JPH0474026B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to an antibacterial agent sustained release urinary catheter. (Prior Art) Patients with spinal cord injury, cerebral hemorrhage, encephalomalacia, or surgery are often accompanied by symptoms such as difficulty in urination and urinary incontinence. In such cases, urinary catheters are widely used to ensure a smooth urinary tract, promote maintenance or improvement of renal function, or prevent urine leakage. However, because urinary catheters are left in the urinary tract for long periods of time, bacteria can enter inside and outside the catheter, leading to frequent infections such as urethritis, cystitis, and nephritis. It is being Conventional countermeasures include bladder irrigation, injection of disinfectants, and prophylactic administration of antibiotics, but these not only require extra operations but also have uncertain effectiveness. Therefore, in order to fundamentally prevent bacterial infection at the site where the urinary catheter is installed, there has been a strong desire for a type of urinary catheter that releases antibacterial agents locally at a constant rate over a long period of time. . The properties required of the materials that make up urinary catheters include appropriate flexibility, water resistance, biocompatibility, non-toxicity, ease of insertion, and deposition of calcium salts, etc., depending on the purpose and form of use. One example is that there is no such thing. Currently, the most commonly used material is natural rubber, which is the cheapest in terms of cost, but its drawbacks include, for example, its poor water resistance, making it unsuitable for long-term placement in the body for more than a week, and its poor biocompatibility. Examples include inflammation of the urinary tract mucosa, etc., difficulty in inserting the catheter smoothly, and obstruction of the flow path due to calcium and other salt deposits on the inner and outer surfaces of the catheter, making removal difficult. Although silicone rubber is expensive in this respect, it is a material that has been rapidly attracting attention in recent years as a material that compensates for the above-mentioned drawbacks. The following methods have been proposed to date for imparting antibacterial properties to silicone rubber urinary catheters. For example, U.S. Pat. Nos. 3,566,874 and 3,695,921 disclose a hydrophilic coating layer on the exterior surface of the catheter by impregnating the catheter with hydrophilic acrylate or methacrylate monomers or oligomers and then completing the polymerization. A method is described in which the area is impregnated with antibiotics and disinfectants. In addition, US Pat. No. 4,055,682 discloses that silicone is graft-polymerized by impregnating it with hydrophilic N-vinylpyrrolidone, etc., and then irradiating it with radiation, and then adding benzalkonium chloride, hexachlorophene, iodine, etc. to the silicone. A method of impregnation is described. In addition, JP-A-49-34179 and JP-A-49-34180 propose catheters coated with polymerized acrylamide monomers and polyvinyl alcohol as hydrophilic polymers, respectively. . However, since all of these catheters have a coating layer made of hydrophilic resin on the outer surface of the catheter, and the antibacterial agent is physically adsorbed to that part, a common drawback of these types of catheters is that ,(1)
(2) Body fluids such as urine are absorbed into the hydrophilic coating layer, resulting in saturated salt concentration. At the same time, it has been pointed out that nucleation occurs in that area, and calcium salts and other solid substances precipitate, clogging the catheter and causing deposits on the external surface. (Problems to be Solved by the Invention) Based on the above technical background, the present inventors have made use of the characteristics of silicone rubber to develop a material that is necessary for preventing urinary tract infections even during long-term indwelling in the body. With the aim of providing an antibacterial agent sustained release urinary catheter made of silicone rubber that continuously releases antibacterial agents at a certain concentration or higher and is free from salt adhesion and blockage, as a result of extensive research, we have found that The present invention was achieved by discovering that the above object can be achieved by incorporating a specific antibacterial agent. (Means for Solving the Problems) That is, the gist of the present invention is an antibacterial agent sustained release urinary catheter made of silicone rubber containing a water-soluble cationic antibacterial agent. Conventionally, various combinations of active substances dispersed within polymer