JPS6036064A - Production of anti-bacterial substance solow releasing urea guiding catheter - 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 The present invention relates to a method for manufacturing a urinary catheter, and more particularly to a method for manufacturing a urinary catheter having sustained release performance of antibacterial substances.

Patients suffering from spinal cord injuries, cerebral hemorrhage, and encephalomalacia9 are often accompanied by symptoms such as difficulty in urination and urinary incontinence. In such cases, ensure a smooth urinary tract.

As a result, urinary catheterization using a urinary catheter is adopted to maintain or improve renal function or to prevent urine leakage. The catheter used in this case is particularly called a urinary catheter.

Urinary catheterization is an extremely useful treatment method that allows prompt urination, so it is frequently used not only in urology but also in surgery, internal medicine, obstetrics and gynecology, etc.; When a urinary catheter is placed in the urinary tract, there is a problem in that infection is unavoidable. In other words, since urinary catheters are left in the urinary tract for long periods of time,
Bacteria enter through this catheter, causing urethritis and cystitis.

Symptoms such as fever occur frequently. If the conventionally frequently used open continuous urinary catheterization method (a method of collecting urine in an unsterilized container such as a glass tube) is performed.

Infection occurs in 42-80% of cases within three days, and it is reported that infection was established on the gold side on the seventh day.

For this reason, methods such as cleaning the bladder and injecting disinfectants have been used to prevent urinary tract infections, but these methods are inconvenient, as drying is troublesome, and this operation itself can become a new source of infection. There are many aspects.

Chemotherapy, such as the prophylactic administration of antibacterial substances, is also used, but if administered in large doses or depending on the type of antibacterial substance, even a small amount may cause frequent side effects, and once an infection occurs, bacterial replacement may occur. Local use of antibacterial substances is strongly desired, to the extent that unplanned chemotherapy is said to be harmful due to problems such as the tendency to cause the development of antibacterial agents.

For local use of antibacterial substances, a coating layer made of a hydrophilic resin such as polyvinyl alcohol resin or poly-2-hydroxyethyl methacrylate-1 resin is applied to the inner and/or outer wall surfaces of the urinary catheter. A urinary catheter is known in which this layer is formed with an antibacterial substance. However, in these cases, the antibacterial substance is water-soluble and simply adsorbed within the hydrophilic resin layer, so when used, the antibacterial substance spreads into the urine and quickly distills out of the body. As a result, there was a drawback that antibacterial substances could not be released into the urine at an appropriate concentration over a long period of time.

In view of the current situation, the present inventors aimed to establish a method for easily manufacturing a urinary catheter that can sustainably release an antibacterial substance at an appropriate rate to prevent urinary tract infection during the period of indwelling in the body. As a result of intensive research, we found that by absorbing a specific antibacterial substance into a urinary catheter and converting this antibacterial substance into a soluble compound, the antibacterial substance is released into the urine over a long period of time, preventing urinary tract infections. The present invention was achieved based on the discovery that a urinary catheter having favorable characteristics can be obtained.

That is, the present invention provides an antibacterial substance sustained release urinary catheter characterized in that a solution containing a biguanide compound is absorbed into a urinary catheter, and then the biguanide compound absorbed into the urinary catheter is converted into a water-resistant compound. This is a manufacturing method.

The Bigayu 1 compound in the present invention is represented by the following general formula (1
) or 01).

NlI NlI 111 RR' N CN II CN 11 ■ N II N 11 (1) (II) Here, R is an alkyl group, an aminoalkyl group, a phenyl group, an alkylphenyl group, a halogenated phenyl group, a hydroxyphenyl group, a methoxyphenyl group. group, carboxyphenyl group, naphthyl group, or nitrile group, and R' is hydrogen or an alkyl group. The value is a positive integer, preferably in the range of 2 to 10. Preferred specific examples of such biguanide compounds include 1,6-di(4-chlorophenylbiguanide)hexane, diamino-xylhigeanide, and L6-di(aminehexylbiguanide).
Hexane etc. Among these, 1,6-di(4-chlorophenylbiguanide)hexane (also known as chloro-xidine) has strong bactericidal activity against a wide range of microorganisms and is low in toxicity to the human body. In addition, there are three disinfectants that are most widely used in the food industry and are particularly preferably used in the present invention.

