JPS62161377A - Medical tool gradually releasing antibacterial agent - 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 (Field of Industrial Application) The present invention relates to a medical device, and more specifically to a sustained release antibacterial agent with excellent urinary tract infection prevention ability and anti-calculi properties (catheter patency). This invention relates to medical devices that release antibacterial agents, such as urinary catheters.

(Prior art) Catheters, cannulae, tubes, as well as sutures, non-woven fabrics, sponges, and wound dressings.

Various medical devices have been developed and widely used, including artificial skin, 2 artificial organs, 2 artificial blood vessels, 1 extracorporeal auxiliary circulation devices, and various containers.

For example, urinary catheters have become an indispensable tool in modern medical technology, and are used to temporarily secure the urinary tract for anatomical or physiological urinary disorders, and to protect the urethra, prostate, and other surrounding tissues. It is widely used to facilitate healing after surgery and for urinary tract management in comatose and incontinent patients. Unfortunately, however, it is known that if managed incorrectly, or even with the utmost care, harm may be caused to the patients who should be cared for, as described below. In other words, it is known that bacteria from the outside world can frequently cause urinary tract infections through the inside and outside of the catheter's lumen, and stone components such as calcium oxalate and calcium phosphate in the patient's urine can reach the surface of the catheter. It is known that the catheter lumen often becomes occluded due to precipitation and adhesion.

By the way, in order to prevent urinary tract infections associated with catheter placement, conventional chemotherapy using antibiotics has been relied upon, but easy chemotherapy can cause new infections even after the sputum-infecting bacteria have disappeared. It has been pointed out that this is actually dangerous, as it can lead to infection by resistant bacteria. Hence chemotherapy today.

It is said that it should be used only in the minimum necessary cases, such as when experiencing fever due to nephritis.

On the other hand, in recent years, closed urinary catheter systems have become popular in order to prevent infections at the site where the catheter is placed, and have been found to be more effective in preventing urinary tract infections than conventional open systems. However, although a closed urinary catheter system is effective in preventing retrograde infection from the intraductal route from a contaminated urine collection bag, it is effective in preventing retrograde infection from the intraductal route from the catheter periphery and the urethral mucosa. It is known that it is ineffective against infection caused by this method and contamination caused by attaching and detaching the connection between the catheter and the urinary tube. Therefore, for example, in patients who are not administered antibiotics, the current situation is that cumulative infections of around 40% are still observed even after 5 days of indwelling in the body.

On the other hand, as a measure to prevent occlusion due to the precipitation and adhesion of urinary salts to the urinary catheter, methods that have been studied in the past include coating the urinary catheter with Teflon or silicone from a simple natural rubber (latex) urinary catheter. Examples include conversion to natural rubber urinary catheters or all-silicone urinary catheters. but,
Although these methods are effective to a certain extent, they are not perfect, and in fact, we often experience cases of occlusion within a short period of one week even with all-silicone urinary catheters. Also.

A urinary catheter treated to prevent stones and having a coating layer made of a hydrophilic resin layer containing a hydroxamic acid compound on its surface has been proposed (Japanese Patent Publication No. 57-22594).

However, this one may be associated with some stones caused by urinary tract infections (
Although effective in preventing ammonium magnesium phosphate (ammonium magnesium phosphate), other types of stones (
Calcium oxalate, calcium phosphate, etc.) are ineffective in preventing urinary tract infections.

As expected from the medicinal properties of hydroxamic acid, little is expected.

Conventionally, the most effective method for imparting sustained antibacterial activity to medical devices has been considered to be a system in which an antibacterial agent of a certain concentration or higher is gradually released from the surface of the substrate during the course of use. and.

The simplest system is a so-called matrix device, which simply has an antimicrobial agent dispersed in a base material. However, matrix devices, although generally capable of long-term release, require constant rate release, i.e., zero-order release (zer).

A major drawback is that order release is not achieved and an abnormal initial bursting release is observed.

For example, 5hepherd et al. U.S. Pat. No. 3,695,9
No. 21 proposes a method of coating the outer periphery of a urinary catheter with a hydrophilic (meth)acrylic acid ester resin and incorporating an antibacterial agent therein. However, according to the results of additional tests conducted by the present inventors, the release behavior of the antibacterial agent is such that on the first day, approximately 90% of the total adsorbed amount of antibacterial agent is released at once, and then the amount released decreases rapidly.

On the other hand, pyridonecarboxylic acid antibacterial agents were introduced in 1962 by W.
Nalidixic acid was first synthesized by Lesher et al. in the inthrop laboratory.

