylpyrrolidone, etc., and mixed solvents mainly composed of these. It will be done.

The reaction with the isocyanate compound during the polyurethane production reaction may be carried out without a catalyst by heating or with L2, but it may also be carried out using a catalyst. As the catalyst, those used in known urethane synthesis can be used, but triethylenediamine, diazabicif[-1 undecene, etc. are particularly preferred from the viewpoint of medical use because they are easy to remove during the purification process.

As the isocyane-1 compound to be used, all diisocyane-1 compounds conventionally used in the production of polyurethane can be used. Examples of preferred diisocyanates include 4,4
'-Diphenylmethane diisocyanate, 1,4-phenylene diisocyanate, 4,4'-dicyclohegycylmethane diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate 1-12,4-tolylene diisocyanate, 2,6-tolylene diisocyanate Isocyanate, cyclo-xane-1,4-diisocyanate, mixture of 2,4-1-lylene diisocyanate and 2゜6-tolylene diisocyanate, xylylene diisocyanate, 1,3-phenylene diisocyanate, naphthalene-1,5- Examples include diisocyanates, which can be used alone or as a mixture.

Examples of chain extenders include chain extenders having active hydrogen groups that react with difunctional isocyanate groups, such as aliphatic diamines such as ethylenediamine, propylene diamine, butylene diamine, and hexamethylene diamine; cyclohexane diamine, piperazine, xylene diamine, etc. alicyclic,
Aliphatic acid diamines; aromatic diamines such as tolylene diamine, phenylene diamine, 4,4'-diphenylmethane diamine, hydrazines, ethylene glycol, 1
．． Glycols such as 4-butanediol and bifunctional chain extenders such as water are used in combination with trifunctional chain extenders.

The polyurethane synthesized in this way can be prepared in the form of a synthetic solution, or the polyurethane produced can be treated with a precipitant, such as water.
After precipitating in alcohol or the like, thoroughly washing with water or ethanol, or repeating reprecipitation if desired to remove impurities, it is again dissolved in a solvent and used as a solution.

In addition, the Boliu I methane of the present invention can be used as a solution to mold the blood contact surface by coating, dipping, or spraying, and can also be made into pellets and molded using conventional thermoplastic synthetic resin molding methods such as extrusion molding, injection molding, and pressing. It can also be formed using molding or the like. In addition, this polyurethane elastomer has an I
-) Of course, it is very stable even when stored in a liquid state, and there is no molecular breakdown due to the influence of moisture, so it is easy to handle, and it has good reproducibility and can exhibit antithrombotic properties. It has certain characteristics.

The mechanical properties of antithrombotic polyurethane generally include a tensile strength of 100 kg/cntl? J-to, elongation is 300~
It is said that it is good as long as it is 500% or more, but the polyurethane of the present invention +: 100 to 500 kg/c+
It has a tensile strength of +I and an elongation of over 300%, and has excellent mechanical properties.

[For production]

In the polyurethane of the present invention, a hydrophobic polyurethane with excellent mechanical properties has mechanical properties, a hydrophilic polyurethane with excellent antithrombotic properties exists on the blood contact surface, and has antithrombotic properties. This parent material, aqueous polyurethane, does not leak and selectively adsorbs albumin in the blood to promote biotransformation, as well as continuous repetition of hydrophilic polyalkylene oxide) as a molecular chain force mobilizing agent at the 1st position. It is effective as a.

From these results, the antithrombotic elastomer of the present invention can be suitably used for blood-contacting surfaces of medical devices that come into face-to-face contact with blood. Specific applications include artificial hearts, pumping chambers for auxiliary circulation devices, balloon pumps, extracorporeal circulation circuits for auxiliary circulation devices such as human T-liver and double heart-lung devices, blood bags, catheter artificial blood vessels, etc. These 11 are included in the blood contact medical device referred to in the present invention.

The present invention will be explained below with reference to Examples.

〔Example〕

Example 1 - Polyurethane containing tetramethylene glycol as a soft segment (using 4,4'-diphenylmethane diisocyanate as the isocyanate and butanediol as the chain extender) was dissolved in sufficiently dehydrated tetrahydrofuran to a concentration of 8%. .

