JPH0152025B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a medical material comprising a cured product of a compound having a crosslinkable silyl group. More specifically, it has at least one crosslinkable silyl group in the molecule, and the main chain consists essentially of at least one of polyether, polyester, polyurethane, polyurethane urea, polysiloxane, polycarbonate, and vinyl polymer. The present invention relates to a medical material that is made of a cured product containing a polymer with a molecular weight of 500 to 15,000 as an active ingredient and has excellent biocompatibility (especially anti-blood coagulability), moldability, and workability. In recent years, with advances in medical technology, blood collection,
Many synthetic polymer materials are used as storage and transportation tools, as well as in the treatment and replacement of living tissues, organs, and organs, and are of great help in restoring and maintaining human health. In this case, the polymeric material used needs to be biocompatible. Biocompatibility refers to "compatibility" with living organisms, and it is difficult to easily define it or indicate its contents. This is because requirements for materials vary widely depending on the location and purpose of use. In general, living organisms require that materials have no effects on biological systems, such as toxicity, irritation, carcinogenicity, mutagenicity, hemolysis, and blood coagulation. As such, materials are required to be free from mechanical, physical, and chemical deterioration. As described above, biocompatibility includes a wide range of properties, but the most important and technically difficult one is anticoagulability. Furthermore, since medical materials need to be molded to suit each individual in most cases, excellent moldability and workability are also required. Traditionally, medical materials include vinyl chloride resin,
Polyurethane resins, polyamide resins, silicone resins, fluororesins, etc. are used, and specific applications include blood collection devices, blood bags, blood transfusion devices, infusion devices, catheters, monitoring tubes, and extracorporeal circulation circuits such as artificial kidneys and heart-lung machines. , AV shunt, blood bypass tube, blood pump, artificial heart, auxiliary artificial heart, etc. However, there has been no material that satisfies biocompatibility, moldability, and workability at the same time, and in particular, there has been no polymeric material that has excellent anti-blood coagulability, good moldability, and workability. In view of these problems, the present inventors conducted intensive studies on medical materials with excellent biocompatibility (particularly anticoagulant properties), moldability, and workability, and as a result, published in Japanese Patent Application Laid-Open No.
-No. 156599, Japanese Patent Application Publication No. 1973-6096, Japanese Patent Application Publication No. 1973-
The present invention was achieved by discovering that a cured product of a compound containing a crosslinkable silyl group, which is disclosed in No. 13767, satisfies these properties. That is, the present invention provides a polymer whose main chain substantially consists of at least one type of polyether, polyester, polyurethane, polyurethaneurea, polysiloxane, polycarbonate, and vinyl polymer, and one molecule of a crosslinkable silyl group represented by the following formula. This medical material is characterized by being made of a cured product of a polymer (hereinafter referred to as component A) having at least one polymer having a molecular weight of 500 to 15,000. (In the formula, R is a substituted or unsubstituted monovalent organic group having 1 to 20 carbon atoms or a triorganosiloxy group, and X is a hydroxyl group, hydride group, halogen group, alkoxy group, acyloxy group, ketoximate group. group, amide group, acid amide group,
A group selected from aminooxy group, alkenyloxy group and mercapto group, a is an integer of 0, 1 or 2, b is an integer of 0 or 1, m is an integer of 0 to 18) where component A is formed or It only needs to be present in an effective amount for curing after application, and in addition to component A, a polymer molecule not having a crosslinkable silyl group may be partially included. The main chain of component A of the present invention essentially consists of at least one type of polyether, polyester, polyurethane, polyurethane urea, polysiloxane, polycarbonate, and vinyl polymer. In order to obtain a material with good in-vivo hydrolysis resistance, it is preferable that the material consists essentially of at least one of polyether, polyurethane, polyurethane urea, and polysiloxane. Among these, especially
Substantially consisting of one of the following: polyether alone, a combination of polyether and polyurethane, a combination of polyether and polyurethane urea, a combination of polyether, polyurethane, and polysiloxane, and a combination of polyether, polyurethane urea, and polysiloxane. preferable. Among the components constituting the main chain, preferred examples of polyether include (-O-CH ₂ -CH ₂ )-
_o ,

