JPS61122869A - Medical appliances and its production - 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 (1) Background of the Invention Technical Field The present invention relates to a medical device having the effect of preventing microbial contamination and a method for manufacturing the same.

■ Prior art and its problems It is necessary to use a fluid circuit device connected to a living body, such as a breathing circuit device or a urinary circuit device, during or after surgery or in an ICU or CCU management system.

In recent years, these improvements include improvements in patient monitoring, advances in medical equipment, and
Due to improvements, they tend to be used for longer periods of time.

Medical instruments such as airways, tracheas, organs, gastrointestinal tracts, urethra, blood vessels, and other catheters, as well as guide wires, stylets, and other medical instruments inserted into these, are inevitably exposed to the body. Introduced and sometimes left in place.

Most of the patients who require such medical treatment have a weakened infection defense function. As a result, resident bacteria that are almost non-pathogenic to normal living organisms can become pathogenic or cause rapid proliferation of pathogenic bacteria in patients with reduced infection defense function. An alternation phenomenon occurs and infection occurs.

In addition, medical devices are often used under humidified and heated conditions, which are extremely favorable conditions for the growth of microorganisms, and in the circulatory system, which must be used continuously for long periods of time. It is a major factor in infectious diseases.

Although these medical tools are used in a sterilized state, they are stored inside the medical tools.

Alternatively, when microorganisms such as bacteria are present in the fluid being circulated or in the contact area, the above-mentioned problems arise.

As for these contamination countermeasures, there are problems specific to each tool, and solutions are devised for each tool.

Therefore, as a countermeasure against contamination, an antibacterial agent is present on the surface of the tool. When using antibacterial agents, methods have been used such as directly adsorbing the antibacterial agent or coating the surface with resin and incorporating the antibacterial agent into this coating layer, but depending on the fluid and area that the antibacterial agent comes into contact with, the equipment may The antibacterial agent and coachib layer are easily removed from the surface, making it impossible to obtain a lasting effect.

Furthermore, coatings containing the above-mentioned antibacterial agents are mostly hydrophobic and have problems in terms of biocompatibility.

Particularly in catheters intended for placement in living organisms, the surface that comes into contact with the living body is hydrophobic.

It did not adhere completely to the living body, leaving a small gap, which was likely to become a breeding ground for bacteria. Furthermore, the gap between the two near the biological introduction port of the catheter was highly likely to become an inlet for bacteria.

II. Purpose of the Invention The purpose of the present invention is to provide a medical device that is safe for the human body, has an excellent effect of preventing bacterial and microbial contamination, and has good sustainability and storage stability, as well as a method for manufacturing the same. There is a particular thing.

Such objects are achieved by the present invention as described below.

That is, the first invention has a hydrophilic coating layer on at least the surface of a base material constituting the medical device, in which a reactive functional group present on the surface and a hydrophilic polymer substance or a derivative thereof are covalently bonded. , and the coating layer contains an antibacterial agent with low solubility in water.

Moreover, the second invention is.

Treating at least the surface of a base material constituting the medical device with a solution of a compound having a reactive functional group, forming a base layer so that the reactive functional group is present on at least the surface of the base material,
Next, the reactive functional group and the hydrophilic polymeric substance are covalently bonded by treatment with a solution containing a hydrophilic polymeric substance or a derivative thereof and an antimicrobial agent having low solubility in water, and the antimicrobial agent is applied onto the base layer. A method for manufacturing a medical device, which comprises forming a coating layer of a hydrophilic polymeric substance containing:

m Specific configuration of the invention Hereinafter, a specific configuration of the present invention will be explained in detail.

The hydrophilic polymer substance used in the medical device of the present invention is fixed on the medical device substrate by covalent bonding. In principle, such hydrophilic polymeric substances are chain-like and non-crosslinked polymeric substances -OH.

-CONH2, -COOH, -NH2.

It has a parent group such as -COO-, -3O3-, -NR3+, etc., and may be either water-soluble or water-insoluble.