This method is still widely used today because it has a broad antibacterial spectrum against Durham-negative bacilli and its resistance is not caused by the R-plasmid. Subsequently, improvements were made to compensate for deficiencies such as antibacterial activity, antibacterial spectrum, and internal metabolism.

In particular, in recent years, the introduction of fluorine has greatly improved antibacterial activity, and products with strong antibacterial activity against Durum-positive bacteria, Pseudomonas aeruginosa, and non-fermenting Durum-negative rods are being developed.

(Problems to be Solved by the Invention) Under such circumstances, the present inventors first developed a system that achieves substantially zero-order release.

A system whose main component is an organic polymer elastomer.

We have proposed an antibacterial latex containing a poorly water-soluble biguanide compound, an acridine compound, a quaternary ammonium salt compound, or a salt thereof, and an antibacterial agent sustained release urinary catheter made by molding a composition thereof (Japanese Patent Application Laid-Open No. 59-
No. 227824, No. 59-228856, No. 60-4
No. 0139.

No. 60-40061, No. 60-81232.

No. 60-80458). However, these materials were not necessarily satisfactory in their antibacterial performance.

Therefore, the first object of the present invention is to provide a medical device with excellent antibacterial performance, such as a urinary catheter that simultaneously solves the two major problems that occur with long-term indwelling: urinary tract infections and urolithiasis. Another object of the present invention is to provide a medical device which is the simplest and cheapest matrix denomination chair and which can achieve substantially zero-order release.

(Means for Solving the Problems) As a result of intensive research to achieve the above objectives, the present inventors have found that pyridonecarboxylic acid is contained in natural rubber, synthetic rubber, or synthetic resin as a base material for medical devices. The present invention was achieved by discovering that the desired purpose could be achieved by dispersing an acid-based antibacterial agent.

That is, the present invention provides a medical device comprising an antibacterial agent in natural rubber, synthetic rubber, or synthetic resin constituting the medical device, which is characterized by containing a pyridonecarboxylic acid-based antibacterial agent as the antibacterial agent. This article focuses on sustained-release medical devices.

Medical devices of the present invention include, for example, catheters, cannulae, tubes, sutures, and nonwoven fabrics.

Examples include sponges, wound dressings 2 artificial skin 2 artificial organs 1 artificial blood vessels 2 artificial valves 9 extracorporeal auxiliary circulation devices, containers, etc. Catheters are particularly suitable, but are not limited to these. A particularly suitable catheter is a urinary catheter. This urinary catheter includes both a type that is indwelled in the urinary catheter and a type that is indwelled in the ureter. Further, a suitable catheter includes a peritoneal dialysis catheter, which is applied to a method of indirectly purifying blood by purifying glue, unlike conventional artificial dialysis, which directly purifies blood. In this peritoneal dialysis method, it is difficult to maintain hygiene at the glue outlet of the catheter, which is left in the body for a long period of time, and there is a high possibility of infection, such as pathogens entering between the catheter and the skin.

The base material constituting the medical device of the present invention may be natural rubber, synthetic rubber, or synthetic resin. Among these, natural rubber, silicone rubber, methyl silicone rubber, fluorine rubber, fluorosilicone rubber, neoprene rubber, chloroprene rubber, styrene-butadiene rubber, etc. are particularly suitable. Other suitable base materials include ethylene and styrene.

Hinyl acetate, vinyl chloride, vinylidene chloride, vinyl fluoride, vinylidene fluoride, acrylonitrile.

(meth)acrylic acid ester, vinylpyridine.

Monopolymers of vinyl monomers such as methyl vinyl ether or copolymers thereof, butadiene, isoprene, 1.3
-Pentadiene, 1,5-hexadiene.

1. A homopolymer of a diene monomer such as 6-hebutadiene or chloroprene or a copolymer thereof, a copolymer of the above-mentioned vinyl monomer and a diene monomer, and an epoxide group or an amino group as other functional groups.

Carboxyl group 1M anhydride group, hydroxyl group, amide group.

Examples include copolymers with the above-mentioned hexamers having N-methylolamide groups, isocyanate groups, and the like.

The medical device of the present invention contains a pyridonecarboxylic acid antibacterial agent in the base material as described above.

The medical device of the present invention may contain an antibacterial agent in a part of the medical device, for example, the antibacterial agent may be contained only in either the inner surface or the outer surface of the medical device, or only in both. It may be something like that.

