JPH0225625B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to improvements in urinary catheters made from olefinic polymers, diene polymers, or silicone polymers.

Patients with spinal cord injury, cerebral hemorrhage, encephalomalacia, or surgery are often accompanied by symptoms such as difficulty urinating and urinary incontinence. In such cases, urinary catheterization using a catheter is used to ensure a smooth urinary tract, thereby promoting maintenance or improvement of renal function or preventing urine leakage. The catheter used in this case is particularly called a urinary catheter.
For its intended use, it is required to have sufficient flexibility, elasticity, and harmlessness to the human body, and most of them are made from olefin polymers, diene polymers, or silicone polymers.

Urinary catheterization is an extremely useful treatment method that allows prompt urination, and is therefore frequently used not only in urology but also in fields such as surgery, internal medicine, and obstetrics and gynecology. However, once a urinary catheter is placed in the urinary tract, infection is inevitable. That is, since a urinary catheter is left in the urinary tract for a long period of time, bacteria can enter the catheter through the catheter, frequently causing symptoms such as urethritis, cystitis, and pyelitis. When the conventional open continuous urinary catheterization method (a method of collecting urine in an unsterilized container such as a glass bottle) was performed, infection occurred in 42 to 80% of cases within 3 days; On the same day, it was reported that all cases were infected.

For this reason, methods such as cleaning the bladder and injecting disinfectants have been used to prevent urinary tract infections, but these procedures are cumbersome and are inconvenient as they can become a source of new infections. There are many faces.

Chemotherapy such as prophylactic administration of antibiotics is also used, but there are problems with side effects that occur frequently even with large doses or depending on the type of antibiotic, and bacterial replacement once an infection occurs. Local use of antibiotics is strongly desired, to the extent that unplanned chemotherapy is said to be harmful due to problems such as the tendency for antibiotics to develop.

Regarding the topical use of antibiotics, there are methods such as applying antibiotic ointment to the urinary catheter, coating the wall with resin, and using this coating layer with antibiotics (Special Publications Act 1977).
However, with these methods, the antibiotic is simply adsorbed to the support layer, so the antibiotic is washed away by urine within a very short period of time after being instilled in the body, and is not released from the body. It cannot be used satisfactorily because it leaks and its antibacterial function is no longer recognized.

In addition, a method of injecting a diluted antibiotic solution directly into the bladder using a so-called three-way catheter is also used as a local treatment method, but it is difficult and cumbersome to handle, so it is not recommended in some urology departments. The current situation is that it has only been adopted and is not used in other clinical areas.

Bacteria can enter the urinary catheter backwards through the gap between the urinary catheter and the urinary mucosa (extraluminal route), through the joint between the urinary catheter and the duct (including procedures such as cleaning), and from the urinary storage area into the duct and the urinary duct. There is retrograde movement inside the urinary catheter (intraluminal route). In the case of invasion through the extraluminal route, bacteria resident in the urethra quickly ascend along the wall of the urinary catheter in the early stages after placement.
reaches the bladder neck. For such infections, the antibiotics present on the wall of the urinary catheter can exert an antibacterial function because they can come into direct contact with bacteria. However, bacteria that enter through the intraluminal route, such as through the urinary collector, that is, fall into or enter the urinary collector, multiply in the collected urine and reach the bladder as the urine flows backward and air bubbles rise. . actual,
In static experiments, it has been confirmed that bacteria travel upstream in the urine like a carp climbing a waterfall. When it comes to invasion from this route, the antibiotics present on the wall of the urinary catheter may not be able to come into direct contact with the bacteria, so there is a high possibility that bacteria that cannot be affected by the antibacterial function will remain. The ability to prevent infection is not sufficient. In order to have the ability to prevent infection from all entry routes, antibiotics must not only exist on the wall of the urinary catheter, but also gradually leave the wall and diffuse into the urine. It is necessary to come into contact with bacteria that float upward. In this case, the speed at which the antibiotic moves away from the wall surface becomes an issue. As mentioned above, when using methods such as adsorbing antibiotics on the urinary catheter, applying ointment containing antibiotics, or coating the wall with resin and impregnating this coating layer with antibiotics. During this period, antibiotics are easily washed away by urine and flow out of the body, and are no longer present on the walls or in the urine in an extremely short period of time. This means that the ability to prevent infection is completely lost after being left in the body for an extremely short period of time. Therefore, it is important to control the rate at which antibiotics leave the wall and maintain what is called the urinary concentration of antibiotics above an effective concentration over a long period of time to prevent infection. .