Among various antibacterial substances, chlorhexidine is known to exhibit antibacterial activity against Gram-positive cocci and Gram-negative bacilli at low concentrations over a wide range of bacteria.
It is an antibacterial substance that is widely used to disinfect skin and mucous membranes and medical instruments.

In the present invention, solutions containing biguanide compounds include:
Liquid 7B containing a biguanide compound at a concentration of 5% by weight or more, particularly 10% by weight or more is preferably used. Preferred solutions include, for example, an aqueous solution of a biguanide compound or a solution of a biguanide compound dissolved in a mixed solution of water and tetrahydrofuran, particularly water such as water-tetrahydrofuran, water-dioxane,
A solution in which the beard anide compound is dissolved in a mixed solution consisting of one or more organic solvents that can mix with water and swell the urinary catheter is preferred. Also.

The solution containing the biguanide compound used in the present invention may contain an anionic surfactant or a nonionic surfactant to an extent that does not impair the antibacterial activity of the biguanide compound.

Examples of the urinary catheter used in the present invention include natural rubber, synthetic rubber, and silicone rubber.

Made of polyurethane, soft polyvinyl chloride, etc.

Walls are molded using methods such as dipping and injection methods. Natural rubber here refers to organic matter and t3W-free materials that flow out when the bark of a rubber plant is cut (4), and the resulting aqueous solution is used as a dispersion medium, and the rubber component is used as a dispersoid. pH adjuster, vulcanizing agent, vulcanization accelerator, softener,
This refers to products containing fillers, anti-aging agents, etc. Seven examples of synthetic rubber include G-yobutadiene, isoprene,
3-Pentagene.

Examples include homopolymers of diene monomers such as 1,5-hexadiene, 1,6-hebutadiene, and chlorobrene, copolymers thereof, and copolymers thereof. Silicone rubber is made of organon j-myrisiloxane with a high degree of polymerization, and if necessary, 2, for example, an inorganic filler.

It means a compound containing a dispersion accelerator, a vulcanizing agent, etc.

Examples of organoborisiloxanes include dimethylborisiloxane, methylphenylpolysiloxane, methylvinylpolysiloxane, and fluoroalkylmethylpolysiloxane. Also.

Polyurethane refers to an elastomer having a urethane bond consisting of 1 and a polyol in the repeating unit of the main chain. Examples of polyisocyanates include toluene diisocyanate and xylene diisocyanate. Diphenylmethane diisocyanate, phenylene diisocyanate, ethylene diisocyanate, cyclo-xylene diisocyanate, triphenylmethane triisocyanate, toluene diisocyanate, etc.
Examples of polyols include polyols such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, cyclohexane diol, pentaerythritol, glycerin, LLL-trimethylolpropane, polyethylene glycol, polypropylene glycol, and bolite. Examples include polyether polyols such as 1-ramethylene glycol and polyethylene glycol/polypropylene glycol copolymers. Examples of polyols include succinic acid, glutaric acid, adipic acid, sebacic acid, isophthalic acid, and fucuric acid.

Also included are polyesters having hydroxyl groups at both ends obtained by condensing dicarboxylic acids such as terephthalic acid with ethylene glycol, propylene glycol, etc. moreover,
It also includes those in which a part of these polyols is replaced with other active hydrogen compounds such as polyamines, polydiols, and polycarboxylic acids.

Examples of soft polyvinyl chloride include polyvinyl chloride homopolymer blended with a plasticizer or internally plasticized by copolymerization with other components. Examples of the former plasticizer include dibutyl phthalate 1-. G2-
・Ethylhexyl fucray-1・, dioctyl phthalate, butyl lauryl phthalate, dilauryl phthalate 1~
．． Phthalic acid esters such as butylbenzyl phthalate-1, dibasic acid esters such as dioctyl adipate, dioctyl azele-1, dioctyl sebaque-1, tricresyl phosphate, tricylenylbosphene +
Phosphate esters such as -, monobutyl dixylenyl bosphe-1, trioquidyl phosphate 1-.

