JPH1024099A - Medical impelentn having smoothed surface when wetted, and manufacture thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical inplenent of which surface is smoothed for facilitating insertion of a catheter or the like into a body cavity, and a manufacturing method thereof. SOLUTION: A composite layer of an inner layer and an outer layer is formed on the surface of a medical device comprising material of polyvinyl chloride, the inner layer is formed by applying water liquid comprising a cross linking agent having less hydrophilic property and reactive polyurethane to the surface of base material, and applying a drying process, and the outer layer is formed by applying solution comprising water-soluble urethane polymer having active hydrogen and water-soluble urethan prepolymer having block isocyanate radicals, and appling a heating process.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical device having a surface which is easily lubricated when wet and a method for producing the same, and more particularly to a medical device which is mainly inserted into a body, and which has a slippery surface so as to be easily inserted into a body cavity. The present invention relates to an improvement of a medical device formed with the above, more specifically, a medical device such as a catheter which can be easily inserted into a body cavity.

[0002]

2. Description of the Related Art When using catheters inserted into a body cavity such as a blood vessel or a urethra or a tissue, it is desirable to minimize damage to the tissue by these medical devices. For this purpose, lubricants such as oil have often been applied to the surfaces of these medical devices at the time of insertion into the body. However, since their operability is not sufficient, various technical improvements such as using a material having a low coefficient of friction or coating these materials have been attempted. Among these, the method of providing a hydrophilic layer on the surface is the best, and various materials have been developed and proposed. However, conventional technologies that are practical can be roughly classified into the following three types. .

Example of graft polymerization: A method in which a radical polymer generated on a substrate surface of a medical device by some method is used to graft-polymerize a hydrophilic polymer. Example of use of isocyanate and organic solvent: A technique in which a number of well-known examples are found. In summary, a layer having an isocyanate group as a reactive functional group is previously provided on the surface of a medical device base material, and active hydrogen is added thereto. A hydrophilic layer is formed on the surface of a medical device by reacting a hydrophilic compound contained therein. As a method of forming an isocyanate layer on the surface of a substrate, a method of applying a stock solution obtained by dissolving an isocyanate compound in an organic solvent such as methyl ethyl ketone (JP-B-59-19582, JP-B 1-333181) is known. . However, these stock solutions tend to be unstable due to moisture absorption and so on, and have a short life span.
The problems of occupational health and pollution prevention due to the use of organic solvent systems were unavoidable. Example in which isocyanate is not used, but use of an organic solvent is unavoidable: a method of exhibiting wettability by using a coating agent composed of an organic solvent, a binder and a hydrophilic polymer (JP-A-7-47120, JP-A-47-47120) 151
59 etc.). The present invention provides a technology belonging to a completely different category from the above.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to solve the problems of the prior art in which the surface of a base material of a medical device has a hydrophilic layer. Process is simple, the process is simple, the use of organic solvents in the process is not required, occupational health and pollution problems can be reduced, and the problem of instability of the isocyanate-containing stock solution can be solved. It is an object of the present invention to provide a highly practical medical device which is stable for a long period of time and further has a surface layer obtained which exhibits excellent lubricity and durability when wet, and a method for producing the same.

[0005]

The medical device of the present invention has a composite layer composed of an inner layer in contact with the surface and an outer layer constituting the outermost surface layer on the surface of the substrate of the medical device, and the inner layer is formed as an outer layer. A substrate adhesion coating film obtained from an aqueous liquid comprising a crosslinking agent and a reactive polyurethane having less hydrophilicity than a water-soluble polymer for use, wherein the outer layer has a water-soluble polymer having active hydrogen and a blocked isocyanate group. A medical device having a surface which is easy to lubricate when wet, characterized in that it is a hydrophilic water-insoluble coating film obtained from an aqueous solution comprising a water-soluble urethane prepolymer. The manufacturing method of the medical device of the present invention, when manufacturing a medical device having a surface which is easy to wet when a surface treatment agent is applied to the medical device, the base surface of the medical device has an inner layer in contact with the surface. Forming a composite layer composed of an outer layer constituting the outermost surface layer, and applying the inner layer to the substrate surface with an aqueous liquid comprising a crosslinking agent and a reactive polyurethane less hydrophilic than the water-soluble polymer for forming the outer layer. And drying, and forming the outer layer by applying an aqueous solution comprising a water-soluble polymer having active hydrogen and a water-soluble urethane prepolymer having a blocked isocyanate group, followed by heat treatment. A method for producing a medical device having a lubricated surface.