In view of the current situation, the present inventors developed a urinary catheter that is easy to use, does not become a new source of infection, and has the ability to prevent infection from all entry routes over a long period of time. As a result of intensive research with the aim of providing When a urinary catheter is left in the body, antibiotics are washed away by urine for a short period of time and do not leak out of the body, but they gradually separate from the wall through ion dissociation at a desired rate and diffuse into the urine, resulting in effective treatment. The present invention was achieved by discovering that the urinary concentration can be maintained for a long period of time.

That is, the present invention provides a urinary catheter made of an olefinic polymer, a diene polymer, or a silicone polymer, which is characterized in that an antibiotic is ionically bonded to the inner or outer wall of the catheter. This is a urinary catheter that has the ability to prevent infection.

The olefinic polymer referred to in the present invention refers to a hydrocarbon having one double bond, such as ethylene, propylene, 1-butene, 3-methyl-1-butene, 3,3-dimethyl-1-butene, 1 -Pentene, 4-methyl-1-pentene, 3-methyl-1
-Pentene, 1-hexene, 4-methyl-1-hexene, 5-methyl-1-hexene, 1-heptene, 1-octene, 1-decene, 1-hexadecene, 1-octadecene, vinylcyclopropane,
Vinylcyclohexane, isobutylene, 2-methyl-1-pentene, cyclobutene, norbornene, etc. are monopolymerized or copolymerized by a known method.

The diene polymer referred to in the present invention is a hydrocarbon having two double bonds, such as butadiene, isoprene, 1,3-pentadiene, 1,5-hexadiene, 1,6-heptadiene, etc. Or it refers to a copolymerized product. As an exception, cis-1,4-polymers of isoprene, which are widely found in nature as natural rubber, are also preferably utilized in the present invention.

Other copolymerization components include vinyl acetate, methyl vinyl ether, styrene, vinyl chloride, vinylidene chloride, maleic anhydride, acrylic acid, methacrylic acid, acrylonitrile, methyl methacrylate, sulfur dioxide, vinylpyridine, chloroprene, ethylene oxide, Examples include formaldehyde.

Examples of silicone polymers used in the present invention include dimethylpolysiloxane, methylphenylpolysiloxane, cyanoalkylmethylpolysiloxane, and fluoroalkylmethylsiloxane, which have high elasticity, high strength, and are harmless to the human body. From this point of view, dimethylpolysiloxane is particularly preferred.

Antibiotics used in the present invention include:
For example, erythromycin ethylsuccinate, erythromycin ethyl carbonate, erythromycin glucoheptonate, erythromycin stearate, erythromycin lauryl sulfate propionate, erythromycin lactobionate, triacetyloleandomycin, oleandomycin phosphate, amikacin sulfate, bekanamycin sulfate, aminodeoxykanamycin, Kanamycin monosulfate, tobramycin, acetylkitasamycin, kitasamycin, kitasamycin succinate, kitasamycin tartrate, chloramphenicol, chloramphenicol succinate arginine, chloramphenicol sodium succinate, chloramphenicol stearate, morpholinoacetic acid Chloramphenicol, chloramphenicol palmitate, chloramphenicol stearoylglycolate, chloramphenicol morpholinoacetate sulfate, colistin hydrochloride, colistin, colistin sodium methanesulfonate, colistin sulfate, diyosamycin, diyosamycin propionate, dihydrochloride Streptomycin, dihydrostreptomycin sulfate, combined streptomycin, streptomycin hydrochloride, streptomycin hydrochloride calcium chloride, streptomycin sulfate, streptomycin sulfate isoniazone, cefacetryl sodium, cefazolin sodium, cefapirin sodium, cephalexin, cefaglycine, cefalotin sodium, Cephaloridine, Ceftezol sodium, Cefrazine, Cefamazone,
Oxytetracycline hydrochloride, oxytetracycline, oxytetracycline calcium, chlortetracycline hydrochloride, chlortetracycline, tetracycline hydrochloride, loritetracycline nitrate, tetracycline methylene lysine, tetracycline metaphosphate, loritetracycline, dimethylchlortetracycline hydrochloride, dimethylchlortetracycline, doxycycline hydrochloride, hydrochloric acid Minocycline, methacycline hydrochloride, actinomycin D, azaromycin F, amphotericin B, enviomycin sulfate, enramycin hydrochloride, aureothricin, capreomycin sulfate, cartinophilin, carbomycin,
Gramicidin, gramicidin hydrochloride S, griseofulvin, chromomycin A ³ , gentamicin sulfate, cycloserine, sarcomycin, cytucanin, dibekacin sulfate, acetylspiramycin,
Spiramycin, spectinomycin hydrochloride, daunorubicin hydrochloride, doxorubicin hydrochloride, trichomycin, nystatin, neocarzinostatin,
Novobiocin calcium, novobiocin sodium, biomycin sulfate, bacitracin, variotin, paromomycin sulfate, pimaricin, pyrrolnitrin, sodium fusidate, fradiomycin palmitate, fradiomycin sulfate, bleomycin hydrochloride, bleomycin sulfate, ampicillin, ampicillin sodium, ampicillin phthalate hydrochloride Zill, carbenicillin sodium, carbenicillin intanil sodium, carbenicillin phenyl sodium, phenoxymethylpenicillin, phenoxymethylpenicillin potassium,
Phenoxymethylpenicillin calcium, phenoxymethylpenicillin benzathine, penicillin potassium, penicillin sodium, penicillin procaine, benzylpenicillin aminomethomidine,
Benzylpenicillin potassium, benzylpenicillin sodium, benzylpenicillin procaine,
Benzylpenicillin benzathine, compound penicillin potassium, compound benzylpenicillin potassium, compound benzylpenicillin sodium, compound benzylpenicillin benzathine, clindamycin hydrochloride,
Clindamycin palmitate hydrochloride, lincomycin hydrochloride, amoxicillin, oxacillin sodium, cloxacillin sodium, cyclacillin,
Dicloxacillin sodium, sulbenicillin sodium, pibmecillinum hydrochloride, pheneticillin potassium, flucloxacillin sodium, propicillin potassium, hetacillin potassium, methicillin sodium, pentamycin, polymyxin sulfate B, mitomycin C, maridomycin propionate, micamycin , midecamycin, rifampicin, lipostamycin sulfate, etc., and these can be used alone or in combination of two or more.