Castor oil derivatives such as methyl acetyl lysyllate and butylacetyl lysylte, epoxidized vegetable oils obtained by epoxidizing unsaturated fatty acids such as soybean oil, mono- or tetraethylenefuglycol esters of fatty acids having 6 to 10 carbon atoms, Examples include ethylene glycol derivatives such as butylphthalyl butyl glycolate, viscous lower polyester plasticizers having an average molecular weight i of ooo to 3,000, and the like. In addition, examples of the latter copolymerizable monomer of vinyl chloride include vinyl acetate.

Examples include vinylidene chloride, acrylic acid or methacrylic acid and its esters, maleic acid and its esters, acrylonitrile, and the like.

Also, in the present invention, it can be used as a urinary catheter.

- It is also possible to use a urinary catheter as described in (A) whose inner and/or outer wall surfaces are coated with a hydrophilic resin.

An example of a method for coating a urinary catheter with a hydrophilic resin is a dipping method using a hydrophilic IL1 lipid solution.

Brushing method or blowing method, immersing the urinary catheter in a solution of a hydrophilic monomer or its partial polymer, pulling it out, and then UV polymerization, radiation polymerization, or radical polymerization using a radical initiator. There is a way to do this. Examples of hydrophilic monomers include 9, 2-hydroxyethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate-1-23-hydroxypropyl acrylate-t
・.

Hydroxy lower alkyl acrylates or methacrylates such as 3-hydroxy methacrylate.

Acrylamide, methacrylamide, N-methylacrylamide, N-methylmethacrylamide, N-ethylacrylamide, N-ethylmethacrylamide 2 N-isopropylacrylamide, N-butylacrylamide, etc. General formula (R+ is hydrogen or has 1 to 4 carbon atoms) Alkyl group.

R2 and R3 are hydrogen or an alkyl group. ), N-vinyl compounds such as acrylic, methacrylic, maleic [1,N-vinylpyrrolidone, etc.]. Further, in order to increase the toughness of the coating layer, it is also possible to use a divinyl compound such as ethylene glycol diacrylate or ethylene glycol dimethacrylate as a crosslinking agent. In addition, examples of the hydrophilic resin include a polymer or copolymer containing at least one of the above monomers as a main component, a compound consisting of polycarboxylic acid and polyethylene oxide or polyvinyl alcohol, polyvinyl alcohol, and ethylene-vinyl acetate. Examples include phosphides.

To produce a sustained-release antibacterial urinary catheter according to the method of the present invention, the urinary catheter is first imbibed with a solution containing a biguanide compound. For this purpose, the simplest method is to immerse the urinary catheter in a solution containing, for example, a biguanide compound. In this case, the temperature of the solution containing the biguanide compound may be any temperature as long as it does not have a significant adverse effect on the antibacterial activity of the biguanide compound or on the material of the urinary catheter.

10 to 150°C, particularly room temperature to 80°C is preferred. The preferred soaking time varies depending on the soaking temperature, but 5 minutes to moderate cooling.
One week, especially about 10 minutes to 4 days is preferable.

In the present invention, it is necessary to subsequently convert the biguanide compound absorbed into the urinary catheter into a water-soluble compound. Poor water solubility here means that the solubility of the compound in 100 g of distilled water at 20°C is o.
, oot~3. Og, preferably 0.005g to 2.0
Refers to the range of g. Solubility in water is 0.001
If it is less than 9J, the local release amount is low, and 9J as a bactericidal agent.
J power decreases. On the other hand, if the amount exceeds 3.0 g, the antibacterial substance will not diffuse into the urine, and the antibacterial agent cannot be sustainedly released over a long period of time.

As a poorly water-soluble biguanide compound.

The biguanide compound itself and its hydrochloride, hydrobromide,
Nitrates, phosphates, sulfates, borates, carbonates monobicarbonate, benzoates, formates, tartrates.

Examples include various acid salts such as acetate.

To convert a biguanide compound absorbed into a urinary catheter into a poorly water-soluble compound 7. For example, a urinary catheter into which a biguanide compound has been absorbed can be treated with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, or carbonic acid.

Solutions of bicarbonate, benzoic acid, formic acid, tartaric acid, acetic acid, etc., solutions containing anions of the above acids, solutions containing polyvalent metal ions such as calcium ions and magnesium ions, or mixed solutions consisting of two or more of these. This can be done by immersion.

