JPS6040061A - Antibacterial agent slow releasing urine guide catheter - 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] The present invention relates to a urinary catheter.

More specifically, the present invention relates to a urinary catheter having sustained release performance of antibacterial substances.

Patients with lung injury, cerebral hemorrhage, encephalomalacia, or after 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, maintain or improve renal function, and 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 cystitis. It has been known. Conventional countermeasures include cleaning the bladder, injecting disinfectants, and prophylactic administration of antibacterial substances such as antibiotics, but these not only require extra operations but are also ineffective. For this reason, recently, in order to fundamentally prevent bacterial infection at the site where the urinary catheter is installed, a type of urinary catheter that releases an antibacterial agent locally at a constant rate over a long period of time has become increasingly popular. desired.

Conventionally, regarding drug control release technology in the medical or pharmaceutical field, 1, for example, chemical engineering, No. 115
Volume, No. 7, 441, Kai (1981), (1) active substances are dispersed in polymers or pores with a matrix structure, (2) active substances are microencapsulated in thin films. something that has become

(3) There are four types: those that utilize an osmotic ink pump and those that coat the outside of a core material containing a +41'/f'r substance with an erosive substance. Among these, zero order release, which is a constant rate of release that does not change the amount of drug released over time, is (Zero order release).
2) It is possible in +31 and +41, but generally requires special ingenuity and advanced technology. On the other hand, (1)
Drugs dispersed within a polymer matrix have long been in practical use in various forms because they are easy to manufacture, but zero-order release is impossible.
Few such examples are known to date. That is, in case (1), an abnormally large amount of release is generally observed at the beginning, and then the amount released rapidly decreases, 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 level of bactericidal efficacy against various types of bacteria, the so-called minimum (growth) inhibitory concentration (formerly n
imal Tnhibitory Concentra
tion, 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.
- Abnormal release of an antibacterial agent of 10,000 MIC or more 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 urinary catheter on 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. Regarding the system with 11% antibacterial agent,
This is the result of careful consideration as to whether zero-order release can be achieved.

Surprisingly, as an antibacterial agent, water-soluble acridine compounds or their salts are present in organic polymer elastomers.
The present invention was based on the discovery that substantially zero-order release is achieved in the i'l system.

The present invention relates to a urinary catheter made of an organic polymer elastomer, which is an antibacterial agent sustained-release catheter characterized in that the catheter contains a poorly water-soluble acridine compound or a salt thereof. It is a urinary catheter.

The present invention can be realized 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. The present invention provides a urinary catheter that achieves zero-order release, and its industrial significance is extremely large. Although it is not clear why substantially zero-order release was achieved in the present invention, 9 in the present invention! jl
It is thought that this is because the low solubility of the water-soluble acridine compound or its salt in water and its interaction with the material matrix acted synergistically.

That is, the acridine compound according to the present invention is characterized in that its chemical structure has a cationic group as a polar group and a hydrophobic cyclic structure.

It is thought that when these 151 disappeared in water, they acted advantageously in interaction with water and hydrophobic organic polymer elastomer materials.

What is the organic polymer elastomer in the present invention?

It has rubber-like elasticity at around room temperature, and examples thereof include natural rubber, synthetic rubber, silicone rubber, polyurethane, and soft polyvinyl chloride. Natural rubber here refers to an aqueous solution containing various molten substances and inorganic substances that flows out when cutting is performed on the bark of a rubber plant as a dispersion medium, rubber as a dispersoid, and PU adjustment as necessary. This refers to compounds containing additives, vulcanizing agents, vulcanization accelerators, softening agents, fillers, anti-aging agents, etc.

Synthetic rubbers include 2, such as butadiene, isoprene, 1
．． 3-pentadiene, 1,5-hexadiene.

Examples include homopolymers of diene monomers such as 1,6-heptadiene and chloroprene, or copolymers thereof.

Silicone rubber means a compound containing 1 coxane with a high degree of polymerization, and 1, for example, 1 inorganic filler, 1 dispersion accelerator, 1 vulcanizing agent, etc. As the organopolysiloxane, 9, for example, dimethylpolysiloxane, Examples include methylphenylpolysiloxane, methylvinylpolysiloxane, and fluoroalkylmethylpolysiloxane.