Natural polymers l) Starch-based carboxymethyl starch, dialdehyde starch 2) Cellulose-based carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose 3) Tannin, nignin-based tannin, nignin 4) Polysaccharide-based alginic acid, gum arabic, Guar gum, tracanth gum, tamarind seeds 5) Protein gelatin, casein, glue, collagen synthetic polymers 1) PVA-based polyvinyl alcohol 2) Polyethylene oxide-based polyethylene oxide, polyethylene glycol 3) Acrylic acid-based polyacrylic acid-based sodium 4) Maleic anhydride-based Methyl vinyl ether maleic anhydride copolymer 5) Phthalic acid-based polyhydroxyethyl phthalate ester 6) Hydrophilic polyester polydimethylol propionate ester 7) Ketone aldehyde resin Methyl isopropyl ketone formaldehyde resin 8) Acrylamide-based polyacrylamide 9) Polyvinylpyrrolidone 10) Polyamine polyethyleneimine II) Polyelectrolyte polystyrene sulfonate 12) Other examples include hydrophilic nylon.

Further, the derivative thereof is not particularly limited as long as it has the above-mentioned polymeric substance as its basic composition, and may be an insolubilized derivative.

For example, esterified products, salts, amidated products, anhydrides, halides, etherified products, hydrolyzed products, acetalized products, formalized products obtained by condensation, addition, substitution, oxidation, reduction reactions, etc. of the above hydrophilic polymeric substances, Alkylorated products, quaternized products, diazotized products, hydrazidated products, sulfonated products, nitrated products, ion complexes.

With substances having two or more reactive functional groups such as diazonium groups, azide groups, isocyanate groups, acid chloride groups, acid anhydride groups, imino carbonate groups, amino groups, carboxyl groups, epoxy groups, hydroxyl groups, aldehyde groups, etc. Crosslinked product.

Examples include copolymers with vinyl compounds, acrylic acid, methacrylic acid, diene compounds, maleic anhydride, and the like.

Further, derivatives obtained by condensation, addition or substitution reactions of these hydrophilic polymeric substances, or partially crosslinked, so-called insolubilized, substances can also be used.

By covalently bonding these with reactive functional groups present or introduced in the substrate or on the surface of the substrate, a hydrophilic surface that does not dissolve in water can be obtained on the substrate.

As mentioned above, there are no particular restrictions on the hydrophilic polymer material for forming the hydrophilic coating layer, but cellulose, maleic anhydride, acrylamide, polyethylene oxide, hydrophilic nylon, hydroxyethyl methacrylate, polyethyl The most typical example is methacrylate. In particular, hydroxypropyl cellulose, methyl vinyl ether, methyl vinyl ether maleic anhydride copolymer, polyacrylamide, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, hydrophilic nylon (AQ-nylon P-70 manufactured by Toshi Co., Ltd.), HEMA, polyHEMA , PMM
A is a substance that is inexpensive, easily available, and has a good safety profile.

The average molecular weight of these hydrophilic polymer substances is not particularly limited, but it is preferably about 3 to 5 million because a layer with an appropriate thickness can be obtained.

The reactive functional group present or introduced into the base material or on the base material surface is not particularly limited as long as it reacts with the hydrophilic polymer substance and fixes it by bonding or crosslinking, but diazonium groups, acid groups, incyanate groups, acid chloride groups, acid anhydride groups, imino carbonate groups, amino groups, carboxyl groups, epoxy groups, hydroxyl groups, aldehyde groups, etc., especially incyanate groups, amine groups, aldehyde groups, etc. and epoxy groups are preferred.

Therefore, polyurethane, polyamide, etc. are suitable as the reactive functional group-containing base material.

Furthermore, base materials that do not contain these reactive functional groups are usually used as base materials constituting the outer walls, inner walls, etc. of various medical devices. In such cases, the substrate is treated with a substance having a reactive functional group as described above, so that the reactive functional group is present in the base material, and a hydrophilic polymeric substance is covalently bonded thereon as in the present invention. There are various forms of bonding, such as covalent bonding, ionic bonding, and physical attachment, but covalent bonding is the most preferred in terms of sustainability.

These methods are not limited to direct bonding to the surface of the base material, but the hydrophilic polymeric substance is covalently bonded to the outermost layer by the presence or introduction of reactive functional groups in or on the polymer layer, as described above. It may also be fixed.