Such antibiotics are ionically bound directly to the inner or outer wall of the urinary catheter or to a coating layer provided on the inner or outer wall of the urinary catheter.

The urinary catheter of the present invention can be prepared by the method listed below.

(1) An ion exchange group is introduced into the polymer before molding or into the urinary catheter after molding, and the introduced ion exchange group and the antibiotic are ionically bonded.

(2) A reactive functional group is introduced into a polymer before molding or a urinary catheter after molding, and then a functional group that has the ability to form a covalent bond with the introduced reactive functional group is introduced into the polymer or urinary catheter. Coating a compound with a molecule to covalently bond the functional group of this compound and the introduced reactive functional group,
Thereafter, unreacted functional groups in the coating layer are ionized, and the ion exchange groups and the antibiotic are ionically bonded.

(3) Coating the urinary catheter with a compound having an ion exchange group, and then covalently bonding the ion exchange group in the coating layer to the antibiotic.

According to these methods, antibiotics are held on the inner or outer wall of the urinary catheter through ionic bonds, so unlike antibiotics that are simply held by physical adsorption or coating, they are retained within a short period of time after indwelling. It is not flushed out of the body through urine. In addition, the ionic bonds gradually dissociate due to the influence of the urine pH and metal ions in the urine, and as a result, the antibiotic gradually diffuses into the urine. The concentration is maintained above the effective concentration.

Examples of the above ion exchange groups include ammonium salts, carboxylate salts, and sulfonate salts, and examples of the reactive functional groups include amino groups,
Examples include carboxyl group, acid anhydride group, isocyanate group, sulfonic acid group, bromoacetyl group, and imidocarbonate group.

In order to introduce the above-mentioned reactive functional groups into a polymer, for example, the methods listed below can be adopted, but for olefin polymers, diene polymers, silicone polymers, etc. The method is preferably applied.

Carboxyl groups, acid anhydride groups, etc. are introduced by copolymerizing vinyl monomers with reactive functional groups such as acrylic acid, methacrylic acid, and maleic anhydride with olefins, dienes, and silicones. Furthermore, a carboxyl group can be converted into a chloroformyl group by chlorination and into an epoxy group by glycidylation. Furthermore, the carboxyl group can be changed from an acid hydrazide group to an azide group.

Amino groups are introduced by plasma treatment in the presence of ammonia or a mixed gas of nitrogen and hydrogen.

An oxidizing agent such as potassium permanganate is used to convert internal double bonds into hydroxyl groups. The hydroxyl group can be bromoacetylated with bromoacetyl bromide and converted into an imidocarbonate group.

A sulfonate group is introduced by sulfochlorination and hydrolysis.

Epoxy groups are introduced using peracid, hydrogen peroxide or peracetic acid.

