JPH0364143B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a urinary catheter,
More specifically, the present invention relates to a urinary catheter having antibacterial agent sustained release performance. 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 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 have included cleaning the bladder, injecting disinfectants, and administering antibiotics prophylactically, but these not only require extra operations but also have uncertain effects. For this reason,
Recently, in order to fundamentally prevent bacterial infection at the site where the urinary catheter is installed, there has been a strong desire for a urinary catheter of the type that releases an antibacterial agent locally at a constant rate over a long period of time. Conventionally, regarding drug control release technology in the medical or pharmaceutical field, for example, as described in the review of Kagaku Kogaku, Vol. 45, No. 7, p. 441 (1981), (1) polymers with matrix structure and pores have been used. active substance dispersed within the substance, (2)
There are four types: (3) those that use an osmotic pump using osmotic pressure, and (4) those that coat the outside of the core material containing the active substance with an erodible substance. be done. Among these, release at a constant rate with no change in release amount over time, i.e. zero order release.
Although it is possible in (2), (3), and (4), special ingenuity and advanced technology are generally required. On the other hand, (1), in which drugs are dispersed within a polymer matrix, is easy to manufacture and has been put into practical use in various forms for a long time, but zero-order release is impossible, and such Few examples are known to date. In other words, in (1), an abnormally large amount of release is generally observed at the beginning, and then the amount released decreases rapidly, and thereafter there is a tendency for it to gradually decline. By the way, it goes without saying that it is important for a urinary catheter to continue releasing the antibacterial agent at a constant rate while the catheter is indwelling in the body.
In other words, in order for an antibacterial agent to have a certain bactericidal effect on various types of bacteria, the so-called minimum inhibitory concentration (minimal inhibitory concentration) is required.
Hereinafter referred to as MIC. ) It is important that the above antibacterial agents continue to be released in a sustained manner during the period of their use.
On the other hand, abnormal release of antibacterial agents exceeding the MIC is not only economically disadvantageous but also undesirable because it causes inflammation as a side effect to the mucous membranes in the urinary tract and bladder. Based on the above-mentioned technical background, the present inventors have developed a matrix for use on the surface and/or inside of a urinary catheter that is mainly composed of a specific organic polymer elastomer as a matrix that is easy to manufacture industrially. As a result of intensive investigation into whether or not zero-order release could be achieved in systems in which antibacterial agents are dispersed, it was surprisingly found that the fourth antibacterial agent was poorly water-soluble.
The present invention was achieved based on the discovery that substantially zero-order release can be achieved in a system in which a class ammonium salt is dispersed in an organic polymer elastomer. That is, the present invention provides a urinary catheter mainly composed of an organic polymer elastomer selected from the group consisting of natural rubber, synthetic rubber, polyurethane, and soft polyvinyl chloride. This is an antibacterial agent sustained release urinary catheter characterized by containing salt. The present invention can be achieved by simply dispersing a poorly water-soluble quaternary ammonium salt in an organic polymer elastomer, which is an extremely easy-to-manufacture polymer matrix without requiring special devices or advanced techniques. This provides a urinary catheter that achieves zero-order release, and its industrial significance is extremely large. The reason why substantially zero-order release was achieved in the present invention is not clear, but the reason is that the poorly water-soluble quaternary ammonium salt in the present invention has low solubility in water and interaction with the material matrix. ,
This is thought to be due to a synergistic effect. That is, the quaternary ammonium salt in the present invention has a cationic group as a polar group in its chemical structure, and
It is characterized by having hydrophobic groups such as alkyl groups and benzyl groups, and it is thought that these have an advantageous effect on the interaction with water and hydrophobic organic polymer elastomer materials when immersed in water. Ru. The organic polymer elastomer in the present invention has rubber-like elasticity at around room temperature,
Natural rubber, synthetic gas, polyurethane or flexible polyvinyl chloride. Here, natural gas refers to an aqueous solution containing various organic and inorganic substances that flows out when cutting the bark of a rubber plant, and uses it as a dispersion medium.