Examples of substances having such reactive functional groups include ethylene diisocyanate, hexamethylene diisocyanate, xylene diisocyanate, toluene diisocyanate, diphenylmethane diisocyanate, naphthalene diisocyanate, diphenylmethane diisocyanate, phenylene diisocyanate, cyclohexylene diisocyanate, triphenylmethane triisocyanate, Polyisocyanates such as toluene diisocyanate, and ducts or prepolymers of these polyincyanates and polyols, etc., for example, low molecular weight polyamines such as ethylenediamine, trimethylenediamine, 1,2-diaminopropane, tetramethylenediamine, 1.3 -Diaminobutane, 2,3-diaminobutane, pentamethylenediamine, 2,4-diaminopentane, hexamethylenediamine, octamethylenediamine, nonamethylenediamine, decamethylenediamine, undecamethylenediamine, dodecamethylenediamine, tridecamethylene Diamine, octadecamethylenediamine, N,N-dimethylethylenediamine, N,N-diethyltrimethylenediamine, N,N-dimethyltrimethylenediamine, N,N-dibutyltrimethylenediamine, N,N,N'-1 Ethylethylenediamine, N-
Methyltrimethylenediamine, N,N-dimethyl-p-
2-enylenediamine, N,N-dimethylhexamethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, heptaethyleneoctamino, nonamethylenediamine, 1,3-bis(2'-
7minoethylamine)propane, bis(3-7minopropal)amine, 1.3-bis(3'-aminopropylamino)propane, 1.2.3-triaminopropane,
Tris(2-7minoethyl)amine, tetra(aminomethyl)methane, methyliminobispropylamine, methyliminobisethylamine, ethyliminobisethylamine, N-7minoprovil-2-morpholine, N-aminoprivyl-2-pipecoline, N-(2-and droxyethyl)trimethylenediamine, xylylenediamine, phenylenediamine, piperazine, N-methylpiperazine,
Examples include N-(2-aminoethyl)ethanolamine, N-7minoethylpiperazine, N,N,N'N'-tetramethylethylenediamine, N,N,N,N'N'-tetramethyltetramethylenediamine, etc. Poly(alkylene polyamine) synthesized from (I) amine and alkylene civalide or epichlorohydrin as a polymeric polyamine [Encyclovidia e of Φ Polymer Φ Science and Technology (Enc7c
ropedia of Po17mer 5science
and Techn-o1og7) I Volume 0, 6
[Page 16], [■] Alkylenepominaceous polymers obtained by ring-opening polymerization of fullkyleneimines such as ethyleneimine and propyleneimine [Ensaucropidia of Polymer Science and Technology, Vol. 1, 734 H.C.], (m) Other polyamines such as polyvinylamine and polylysine.

In addition, glutaraldehyde, terephthalaldehyde,
Isophthalaldehyde, dialdehyde, starch, gallyoxal, malonaldehyde, succinic aldohyde,
Adipaldehyde, pimelindialdehyde, superingialdehyde, malealdehyde, 2-pentene],
There are polyaldehydes such as 5-dialdehyde, and polyepoxides such as ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene diglycidyl ether, hexanediol diglycidyl ether, and trimethylolpropane triglycidyl ether. .

Among these, 4,4'-diphenylmethane diisocyanate, 7-duct (adduct) of tolylene diisocyanate and trimethylolpropane, 7-duct of hexamethylene diisocyanate and trimethylolpropane, or their trimer, diethylenetriamine are the most preferred. preferable.

In the present invention, the base material applied to the outermost layer includes, for example, polyamide, polyester, polyvinyl chloride,
Polystyrene, polyacrylic acid ester, polymethacrylic acid ester, polyacrylonitrile, polyacrylamide, polyacrylic acid, polymethacrylic acid, polyethylene, polypropylene, polyvinyl alcohol, polymaleic anhydride, polyethyleneimine, polyurethane, polyvinyl acetate, silicone resin, various It may be any of various organic polymer base materials such as latex, various copolymers and blends thereof, and various inorganic or metal base materials such as glass, ceramics, and stainless steel.

These base materials may contain various additives as necessary.

The base material is preferably polyvinyl chloride, polyurethane, polyamide, latex, or polyester.

Therefore, when using these other resins, metals, glass, etc. as a base material, a layer consisting of various organic polymer resins similar to those used for the above-mentioned base material is used.

More preferable results can be obtained by forming a lubricating layer on the surface of the base material in advance and introducing a reactive functional group therein, or by blending the resin with a substance having a reactive functional group.

To form the coating layer of the present invention on such a base material,
You can do as follows.

When using an ordinary base material that does not contain reactive functional groups, first, a base layer is formed.

To form the base layer, the base material may be immersed in a solution containing the above-mentioned compound having a reactive functional group, and then dried.