(anhydride) is modified with maleic acid to introduce an acid (anhydride) group.

Chlorformylation using oxalic acid dichloride.

Treat with γ-aminopropyltriethoxysilane to introduce amino groups.

The introduction of ion exchange groups into the polymer is carried out by hydrolyzing the reactive functional groups such as amino groups, sulfonic acid groups, and carboxyl groups introduced by the method described above, or by ionizing them by known methods such as quaternary salt formation. This is achieved by

Compounds used for coating in methods (2) and (3) above include, for example, glutaraldehyde, terephthalaldehyde, isophthalaldehyde, polyaldehydes such as dialdehyde starch, hexamethylene diisocyanate, toluene diisocyanate, xylene diisocyanate, etc. Polyisocyanates such as isocyanates, phenylene diisocyanate, isocyanate derivatives of aniline-formaldehyde, acid chlorides such as azhifoyl chloride, isophthaloyl chloride, terephthalol chloride, cyanuric chloride, polythioisocyanates such as hexamethylenethioisocyanate. , N,N′- such as N,N′-ethylene bis iodoacetamide
Polyepoxides such as polymethylene biiodoacetamide, tetramethylene glycol, glycidyl ether, diglycidyl ether of diethylene glycol, polymaleic anhydride, polyitaconic anhydride, maleic anhydride-butanediol divinyl ether copolymer, maleic anhydride-polypropylene graft Copolymer, maleic anhydride
Polycarboxylic acid anhydrides such as methyl vinyl ether copolymer, maleic anhydride-ethylene copolymer, maleic anhydride-styrene copolymer, N,
Bismaleimides such as N'-ethylene bismaleimide, N,N'-methylenebis(meth)acrylamide, N,N'-hexamethylenebis(meth)
Poly(meth)acryloyl compounds such as acrylamide, N,N′,N″-triacryloylhexahydrotriazine, alginic acid, pectylic acid, acrylic acid, methacrylic acid, maleic acid, fumaric acid, itaconic acid, aspartic acid, glutamic acid, etc. Homopolymers or copolymers or alkyl esters of these acids with methyl, ethyl, propyl, butyl, amyl, hexyl, octyl, dodecyl, etc., halogenated alkyl esters of chloromethyl, 2-chloroethyl, 2-bromoethyl, etc., 2-ethoxy Esters with ether groups such as ethyl, 2-butoxyethyl, 2-(2-ethoxymethoxy)ethyl, phenoxyethyl, glycidyl, 2-aminoethyl, 2-N,N'-dimethylaminoethyl, 2-
N,N'-diethylaminoethyl, 2-N,N'-
Examples include esters with basic nitrogen such as dipropylaminoethyl, monoesters or diesters with ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, etc., and cellulose acetate, cellulose propionate, cellulose butyrate, Esterified derivatives of cellulose such as nitrocellulose, cellulose acetate, cellulose phosphate, cellulose dithiocarboxylate, etherified derivatives of cellulose such as methylcellulose, ethylcellulose, benzylcellulose, trimethylcellulose, cyanoethylcellulose, aminoethylcellulose, oxyethylcellulose,
Polyvinyl alcohol, copolymers of polyvinyl alcohol with ethylene, propylene, vinyl chloride, allyl alcohol, N-vinylpyrrolidone, etc., ether derivatives of polyvinyl alcohol such as methyl, ethyl, propyl, butyl, octyl, dodecyl, phenyl, etc., polyvinyl alcohol Formal, ethanal, butyral, acetal derivatives such as aminoacetal, ester derivatives of polyvinyl alcohol such as acetic acid, formic acid, butyric acid, caproic acid, lauric acid, stearic acid, benzoic acid, ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, Polyols such as cyclohexanediol, pentaerythritol, glycerin, 1,1,1-trimethylolpropane and their carboxymethylated products, polyether polyols such as polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyethylene-polypropylene glycol and their carboxymethylated products Hydroxyl groups at both ends obtained by condensation of dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, sebacic acid, isophthalic acid, phthalic acid, and terephthalic acid with glycols such as ethylene glycol, propylene glycol, and butylene glycol. natural polymers such as starch, gelatin, dextran, carboxymethylated products thereof, and polyamines. Examples of the polyamine include ethylene diamine, trimethylene diamine, 1,2
-Diaminopropane, tetramethylenediamine,
1,3-diaminobutane, 2,3-diaminobutane, pentamethylenediamine, 2,4-diaminopentane, hexamethylenediamine, octamethylenediamine, nonamethylenediamine, decamethylenediamine, undecamethylenediamine, dodecamethylenediamine, Tridecamethylenediamine, octadecamethylenediamine, N,N-dimethylethylenediamine, N,N-diethyltrimethylenediamine, N,N-dimethyltrimethylenediamine, N,N-dibutyltrimethylenediamine, N,N,N' -triethylethylenediamine,
N-methyltrimethylenediamine, N,N-dimethyl-p-phenylenediamine, N,N-dimethylhexamethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, heptaethyleneoctamine, nonaethylenedecamine, 1 , 3-bis(2'-aminoethylamino)propane, bis(3'-aminopropal)
Amine, 1,3-bis(3'-aminopropylamino)propane, 1,23-triaminopropane, tris(2-aminoethyl)amine, tetra(aminomethyl)methane, methyliminobispropylamine, methyliminobis Ethylamine, ethyliminobisethylamine, N-aminopropyl-2
Morpholine, N-aminopropyl-2-pipecoline, N-(2-hydroxyethyl)trimethylenediamine, xylylenediamine, phenylenediamine, piperazine, N-methylpiperazine, N-
(2-aminoethyl)ethanolamine, N-aminoethylpiperazine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-
Poly(alkylene polyamines) synthesized from (i) amines and alkylene dihalides or epichlorohydrin [Encyclopedia of Polymer Science and Technology, (Encyclopedia of Polymer Science and Technology)
Polymer Science and Technology) Volume 10, 616
Page], (ii) Alkylene imine polymers obtained by ring-opening polymerization of alkylene imines such as ethyleneimine and propylene imine [Encyclopedia of Polymer Science and Technology, Vol. 1, p. 734], (iii) Others Examples include polyvinylamine, polylysine, etc. Among these polyamines, polyethyleneimine is particularly preferably used because it is inexpensive, has a large number of NH ₂ groups, and is effective.

