JP2636838B2 - Antimicrobial sustained release urinary catheter - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a medical device, and more particularly, to a sustained release of an antibacterial agent excellent in urinary tract infection prevention and anti-calculus (catheter patency). The present invention relates to a medical device for sustained release of an antibacterial agent represented by a sexual urinary catheter.

(Prior art) Catheters, cannulae, tubes, sutures, non-woven fabrics, sponges, wound dressings, artificial skin, artificial organs, artificial blood vessels, artificial valves, extracorporeal circulators, and various containers. Various medical devices have been developed and widely used.

For example, urinary catheters have become an essential tool in modern medical technology, providing temporary urinary tract access to anatomical or physiological dysuria, and to the urethra, prostate and other surrounding tissues. It is widely used to facilitate healing after surgery and for urinary tract management in comatose and urinary incontinence patients. However, it is known that, if unfortunately mismanaged, or even with the utmost care, harms patients who should be nursing as follows. That is, it is known that urinary tract infections caused by bacteria from the outside world occur frequently through the inside and outside of the lumen of the catheter, and the calculus components such as calcium oxalate and calcium phosphate in the urine of the patient are transferred to the catheter surface. It is known that the catheter lumen is often obstructed by deposition and adhesion.

By the way, in order to prevent urinary tract infections associated with catheter indwelling, chemotherapy with antibiotics had often relied on, but simple chemotherapy was newly added even if the infectious bacteria disappeared. It can lead to infection by resistant bacteria,
It is pointed out that it is dangerous. Therefore, it is nowadays stated that chemotherapy should be given only in the minimum necessary cases, such as during fever due to pyelonephritis.

On the other hand, in recent years, a closed urinary system has become widespread in order to prevent infection at the site where a catheter is indwelled. However, even though a closed urinary drainage system is effective in preventing retrograde infection from a contaminated urine collection bag through the intraluminal route, infection by an extravascular route between the outer periphery of the catheter and the urethral mucosa can be prevented. It is known that it is ineffective against contamination due to attachment and detachment of the connection between the catheter and the urinary tube. Therefore, for example, a cumulative infection rate of about 40% is still observed even in the case of indwelling for 5 days in the non-administered antibiotic group.

On the other hand, as a countermeasure to prevent obstruction due to precipitation and adhesion of urinary salts to urinary catheters, a method that has been studied in the past is to use a simple natural rubber (latex) urinary catheter with Teflon coating or silicon coating. Conversion to a natural rubber urinary catheter or an all-silicone urinary catheter. However, these effects are not complete although they have a certain effect, and even though all-silicone urinary catheters are actually obstructed in a short period of time within one week, we often experience them daily. There has also been proposed a urinary catheter having a calculus prevention treatment having a coating layer of a hydrophilic resin layer containing a hydroxamic acid compound on its surface (Japanese Patent Publication No. 57-22594). However, although it is effective in preventing some stones (magnesium ammonium phosphate) due to urinary tract infections, other types of stones (calcium oxalate,
It is ineffective in the prevention of calcium phosphate (and others), and little to no effect on urinary tract infections, as expected from the efficacy of hydroxamic acid.

Conventionally, the most effective method of imparting a continuous antibacterial activity to a medical device is a system that gradually releases an antibacterial agent having a certain concentration or more gradually from the surface of the base material during the use process. The simplest system is a so-called matrix device in which an antibacterial agent is simply dispersed in a base material. However, matrix devices generally allow long-term release, but release at a constant rate, ie, zero order release.
er release is not achieved and the initial abnormal mass release (bu
A major drawback is the observed rsting release.

For example, Shepherd et al. In U.S. Pat. No. 3,695,921 propose a method in which the outer circumference of a urinary catheter is coated with a hydrophilic (meth) acrylate resin and an antibacterial agent is contained therein. However, according to the results of additional tests by the present inventors, the release behavior of the antibacterial agent therefrom is such that the antibacterial agent corresponding to approximately 90% of the total amount adsorbed is released at a stretch on the first day, and thereafter the release amount sharply decreases.