In such a case, examples of solvents used include ketones such as methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone, butyl acetate, ethyl acetate, and carpitol acetate.

Any of ester systems such as butyl carpitol acetate, ether systems such as methyl cellosolve, ethyl cellosolve, and tetrahydrofuran, aromatic systems such as toluene and xylene, halogenated alkyl systems such as dichloroethane, and alcohol systems may be used.

However, the solvent is preferably one that dissolves or swells the resin base material (in some cases, the resin coating layer previously formed on the surface of the base material).
This is because the adhesion strength of the coating layer improves and the lasting effect becomes greater.

Particularly suitable solvents include methyl ethyl ketone, cyclohexanone, tetrahydrofuran, xylene, and methyl alcohol.

In addition to dipping treatment, brush painting, spinner coating, etc. are also possible.

The subsequent drying step is to evaporate the solvent, and is usually carried out at room temperature to about 80"0 for about 5 minutes to 48 hours.

In addition, as described above, when coating the base material surface with the contact layer J in advance, a conventional method may be followed.

The substrate on which the underlayer has been formed is then treated (in some cases without forming an underlayer) with a solution containing the hydrophilic polymeric substance of the present invention and an antibacterial agent with low water solubility.

The solvent used in this case is one that does not react with the reactive functional groups present in the base material or adhesive layer, that is, one that does not react with incyanate groups and amine groups, and methyl ethyl ketone, tetrahydrofuran, acetone, etc. are particularly preferred. Particularly suitable are those that have solubility and swelling properties in the base material.

Antibacterial agents with low water solubility to be included in the hydrophilic coating layer of the present invention include N-(fluorodimethylthio)-phthalimide, 2-(4-thiazolyl)-benzimidazole, N-dimethyl-N' -Phenyl-(N
”-fluorodichloromethylthio)-sulfamide, 2
゜4.5.6-Titrachloroisophthalonitrile, parachloromethaxylenol, 2-pyridinethiol-1-
Ogo site sodium salt.

One or more compounds from the group consisting of 2-pyridinethiothyl-1-oxide zinc salt and 2,4.4''-trichloro-2'-hydroxydiphenyl ether are included.

In this case, particularly preferably used compounds are N-(fluorodichloromethylthio)-phthalimide, 2-(4-thiazolyl)-benzimiguzole, N-dimethyl-N
'-Phenyl-(N'-fluorodichloromethylthio)-
The compound is one or more compounds selected from the group consisting of sulfamide, 2.4.5.6-titrachloroisophthalonitrile, and 2,4.4'-trichloro-2'-hydroxydiphenyl ether.

These compounds contact and kill microorganisms present in fluids such as gases or liquids.

The concentration of the hydrophilic polymer substance is preferably 0.1 to 15%, particularly 0.5 to 10%, and the concentration of the antibacterial agent is preferably 0.5 to 20%.

Further, the treatment is usually carried out by dipping treatment as described above, but in addition to this, various coating methods can also be used.

The processing temperature is room temperature to 80°C, and the processing time is 1 second to 4
It will take about 8 hours.

The subsequent drying process is performed at room temperature to about 80°C.
It may be done for about 5 minutes to 48 hours.

In this way, the hydrophilic polymeric substance of the present invention is covalently bonded to the reactive functional group to form a coating layer, and the antibacterial agent is contained in the coating layer.

Note that the thickness of the coating layer is approximately 500 gra or more.

Further, it is preferable to perform neutralization treatment with an aqueous solution of a base such as aminomethylpropanediol.

Note that the neutralization treatment time is about 1 second to 10 minutes, and the aqueous solution concentration is about 0.61 to 10%.

In the present invention, the structure of the first layer containing an antibacterial agent with low solubility in water that is fixed to the base material by covalent bonding or the like differs depending on whether the polymeric substance is hydrophilic or not. If the hydrophilic polymer material is used, the coating layer maintains lubricity for a long time.

When the antibacterial agent is impregnated with body fluids and becomes wet, the antibacterial agent has low solubility in water, so not all of it is transferred or dissolved in the body fluids, so the antibacterial effect remains for a long time. It is assumed that the

Further, although the detailed mechanism regarding the lubricity of the coating layer is not clear, it is thought to be as follows.

Hydrophilic polymers are generally in an aqueous solution or gel state,
Hydrates through parent groups such as -NH2, -COOH, and -OH.