In methods (2) and (3), the above-mentioned coating compound is used after being dissolved in an appropriate solvent, or if it is a liquid itself, it is used as is, and the coating compound is used by dipping, spraying, or brushing. It is coated by a known method such as. During coating, the coating compounds may be used alone or in combination. It is especially preferable to use a plurality of coating layers in method (2). For example, in a urinary catheter in which only an insufficient amount of acidic reactive functional groups are introduced,
When it is desired to ionically bond a large amount of antibiotics that only have anion exchange groups, it is necessary to first coat a compound with a sufficient amount of basic functional groups, such as polyethyleneimine, and then coat it with an acidic reactive compound. A compound having an excess of functional groups, such as a maleic anhydride copolymer, is coated. This is achieved by subsequently ionizing the reactive functional groups to obtain cation exchange groups and forming ionic bonds with the anion exchange groups of the antibiotic.
In addition, it is especially preferable to use it in combination with a coating compound in method (3).
In this case, it is expected that the coating layer will be strengthened and the urine insolubilized due to crosslinking between the mixed compounds. Specifically, polyaldehyde, polyisocyanate, acid chloride, polythioisocyanate, N, N ′-Polymethylene biiodine, acetamide, polyepoxide, polycarboxylic acid anhydride, bismaleide, poly(meth)acryloyl compound, etc., mixed with polyamine, polyol, carboxymethylated polyol, etc. are mixed and coated to coat the wall of the urinary catheter. A method in which one compound selected from one of the above compound groups is adsorbed on a urinary catheter in advance before the above reaction or mixing, and then one compound selected from the other group is added and reacted. will be adopted. Among these, combinations of maleic anhydride copolymers and polyvinyl alcohol, polyethylene glycol, polyethylene imine, etc. are particularly preferably used because of their insolubility, biocompatibility, ability to form ionic bonds with antibiotics, and the like.

The solvent used for coating may be any solvent as long as it dissolves the coating compound and does not corrode the urinary catheter material. Solvents that do not compromise stability (eg, tetrahydrofuran-water mixtures for natural rubber) are very useful for efficient coating.

The layer coated using method (2) is completely insoluble in urine and is covalently bonded to the entire inner or outer wall of the urinary catheter, so it will not leak out into the urine or peel off during indwelling. However, when using method (3), depending on the compound used for coating and the material of the urinary catheter, it may be necessary to provide an adhesive layer or mix an adhesive into the coating compound. It is desirable to

To ionicly bond antibiotics, methods such as spraying an antibiotic solution or circulating an antibiotic solution inside a urinary catheter are also used, but the simplest method is to attach an antibiotic solution to a urinary catheter. This method involves immersing the substance in a solution. Generally, it is desirable to adjust the pH of the antibiotic solution to a suitable range in order to efficiently perform ionic bonding. For example, in the case of antibiotics with anion exchange groups, efficient ionic bonding can be obtained by keeping the antibiotic solution alkaline, and in the case of antibiotics with cation exchange groups, keeping it acidic. There are many. This can be achieved, for example, by constantly adding an acid or alkali dropwise while the ionic bonding reaction is progressing.