Separately, polyethylene glycol (molecule 1600) having hydroxyl groups at both ends was placed in a sufficiently dried reaction vessel, and heated at 90°C.
Dehydration was carried out for 5 hours under reduced pressure of 0.1 mm/11 g or less. The temperature was lowered to 45 DEG C., and 4 times the amount of tetrahydrofuran dehydrated to a water content of 5 ppm or less was added thereto, and then 4,4'-diphenylmethane diisocyanate was added in a conventional manner, followed by stirring and reaction.

Diazabicycloundecene was added as a catalyst in an amount of 0.03% based on the isocyanate used, and the mixture was reacted for 2 hours to produce a prepolymer. This prepolymer solution was mixed with the polyurethane solution, 1,4-butanediol containing 10% pentaerythritol was added thereto, and the mixture was reacted at 50 DEG C. with stirring for 3 hours to produce polyurethane. To eliminate unreacted isocyanate groups]00m7
! of ethanol was added. This solution composition can provide excellent antithrombotic properties as shown in the Examples below.

In this example, the ratio of hydrophobic polyurethane to hydrophilic polyurethane was 90:10.

Inujyo case-? The polyurethane composition prepared in Example 1? ``Polyurethane was purified from the 4 liquid.

Purification of poly1-lyrethane is carried out by adding methanol to the main rudder reaction product to precipitate °ζ polyurethane, redissolving this precipitate in a mixed solvent of dioxane-dimethylacetamide (7:3 weight ratio), and adding methanol. The precipitation operation was repeated three times and the polyurethane was then dried under reduced pressure.

Example 11 - Terminated isocyanate-1 prepared under the same conditions as Example 1.
Example 1 using a prepolymer of polyethylene glycol (however, polyethylene glycol with a molecular weight of 900 was used)
A hydrophilic polyurethane entangled composition was prepared under almost the same conditions. However, in this example, when chain-extending a hydrophilic prepolymer, the required amount (70% of the chain extender) of butanediol was first reacted at 50°C for 1 hour, and then a mixture of butanediol and glycerin was added. <50750) to 4
0% was added and the reaction was continued at 50°C for an additional 4 hours with stirring.

The rest of the processing method is the same as in Example I. The weight ratio of hydrophobic polyurethane to hydrophilic polyurethane was 75:25.

Dog Chrysanthemum Example 4 - In the same manner as in Example 1, hydrophilic polyruthane was five-dimensionally synthesized in the presence of polyether polyurethane (Nisten 5714; manufactured by Gudrich) having polytetramethylene oxide as a soft segment. However, in this example, as a synthetic component of hydrophilic polyurethane, the terminal is water H2.
1 volip [1 pyrene glycol (molecular weight 550) 4
．． A prepolymer prepared primarily by reaction with 4'-cyphenylmethane diisocyanate-1 was used. In this example, dimethylacetamide was used as the synthesis solvent, and a mixture of ethyl/nglyl:1-l and pentaerythritol (mixing ratio 65:35) was used as the chain extender for the prepolymer.

Tai Chung Example-y Block copoly-ether diol 110-(EO)a of ethylene oxide (EO) and propylene oxide:tosi 15(PO) using dimethylsulfoxy 1'' as solvent
-(PO)h (lio)a-011(iiHshi, a:
b-1:2, molecular weight 1200) and 4.4'-Schiff T
, :'-lmethane diisocyanate was reacted to produce a hydrophilic prepolymer (+) with terminal diisocyanate-1-.

Independently of this, molecules! r! A monopolymer was prepared from +800 polytetramethane/glycol and 4,4'-diphenylmethane diisocyanate, and this prepolymer was chain-extended with diamine diamine to synthesize a polyurethane urea. This polyurethane urea is dissolved in dimethyl sulfoxy 1゛' and it becomes 11%? It was a night. this? The hydrophilic prepolymer (1) prepared by the method described in 1-1 is dissolved in the solution, and a mixture of ethylenediamine-1 and lyaminotanan (7:3) is added to carry out crosslinking to obtain IPN.
I made a prosthetic product. In this example, hydrophilic polyurethane/
The weight ratio of hydrophobic polyurethane was 3/97.

As a catalyst, 0.04% of diary'bicycloundecene was used based on the used isocyanate-I.