[Formula] (-O-CH ₂ CH ₂ CH ₂ - CH ₂ ) - _o , Examples of the polyurethane include at least one type of polyether glycol (e.g., polyethylene glycol, polypropylene glycol, polytetramethylene glycol, Pluronic type glycol, etc.) and at least one type of diisocyanate compound (e.g., 4,4'-diphenylmethane diisocyanate). , hexamethylene diisocyanate, 2,4-tolylene diisocyanate, 2,6
- tolylene diisocyanate, etc.) and, if necessary, at least one type of chain extender (e.g., ethylene glycol, propylene glycol, butanediol, etc.). Examples of the extender include those using ethylene diamine, propylene diamine, butylene diamine, hexamethylene diamine, diphenylmethane diamine, hydrazine, water, etc. in part or in whole, and examples of the polysiloxane include polydimethylsiloxane, methyl fluoride, etc. Examples include enylpolysiloxane, fluoroalkylmethylpolysiloxane, polydimethylsiloxane, and the like. In the present invention, at least one crosslinkable silyl group may exist in one molecule of the polymer of component A, but it is preferable that at least one crosslinkable silyl group exists in one molecule at the polymer terminal and/or side chain. Further, it is preferable that the polymer having a crosslinkable silyl group is cured at room temperature by moisture, particularly moisture to the extent that it is contained in the air. The molecular weight of component A in the present invention is preferably 500 to 15,000 in view of the balance of anticoagulability, strength, and workability. The curable product containing component A as an active ingredient in the present invention is cured without a catalyst or with a curing catalyst, and surprisingly, the cured product exhibits excellent anticoagulant properties when it comes into contact with blood. show. In addition, component A in the present invention has a relatively small molecular weight and dissolves in most organic solvents, so when obtaining a molded article or using it as a coating agent, it exhibits excellent moldability and workability, and has a complex Even when producing a molded article with a complicated shape or coating the surface of a molded article with a complicated shape, it can be easily and quickly molded or coated, and after that,
When cured, a cured product with a very smooth surface can be obtained. Therefore, a cured product containing component A as an active ingredient has such excellent anticoagulability, moldability, and workability, and can be used as a variety of medical materials. It can be suitably used for medical materials in contact with blood in medical devices. for example,
It is suitable for use as a surface coating material for medical devices formed into membranes, tubes, connectors, etc., and medical devices made of metals, ceramics, plastics, etc. that come into contact with living tissue or infusion fluids. Specific applications include blood collection tools, blood bags, blood transfusion tools, infusion devices, catheters, monitoring tubes, extracorporeal circulation circuits such as artificial kidneys and heart-lung machines, A-
These include V-shunts, blood bypass tubes, blood pumps, artificial hearts, and auxiliary artificial hearts. Also, to add mechanical strength and other functions,
A cured product may be obtained after mixing component A in the present invention and a thermoplastic resin. The thermoplastic resin is not particularly limited as long as it is a resin that dissolves in the same solvent as component A in the present invention and does not contain impurities that can be eluted into living organisms, but preferably vinyl chloride resin, silicone resin, polyurethane resin, Polyamide resin is good. Next, the manufacturing method and curing method of component A in the present invention will be explained. There are no particular limitations on the method for producing component A, and it can be produced by any conventional method. If the crosslinkable silyl group is one that cures at room temperature with moisture, conventional manufacturing methods for room temperature curable sealants, such as JP-A-1989-1000-1, are used.
It can be manufactured by the method described in No. 156599, JP-A-55-13767, etc. An example of such a production method is a main chain consisting essentially of at least one type of polyether, polyester, polyurethane, polyurethane urea, polysiloxane, polycarbonate, or vinyl polymer, and a terminal consisting of a hydroxy group. The terminal hydroxy group of the substance is converted into an alkoxy group by reacting with an alkali metal compound selected from alkali metals, alkali metal hydroxides, and alkali metal hydrides. Subsequently, the expression

