JPH0328224B2 - - 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 the ability to release antibacterial substances in a sustained manner. 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, bladder infection, and pyelitis. ing. Conventional countermeasures have included cleaning the bladder, injecting disinfectants, and administering prophylactic antibacterial substances such as antibiotics, but these not only require extra procedures but also have uncertain effects. be. For this reason, recently, in order to fundamentally prevent bacterial infection at the site where the urinary catheter is installed,
There is a strong desire for a type of urinary catheter that can locally release antibacterial agents at a constant rate over a long period of time. Conventionally, regarding controlled release technology for drugs in the field of medicine and pharmacy, for example, as described in the review of Kagaku Kogaku, Vol. 45, No. 7, p. 441 (1981), (1) matrix-structured polymers and fine particles have been used. active substances dispersed within pores, (2)
There are four types: (3) those that use an osmotic pump using osmotic pressure, and (4) those that coat the outside of the cocoa 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) Drugs dispersed within polymer matrices are easy to manufacture and have been in 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),
Generally, an abnormally large amount of release is observed at the beginning, and then the amount released decreases rapidly, and thereafter there is a tendency for it to gradually decrease. 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 use. On the other hand, abnormal release of antibacterial agents above the MIC is not only economically disadvantageous, but also causes damage to the mucous membranes in the urinary tract and bladder. This is not preferable because it causes inflammation as a side effect. Based on the above technical background, the present inventors applied an antibacterial agent to the surface and/or inside of a urinary catheter whose main component is an 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 a system in which antibacterial agents are dispersed, it was surprisingly discovered that a poorly water-soluble acridine compound or its salt as an antibacterial agent was dispersed in an organic polymer elastomer. The present invention was achieved based on the discovery that substantially zero-order release can be achieved in the system. That is, the present invention provides a urinary catheter mainly composed of an organic polymer elastomer, which is an antibacterial catheter characterized in that a sparingly water-soluble acridine compound or a salt thereof is dispersed in a matrix of the organic polymer elastomer. This is a sustained release urinary catheter. The present invention can be achieved by simply dispersing a poorly water-soluble acridine compound or its salt in an organic polymer elastomer as a polymer matrix, which is extremely easy to manufacture 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 acridine compound or its 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 acridine compound in the present invention is characterized by having a cationic group as a polar group and a hydrophobic cyclic structure in its chemical structure.
It is thought that when these were immersed in water, they had an advantageous effect on the interaction with water and the hydrophobic organic polymer elastomer material. The organic polymer elastomer in the present invention has rubber-like elasticity at around room temperature,
Examples include natural rubber, synthetic rubber, silicone rubber, polyurethane, soft polyvinyl chloride, and the like. Here, natural rubber is made by using an aqueous solution containing various organic and inorganic substances that flows out when cutting the bark of a rubber plant as a dispersion medium, and using the rubber component as a dispersoid.
This means a product containing a PH adjuster, vulcanizing agent, vulcanization accelerator, softener, filler, anti-aging agent, etc. as necessary. Examples of synthetic rubber include butadiene,
Examples include homopolymers of diene monomers such as isoprene, 1,3-pentadiene, 1,5-hexadiene, 1,6-heptadiene, and chloroprene, or copolymers thereof. Silicone rubber refers to organopolysiloxane with a high degree of polymerization mixed with, for example, an inorganic filler, a dispersion accelerator, a vulcanizing agent, etc. as necessary. Examples of organopolysiloxane include dimethylpolysiloxane, Examples include methylphenylpolyhsiloxane, methylvinylpolysiloxane, and fluoroalkylmethylpolysiloxane. Moreover, polyurethane means an elastomer having urethane bonds made of polyisocyanate and polyol in the repeating unit of the main chain. Examples of the polyisocyanate include toluene diisocyanate, xylene diisocyanate, naphthalene diisocyanate, diphenylmethane diisocyanate, phenylene diisocyanate, ethylene diisocyanate, cyclohexylene diisocyanate, and triphenylmethane diisocyanate. Isocyanate, toluene isocyanate, etc., and examples of polyols include polyols such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, cyclohexanediol, pentaerythritol, glycerin, 1,1,1-trimethylolpropane, and polyethylene. Examples include polyether polyols such as 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, abipic 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. The former plasticizers include phthalic acid esters such as dibutyl phthalate, di-2-ethylhexyl phthalate, dioctyl phthalate, butyl lauryl phthalate, dilauryl phthalate, butyl benzyl phthalate, dioctyl adipate, dioctyl azelate, dioctyl sebacate, etc. Linear dibasic acid esters, phosphate esters such as tricresyl phosphate, tricylene phosphate, monobutyl dixylenyl phosphate, trioctyl phosphate, methyl acetyl ricinoleate, butylacetyl ricinoleate, etc. Castor oil derivatives, epoxidized vegetable oils obtained by epoxidizing unsaturated fatty acids such as soybean oil, tri- or tetraethylene glycol esters of fatty acids having 6 to 10 carbon atoms, ethylene glycol derivatives such as butylphthalbutyl glycolate, average molecular weight, 1000 to 3000
Examples include viscous lower polyester plasticizers. Examples of the latter vinyl chloride copolymer monomer include vinyl acetate, vinylidene chloride, acrylic acid or methacrylic acid and its ester, maleic acid and its ester, acrylonitrile, and the like. The acridine compound in the present invention is a compound having the following acridine skeleton, and is a compound having the following acridine skeleton. Various derivatives are described on pages 286 to 326 (Asakura Shoten, 1960). Preferred specific examples of such acridine compounds include 9-aminoacridine, 3,
6-aminoacridine, 6,9-diamino-2-
These include ethoxyacridine, which has strong sterilizing power against a wide range of microorganisms and low toxicity to the human body, so it is one of the most widely used sterilizing agents in the medical, hygiene, and food industries today. It is one of these, and is particularly preferably used in the present invention. Poor water solubility as used in the present invention refers to
The solubility in 100 g of distilled water is 0.001 to 1.0 g, preferably 0.005 to 0.7 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, 1.0g
If the amount exceeds 100%, initial abnormal release will be observed and zero-order release will not be achieved. The content of the poorly water-soluble acridine compound or its salt in the urinary catheter of the present invention varies depending on the intended purpose, but is preferably 0.01 to 0.01.