matrix structures have been known, but in this case, differences in physical or chemical properties between the matrix component and filler component, or Due to the interaction between the two, it has not always been easy to obtain something with the desired functionality. Rather, compared to the ease of mixing operations, it is generally more difficult and there are few success stories. However, the present invention has disclosed that a water-soluble cationic antibacterial agent dispersed in the silicone rubber of a urinary catheter made of silicone rubber can be used in relatively high concentrations such as urine without losing its properties as silicone rubber. Even if you come into contact with body fluids containing salt, organic wastes, or proteins,
This method is based on the discovery that the antibacterial agent is continuously released into the urine over a long period of time and that no blockage due to precipitation or deposition of calcium salts is observed, and no such case has been reported to date. It is not clear why such a water-soluble cationic antibacterial agent is uniformly dispersed in a highly hydrophobic matrix such as silicone rubber and exhibits sustained release over a long period of time. However, in terms of dispersibility, the water-soluble cationic antibacterial agent is uniform in its water-soluble state, and since it is mixed with the raw silicone rubber, it is thought that good dispersibility can be obtained. In order to manufacture the antibacterial agent sustained release urinary catheter of the present invention, for example, a compound prepared by mixing raw rubber made of organopolysiloxane with a high degree of polymerization with a filler and a vulcanizing agent, and a water-soluble cationic antibacterial agent are used. What is necessary is to mold a composition in which additives such as a dispersion accelerator and a pigment are further mixed with the composition. More specifically, for example, a filler, a vulcanizing agent, and a water-soluble cationic antibacterial agent may be added and mixed during the mastication stage of raw rubber, and then extrusion molding or compression molding may be performed. Various conventionally known devices and methods can be appropriately employed for mastication and molding. Examples of organopolysiloxane include dimethylpolysiloxane, methylphenylpolysiloxane,
Methylvinylpolysiloxane, fluoroalkylmethylpolysiloxane, and the like are preferably used. As the filler, fine silica powder is typically used as a reinforcing filler, but calcium carbonate, titanium oxide, zinc oxide, etc. may also be used. In addition, examples of dispersion accelerators for these fillers include silicone resins, alkoxysilanes and siloxanes,
Hydroxysilane, siloxanes, organic acid esters, polyhydric alcohols, etc. are used. Vulcanizing agents include organic peroxides, fatty acids, azo compounds,
Platinum, palladium, and sulfur are used, but organic peroxides are preferred. Examples of organic peroxides include benzoyl peroxide, bis-2,4
-dichlorobenzoyl peroxide, dicumyl peroxide, tertiary butyl peroxide, tertiary butyl perbenzoate, p-
Monochlorobenzoyl peroxide, 2,5-
Dimethyl-2,5-bis(tert-butylperoxy)hexane and the like are preferably used. If the antibacterial agent used in the present invention can withstand the vulcanization temperature, heat-vulcanizing silicone rubber may be used, but if not, it is preferable to use room-temperature vulcanizing silicone rubber. . The water-soluble cationic antibacterial agent in the present invention refers to an antibacterial agent having a positive charge and a hydrophobic group in the molecule, and preferred specific examples include water-soluble biguanide compounds, water-soluble salts of biguanide compounds, and water-soluble antibacterial agents. Examples include acridine compounds, water-soluble salts of acridine compounds, and water-soluble quaternary ammonium salt compounds. The biguanide compound is represented by the following general formula () or () or (). Here, R is an alkyl group, an aminoalkyl group,
It is a phenyl group, an alkylphenyl group, a halogenated phenyl group, a hydroxyphenyl group, a methoxyphenyl group, a carboxyphenyl group, a naphthyl group or a nitrile group, and R' is hydrogen or an alkyl group. Note that m and n are positive integers, but 2
A range of ~10 is preferred. Preferred specific examples of the water-soluble biguanide compound or the water-soluble salt of the biguanide compound used in the present invention include 1,6-
Di-(4-chlorophenyl biguanide) hexane gluconate and the like. Acridine compounds are compounds having the following acridine skeleton (), and are