The urinary catheter of the present invention has the same ability to prevent infection for a long time regardless of which method (1), (2), or (3) is used. The manufacturing process is simple because no manipulation is required, and method (2) allows a large amount of any antibiotic to be ionically bonded, and the coating layer has good adhesion to the urinary catheter. In method (3), there is no need to introduce a reactive functional group, so there is no possibility of impairing physical properties such as strength and elongation of the urinary catheter during the introduction reaction, and the selection process is simple and arbitrary. It is possible to ionically bond large amounts of antibiotics. Furthermore, in the case of methods (2) and (3), selecting a coating compound with high hydrophilic properties, such as carboxymethylated polyvinyl alcohol, has the advantage of reducing pain during indwelling. be.

Hereinafter, the present invention will be explained in more detail with reference to Examples. Note that "parts" in the examples mean "parts by weight."

Example 1 Method of J. Le Bras et al. (Industrial and Engineering Chemistry Product Research and Development Part 2)
Vol., p. 22 (1963)], natural rubber and maleic anhydride are reacted, and per isoprene unit
Natural rubber into which 5.2 mol% of acid anhydride groups were introduced was obtained, and a urinary catheter was molded from this material. After immersing the obtained urinary catheter in water at 100°C for 2 hours, dibekacin sulfate aqueous solution [50 mg
(potency)/100ml] for 2 hours at 7°C while adjusting the pH to 8 using 0.1N sodium hydroxide to obtain a urinary catheter with dibekacin sulfate ionically bonded to its inner and outer walls. Ta.

This material was immersed in test urine at 37°C under sterile conditions.
After one day, Bacillus Subtilis was detected in the test bacteria.
When testing the antibacterial activity of this urine by dropping 2 to 3 drops of test urine onto a cylindrical plate using ATCC6633 using the cylindrical plate method, an inhibition circle was generated, indicating the presence of active antibiotics in the test urine. was confirmed. Furthermore, when the test urine was replaced with new test urine every day and the activity test was repeated in the same manner, an inhibition circle was observed in the test urine collected on the 30th day, and activity was confirmed.

Comparative Example 1 The urinary catheter obtained in Example 1 into which an acid anhydride group had been introduced was treated with dibekacin sulfate aqueous solution in the same manner as in Example 1, without performing hot water treatment at 100°C.

When the urinary catheter thus obtained was subjected to the same activity test as in Example 1, no inhibition circle was observed.

Comparative Examples 2 and 3 A urinary catheter was molded using the natural rubber used in Example 1, treated with dibekacin sulfate aqueous solution in the same manner as in Example 1, and then subjected to the same activity test as in Example 1. However, no inhibition zone was observed in the test urine collected on the third day.

In addition, before ionically bonding the antibiotic to the urinary catheter obtained in Example 1 into which the acid anhydride group was introduced, an activity test similar to that in Example 1 was conducted, but the inhibition circle was It was also not observed in test urine.

Example 2 Natural rubber urinary catheter [Argyle Foley catheter, manufactured by Nihon Sha Wood Co., Ltd.] 100
parts with 20 parts of maleic anhydride and 0.1 part of _FeSO4 .
0.3 parts of Perbutyl H [manufactured by NOF Corporation, t-butyl hydroperoxide] was immersed in an aqueous solution of 300 parts of water, and reacted at 70°C for 8 hours to convert the carboxylate salt into isoprene units. 3 mol% was introduced. This catheter was immersed in an aqueous cyclacillin solution [50 mg (potency)/100 ml] at 70°C for 2 hours, then taken out and dried at room temperature.

About this catheter test bacteria Sarcina
When the same activity test as in Example 1 was conducted using L. lutea ATCC9341, an inhibition zone was observed even in the test urine on the 30th day.

Example 3 The acid anhydride group-introduced urinary catheter obtained in Example 1 was immersed in a 10 wt% polyethyleneimine aqueous solution at 7°C for 30 minutes, and then 2 wt%
It was immersed in a methanol solution of N,N'-dicyclohexylcarbodiimide at 7°C for 20 minutes, then washed with methanol, water, and dried. Furthermore, this catheter was immersed in a water-containing ethanol solution of ethyl bromide (3.3 wt% ethyl bromide dissolved in an equal volume mixture of ethanol and water) at 30°C for 4 hours.
Then, it was thoroughly washed with a mixture of equal amounts of ethanol and water. After cleaning, soak the catheter in aqueous cephalothin sodium solution [50 mg (potency)/100 ml] at room temperature for 2 hours.
After soaking for a period of time, the catheter was washed with water and dried to obtain a urinary catheter with an ionically bound antibiotic.