1 Implementation-Example-6-1 JPN silk composition was purified from the solution of Example 5.

That is, methanol was poured into the solution to precipitate polyurethane, reprecipitation was repeated three times using a dimethylacetamide-methanol system, and ethanol extraction was performed using a Soxhlet machine, followed by drying.

Change this polyurethane to dimethylacetamide 1' again? Do you understand? Yong? At night, a film was prepared by casting on a glass cloth. This film was transparent with no coloration and was extremely smooth when observed under a scanning electron microscope or an optical microscope. When this film was subjected to a tensile test and the tensile strength and elongation at break were determined, the tensile strength was 0.69k.
g/■carbonate and the elongation at break was 660%, indicating that it had sufficient mechanical properties. As a measure of anti-thrombotic properties, a Shishiri-honoid test was conducted and it was found to be 96 minutes, which is a dramatic improvement compared to 55 minutes for commercially available biomers.

The solution composition of Example 1.3.4.5 and the solution of polyurethane purified according to Example 2.6 in Example 2.6 were cast onto a glass plate to create a film J1. . This film was colorless and transparent, and was extremely smooth when observed under an optical microscope and a scanning electron microscope. The film was also subjected to a tensile test to determine its tensile strength and elongation at break.

Antithrombotic properties were measured using a test tube (inner diameter 10 mm, length 100 m++) that had a coating formed on the inner surface by coating the test tube twice with the polymer solution and thoroughly evaporating the solvent.
), and the blood coagulation time was measured by the Lee-White method (edited by Izumi Kanai and Masamitsu Kanai: Summary of Clinical Testing Methods, Vl-8m Kanehara Publishing Co., Ltd.).

The results are summarized in the table below, including the results of tests on commercially available polyurethane (Hiomer: Biomer, a product of Ethicon).

(1 space below) Table 1 Example 1 93 0.67 63
41 Example 2 92 0.62
640 Example 3 95 0.65
fi55 Example 4 9] 0.6
1 850 Example 5 88 0.
69 760 Example 6 89 0
．． 62 650 biomer 55
0.59 610 Polyurethane using only polyalkylene glycol as a polyester component has a tensile strength of about 0.02 kg/tm 2 and is completely usable for practical use, and also absorbs water and swells significantly upon contact with water. It was thought that it would be impossible to put it into practical use as it was partially lost in water.

Using the polyurethanes of the present invention of Examples 1, 2, 3, 4, 5, and 6, tubes with a diameter of 4 mm were made.

For comparison, these tubes and a commercially available biomer tube were connected to the end of the femoral ΦIJ vein of a hybrid adult.
When the patency state was examined after several months, it was found that Example 1.2.3.
4.5 The polyurethane tubes manufactured by L31"1 were all patent, but the commercially available Biomer tube L31"1
After several months, it was completely blocked.

Example 9 The composition of Example 1, 3, 4, and 5 was applied to the inner surface of a canyule, and the dirt was applied to a goat's auxiliary heavenly heart canyule. Even after 6 months, no thrombus or calcification was observed in these cannulae.

〔Effect of the invention〕

The polyurethane elastomer composition of the present invention is a completely new anti-thrombotic elastomer that sufficiently maintains mechanical properties and is imparted with hydrophilicity, and has novel and practical antithrombotic H'! Furthermore, the blood contacting medical device of the present invention has excellent antithrombotic properties on the blood contacting surface, contributing to the development of blood contacting medical devices.

Claims (1)

[Claims] 1. In the presence of polyurethane having a polytetramethylene oxide chain in the main chain, a chain extender containing a trifunctional chain extender is used to form a polyalkylene oxide chain (monomer) in the main chain. The number of carbon atoms in each alkylene oxide that constitutes the unit is 2 or 3
A polyurethane-based elastomer composition obtained by synthesizing a polyurethane containing any of the following. 2. A blood-contacting medical device whose blood-contacting surface is made of hydrophobic polyurethane having a polytetramethylene oxide chain in the main chain and a polyalkylene oxide chain in the main chain (each alkylene oxide constituting the monomer unit). Number of carbons is 2 or 3
A blood-contact medical device, characterized in that the hydrophilic polyurethane contains a crosslinked structure.