It is 30wt%, more preferably 0.1 to 10wt%. 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 immersing a dipping mold in a natural rubber latex dipping solution, it is immersed at least once in a dipping solution in which the antibacterial agent is uniformly dispersed, and then heat-treated. can be manufactured. Also,
When manufacturing by extrusion molding or compression molding, such as silicone rubber, the above antibacterial agent is added during the mastication stage before being applied to the molding machine, and then molded and vulcanized in the usual manner. can do.
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. . When added to silicone rubber, dispersibility can be improved by using a dispersion accelerator such as silicone resin, alkoxysilane and siloxane, hydroxysilane and siloxane, organic acid ester, and polyhydric alcohol. As described above, the present invention is directed to a urinary catheter mainly composed of an organic polymer elastomer containing a poorly water-soluble acridine compound or its salt; however, when the urinary catheter is placed in the body, In order to prevent inflammation of the urinary tract mucosa caused by the release of high concentrations of antibacterial agents on the outer surface, which is the surface that comes into contact with the urinary tract mucosa, a thin coating layer made only of an organic polymer elastomer that does not contain the above antibacterial agent is used. is preferably provided on the outer surface. Furthermore, on the inner surface of the urinary catheter, which is the urine drainage path, after the antibacterial agent has been eluted, salt and calcium components in the urine are deposited on the concave surface, and this is to prevent the situation where the salt and calcium components in the urine are deposited, which may lead to obstruction of the urinary tract. In addition, it is preferable to provide a thin coating layer made of an organic polymer elastomer containing no antibacterial agent on the inner surface. 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 1 100 parts of 6,9-diamino-2-ethoxyacridine hydrochloride and 100 parts of distilled water were mixed in a ball mill to 100 parts
The antibacterial agent dispersion liquid (hereinafter referred to as liquid A) is obtained by grinding and dispersing it over time. was prepared. On the other hand, the solid content concentration is approx.
A blended latex liquid (hereinafter referred to as liquid B) was prepared by adding 0.3 parts of zinc dimethyldithiocarbamate, 1.5 parts of sulfur, 3 parts of zinc white, and 1.2 parts of stearic acid to 100 parts of 50 wt% natural rubber latex. Next, add 10 parts of liquid A to 100 parts of liquid B to make the immersion liquid (hereinafter referred to as C).
It is called liquid. ) was prepared. 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. The obtained urinary catheter was heated to 37°C with 100% test urine.
ml, and after 1 day, use it as a test bacterium.
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 fabricated urinary catheter was applied clinically to five patients, no urinary tract infection was observed in any of the cases 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 only of 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 urinary catheter was obtained in the same manner as in Example 1, except that 16 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 3,6-diaminoacridine sulfate was used instead of 6,9-diamino-2-ethoxyacridine hydrochloride, and a urinary catheter was obtained in the same manner as in Example 1. The same antibacterial activity test was performed. The results obtained are shown in Table-1. Example 4 100 parts of methylvinyl polysiloxane raw rubber, 20 parts of silica fine powder, 2 parts of benzoyl peroxide and 9-
A urinary catheter was prepared by adding 25 parts of aminoacridine sulfate and thoroughly masticating the mixture using a rubber roll machine, followed by extrusion molding and compression molding. The same antibacterial activity test as in Example 1 was conducted on the obtained urinary catheter. The results are shown in Table-1. Example 5 On the inner and outer surfaces of the urinary catheter produced in Example 1, a thickness of approximately 30 μm consisting only of liquid B was coated.
A coating layer containing no antibacterial agent 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)

[Claims] 1. A urinary catheter mainly composed of an organic polymer elastomer, characterized in that a poorly water-soluble acridine compound or a salt thereof is dispersed in the matrix of the organic polymer elastomer. Antibacterial sustained release urinary catheter. 2. The antibacterial agent sustained release urinary catheter according to claim 1, wherein a thin coating layer made only of an organic polymer elastomer is provided on the outer surface and/or the inner surface of the urinary catheter. 3. The antibacterial agent sustained release urinary catheter according to claim 1, wherein a layer consisting 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 organic polymer elastomer is natural rubber or silicone rubber. 5. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the acridine compound is 9-aminoacridine. 6. The antibacterial agent sustained release urinary catheter according to claim 1, wherein the acridine compound is 3,6-diaminoacridine. 7 The acridine compound is 6,9-diamino-2-
The antibacterial agent sustained release urinary catheter according to claim 1, which is ethoxyacridine.