When the same activity test as in Example 1 was carried out using the obtained catheter, an inhibition zone was also produced in the test urine on the 40th day, confirming that an active antibiotic was present in the urine.

Example 4 Silicone urinary catheters (Argyle Silicone Foley Catheters, manufactured by Nippon Shawood Co., Ltd.) were sequentially subjected to the following treatments.

1.7 in an equal volume mixture of 20wt% glutaraldehyde and 1/15M phosphate buffer (PH7.5).
After standing at ℃ for 30 minutes, it was dried at room temperature for 1 hour.

2 It was left standing in a 10wt% polyethyleneimine aqueous solution at room temperature for 1 hour, and then washed with water.

3 In the same manner as in Example 3, it was treated with a water-containing ethanol solution of ethyl bromide and washed.

4 Methicillin aqueous solution [50mg (potency)/100ml]
After leaving it in a container at 7°C for 24 hours, it was taken out, washed with water, and dried.

When the catheter treated above was subjected to the same activity test as in Example 1 using Sarcina lutea ATCC9341 as the test bacterium, an inhibition zone was also observed in the test urine on the 35th day.

Examples 5 and 6 CGGebelein [Journal of Macromolecule Science Chemistry, 5433
(1970)], an iodoisocyanate group was introduced into the wall of the natural rubber urinary catheter used in Example 2, and then immersed in a 30 wt% polyethyleneimine aqueous solution, and immediately removed after immersion.
After heat treatment at ℃ for 60 minutes, it was treated with a water-containing ethanol solution of ethyl bromide and washed in the same manner as in Example 3.

In addition, the natural rubber urinary catheter used in Example 2 was placed in Perhexa 3M [manufactured by NOF Corporation, 1,1-bis(t-butylperoxy)3,3,5-trimethylcyclohexane] for 30 minutes at room temperature. After being immersed for a minute, it was immersed in a 20 wt % aqueous polyamide (-SO ₃ Na content: 4 mol %) aqueous solution for 5 minutes at room temperature, taken out, and heat treated at 140° C. for 15 hours under nitrogen.

The urinary catheter obtained as above was mixed with cephalothin sodium aqueous solution [50 mg (potency)/100 ml] and dipecadine sulfate aqueous solution [500 ml].
mg (potency)/100 ml] at 7° C. for 1 hour while adjusting the pH to 6 and 9, respectively. When the same activity test as in Example 1 was carried out using this product, inhibition circles were produced in both cases even in the sample urine on the 40th day.

Example 6 The silicone urinary catheter used in Example 4 was treated with 10wt of γ-aminopropyltriethoxysilane.
% chloroform solution at room temperature for 24 hours, washed with chloroform, and dried. After drying, the catheter was coated with Guntrez169 [manufactured by GAF, 1:1 copolymer of maleic anhydride and methyl vinyl ether].
% acetone solution for 60 minutes at room temperature, washed with acetone, and dried. This material was immersed in hot water at 100℃ for 2 hours, then taken out and cooled in the air, and then immersed in a 1/15M phosphate buffer (PH7.5) solution of gentamicin [50mg (potency)/100ml] at 7℃ for 2 hours. Then, it was washed with water and dried.

Staphy to test bacteria about this catheter
When the same activity test as in Example 1 was carried out using lococcus epidermidis ATCC12228, an inhibition zone was also produced in the sample urine on the 40th day.

Example 7 The natural rubber urinary catheter used in Example 2 was
After immersing 4 parts of Magrogol 400 (manufactured by Matsumoto Yushi Co., Ltd., polyethylene glycol) and 169.2 parts of Guntrez in 100 parts of an equal volume mixture of tetrahydrofuran and water at room temperature for 5 minutes, the mixture was immersed in a nitrogen atmosphere. in
Heat treatment was performed at 140°C for 2 hours. The obtained catheter was immersed in hot water at 100°C for 2 hours, then air cooled.
Next, sulfate polymyxin B aqueous solution [50,000 units/
100ml] at 7°C for 30 minutes while adjusting the pH to 9.

The obtained catheter was used as a test bacterium.
When the same activity test as in Example 1 was carried out using Escherichia coli NIHJ, an inhibition zone was also produced in the sample urine on the 40th day.