Moreover, polyurethane means an elastomer having a bond in the repeating unit of the main chain. Examples of polyisocyanates include toluene diisocyanate, xylene diisocyanate, naphclean diisocyanate, diphenylmethane diisocyanate, phenylene diisocyanate, ethylene diisocyanate, cyclohexylene diisocyanate, triphenylmethane triisocyanate, and toluene diisocyanate. Examples include entry isocyanates.

Examples of polyols include ethylene glyfur.

1 Copylene gelicol, ethylene gelicol, diethylene glycol, cyclohexanediol.

Examples thereof include polyols such as pentaerythritol, glycerin, and 1.1.1-trimethylolpropane; polyether polyols such as polyethylene glycol, polybutylene glycol, polytetramethylene glycol, and polyethylene glycol/polypropylene glycol copolymer. Also.

Examples of polyols include succinic acid and glutaric acid.

Also included are polyesters having hydroxyl groups at both ends obtained by condensing dicarboxylic acids such as avivic acid, sebacic acid, isophthalic acid, phthalic acid, and terephthalic acid with ethylene glycol, propylene glycol, and the like. Furthermore, some of these polyols can be converted into polyamines, polythiols,
It also includes those substituted with other active hydrogen compounds such as polycarboxylic acids. Examples of soft polyvinyl chloride include those prepared by blending a plasticizer with a polyvinyl chloride polymer, or those made internally by copolymerization with other components. As for the former plasticizer.

Phthalic acid esters such as dibutyl phthalate, di-2-ethylhexyl phthalate, dioctyl phthalate, butyl lauryl phthalate, dilauryl fucrate, butylbenzyl phthalate, and direct esters such as dioctylazibe-1, dioctyl azelate, dioctyl sebacate, Chain dibasic acid esters.

Phosphate esters such as tricresyl phosphate, tricylenyl phosphate, monobutyl dixylenyl phosphate trioff, and thyl phosphate.

Castor oil derivatives such as methyl acetyl lysyl-tobutylacetyl lysyl, 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, butyl phthalyl butyl Examples include ethylene glycol derivatives such as glycolate, and viscous lower polyester plasticizers having an average molecular I of 1,000 to 3,000. In addition, examples of the latter copolymerizable monomer of vinyl chloride include 1, such as vinyl acetate,
Examples include vinylidene chloride, acrylic acid or methacrylic acid and its esters, maleic acid and its esters, and acrylconitrile.

The acridine compound in the present invention is a compound having the following acridine skeleton, and various derivatives thereof are described in "Ichidai Organic Chemistry", Vol. 16, pp. 286-326 (Asakura Shoten, 1960). A preferred specific example of such an acridine compound is 9-aminoacridine.

3.6-diamitacridine, 6.9-diamino-2-
Etquinacridine is one of the most widely used sterilizing agents in the medical, hygiene, and food industries today because it has strong sterilizing power against a wide range of microorganisms and low toxicity to the human body. one and two
It is particularly preferably used in the present invention.

In the present invention: 11 Water-soluble means 10
The solubility in 0 g of distilled water is o, ooi to 1. Og
, preferably in the range of 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.

If the weight exceeds 1.0g, initial abnormal release is observed.
Zero order release will no longer be possible.

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 301%, more preferably 0.1 to 10% by weight.

The antibacterial agent sustained release urinary catheter of the present invention can be easily manufactured using conventionally known manufacturing methods. For example, natural rubber latex? ＋? - When manufacturing a urinary catheter by immersing the urinary catheter in the 1lj liquid, the catheter is immersed at least once in the immersion liquid in which the antibacterial agent is uniformly dispersed, and then heat treatment is performed. be able to. Also.

When manufacturing silicone rubber by extrusion molding or compression molding, the above-mentioned antibacterial agent is added during the mastication stage before being applied to the molding machine, and then molded and vulcanized using the 5-strike method. It can be manufactured using

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, the antibacterial agent may be ground in a ball mill together with a surfactant, thickener, and protective colloid to form a uniform paste-like aqueous dispersion, and then added. preferable. Also, silicone resin when added to silicone rubber.