On the other hand, pyridone carboxylic acid antibacterials were
Nalidixic acid (Nalid) by Lesher et al.
ixic acid) was first synthesized. This drug has an advantage in that it has a broad antibacterial spectrum against Gram-negative bacilli and its resistance is not caused by R-plasmid, and is widely used today. After that, improvements were made to compensate for defects such as antibacterial activity, antibacterial spectrum, and metabolism in the body. Also, those having strong antibacterial activity are being developed.

(Problems to be Solved by the Invention) In such a situation, the present inventors have previously found it difficult to use a system containing an organic polymer elastomer as a main component as a system capable of realizing substantially zero-order release. An antimicrobial latex containing a water-soluble biguanide compound or acridine compound or a quaternary ammonium salt compound or a salt thereof, and an antimicrobial agent sustained-release urinary catheter formed by molding these compositions have been proposed (Japanese Patent Application Laid-Open No. 59-1984). −227824, 59-2288
No. 56, No. 60-40139, No. 60-40061, No. 60-81232
No. 60-80458). However, these were not always satisfactory in their antibacterial performance.

Accordingly, a first object of the present invention is to provide a urinary catheter having excellent antibacterial performance, for example, a urinary catheter capable of simultaneously solving two major problems that occur with long-term indwelling, urinary tract infection and urolithiasis. Another object of the present invention is to provide a urinary catheter capable of realizing substantially zero-order release while being the simplest and inexpensive matrix device.

(Means for Solving the Problems) The inventors of the present invention have conducted intensive studies to achieve the above-mentioned object, and as a result, have found that pyridone carboxylic acid is contained in natural rubber, synthetic rubber or synthetic resin as a base material for medical devices. The present inventors have found that the intended purpose can be achieved by dispersing an acid antibacterial agent, and have reached the present invention.

That is, the present invention provides a sustained-release antimicrobial urinary catheter characterized in that a pyridonecarboxylic acid-based antimicrobial agent is dispersed as an antimicrobial agent in natural rubber, synthetic rubber or synthetic resin constituting a urinary catheter. It is assumed that.

The urinary catheter of the present invention includes both a type indwelled in the urethra and a type indwelled in the ureter.

Examples of the base material constituting the urinary catheter of the present invention include natural rubber, synthetic rubber and synthetic resin. Of these, natural rubber, silicone rubber, methyl silicone rubber, fluorine rubber, fluorosilicone rubber, neoprene rubber, chloroprene rubber, styrene butadiene rubber and the like are particularly preferred. Other suitable substrates include ethylene, styrene, vinyl acetate, vinyl chloride, vinylidene chloride, vinyl fluoride, vinylidene fluoride, acrylonitrile, (meth) acrylate, vinylpyridine,
Homopolymers of vinyl monomers such as methyl vinyl ether or copolymers thereof, homopolymers of diene monomers such as butadiene, isoprene, 1,3-pentadiene, 1,5-hexadiene, 1,6-heptadiene, chloroprene or The copolymer, a copolymer of the above vinyl monomer and diene monomer, and other functional groups such as epoxide group, amino group, carboxyl group, acid anhydride group, hydroxyl group, amide group, N-methylolamide group, isocyanate group, etc. And copolymers of the above with the above-mentioned monomers.

The urinary catheter of the present invention contains a pyridonecarboxylic acid-based antibacterial agent in the base material as described above.

The urinary catheter of the present invention may be one in which the antimicrobial agent is contained in a part of the urinary catheter. For example, only the inner surface or the outer surface of the urinary catheter, or both, may be used. May be contained.

The pyridonecarboxylic acid antibacterial agents in the present invention include naphthiridine, quinoline and the like.
e) is a generic term for carboxylic acid compounds having a nucleus such as Cinnoline. Typical examples thereof include nalidixic acid, pyromidic acid, pipemidic acid, and enoxacin as the core of naphthyridine, and oxolinic acid, pefloxacin norfloxacin, ofloxacin, and quinoline as the core. Examples of those having ciprofloxacin or sinorin as a mother nucleus include sinoxacin.