Hereinafter, the present invention will be described in detail. The feature of the medical device of the present invention lies in its surface layer, and as long as it is a medical device that needs to have a slippery surface when wet, its type is not particularly limited, and a typical example thereof is a catheter. . The substrate of the medical device to which the surface layer of the present invention is to be provided is not particularly limited, but those having a lower price than urethane polymers such as vinyl chloride polymers and olefin polymers are preferably used. In the present invention, a predetermined inner layer and an outer layer are provided on the substrate surface of these medical devices. First, the processing solution for forming the outermost surface layer exhibiting excellent lubricity when wet is an aqueous solution, a crosslinking agent component and a main chain component coexist in an aqueous solution, and a blocked isocyanate group as a crosslinking agent component. And a water-soluble urethane prepolymer having active hydrogen as a main chain component.

The type of the water-soluble polymer which is one of the main components constituting the processing solution for forming an outer layer of the present invention is not particularly limited as long as it is a water-soluble polymer having an active hydrogen capable of reacting with an isocyanate group. Examples include water-soluble polymers having active hydrogen based on hydroxyl groups, such as glycol, polyethylene oxide, polyvinyl alcohol, and hydroxyethyl cellulose. The degree of polymerization of these water-soluble polymers is not particularly limited, but is preferably 100 or more. Particularly preferred as the water-soluble polymer is polyethylene glycol. A water-soluble urethane prepolymer having a blocked isocyanate group, which is one of the main components constituting the treatment liquid of the present invention, forms a urethane prepolymer having an isocyanate group less than a diol and a diisocyanate, as is well known. The isocyanate group is blocked with a blocking agent. The blocking agent protects the isocyanate group and removes it by heating to regenerate the isocyanate group. Oxime, lactam,
Those which form an amide type compound by reacting with isocyanate groups such as secondary alcohols, phenols, secondary aromatic amines, acetylacetone, and bisulfite are known. This technology is based on “Treateseon Corti” edited by RR Myersra et al.
ng “Vol. 1. A. Damusis et al.“ Urethane Coating ”p431
And so on. The dissociation temperature varies depending on the type of blocking agent. Low dissociation temperature, usually 150 ° C in the present invention
Or less, preferably 100 ° C. or less, particularly preferably 80 ° C.
Blocking agents having the following pulverization temperatures are preferred, and bisulfite is a particularly preferred blocking agent (JP-B-52-39).
720, JP-B-53-29198). In the present invention, the term "water-soluble urethane prepolymer" is used, but the degree of polymerization is not particularly limited as long as the polymer exhibits water-solubility, and includes polymers in a narrow sense (dimer or more).

The amounts of the water-soluble polymer and the water-soluble urethane prepolymer can be appropriately determined according to the intended cross-linking density and the degree of polymerization of each. Usually, 0.5 to 30 parts by weight per 100 parts by weight of the water-soluble polymer is used. A water-soluble urethane prepolymer (solid component) is used. The concentration of these main components in the treatment liquid can also be appropriately determined according to the application means, the degree of polymerization of each, and the like. Usually, about 3 to 40% by weight in terms of solid content concentration is used. The treatment liquid can be easily prepared by mixing aqueous solutions of both main components. The treatment liquid thus prepared is applied to an inner layer previously applied to the surface of the medical article substrate by an appropriate means. Specific examples of the application means include immersion in a processing solution, application using a brush, and spraying using a spray. After the treatment liquid is applied in this manner, the surface is dried and heat-treated. Drying is preferably performed at a temperature lower than the dissociation temperature of the blocked isocyanate, and is usually from room temperature to 50 ° C.
Air dried at about ℃. The optimum temperature of the heat treatment varies depending on the dissociation temperature of the blocked isocyanate which varies depending on the type of the blocking agent, but is usually about 80 to 150 ° C, preferably about 90 to 120 ° C. The heat treatment time is usually about 5 to 20 minutes. Of course, the optimum conditions vary depending on the type of the base material of the medical supplies and the engineering requirements of the heat treatment furnace to be used, etc. However, those skilled in the art can easily determine them by simple experiments according to the respective combinations.

By performing the heat treatment in this manner,
The blocked isocyanate group of the water-soluble urethane prepolymer is converted into a free isocyanate group and reacts with the active hydrogen of the water-soluble polymer to form a crosslink, thereby forming a high-quality hydrophilic water-insoluble coating film. Since there is a possibility that some water-soluble components such as unreacted substances may remain after the heat treatment, it is preferable to perform the extraction treatment with warm water. This extraction process is, for example, 5
It is performed for about 10 minutes to 3 hours with warm water of 0 to 80 ° C. Then, by drying, a surface having excellent lubricity in a wet state is provided as the outermost surface layer of the medical device.