Although the hydration state is not necessarily clear, it is thought that there are two types of water: bound water, which is incorporated into the polymer and has relatively little movement, and water with a high degree of freedom.

It is thought that one of the reasons for the development of lubricity when wetted with water is the presence of this free water. Although they absorb water and swell very well, they have poor lubricity, and the reason why some materials with relatively low molecular weights have low lubricity is due to this lack of free water, and this is affected by the structure and polarity of the polymer. It is thought that

That is, materials with crystalline molecular structures such as cellulose-based polymers do not have much free water, and the movement of the entire molecule is not as smooth as in those with chain structures.

Therefore, CMC, HPC, etc. do not have much lubricity, and P
VM/MA (Gaff 1, Tsu), PVP, FAA
It is thought that this is the reason why these materials have high lubricity.

In addition, even those that have a chain structure and a parent group, those that are bonded to the base material at various places, and those that have cross-linked molecules,
The molecules themselves lose their degree of freedom and their lubricity decreases.

Furthermore, when the bond with the base material is a strong bond such as a covalent bond, it is very advantageous for maintaining lubricity.

Therefore, a state in which the chain structure molecules having a hydrophilic group and being fixed to the base material by covalent bonds extend relatively long is the state in which the lubricity is highest.

If the polymeric substance is water-insoluble, when the coating layer comes into contact with body fluids, only the antibacterial agent exposed on the surface comes into contact with the body fluids.

Since the antibacterial agent has low solubility in water, it does not dissolve easily in body fluids, etc., and even if it dissolves, the antibacterial agent in the coating layer migrates to the surface, so it has an antibacterial effect for a long time. Think of it as something.

Therefore, as the medical device of the present invention, there are the following medical devices provided with the coating layer of the present invention on the surface as described below.

1) The outer or inner surface of catheters that are inserted or indwelled into the gastrointestinal tract orally or nasally, such as gastric tube catheters, feeding catheters, and ED (enteral feeding) tubes.

2) Catheters that are inserted or indwelled into the airway or trachea orally or nasally, such as oxygen catheters, oxygen cameras, tubes and cuffs for endotracheal tubes, tubes and cuffs for tracheostomy tubes, and endotracheal suction catheters. surface or inner surface.

3) The outer or inner surface of catheters for insertion or indwelling into the urethra or ureter, such as urinary catheters, urinary catheters, balloon catheters, and balloons.

At this time, since the frictional resistance is low, insertion is easy and pain to the patient is reduced. Furthermore, while the balloon is indwelled in tissue, it has low frictional resistance with the mucous membrane, and contains an antibacterial agent, so there is little risk of inflammation or damage. Even when applied to such an elastic body, its physical properties do not change at all.

4) External or internal surfaces of catheters for use in various body cavities or tissues such as suction catheters, drainage catheters, rectal catheters, etc.

In addition, by forming the coating layer of the present invention on the inner surface of these catheters 1) to 4), there are advantages such as reducing adhesion of nutrients, tissue fluid, etc., and not inhibiting the lumen flow path.

5) The outer or inner surface of catheters for insertion into or placement in blood vessels, such as indwelling catheters, IVH catheters, thermodilution catheters, angiography catheters, dilators, and introducers.

In the catheter of the present invention using a hydrophilic polymer substance, the hydrophilic substance on the surface maintains extremely excellent lubricity over a long period of time.

This reduces inflammation and damage caused by physical pressure and abrasion on the urethral wall and bladder during insertion and indwelling, and is effective in preventing infection.

Furthermore, the antibacterial agent contained in the hydrophilic substance is gradually eluted into urine, secretions, etc., and in the event of a urinary tract infection, it is present in the gap between the catheter and the urethral wall and on the inner wall of the catheter, where bacteria can enter. .

The elution concentration of the antibacterial agent can be controlled by adjusting the amount of the antibacterial agent included in the hydrophilic substance. Additionally, the antimicrobial agents used here are extremely difficult to dissolve, allowing their effective concentrations to be maintained over long periods of time.

That is, by including an antibacterial agent in the coating layer of a hydrophilic substance, it is possible to provide a catheter with an even higher infection prevention effect.

In addition, since the antibacterial agent is contained in a hydrophilic substance, the initial elution of the antibacterial agent is rapid, making it possible to reach an effective concentration in a short period of time, making it effective against recent invasions associated with insertion. Since the medical device of the present invention contains an antibacterial agent with extremely low solubility in water in the coating layer, it has excellent microbial contamination protection even when used for a fairly long period of time. ]E effect and suppresses the occurrence of infectious diseases.