Although the above antibacterial agent is generally poorly water-soluble, the method for producing the urinary catheter of the present invention using the above-mentioned substrate and the antibacterial agent may be any conventionally known method. For example, urinary catheters based on natural rubber are usually made by immersion molding from natural rubber latex. Therefore, by preparing a natural rubber latex solution containing the above antibacterial agent (solid dispersion), the conventional method can be used. It can be manufactured using exactly the same production line. Further, it may be manufactured by a dip molding method using another synthetic polymer latex (emulsion), or may be manufactured by a method of coating a semi-finished product. The antibacterial agent is an organic solvent solution dissolved in a common solvent with a synthetic resin such as chloroform, dimethylformamide, dichloromethane, acetone, glacial acetic acid, etc., and is manufactured by the immersion molding method, the coating method or the spray method described above. You may. Further, the synthetic resin and the antibacterial agent may be manufactured by extruding at a temperature not lower than the melting point of the synthetic resin and not higher than the decomposition point of the antibacterial agent, and performing injection molding or compression molding. The antimicrobial agent may be evenly incorporated in all layers of the catheter, but depending on the purpose and site of use of the catheter in view of manufacturing costs, it is generally 0.01 to 50 for natural rubber synthetic rubber or synthetic resin. % (W / W), especially 0.1 to 30% (W / W).

(Action) The mechanism by which the antimicrobial agent sustained-release urinary catheter of the present invention exhibits sustained antimicrobial activity and anti-calculus properties is not necessarily clear. However, the following mechanism is considered as one possibility.

The mechanism by which urinary stone components adhere to urinary catheters is that salt components such as calcium oxalate and calcium phosphate dissolved in urine adhere to the urinary catheter surface as scaffolds (nuclei) for precipitation and crystallization. In this case, it is considered that in this case, as a scaffold for crystallization, a pseudo-aggregate of infectious bacteria attached to the catheter surface and a viscous substance produced by them are considered. On the other hand, in the urinary catheter according to the present invention, since an antibacterial agent having a stronger bactericidal action is constantly released from the catheter surface, there is no need to create a parasitic environment in which bacteria adhere to and proliferate on the catheter surface. It is conceivable that stones hardly precipitate on the catheter surface. It may also be that some kind of physicochemical interaction is acting so that the pyridone carboxylic acid antibacterial agent, which dissolves and diffuses in urine from the catheter surface, suppresses precipitation and crystallization of the calcium salt and the like. Absent.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1 Raw material natural rubber latex 1 having a solid content of 55% (W / W)
To 100 parts (hereinafter referred to as "parts by weight") is added a paste obtained by sufficiently grinding and dispersing 0.5 part of sulfur, 0.7 part of zinc dibutyldithiocarbamate and 0.3 part of zinc white in a ball mill for 50 hours. (Late A) was obtained. Next, a solid powder of nalidixic acid was added to the solution A for 5 minutes.
Then, the mixture was sufficiently stirred and mixed to obtain a liquid B.

Next, this solution B was cast on a glass plate, dried at room temperature for 24 hours, and then heated at 80 ° C for 24 hours to obtain a size of 60 mm x 100 mm and a thickness of 1 mm.
Vulcanized natural rubber sheet containing nalidixic acid was prepared.

The natural rubber sheet thus obtained was immersed in 100 ml of test water at 37 ° C, and after one day, Bacillus was used as a test bacterium.
The antibacterial activity of the above test water was tested using the subtilis ATCC 6633 (medium Nutrient Agar) by the cylindrical plate method.
It was confirmed that nalidixic acid was released into the test water. Further, the same antibacterial activity test was repeated by replacing the test water with a new test water every day, and the concentration of nalidixic acid released from the natural rubber sheet was quantified over a month from a calibration curve obtained in advance. The results in Table 1 were obtained.

In a normal natural rubber urinary catheter manufacturing line by immersion molding method, the first immersion step uses liquid B, and the last immersion step uses the same liquid as the above liquid B except that the amount of nalidixic acid is 1 part. In use and other immersion steps, the urinary catheter was prepared using Nasidic acid only on the outer surface and inner surface of the urinary catheter using the solution A.