The pyridonecarboxylic acid antibacterial agents in the present invention include naphthyridine, quinoline, and cinnoline.
It is a general term for carboxylic acid compounds whose core is 1 1ne). Typical specific examples include nalidixic acid, pyromidic acid, pipemidic acid, and enoxacin that have naphthyridine as their core, and oxolinic acid, peprosaxine, norfloxacin, and ofloxacin as those that have quinoline as their core. , ciprofloxacin, and dinoline as the core.

Dinoxazine, etc. can be mentioned.

Although the above-mentioned antibacterial agent is generally poorly water-soluble, any conventionally known method may be used to manufacture the medical device of the present invention using the above-mentioned base material and antibacterial agent. For example, to explain the method for manufacturing a urinary catheter, a urinary catheter based on natural rubber is usually made from natural rubber latex by dip molding, so a natural rubber latex solution containing the above-mentioned antibacterial agent (solid dispersion) is used. By specially preparing it, it can be manufactured using exactly the same production line as conventional ones. It may also be manufactured by dip molding using other synthetic polymer latexes (emulsions) or by coating on semi-finished products.

Alternatively, the above-mentioned antibacterial agent may be dissolved in an organic solvent solution with a synthetic resin such as chloroform, dimethylformamide, dichloromethane, acetone, glacial acetic acid, etc., and produced by the dip molding method, coating method, or spray method described above. It's okay. Also.

The synthetic resin and the antibacterial agent may be extruded, molded, injection molded, or compression molded at a temperature that is higher than the melting point of the synthetic resin and lower than the decomposition point of the antibacterial agent.

The antibacterial agent may be blended evenly into all layers of the catheter, but considering manufacturing costs, it varies depending on the purpose and site of use of the catheter, but it is generally 0.01% for natural rubber, synthetic rubber, or synthetic resin. ~50% (enemy), especially 0.1~30% (W/W).

(Function) When the antibacterial agent sustained release medical device of the present invention is a urinary catheter, the mechanism by which the device exhibits sustained antibacterial activity and anti-stone properties is not necessarily clear.

However, one possibility is the following mechanism.

The mechanism by which urinary stone components adhere to the urinary catheter is as follows:
It is thought that the process begins when salt components such as calcium oxalate and calcium phosphate dissolved in urine adhere to the surface of the urinary catheter, which serves as a scaffold (nucleus) for precipitation and crystallization. Aggregates of infectious bacteria adhering to the catheter surface and the viscous substances produced by them are considered to be the cause. Point 2: In the urinary catheter according to the present invention, an antibacterial agent having a strong bactericidal effect is constantly released from the surface of the catheter.

Since a parasitic environment in which bacteria adhere to and proliferate on the catheter surface is not created, it is thought that stones are less likely to be deposited on the catheter surface. In addition, some kind of physicochemical interaction may be working so that the pyridonecarboxylic acid-based antibacterial agent that dissolves and diffuses into the urine from the catheter surface suppresses the precipitation and crystallization of the calcium salts, etc. do not have.

(Examples) Hereinafter, the present invention will be explained in more detail by giving examples.

Example 1 0.5 parts of sulfur was added to 100 parts of raw natural rubber latex (hereinafter referred to as parts by weight) with a solid content concentration of 55% (W/W).
A paste obtained by grinding and dispersing 0.7 parts of zinc dibutyldithiocarbamate and 0.3 parts of zinc white in a ball mill for 50 hours was added to obtain a blended latex (liquid A) containing natural rubber as the main component. Ta. Next, 5 parts of solid powder of nalidixic acid was added to this A liquid and thoroughly stirred and mixed to obtain a B liquid.

Next, this B solution was cast onto a glass plate, dried at room temperature day and night, heated at 80°C for 24 hours, and made into a glass plate with a size of 60 mm x
A nalidixic acid-containing vulcanized natural rubber sheet having a size of 100 mm and a thickness of 1 mm was prepared.

The natural rubber sheet thus obtained was immersed in 100 mβ of test water at 37°C, and after one day, Bacillus us 5ubtilis ATCC66 was added as a test bacterium.
When the antibacterial activity test of the above test water was conducted using the cylindrical plate method using 33 (Medium Nutrient Agar),
The formation of an inhibition zone, which is an inhibition zone for bacteria, was observed, and it was confirmed that nalidixic acid was released into the test water.

Then, the same antibacterial activity test was repeated by replacing the test water with new test water every day, and the concentration of nalidixic acid released from the natural rubber sheet was determined over a period of one month using a calibration curve determined in advance. 1 The results shown in Table 1 were obtained.