Various derivatives are described in Vol. 286-326 (Asakura Shoten, 1960). Preferred specific examples of the water-soluble acridine compound or water-soluble salt of the acridine compound used in the present invention include 6,9-diamino-2-ethoxyacridine lactate. The quaternary ammonium salt is represented by the following structural formula (). Here, R ₁ , R ₂ , R ₃ and R ₄ are alkyl groups, benzyl groups, carboxyalkyl groups, alkyl groups or benzyl groups substituted with nitro groups or chlorine atoms, hydroxyalkyl groups, acetoxyalkyl groups, alkyl groups, etc. Enoxyalkoxyalkyl groups, etc. Encyclopedia of Chemical
Technology Vol. 19, pp. 521-531 (1932,
Wiley International Publication) Nishi, Imai,
"Surfactant Handbook" co-edited by Kasai, pp. 737-747 (1960
Journal of
American Chemical Society, Volume 68, No. 753
759 (1964) describes various quaternary ammonium salts in which R ₁ , R ₂ , R ₃ , and R ₄ are combined. Among these, R ₁ is a benzyl group,
Benzyldimethyldodecylammonium salt where R ₂ and R ₃ are methyl groups and R ₄ is dodecyl group; benzyldimethyltetradecylammonium salt where R ₁ is benzyl group, R ₂ and R ₃ are methyl groups, and R ₄ is tetradecyl group , benzyldimethylhexadecyl ammonium salt where R ₁ is a benzyl group, R ₂ and R ₃ are a methyl group, and R ₄ is a hexadecyl group, trimethyl where R ₁ , R ₂ and R ₃ are a methyl group, and R ₄ is a tetradecyl group Water-soluble quaternary ammonium salts preferably used in the present invention include tetradecylammonium salts and benzethonium salts such as (2-(2-p-(1,1,3,3-tetramethylbutyl)phenoxy)ethoxy)ethyl. Listed as salt. Examples of X include common chloride, bromide, iodide, citrate, sulfate, phosphate, borate, and the like. Also,
Polymer-type quaternary ammonium salt compounds in which one of R ₁ , R ₂ , R ₃ , and R ₄ is a polymer main chain and these quaternary ammonium salts are incorporated into the side chain are also used in the present invention. It is effective for Even in urinary catheters, antibacterial agents continue to be released at a constant rate while they remain in the body, i.e., zero-order release.
Needless to say, order release is preferable. Abnormal release of antibacterial agents in excess of the so-called minimum inhibitory concentration is not only economically disadvantageous, but also causes inflammation of the mucous membranes in the urinary tract and bladder as a side effect. Undesirable. Generally, it is difficult to achieve zero-order release with drugs dispersed within a polymer matrix, but the water-soluble cationic antibacterial agent used in the present invention substantially achieves zero-order release. Something,
In particular, water-soluble biguanide compounds or water-soluble salts of biguanide compounds, water-soluble acridine compounds or water-soluble salts of acridine compounds, and water-soluble quaternary ammonium salts are preferably used. Water-soluble herein refers to a substance whose solubility in 100 g of water at 20°C exceeds 3.0 g. Among the water-soluble cationic antibacterial agents used in the present invention, particularly preferred water-soluble antibacterial agents include 1,6-di-(4-chlorophenylbiguanide)hexane gluconate, etc. , 9-diamino-2-ethoxyacridine lactate, acraneal (6-chloro-9-(3-diethylamino-
(2-oxy)propylamino-2-methoxyacridine), benzyldimethyltetradecylammonium chloride, methylbenzethonium chloride, benzethonium chloride, benzalkonium chloride, and the like. The amount of the water-soluble cationic antibacterial agent incorporated into the silicone rubber in the present invention varies depending on the type and combination, but is generally 0.1 to 50% by weight, more preferably 0.5 to 25% by weight based on the silicone rubber.
Weight % is appropriate. In this case, if it is less than 0.1% by weight, it is difficult to obtain the desired antibacterial activity;
If the amount exceeds % by weight, the physical properties of the silicone rubber as an elastomer tend to be impaired. (Example) Hereinafter, the present invention will be described in more detail with reference to Examples. In addition, in the examples, "part" means "part by weight". Example 1 100 parts of methylvinylpolysiloxane raw rubber, 25 parts of fumed silica, 0.5 parts of bis-2,4-dichlorobenzoyl peroxide, and easily water-soluble 1,6-di-(4-chlorophenyl biguanide) as an antibacterial agent. ) Add 15 parts of hexane gluconate, masticate well with a rubber roll machine, extrude and heat at 200℃ for 2 minutes to make a tube with an outer diameter of 5 mm, an inner diameter of 3 mm, and a length of 350 mm. did. This was post-vulcanized at 130° C. for one week, and then a urinary catheter was prepared using a conventional method. The obtained urinary catheter was immersed in 100 ml of test urine at 37°C, and after one day, Bacillus subtilis was detected as a test bacterium.