It also prevents cross-infection caused by medical staff handling medical equipment, and in the past, it was necessary to frequently replace medical equipment to prevent the risk of infectious diseases. Since these are no longer necessary, the period in which instruments can be used is extended, which also helps reduce medical costs.

Furthermore, it is easy to use because it has antibacterial and antimagnetic effects without requiring any special equipment or operations.

Example 1 Below, an example of the present invention will be specifically shown regarding a Foley catheter made of natural rubber.

The catheter was immersed in a 1% MEK solution of diphenylmethane diisocyanate at room temperature for about 30 minutes, then taken out and dried at 60° C. for about 30 minutes to obtain a coating having reactive functional organs on the inner and outer surfaces.

Next, the catheter was immersed for about 2 seconds at room temperature in a solution of 1 part of Hafestel, a polymethyl vinyl ether maleic anhydride copolymer, and 5 parts of N-(fluorodichloromethylthio)-phthalimide dissolved in 100 parts of THF. ,
It was taken out and dried at 60°C for 24 hours to obtain a layer of halfester of polymethyl vinyl ether maleic anhydride copolymer containing N-(fluorodichloromethylthio)-phthalimide.

Next, as a post-treatment, aminomethylpropanediol 0.
The catheter was immersed in a solution prepared by dissolving 1 part of sodium chloride and 1.0 part of sodium chloride in 100 parts of water at 50° C. for 2 hours, and then washed with water at room temperature for 24 hours to remove residual aminomethylpropanediol. Furthermore, the catheter according to the present invention was obtained by drying at 60° C. for 24 hours.

Example 2 Approximately half of the total length of a polyvinyl chloride endotracheal tube (if equipped with a cuff, inflate by injecting air equivalent to the remaining volume of the cuff) into a 1% MEK solution of diphenylmethane diisocyanate at room temperature. After being immersed for about 30 seconds, it was dried at about 60° C. for 30 minutes.

Next, 1 part of an esterified product of polymethyl vinyl ether maleic anhydride copolymer, 2,4°4'-trichloro-2
'-Hydroxydiphenyl ether 10 parts, THF89
The endotracheal tube was immersed in a mixed solution of ~90 parts at room temperature for about 1 hour, and then dried at 60°C for 24 hours to obtain an endotracheal tube containing the antibacterial agent in the hydrophilic layer.

[Antibacterial effect test]

Sample 1> A 0.411 m thick sheet of polyvinyl chloride was immersed in a 1% MEK solution of diphenylmethane diisocyanate for 30 seconds, and then dried at 60°C for 30 minutes.

Next, 1 part of esterified product of methyl vinyl ether maleic anhydride copolymer, N-(fluorodichloromethylthio)
-0.1 part, 1 part, 5 parts of phthalimide, THF89~
After being immersed in 90 parts of the mixed solution for 1 second, it was dried at 60° for 24 hours.

Furthermore, an aqueous solution of 0.01% aminomethylpropanediol and 1.0% sodium chloride was heated to 50°C, immersed for 2 hours, washed with water at room temperature, and dried at 60°C for 24 hours. After cutting it to size, it was sterilized with ethylene oxide gas.

Trial j142> Sample 2 was prepared in the same manner as Sample 1 except that N-dimethyl-N'-phenyl (N'-fluorodichloromethylthio)-sulfamide was used as the antibacterial agent.

Test Method> The above bacteria were cultured in TBS medium at 37° C. for 20 hours with shaking, and a suspension of each strain in distilled water of 10 6 /+JL was obtained.

100 rs of this bacterial suspension was placed on the sample, placed in a glass Petri dish moistened with sterile water to prevent the bacterial suspension from drying out, and cultured at 25°C for 24 hours.

After culturing, the bacterial solution was sucked out, diluted with a 100 m magazine of sterile distilled water, and the solution was discharged through a filter. The filters were then cultured in TSA medium. After culturing, the presence or absence of colonies formed on the felter was observed.

The results were as shown in Tables 1 and 2.

Table 1 (Sample 1) Concentration E, coli Sta, au
reus Ps, aergrnosa
K1. pneumoniae 1% --10+ 1% -1115% ----- Table 2 (Sample 2) Concentration E, coli SLa, aureus
Pg, aerginosa K1. pneu
Maniaeo, 1% +-++ 1% --++ 5% ---- Confirmation test for continuous elution of antibacterial agent> A 0.4 mm thick sheet of polyvinyl chloride was placed in a 1% MEK solution of diphenylmethane diisocyanate for 30 seconds. After dipping, it was dried at 60°C for 30 minutes.