[Formula] (wherein, Q is a halogen atom selected from chlorine, bromine, and iodine, R' is hydrogen or a monovalent organic group having 1 to 20 carbon atoms, and R'' is a divalent organic group having 1 to 20 carbon atoms. ) is reacted with an unsaturated halogen compound represented by the formula (In the formula, R is a substituted or unsubstituted monovalent organic group having 1 to 20 carbon atoms or a triorganosiloxy group, and X is a hydroxyl group, hydride group, halogen group, alkoxy group, acyloxy group, ketoximate group. group, amide group, acid amide group,
A group selected from an aminooxy group, an alkenyloxy group and a mercapto group, a is an integer of 0, 1 or 2, b is an integer of 0 or 1, and m is an integer of 0 to 18. ) Component A can be produced by subjecting a silicon hydride compound represented by the following formula to an addition reaction using a platinum-based catalyst. Component A of the present invention produced in this way is:
It is cured alone or after being mixed with other components, or after being diluted with an organic solvent. The curing method is a normal curing method. For example, in the case of a component A polymer having a crosslinkable silyl group that can be cured by moisture at room temperature, it may be cured by moisture at room temperature. Further, a silanol condensation catalyst may or may not be used. When using condensation catalysts, metal salts of carboxylic acids such as alkyl titanates, organosilicon titanates, tin octylate, dibutyltin laurate and dibutyltin maleate, dibutyltin phthalate, dibutylamine-2-ethyl Known silanol condensation catalysts such as amine salts, such as xoates, and other acidic and basic catalysts are usefully used. The anti-blood coagulation properties of the medical material made of the cured product containing component A of the present invention as an active ingredient, produced in this way, were determined by an in vitro anti-blood coagulation test [Lee
White method (edited by Izumi Kanai and Masamitsu Kanai, Summary of Clinical Testing Laws, VI-82, Kanehara Publishing Co., Ltd., 1978),
Imai-Nose method (Y. Imai, et al, J. Biomed.
Mater.Res., 6, 165 (1972)] and showed excellent anticoagulant properties. The medical material of the present invention can be used as the active ingredient of component A, using the resin component alone or as a solution, by a coating method, a dipping method, a casting method, etc.
It is possible to create molded objects and coatings, and even complex molded objects can be easily molded, and molding methods similar to dipping and casting methods that conventionally used large amounts of solvent can be processed without solvent or with a small amount of solvent. It also has good workability. From these results, the medical material of the present invention can be suitably used for medical devices, particularly blood contact surfaces of medical devices that come into direct contact with blood. The present invention will be explained below with reference to Examples. Example 1 800 g of polypropylene oxide containing an allyl ether group (CH ₂ =CHCH ₂ O-) at the end and having an average molecular weight of 8000 was placed in a pressure-resistant reaction vessel equipped with a stirrer.

Add 20 g of a silicon hydride compound having the structure of [Formula], and then add 8.9 g of a catalyst solution of chloroplatinic acid (H ₂ PtCl ₆ 6H ₂ O to isopropyl alcohol).
18ml, solution dissolved in 160ml of tetrahydrofuran)
0.34 ml was added and reacted at 80°C for 6 hours. As a result of quantifying the residual hydrosilyl group from the IR spectrum,
It was found that most of the reaction occurred, and (CH ₃ O) ₃ Si
A polyether terminated with -CH ₂ CH ₂ CH ₂ O- groups was obtained. To this was added 16 g of dibutyltin dilaurylate as a curing agent, and the mixture was cured at room temperature in the air on a flat shear to produce a film with a thickness of 1 mm. The membrane was easily formed. To measure the anticoagulant property, place the membrane cut into 3cm x 3cm squares on a watch glass with a lid in a constant temperature bath at 37°C, and add dog ACD blood (citrate) onto the membrane and the glass of the watch glass. After a certain volume of stored blood (preserved blood made non-coagulable by adding soda, glucose, etc.) was added, an aqueous calcium chloride solution was added, and the amount of coagulated blood (thrombus) was measured at predetermined intervals. The results were determined as thrombus formation rate (%) = weight of thrombus formed on the sample after a certain period of time / final weight of thrombus formed on glass x 100. For comparison, a polyvinyl chloride resin film and glass were tested at the same time with the same blood. The results are shown in FIG. 1, and as can be seen from this figure, the cured product of the present invention has excellent anti-blood coagulability. Example 2 Dehydrated polytetramethylene glycol with an average molecular weight of 2000 was placed in a pressure-resistant reaction vessel equipped with a stirrer and replaced with nitrogen.
I took 200g. followed by dehydrated tetrahydrofuran
500ml, 4,4'-diphenylmethane diisocyanate 12.5g, diazabicycloundecene 0.01g
was added, and the reaction was carried out at 50°C for 2 hours. Subsequently, 8.3 g of allyl isocyanate was added and reacted at 50° C. for 10 hours to obtain a polyether urethane having an average molecular weight of about 4,400 and having unsaturated groups at both ends. Subsequently, 8.5 g of methyldimethoxysilane and 0.2 ml of a catalyst solution of chloroplatinic acid (a solution of 2 g of H ₂ PtCl _{6.6H 2} O dissolved in 9 ml of isopropanol and 82 ml of tetrahydrofuran) were added, and the mixture was reacted at 80°C for 10 hours to form a polyether main chain. inside Contains one group on average,