Dispersibility is improved by using a dispersion accelerator such as alkoxysilane and siloxane, hydroxysilane and siloxane, organic acid ester, and polyhydric alcohol.

As described above, the present invention is a urinary catheter mainly composed of an organic polymeric elastomer, which contains a water-soluble acridine compound or a salt thereof. 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 contact surface with the urinary tract mucosa, 3. Preferably, the FM and M are provided on the outer surface. Further, on the inner surface of the urinary catheter, which is the urine drainage path, salt and calcium components in the urine are deposited on the concave surface after the antibacterial agent has been eluted.

Furthermore, in order to avoid a situation that would cause 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 system (f) stomer containing no antibacterial agent between the outer surface and the inner surface of the urinary catheter.

The present invention will be described in detail below with reference to specific examples.

Note that "1 part in one example" means "part by weight."

Example 1 6.9-Diamino-2-ethoxyacridine hydrochloride 1
00 parts and 100 parts of distilled water were ground and dispersed in a ball mill for 100 hours to prepare an antibacterial agent dispersion (hereinafter referred to as liquid A). On the other hand, a compounded latex solution (hereinafter referred to as "latex liquid") 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 natural rubber latex with a solid content concentration of about 50 iyt% (referred to as Solution B) was prepared. Next, add 1 part of liquid A to 100 parts of liquid B.
An immersion liquid (hereinafter referred to as liquid C) 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 with a weight of 12 g was prepared.

The obtained urinary catheter was heated to 100 ml of test urine at 37°C.
After one day, Bacillus was added as a test bacterium.
sSubLilis ATCC6633 (medium NIIT
An antibacterial activity test I was performed using the 1-cylinder plate method (disk method) using a RIENT AGAR, and the thickness of the inhibition circle produced there was determined, and the concentration of the antibacterial agent released was estimated from the calibration curve. Ta. 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.

In addition, when the urinary catheter manufactured in 8 was clinically applied to 5 patients, no urinary tract infection was observed on the gold side even after 2 weeks of indwelling in the body. In addition, discomfort associated with use and inflammation of the urinary tract mucosa were not particularly reported.

Comparative Example I An immersion liquid consisting only of liquid B was prepared without using 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 prepared in the same manner as in Example 1 except that the amount of liquid A added to 100 parts of liquid B was changed to fL Example 1.
The same antibacterial activity test was performed. Table 1 shows the results obtained.
Not shown.

Example 3 A urinary catheter was obtained in the same manner as in Example 1 except that 3,6-diamitacridine sulfate was used instead of 6.9-diamino-2-ethoxyacridine hydrochloride, and Example 1 The same antibacterial activity test was performed. The results obtained are shown in Table-1.

Example 4 20 parts of fine silica powder, 2 parts of benzoyl peroxide and 25 parts of 9-aminoacridine sulfate were added to 100 parts of methylvinylpolysiloxane raw rubber, thoroughly masticated on a rubber roll machine, and then extruded and compressed. A urinary catheter was made by molding.

The same antibacterial activity test as in Example 1 was performed 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 coating layer containing no antibacterial agent and having a thickness of approximately 30 μm and consisting only of liquid B 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-1 Patent applicant: Unitika Co., Ltd.

Claims (1)

[Scope of Claims] (A urinary catheter mainly composed of a 1,1 organic polymer elastomer, characterized in that the catheter contains a poorly water-soluble acridine compound or a salt thereof. Release urinary catheter. (2) The sustained release antibacterial agent 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 urinary catheter made of only an organic polymer elastomer is provided between the outer surface and the inner surface of the urinary catheter. Catheter. (4) An antibacterial agent sustained release urinary catheter according to claim 1, wherein the organic polymer elastomer is natural rubber or silicone rubber. (5) A patent claim, wherein the acridine compound is 9-aminoacridine. The antibacterial agent sustained release urinary catheter according to claim 1. (6) The antibacterial agent sustained release urinary catheter according to claim 1, wherein the acridine compound is 3,6-diamitacridine. 7) The antibacterial agent sustained release urinary catheter according to claim 1, wherein the acridine compound is 6,9-diamino-2-ethoxyacridine.