Next, the inner layer will be described. The inner layer is formed by applying an aqueous stock solution comprising a cross-linking agent having less hydrophilicity than the water-soluble polymer used for forming the outer layer and a reactive polyurethane having an active group that binds to the cross-linking agent to the substrate surface of the medical device. It is formed by drying at room temperature or under heating. The cross-linking agent, which is one of the components, is less hydrophilic than the water-soluble polymer used for forming the outer layer, and thus has a high affinity for hydrophobic polymer substrates such as vinyl chloride polymers and polyolefin polymers. The type of these crosslinks is not particularly limited. One example is a water-soluble or water-dispersible epoxy compound, and commercially available products include "Denacol" manufactured by Nagase Kasei Kogyo Co., Ltd. The reactive polyurethane, which is the other component, has an active group that has an affinity for the outer layer and can react with the crosslinking agent, and examples of the active group include a free isocyanate group. These commercial products include a reactive polyurethane dispersion "Superflex" manufactured by Daiichi Kogyo Seiyaku Co., Ltd.
There are systems.

An aqueous solution or aqueous dispersion containing these two components is applied to the surface of a medical device base material. Specific examples of the application means include immersion in a processing solution, application using a brush, and spraying using a spray. After the application, the coating is dried at room temperature or under heating (for example, at about 90 ° C.) to form a coating film which is in close contact with the substrate surface. At this time, unreacted substances that may remain can be removed by extraction with warm water or the like. By forming the outer layer on the inner layer thus formed, the adhesion between the substrate surface and the outer layer is significantly improved, and the properties of the outer layer of the present invention can be maximized. Become.

[0012]

Next, the present invention will be described by way of examples.

(Measurement of Coefficient of Friction) Two cylindrical devices such as catheters are stuck to a glass plate in parallel, a weight of 50 g with a flat bottom is placed on the device, and the glass is gradually inclined in saline. Angle θ when the weight starts
Was measured. The coefficient of friction μ was determined as μ = tan θ.
When the equipment was in the catheter, the measurement was performed by inserting a core wire that fits into the hollow of the catheter to avoid deformation during measurement. In addition, the measured value with respect to the typical commercially available catheter [A] measured by the same means is 0.03 to 0.04, and that of the commercially available catheter [B] is 0.12 to 0.15.
Met.

(Durability test) (1) Mechanical friction resistance test and (2) dry / wet repeated test were performed. (1) In the mechanical friction resistance test, a sample was set in the same manner as in the measurement of the static friction coefficient, and was moistened with a 50 g weight under a 1,000-gram weight.
The coefficient of static friction before and after rubbing was measured and compared. (2) The dry / wet repetition test is to measure the change of the cycle and the static friction coefficient by repeating the wetting in water and the drying at 50 ° C., and has a feature that also reflects the structure of the coated wet film.

Example 1 An example in which an inner layer was formed first to make a polyvinyl chloride tube easy to lubricate. In particular, the stock solution composition and drying conditions were examined. In addition, as a method of evaluating the effect, as described later, a hydrophilic outer layer was formed under certain conditions, and the static friction coefficient was measured. First, a commercially available reactive polyurethane aqueous dispersion “Superflex” R-3000 (Daiichi Pharmaceutical Co., Ltd.) and an epoxy crosslinking agent “Denacol”
EX614B (Nagase Kasei Kogyo Co., Ltd.) was mixed to give an aqueous treatment stock solution for forming an inner layer. Stock solution composition for dip, ie, concentration of R-3000 (100%) (Experiment No. 1 to
Table 7 shows 7), the diluted solution (concentration: 50%) (Experiment Nos. 8 to 10), the added amount of the epoxy-based crosslinking agent, and the drying conditions. In addition, EX-
614B in 1.5 parts (Experiment Nos. 1 to 3) and 3.0 parts (Experiment Nos. 4 to 10).
C.) for 24 hours (Experiment Nos. 1, 4, 8), and then at 90 ° C. (Experiment No. 5), 95 ° C. (Experiment Nos. 2, 6, 8) and 110 ° C. (Experiment conditions 3, 7, 10), respectively.
And drying for 20 minutes. The outer layer was formed under the same conditions in order to evaluate the inner layer with the product after lubricity. The outer layer is formed by the following method. As a water-soluble polymer, polyethylene glycol (molecular weight 35,000)
0 (PEG35000)) was used as a 15 wt% aqueous solution. In addition, "Elastron" manufactured by Daiichi Kogyo Seiyaku Co., Ltd. was used as a water-soluble urethane prepolymer containing blocked isocyanate using bisulfite as a blocking agent. 90 parts of water-soluble polymer and "Elastron" (active ingredient 20%,
(NCO content: 5%) was mixed with 6.7 parts, and further, 0.7 parts of a 10 wt% aqueous zinc acetate solution was mixed as a thermal dissociation catalyst.
To improve the wettability, 3 parts of a perfluoroalkylcarboxylic acid potassium salt solution (manufactured by Dainippon Ink and Chemicals, Inc.) was added to prepare an aqueous stock solution for coating. This stock solution was applied to the surface of the substrate on which the inner layer was formed by a dipping method. Table 1 summarizes the composition of the inner layer stock solution and the effect of drying conditions after application to the substrate. The effect of the thermal drying conditions during the formation of the inner layer is not problematic in practice, although the dried product at room temperature appears to be slightly inferior. Further, the response to the difference in the composition of the stock solution for the inner layer is slow, and the overall process stability is recognized.