The urinary tract infection preventing effect of the urinary catheter manufactured in this manner was evaluated in an in vitro urinary tract infection model experiment shown in FIG.

That is, as shown in FIG.
Case soy broth connected at 37 ℃ from pseudo-bladder 1
3a, by means of a pump 5 to the receiver 6 through the catheter 4 and connecting tube 3b at a flow rate of 100 ml / day, as test bacteria outlet of the catheter 4 (shown in position I) Escherichi
A 20 μl suspension of E. coli IFO 3302 is inoculated once a day, and the number of days for bacteria to infect the medium on the simulated bladder side against the flow of the medium (indicated by F) is determined by the usual control method. Evaluation was made in comparison with a silicone urinary catheter. Table 2 shows the results.

The urinary tract stone prevention effect of this urinary catheter was
It was studied in model experiments in vitro. The experimental device in this case is basically the same as the device in FIG.
As the medium, natural urine of five healthy healthy men was flowed at 37 ° C. at a flow rate of 100 ml / day in place of the synthetic medium, and the inoculation of the test bacteria at the catheter outlet was not performed. As a control in this case, an all-silicone urinary catheter, which is said to have relatively excellent anti-calculus properties, was used.
In this way, the catheter was cut open for observation of the patency of the catheter when it was allowed to flow for one month, and stones and other deposits on the inner surface of the catheter.

 Table 3 shows the results.

Example 2 Instead of nalidixic acid, the generic name norfloxacin,
Chemical name 1-ethyl-6-fluoro-1,4-dihydro-
A solution having the same composition ratio as the solution B of Example 1 was prepared except that 4-oxo-7- (1-piperazyl) -3-quinoline carboxylic acid was used, and the norfloxacin was gradually reduced from the natural rubber sheet produced therefrom. The release behavior was tracked in the same manner as in Example 1, and as a result, it was almost constant at 30 μg / ml for one month.
It became clear that the above-mentioned norfloxacin was released sustainedly.

Next, in accordance with Example 1, a catheter in which norfloxacin was blended in the outer layer and the inner layer of the catheter was produced, and was subjected to the in vitro urinary tract infection model experiment and urinary calculus model experiment in Example 1.

As a result, regarding the effect of preventing urinary tract infection, the number of days required to cause infection was 53 days on average in 5 patients. In addition, as for the effect of urinary calculus, almost no deposits such as calculus were observed in any one month.

Example 3 Instead of nalidixic acid, common name ofloxacin, chemical name 9-fluoro-2,3-dihydro-3-methyl-10-
Same as solution B in Example 1 except that (4-methyl-1-piperazyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was used A liquid having a composition ratio was prepared, and the sustained release behavior of ofloxacin from the natural rubber sheet produced therefrom was tracked in the same manner as in Example 1. As a result, the sustained release of more than 45 μg / ml of ofloxacin was almost constant over a month. It became clear that there was.

[Brief description of the drawings]

FIG. 1 is a schematic diagram of a urinary tract infection model experiment apparatus implemented in Example 1 of the present invention. 1 ... pseudo-bladder, 2 ... sterile medium, 3a, 3b ... connection tube, 4 ... catheter, 5 ... pump, 6 ... receiver, F ... direction of medium flow, I ... test bacteria Inoculation position.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-59-227824 (JP, A) JP-A-60-80458 (JP, A) JP-A-55-165927 (JP, A)

Claims (2)

(57) [Claims] An antimicrobial agent sustained release urinary catheter characterized in that a pyridonecarboxylic acid antimicrobial agent is dispersed as an antimicrobial agent in natural rubber, synthetic rubber or synthetic resin constituting the urinary catheter. 2. The method according to claim 1, wherein the thiridonecarboxylic acid antibacterial agent is nalidixic acid, pyromidic acid, hypomidic acid, sinoxane, oxophosphoric acid, norfloxacin, ofloxacin, enoxacin, ciprofloxacin or pefloxacin. Antimicrobial sustained release urinary catheter.