This refers to vulcanized latex containing rubber as a dispersoid and optionally containing a PH regulator, vulcanizing agent, vulcanization accelerator, softener, filler, anti-aging agent, etc. Examples of the synthetic rubber include homopolymers of diene monomers such as butadiene, isoprene, 1,3-pentadiene, 1,5-hexadiene, 1,6-heptadiene, and chloroprene, or copolymers thereof. Moreover, polyurethane means an elastomer having urethane bonds made of polyisocyanate and polyol in the repeating unit of the main chain. Examples of polyisocyanates include toluene diisocyanate, xylene diisocyanate, naphthalene diisocyanate, diphenylmethane diisocyanate, phenylene diisocyanate, ethylene diisocyanate, cyclohexylene diisocyanate, and triphenylmethane diisocyanate. Isocyanate, toluene isocyanate, etc., and polyols include, for example, ethylene glycol, propylene glycol,
Butylene glycol, diethylene glycol, cyclohexanediol, pentaerythritol,
Examples include polyols such as glycerin and 1,1,1-trimethylolpropane, polyether polyols such as polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and polyethylene glycol/polypropylene glycol copolymers. Polyols also have hydroxyl groups at both ends obtained by condensing dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, sebacic acid, isophthalic acid, phthalic acid, and terephthalic acid with ethylene glycol or propylene glycol. It also includes polyester and the like. Furthermore, those in which a part of these polyols are replaced with other active hydrogen compounds such as polyamines, polythiols, and polycarboxylic acids are also included. 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 phthalic acid esters such as dibutyl phthalate, di-2-ethylhexyl phthalate, diocdel phthalate, butyl lauryl phthalate, dilauryl phthalate, butyl benzyl phthalate, dioctyl adipate, dioctyl azelate, and dioctyl sebacate. Linear dibasic acid esters such as tricresyl phosphate, tricylenyl phosphate, monobutyl dixylenyl phosphate, trioctyl phosphate, etc., methyl acetyl ricinoleate, butylacetyl ricinoleate Castor oil derivatives such as, epoxidized vegetable oils made by epoxidizing unsaturated fatty acids such as soybean oil, carbon atoms 6 to 10
Tri- or tetraethylene glycol esters of fatty acids, ethylene glycol derivatives such as butylphthalyl butyl glycolate, average molecular weight 1000 ~
Examples include 3000 viscous lower polyester plasticizers. Examples of the latter copolymerized monomer of vinyl chloride include vinyl acetate, vinylidene chloride, acrylic acid or methacrylic acid and its ester, macraic acid and its ester, acrylonitrile, and the like. The quaternary ammonium salt in the present invention is represented by the following structural formula (). Here, R ¹ , R ² , R ³ and R ⁴ are an alkyl group, a benzyl group, a carboxyl alkyl group, a benzyl group substituted with an alkyl group or a nitro group or a chloro group, a hydroxyalkyl group, an acetoxyalkyl group, an alkylphenol group. cy group, alkoxyalkyl group, etc. Encyclopedia of Chemical
Technology, Vol. 19, pp. 521-531 (1982,
Wiley International Publication), Nishi, Imai,
Co-edited by Kasai, "Handbook of Sea Surface Active Agents", pp. 737-747 (1960
Journal of
American Chemical Society, Vol. 68, pp. 753-759 (1946) describes various quaternary ammonium salts in which R ¹ , R ² , R ³ , and R ⁴ are combined, among which R ¹ is benzyl. group, R ² and R ³ are methyl groups, R ⁴
benzyldimethyldodecylammonium salt in which is a dodecyl group, benzyldimethyltetradecylammonium salt in which R ¹ is a benzyl group, R ² and R ³ are a methyl group, and R ⁴ is a tetradecyl group, R ¹ is a benzyl group, R ² and R Benzyldimethylhexadecyl ammonium salt in which ³ is a methyl group and R ⁴ is a hexadecyl group; trimethyltetradecylammonium salt in which R ¹ , R ² and R ³ are a methyl group, and R ⁴ is a tetradecyl group; and (2-(2- p-(1,1,3,3
-tetramethylbutyl)phenoxy)ethoxy)
Ethyl benzethonium salt is the most widely used sterilizing agent in the medical, hygiene, and food industries today because it has strong sterilizing power against a wide range of microorganisms and has low toxicity to the human body. It is also preferably used in the present invention.