[Formula] A silyl group-terminated polyether urethane containing a group at the end was obtained. Next, add 4 g of dibutyltin dilaurate to this solution.
added. A glass rod with a diameter of 5 mm was attached to this solution, and a tube was prepared by the so-called dipping method.
Curing was carried out in a dust-free room at room temperature for one day. Tubes of constant thickness were easily obtained in a short time. The anticoagulability of this cured product was measured using an inner diameter of 10
After coating the inner wall of a glass test tube with a diameter of 100 mm and a length of 100 mm with this solution, approximately 1 ml of freshly drawn blood was poured into the tube, and the coagulation time at 37° C. was measured. For comparison, similar test tubes coated with vinyl chloride resin and similar test tubes without coating were tested with the same blood at the same time. The results are shown in Table 1. As can be seen from this table, the cured product of the present invention had excellent anti-blood coagulability.

[Table] Example 3 30% tetrahydrofuran solution of silyl group-terminated polyether urethane prepared by the method of Example 2
To 100ml, 3g of terminal trimethoxypolydimethylsiloxane with a molecular weight of 3500, dibutyltin dilaurate
0.5g was added and mixed by stirring. The mixture was coated on the blood-contacting surface of a sheet cut out from a blood bag (made of vinyl chloride), and then the tetrahydrofuran was removed by drying, followed by curing. The cured product was cured in a dust-free room at room temperature for one day. The anticoagulant properties were measured in the same manner as in Example 1. For comparison, the blood-contacting surface of an uncoated blood bag and the glass were tested with the same blood at the same time. The results are shown in FIG. 2, and as can be seen from this figure, the cured product of the present invention has excellent anti-blood coagulability.

[Brief explanation of drawings]

FIGS. 1 and 2 are graphs showing the results of the anti-blood coagulability test of the cured products in Example 1 and Example 3, respectively.

Claims (1)

[Scope of Claims] 1 The main chain consists essentially of at least one kind of polyether, polyester, polyurethane, polyurethane urea, polysiloxane, polycarbonate, and vinyl polymer, and has a crosslinkable silyl group represented by the following formula. A medical material comprising a cured product of a polymer having a molecular weight of 500 to 15,000 (hereinafter referred to as component A) having at least one component in one molecule. (In the formula, R is a substituted or unsubstituted monovalent organic group having 1 to 20 carbon atoms or a triorganosiloxy group, and X is a hydroxyl group, hydride group, halogen group, alkoxy group, acyloxy group, ketoximate group. group, amide group, acid amide group,
a group selected from aminooxy group, alkenyloxy group and mercapto group, a is an integer of 0, 1 or 2, b is an integer of 0 or 1, m is an integer of 0 to 18) 2 a crosslinkable silyl group, The medical material according to claim 1, comprising at least one A component per molecule at the terminal and/or side chain. 3. Claim 1, in which the polymer having a crosslinkable silyl group is cured at room temperature by moisture.
Medical materials listed in section. 4. The medical material according to claim 1, which is used in a part of a medical device that comes into contact with blood in at least one part thereof. 5. The medical material according to claim 1, which is in the form of a membrane. 6. The medical material according to claim 1, which has a tube shape. 7. The medical material according to claim 1, which is a surface coating material for an instrument that comes into contact with living tissue or infusion fluid.