Example 8 The silicone urinary catheter used in Example 4 was
After soaking in KE 42S-RTV (silicon rubber compound manufactured by Shin-Etsu Silicone) for 2 minutes at room temperature,
Heat treatment was performed at 100°C for 1 hour, and after cooling, it was subsequently immersed at room temperature for 10 minutes in a solution of 2 parts of polyvinyl alcohol (degree of polymerization 1700, completely saponified) and 169.4 parts of Guntrez dissolved in 100 parts of water. 1 at 160℃
Heat treated for hours. The obtained catheter was immersed in hot water at 100°C for 2 hours, and then air-cooled and immersed in an aqueous solution of gentamicin [50mg (potency)/100ml] at 7°C for 30 minutes while adjusting the pH to 8.

Test bacteria were added to the obtained catheter.
When the same activity test as in Example 1 was conducted using Staphylococcus epidermidis ATCC12228, an inhibition zone was also generated for the test bacteria on the 40th day.

Example 9 A natural rubber urinary catheter [Argyle Foley catheter, manufactured by Nippon Showwood Co., Ltd.] was
9000 parts of polyvinyl alcohol with a saponification degree of 99.9 mol% and a polymerization degree of 1700 and 1 part of ammonium dichromate.
Immerse in a solution of 100,000 parts of water in a dark place,
It was immediately pulled up, irradiated with light for 5 minutes using a fluorescent lamp, and then dried at 80°C for 1 hour. Thereafter, heat treatment was performed at 200° C. for 1 minute in a nitrogen atmosphere. Subsequently, this polyvinyl alcohol-coated urinary catheter was left standing in a 10 wt% sodium monochloroacetate aqueous solution at room temperature for 1 hour, and then
Add 10wt% sodium hydroxide aqueous solution and
The temperature was raised to ℃ and allowed to react for 2 hours.

The obtained catheter was treated with dibekacin sulfate in the same manner as in Example 1, and the same activity test as in Example 1 was conducted, and an inhibition zone was also observed in the test urine on the 40th day.

Comparative Example 4 A catheter was obtained in exactly the same manner as in Example 9, except that no treatment after the monochloroacetic acid treatment was performed. The obtained catheter was treated with dibekacin sulfate in the same manner as in Example 1, and an activity test was conducted in the same manner as in Example 1. As a result, no inhibition zone was observed in the test urine on the 10th day.

Example 10 Satoshi Watanabe et al.'s method [Artificial Organs 7(1): 206, 1978]
A urinary catheter was molded using the polyethylene-collagen synthetic polymer composite obtained according to the above procedure. This catheter was mixed with an aqueous solution of polymyxin B [1 g/
100ml] for 2 hours at 4°C while keeping the pH at 8.

Test bacteria were added to the obtained catheter.
When the same activity test as in Example 1 was conducted using Bordetella bronchiseptica ATCC4617, 40
An inhibition circle was also observed in the test urine on the day of the test.

Comparative Example 5 A urinary catheter made of a polyethylene-collagen synthetic polymer composite was molded in the same manner as in Example 10. This catheter was immersed in a 0.1M N-hydroxysucciimide aqueous solution, and while stirring well, 0.1M of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide was added, and 0.1N-
The reaction was carried out at room temperature for about 12 hours while keeping the pH at 5 to 6 with NaOH. After the reaction, the catheter was thoroughly washed several times with distilled water, and then immersed in 0.06M phosphate buffer of polymyxin B (PH7.4) [1 g/100 ml] at 4°C for 2 hours to ensure that polymyxin B was covalently bound. A urinary catheter was obtained.

When the obtained catheter was subjected to the same activity test as in Example 10, no inhibition circle was observed.

Example 11 A catheter was obtained in exactly the same manner as in Example 7, except that polymyxin B sulfate ointment was applied instead of immersing it in the aqueous solution of polymyxin B sulfate.

When the obtained catheter was subjected to the same activity test as in Example 7, an inhibition zone was also observed in the test urine on the 20th day.

Comparative Example 6 The untreated natural rubber urinary catheter used in Example 7 was coated with the sulfuric acid polymyxin B ointment used in Example 11.

When the obtained catheter was subjected to the same activity test as in Example 11, no inhibition zone was observed in the test urine on the third day.

Claims (1)

[Claims] 1. A urinary catheter made of an olefin polymer, a diene polymer, or a silicone polymer, which has the ability to prevent urinary tract infections, characterized in that an antibiotic is ionically bonded to the inner or outer wall of the catheter. with a urinary catheter.