In addition, after the urinary catheter has previously absorbed a salt containing an anion of the acid mentioned above, the catheter is immersed in a solution containing a biguanide compound, so that the biguanide compound absorbed into the urinary catheter can be absorbed into the water. It can also be converted into a soluble compound. p of the solution during immersion
l+, the temperature may be any condition as long as it does not have a significant adverse effect on the antibacterial properties of the biguanide compound or the material of the urinary catheter;
Particularly preferred is 10 to 80°C. The preferred immersion time varies depending on the immersion temperature, but is usually about 1 hour to 1 week, particularly about 2 hours to 48 hours.

In the present invention, after these treatments, if necessary, 10
The urinary catheter may be dried at a temperature ranging from 70°C to 80°C, preferably from 30°C to 70°C.

Biguanide compounds form salts with various acids.

The solubility of the formed salt in water varies greatly depending on the type of acid used, and when a soluble salt is formed in water, the antibacterial activity of the solution may be reduced. However, the concentration of chlorhexidine gluconate generally used for bladder irrigation is quite low at 0.02 (W/'V)%, and Akio Hatada et al.
2193 (1973), Pseudomonas seruginosa is the causative agent of urinary tract infections.

Proteus vulgaris, [! 5cher
ichiacoli, 5taphylo-COCCL
The minimum inhibitory concentrations (MI(:)) of chlorhexidine against IS allreL13 are 10, 12, and 5, respectively.
Since it is 1.25°1, Oug/ml, the solubility of the poorly water-soluble biguanide compound is 0.25°1. Even if it is at the level of OpLg, it has sufficient antibacterial activity.

As described above, the solubility of poorly water-soluble biguanide compounds differs depending on the type of acid salt, so according to the present invention, the type of acid, anion, or polyvalent metal ion is changed when converting a biguanide compound into a water-insoluble compound. By making various selections and changing the solubility of the biguanide compound, it is possible to arbitrarily adjust the rate of sustained release of the antibacterial substance from the urinary catheter into the urine.

As a result of performing the series of operations described above, if the amount of water-lit soluble biguanide compound held in the urinary catheter is small, the series of operations may be repeated until the desired amount is reached.

As described above, according to the manufacturing method of the present invention, an antibacterial substance sustained release urinary catheter having a desired sustained release rate and sustained release period can be produced using a simpler method than conventional methods.

The present invention will be explained in more detail below by giving examples.

In addition, "parts" in Examples means "parts by weight".

Example 1 Natural rubber Foley balloon catheter (Kousan Shoji)
, 50 parts of chlorhexidyl gluconate and 50 parts of distilled water
After being immersed in a solution containing 25% of water at room temperature for 72 hours,
It was dried at 0°C. The dried catheter was soaked in an aqueous solution consisting of 10 parts of sodium chloride and 90 parts of distilled water at room temperature for 10 minutes.
After soaking for an hour, it was dried at 5 (1'c).

Example 2 10 g I% of sodium chloride was added to 1 part of sodium sulfate heptahydrate
The same operation as in Example 1 was performed except that the amount was changed to 0 parts.

Example 3 The same operation as in Example 1 was performed except that 10 parts of sodium chloride was replaced with 10 parts of sodium carbonate monohydrate.

Example 4 The same operation as in Example 1 was performed except that 10 parts of sodium chloride was replaced with 10 parts of sodium nitrate.

Example 5 The procedure of Example 1 was repeated twice.

Comparative example 1 Natural rubber Foley balloon catheter (Kousan Shoji)
50 parts of chlorhexidyl gluconate and 50 parts of distilled water
50℃ after 72 hours at room temperature in a solution consisting of
It was dried.

The catheters obtained in Examples 1 to 5 and Comparative Example 1 above were each immersed in test urine at 37°C, and 1laci-1
Antibacterial activity tests were conducted for each strain using the cylindrical plate method (paper disk method) using 1us 5ubtilis ATCC6633 as a test bacterium. The same antibacterial activity test was repeated by replacing the test urine with fresh test urine every day.

The results are shown in Table 11 Table 1

Claims (2)

[Claims] (1) A method for producing an antibacterial substance sustained release urinary catheter, which comprises absorbing a solution containing a biguanide compound into a urinary catheter, and then converting the biguanide compound absorbed into the urinary catheter into a poorly water-soluble compound. (2) The method according to claim 1, wherein the biguanide compound is 1,6-dihe(4-chlorophenylbiguanide)hexane.