[0016]

[Table 1]

Example 2 In this example, the effect of the extraction treatment of the inner layer forming coating film layer was examined. The composition of the inner layer forming stock solution and the drying conditions were Experiment Nos. 4 to 7 of Example 1. After drying, the film was washed with hot water at 70 ° C. for 1 hour. The outer layer was coated under the same conditions as in Example 1. The measurement results of the coefficient of static friction of the 70 ° C. washed product were 0.06, 0.05, 0.05, and 0.05, respectively. I have. Therefore, the positive effect of the cleaning and the negative effect of the additional cleaning step can be selected according to the purpose.

Example 3 In this example, the results of a durability test were shown. (1) Mechanical friction resistance test: 100 with a 50 g weight
A zero rub test was performed using the samples of Experiment Nos. 6 and 9 of Example 1. No significant difference was observed between the static friction coefficients before and after the test. It should be noted that no change was observed between the commercially available catheters [A] and [B] before and after the test. (2) Dry and wet repetition test: The samples of Experiment Nos. 6 and 10 of Example 1 were used in this test. After 10 cycles of dry and wet cycles, no significant difference was observed between the static friction coefficients before and after the test. In the commercial catheter [A], the value did not change after 10 cycles, but in the commercial catheter [B], the coefficient of static friction increased sharply after 4 cycles, and reached 0.5 or more after 5 cycles.

Example 4 In Vitro of Lubricated Polyvinyl Chloride According to the Invention
o Hemocompatibility evaluation was performed. The sample is a polyvinyl chloride plate having an area of 25 mm ² (5 mm × 5 mm) and a thickness of 1 mm. Example 1 The inner layer is formed under the conditions of Experiment No. 4, and the outer layer is treated in the same manner as in Example 1 and washed with hot water. Thus, a hydrophilic coating film was formed. On the other hand, an untreated plate was prepared as a control sample. For evaluation, dog PRP was poured into a plate placed on the bottom of a petri dish and incubated at 37 ° C. for 2 hours. Platelets adhered to the plate were fixed with glutaraldehyde. The control sample was treated in the same manner, and the state of adhesion of both platelets was compared and observed with a scanning electron microscope. As a result, the coated material according to the technology of the present invention is:
Apparently, the amount of adhered platelets was small, and the aggregation state was mild.

[0020]

Industrial Applicability The present invention enables a medical device made of polyvinyl chloride or the like to be easily lubricated, does not use an organic solvent in the treatment process, and reduces pollution and occupational health problems. It's a simple technology that doesn't happen very often. The lubricated medical device has excellent lubricity when wet and its durability, and is easy to insert into a body cavity or the like.

Claims (2)

[Claims] 1. A medical device comprising a substrate having a composite layer comprising an inner layer in contact with the surface and an outer layer constituting an outermost surface layer, wherein the inner layer is less hydrophilic than a water-soluble polymer for forming an outer layer. A substrate adhesion coating film obtained from an aqueous liquid comprising a crosslinker and a reactive polyurethane, wherein the outer layer is obtained from an aqueous solution comprising a water-soluble polymer having active hydrogen and a water-soluble urethane prepolymer having a blocked isocyanate group. A medical device having a surface which is easy to lubricate when wet, characterized in that it is a hydrophilic water-insoluble coating film. 2. A method for producing a medical device having a surface which is easy to lubricate when wet by applying a surface treating agent to the medical device, wherein an inner layer and an outermost surface layer which are in contact with the surface are provided on the surface of the base material of the medical device. Forming a composite layer consisting of an outer layer constituting the outer layer, the inner layer is coated with an aqueous liquid comprising a crosslinking agent and a reactive polyurethane less hydrophilic than the water-soluble polymer for forming the outer layer on the surface of the substrate, and dried. Forming an outer layer by applying an aqueous solution comprising a water-soluble polymer having active hydrogen and a water-soluble urethane prepolymer having a blocked isocyanate group, followed by heat treatment to form a surface which is easy to lubricate when wet. Manufacturing method for medical devices.