Among the above-mentioned quaternary ammonium salts, salts in which X ^- is iodide, citrate, sulfate, phosphate, borate, etc. are poorly water-soluble. Poor water solubility in the present invention means 100%
The solubility in distilled water is 0.001 to 3.0 g, preferably 0.005 to 2.0 g. If the solubility in water is less than 0.001 g, the amount of local release is low and the efficacy as a bactericidal agent is reduced. On the other hand, 3.0
For those exceeding g, initial abnormal release is observed,
Zero order release will no longer be possible. The content of the poorly water-soluble quaternary ammonium salt in the urinary catheter of the present invention varies depending on the purpose, but is preferably 0.01 to 30 wt%, more preferably 0.1 to 10 wt% based on the organic polymer elastomer. %. The antibacterial agent sustained release urinary catheter of the present invention can be easily manufactured using conventionally known manufacturing methods. For example, when manufacturing a urinary catheter by dipping a dipping mold in a natural rubber latex dipping solution, the catheter is dipped at least once in the dipping mold in which the antibacterial agent is uniformly dispersed, and then heat-treated. can do. In addition, in the case of manufacturing by extrusion molding or compression molding, the antibacterial agent can be added at the pre-shaping stage before being applied to a molding machine, and then molded by a normal method. In addition, when adding the above-mentioned antibacterial agent, it is possible to obtain a more uniform and stable antibacterial agent dispersion composition by using a conventionally used dispersant or dispersion promoter. For example, when adding an antibacterial agent to natural rubber latex, it is preferable to grind the antibacterial agent together with a surfactant, thickener, and protective colloid in a ball mill to form a uniform paste-like aqueous dispersion before adding it. . As described above, the present invention is a urinary catheter mainly composed of an organic polymer elastomer that contains a poorly water-soluble quaternary ammonium salt. ,
In order to prevent inflammation of the urinary tract mucosa due to the release of high concentrations of antibacterial agents on the outer surface, which is the surface in contact with the urinary tract mucosa, a thin coating layer made only of an organic polymer elastomer that does not contain the above antibacterial agents is applied. Preferably, it is provided on the outer surface. In addition, on the inner surface of the urinary catheter, which is the urine drainage path, salt and calcium components in the urine are deposited in the recesses after the antibacterial agent has been eluted.
In order to avoid further obstruction of the urinary tract, it is preferable to provide the inner surface with a thin coating layer made only of an organic polymeric elastomer that does not contain the above-mentioned antibacterial agent. Furthermore, the mechanical strength of the urinary catheter decreases due to the elution of the antibacterial agent,
For example, to avoid situations such as balloon bursting,
It is also preferable to provide a layer consisting only of an organic polymer elastomer containing no antibacterial agent between the outer surface and the inner surface of the urinary catheter, for example in the middle. The present invention will be described in detail below with reference to specific examples.