Using ATCC6633 (medium NUTRIENT AGAR),
An antibacterial activity test was conducted using the cylindrical plate method (disk method), and the concentration of the antibacterial agent released was determined from the size of the inhibition circle generated in advance using a calibration curve. Furthermore, the same activity test was repeated up to 14 times by replacing the test urine with fresh test urine every day. Table 1 shows the results obtained in this way.
Shown below. Furthermore, when the catheter was actually applied clinically to five patients, no urinary tract infection was observed in any of the patients even after the catheter was left in the body for two weeks. Furthermore, no obstruction of the urinary tract due to solid matter deposited inside the catheter was observed, and the catheter was removed smoothly without causing any pain to the patient. Comparative Example 1 A commercially available silicone rubber urinary catheter that does not contain antibacterial agents was clinically applied to 5 patients in the same manner as in Example 1, and 1 patient was treated on the 3rd day and 2 patients were treated on the 5th day. In one patient, a urinary tract infection was observed on the seventh day. Example 2 100 parts of methylphenyl silicone raw rubber, 20 parts of fumed silica, 0.2 parts of benzoyl peroxide and water-soluble 6,9-diamino-2 as an antibacterial agent.
- Lactate of ethoxyacridine (water at 20°C)
Add 20 parts of the solubility (approximately 5 g per 100 g), masticate it well with a rubber roll machine, extrude it, and heat it at 200℃ for 2 minutes to form a tube with an outer diameter of 5 mm, an inner diameter of 3 mm, and a length of 350 mm. Created. This was post-vulcanized at 180℃ for 2 days,
Thereafter, a urinary catheter was prepared using a conventional method. The obtained urinary catheter was subjected to the same antibacterial activity test as in Example 1, and the results shown in Table 1 were obtained. Furthermore, when this catheter was actually applied clinically to five patients, no urinary tract infection was observed in any of the patients even after three weeks of indwelling. Furthermore, no obstruction of the urinary tract due to solid matter deposited inside the catheter was observed, and the catheter was removed smoothly without causing any pain to the patient. Example 3 100 parts of dimethylpolysiloxane end-capped with hydroxyl groups, 10 parts of silica airgel, 2 parts of methyltriethoxysilane, dibutyltin dilaurate
After mixing 0.2 parts and 10 parts of readily water-soluble benzyldimethyltetradecylammonium chloride as an antibacterial agent, the mixture was immediately poured into a casting mold and cured at room temperature to produce a tube with an outer diameter of 5 mm, an inner diameter of 3 mm, and a length of 350 mm. did. A urinary catheter was prepared using this in a conventional manner, and an antibacterial activity test was conducted in the same manner as in Example 1. The results shown in Table 1 were obtained. Furthermore, when this catheter was actually applied clinically to five patients, no urinary tract infection was observed in any of the patients even after the catheter was left in the body for two weeks. Furthermore, no obstruction of the urinary tract due to solid matter deposited inside the catheter was observed, and the catheter was removed smoothly without causing any pain to the patient.

[Table] (Effects of the invention) As is clear from the examples above, the urinary catheter of the present invention has a sustained release property of antibacterial agents, so it is effective against urinary tract infections caused by long-term indwelling in the body. In addition to being suitably used as a urinary catheter, it can also be applied to a drain tube for draining blood and body fluids remaining in a patient's body after surgery.

Claims (1)

[Scope of Claims] 1. An antibacterial agent sustained release urinary catheter made of silicone rubber containing a water-soluble cationic antibacterial agent. 2. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the water-soluble cationic antibacterial agent is a water-soluble biguanide compound or a water-soluble salt of a biguanide compound. 3. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the water-soluble cationic antibacterial agent is a water-soluble acridine compound or a water-soluble salt of an acridine compound. 4 Scope of the patent applicant where the water-soluble cationic antibacterial agent is a water-soluble quaternary ammonium salt compound No. 1
Antibacterial agent sustained release urinary catheter as described in Section 1.