Table 1 In a normal natural rubber urinary catheter manufacturing line using the dip molding method, the first dipping step uses Solution B, and the final dipping step is the same as the B solution except that the amount of nalidixic acid is 1 part. A urinary catheter in which nalidixic acid was blended only on the outer and inner surfaces of the urinary catheter was manufactured by using the liquid A in the other dipping steps.

The effectiveness of the urinary catheter thus produced in preventing urinary tract infection was evaluated in an in vitro urinary tract infection model experiment shown in FIG.

That is, in FIG. 1, Tryp as the sterile medium 2
Ticase soy broth was passed from the simulated bladder 1 through the connecting tube 3a, the catheter 4, and the connecting tube 3b at 37°C to the receiver 6 using the pump 5 for 100 m#.
/day at a flow rate of
i Inoculate 20 ttl of IFO3302 suspension once every day, and wait for the number of days required for bacteria to cause infection against the flow of the medium (in the direction indicated by F) to the simulated bladder side of the catheter. It was evaluated in comparison with a urinary catheter.

The results are shown in Table 2. In addition, the effectiveness of this urinary catheter in preventing urinary stones is shown in Table 2.
This was investigated in a model experiment in vitro.

Experimental apparatus 1 in this case is basically the same as the apparatus shown in Figure 1, but instead of a synthetic medium, natural urine from five healthy adult males was used at 37°C at a flow rate of 100 m 1 /d.
The test bacteria were not inoculated at the catheter outlet. In addition, the control in this case is
An all-silicone urinary catheter, which is said to have relatively excellent anti-calculi properties, was used. The catheter was cut open and observed for patency of the catheter and stones and other deposits on its lumen surface after the catheter was allowed to flow in this manner for one month.

The results are shown in Table 3.

Table 3 Example 2 In place of nalidixic acid, - ship name norfloxacin, chemical name 1-ethyl-6-fluoro-1,4-cibidro-4-oxo-7-(1-piperazyl)-3-quinolinecarboxylic acid A solution having the same composition ratio as Solution B of Example 1 was prepared except that the same composition was used, and the sustained release behavior of norfloxacin from a natural rubber sheet prepared from the solution was tracked in the same manner as in Example 1.

It was revealed that 30 μg/m 1 or more of norfloxacin was almost constantly released over a period of one month.

Next, according to Example 1, a catheter in which norfloxacin was blended in the outer and inner layers of the catheter was manufactured and subjected to the in vitro urinary tract infection model experiment and urinary stone stone model experiment of Example 1.

As a result, regarding the effect of preventing urinary tract infection, the number of days required for infection to occur was 53 days on average in 5 cases. Furthermore, as for the effect of preventing urinary tract stones, almost no deposits such as stones were observed after one month.

Example 3 Generic name ofloxacin instead of nalidixic acid.

Chemical name: 9-Fluoro-2,3-sibidro-3-methyl-10-(4-methyl-1-piperazyl)-7-oxo-7H-pyrido(1,2,3-de)(1,4)benzoxazine- B of Example 1 except that 6-carboxylic acid was used.
? A liquid with the same composition ratio as & was prepared, and the sustained release behavior of ofloxacin from a natural rubber sheet prepared from it was tracked in the same manner as in Example 1. As a result, ofloxacin of 45 μg/ml or more was almost constitutively released over a period of one month. It became clear that the drug was released slowly.

[Brief explanation of drawings]

FIG. 1 is a schematic diagram of a urinary tract infection model experimental apparatus carried out in Example 1 of the present invention. 1 - Condensed bladder, 2 - Sterile culture medium, 3a, 3b...-Connecting tube, 4- Catheter, 5- Pump, 6- Receptacle. F. - Direction of medium flow, ■...Connection position of test bacteria.

Claims (5)

[Claims] (1) A medical device containing an antibacterial agent in natural rubber, synthetic rubber, or synthetic resin constituting the medical device, characterized in that it contains a pyridonecarboxylic acid-based antibacterial agent as the antibacterial agent. Sexual medical equipment. (2) Claim 1 in which the medical device is a catheter
Medical equipment listed in section. (3) The medical device according to claim 2, wherein the catheter is a urinary catheter. (4) The medical device according to claim 2, wherein the catheter is a peritoneal dialysis catheter. (5) The pyridonecarboxylic acid antibacterial agent is nalidixic acid,
Pyromidic acid, hypermic acid, cinoxane, oxolinic acid,
The medical device according to any one of claims 1 to 4, which is norfloxacin, ofloxacin, enoxacin, ciprofloxacin, or peproxacin.