Next, 1 part of esterified product of methyl vinyl ether maleic anhydride copolymer, N-(fluorodichloromethylthio)
- 1 part in a mixture of 5 parts of phthalimide and 89 to 90 parts of THF
After immersion for a second, dry at 60°C for 24 hours. moreover,
Aminomethylpropanediol o, oi% An aqueous solution of 1.0% sodium chloride was heated to 50°C and immersed for 2 hours,
Thereafter, the sample was washed with water at room temperature and dried at 60° C. for 24 hours, and the elution concentration of N-(fluorodichloromethylthio)-phthalimide was measured.

The elution concentration was measured using a liquid chromatograph on a liquid obtained by extracting the surface a10CII12 of the sample with IIIfL of distilled water at 37°C. Note that the extract solution was replaced every 24 hours.

The results were as shown in Table 3.

Table 3 Elapsed time 5% (pp@) 3 hours 4.3 6 hours 4.6 1 day 4
, 52 days 3.8 5 days 3,5 6 days 3.6 8 days 3.4 28 days 3.0

Claims (10)

[Claims] (1) At least the surface of the base material constituting the medical device has a hydrophilic coating layer in which a reactive functional group present on the surface and a hydrophilic polymer substance or a derivative thereof are covalently bonded, and the coating A medical device characterized in that the layer contains an antibacterial agent with low solubility in water. (2) Claim 1, wherein the hydrophilic polymeric substance is any one of hydroxypropyl cellulose, methyl vinyl ether maleic anhydride copolymer, polyacrylamide, polyethylene glycol, polyvinylpyrrolidone, or polyvinyl alcohol. medical equipment. (3) The antibacterial agent is N-(fluorodichloromethylthio)-phthalimide, N-dimethyl-N'-phenyl (N
'-fluorodichloromethylthio)-sulfamide, 2-
(4-thiazolyl)-benzimidazole, 2,4,
5,6-tetrachloroisophthalonitrile, 2,4,4
A patent claim that is at least one antibacterial agent selected from the group consisting of '-trichloro-2'-hydroxydiphenyl ether, 2-pyridinethiol-1-oxide sodium salt, and 2-pyridinethiol-1-oxide zinc salt. The medical device described in item 1 of the scope. (4) The medical device according to claim 1, wherein the medical device is a catheter. (5) The medical device according to claim 4, wherein the hydrophilic coating layer containing the antibacterial agent is formed on at least the outer surface of the portion to be inserted into the human body. (6) Treat at least the surface of a base material constituting a medical device with a solution of a compound having a reactive functional group, form a base layer so that the reactive functional group is present on at least the surface of the base material, and then treated with a solution containing a hydrophilic polymeric substance or its derivative and an antibacterial agent with low solubility in water,
A method for manufacturing a medical device, comprising covalently bonding the reactive functional group and the hydrophilic polymer substance to form a coating layer of the hydrophilic polymer substance containing an antibacterial agent on the base layer. (7) Claim 6, wherein the hydrophilic polymeric substance is any one of hydroxypropyl cellulose, methyl vinyl ether maleic anhydride copolymer, polyacrylamide, polyethylene glycol, polyvinylpyrrolidone, or polyvinyl alcohol. Method of manufacturing medical devices. (8) The antibacterial agent is N-(fluorodichloromethylthio)-phthalimide, N-dimethyl-N'-phenyl (N
'-fluorodichloromethylthio)-sulfamide, 2-
(4-thiazolyl)-benzimidazole, 2,4,
5,6-tetrachloroisophthalonitrile, 2,4,4
A patent claim that is at least one antibacterial agent selected from the group consisting of '-trichloro-2'-hydroxydiphenyl ether, 2-pyridinethiol-1-oxide sodium salt, and 2-pyridinethiol-1-oxide zinc salt. A method for manufacturing a medical device according to item 6. (9) The method for manufacturing a medical device according to claim 6, wherein the medical device is a catheter. (10) The method for manufacturing a medical device according to claim 9, wherein the hydrophilic coating layer containing the antibacterial agent is formed on at least the outer surface of the portion to be inserted into the human body.