Note that "parts" in the examples mean "parts by weight." Example 1 30 parts of benzyldimethylhexadecyl ammonium iodide and 100 parts of distilled water were ground and dispersed in a ball mill for 100 hours to prepare an antibacterial agent dispersion liquid (hereinafter referred to as liquid A). On the other hand, 100 parts of natural rubber latex with a solid content concentration of approximately 50 wt%, 0.3 parts of zinc dimethyldithiocarbamate, and sulfur
A mixed latex liquid (hereinafter referred to as liquid B) was prepared by adding 1.5 parts of zinc white, 3 parts of zinc white, and 1.2 parts of stearic acid. Next, 5 parts of Solution A were added to 100 parts of Solution B to prepare an immersion solution (hereinafter referred to as Solution C). Next, the immersion type for urinary catheter was immersed in the above-mentioned immersion liquid, then pulled out and dried (80℃ x 5 minutes), which was repeated 5 times.Finally, heat treatment was performed at 70℃ for 10 hours, resulting in a dry weight. A urinary catheter weighing approximately 12 g was prepared. Place the obtained urinary catheter in test urine at 37°C.
Immerse it in 100ml and use it as a test bacterium after 1 day.
Bacillus subtilis ATCC 6633 (medium
An antibacterial activity test was conducted using the cylinder plate method (disk method) using a NUTRIENT AGAR, and the concentration of the released antibacterial agent was determined from the size of the inhibition circle generated in advance from the calibration curve. Furthermore, the test urine was replaced with fresh test urine every day and the same activity test was repeated up to 14 times. The results thus obtained are shown in Table 1. Furthermore, when the manufactured urinary catheter was applied clinically to five patients, no urinary tract infection was observed in any of the patients even after indwelling in the body for two weeks. Furthermore, no discomfort or inflammation of the urinary tract mucosa was observed during use. Comparative Example 1 A urinary catheter was produced in the same manner as in Example 1 except that an immersion liquid consisting of only liquid B was used instead of liquid A. When this urinary catheter was clinically applied to five patients in the same manner as in Example 1, two patients were treated on the third day, one on the fourth day, and the other on the fifth day. , each of whom had a urinary tract infection. Example 2 A urea catheter was obtained in the same manner as in Example 1, except that 10 parts of liquid A was added to 100 parts of liquid B, and the same antibacterial activity test as in Example 1 was conducted. The results obtained are shown in Table-1. Example 3 A urinary catheter was obtained in the same manner as in Example 1, except that benzethonium iodide was used instead of benzyldimethylhexadecyl ammonium iodide, and the same antibacterial activity test as in Example 1 was conducted. The results obtained are shown in Table-1. Example 4 A urinary catheter was obtained in the same manner as in Example 1, except that benzyldimethylhexadecyl ammonium phosphate was used instead of benzyldimethylhexadecyl ammonium iodide, and anionic chloroprene latex was used instead of natural rubber latex. The same antibacterial activity test as in Example 1 was conducted. The results obtained are shown in Table-1. Example 5 A layer of approximately 30μ thick consisting only of liquid B was placed on the inner and outer surfaces of the urinary catheter produced in Example 1.
A skin layer free of antibacterial agents was provided. Regarding this urinary catheter, the antibacterial agent release behavior was examined in the same manner as in Example 1, and the results shown in Table 1 were obtained. 【table】

Claims (1)

[Scope of Claims] 1. A urinary catheter whose main component is an organic polymer elastomer selected from the group consisting of natural rubber, synthetic rubber, polyurethane, and soft polyvinyl chloride, in which the catheter contains a poorly water-soluble fourth elastomer. An antibacterial agent sustained release urinary catheter characterized by containing grade ammonium salt. 2. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the outer surface and/or inner surface of the urinary catheter is provided with a thin coating layer made only of an organic polymer elastomer. 3. The antibacterial agent sustained release urinary catheter according to claim 1, wherein a layer made only of an organic polymer elastomer is provided between the outer surface and the inner surface of the urinary catheter. 4. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the quaternary ammonium salt is trimethyltetradecylammonium salt. 5 Claim 1 in which the quaternary ammonium salt is benzyldimethyldodecylammonium salt
Antibacterial agent sustained release urinary catheter as described in Section 1. 6. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the quaternary ammonium salt is benzyldimethyltetradecylammonium salt. 7. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the quaternary ammonium salt is benzyldimethylhexadecyl ammonium salt. 8. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the quaternary ammonium salt is a benzethonium salt.