JPS6080457A - Antibacterial agent slow releasing urethral 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 an antimicrobial agent sustained release urinary catheter.

Patients with spinal cord 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, 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 cystitis. It is being Conventional countermeasures include bladder irrigation, injection of disinfectants, and prophylactic administration of antibiotics, but these not only require extra operations but also have uncertain effectiveness. Therefore, in order to basically prevent bacterial infection at the site where the urinary catheter is installed, there has been a strong desire for a type of urinary catheter that releases antibacterial agents locally at a constant rate over a long period of time. .

Special features required for the materials that make up urinary catheters include appropriate flexibility, water resistance, biocompatibility, non-toxicity, ease of insertion, and no deposits of calcium salts, etc., depending on the purpose and form of use. One example is that there is no. Currently, the most commonly used material is natural rubber, which is the cheapest in terms of cost, but its drawbacks include, for example, its poor water resistance, making it unsuitable for long-term placement in the body for more than a week, and its poor biocompatibility. Examples include causing inflammation of the urinary tract mucosa, making it difficult to insert the catheter smoothly, and blocking the flow path and making removal difficult due to the deposition of calcium and its masses on the inner and outer surfaces of the catheter. Although silicone rubber is expensive in this respect, it is a material that has been rapidly attracting attention in recent years as a material that compensates for the above-mentioned drawbacks.

The following methods have been proposed to date for imparting antibacterial properties to silicone rubber urinary catheters. For example, U.S. Pat. No. 3,566.874 and 3,6
No. 95,921 discloses that a catheter is impregnated with a hydrophilic acrylate or methacrylate monomer or oligomer, and then a hydrophilic coating layer is applied on the outer surface of the catheter by completing 7 polymerization, and that portion is coated with antibiotics. Methods for impregnating substances and fungicides are described.

In addition, US Pat. No. 4,055,682 discloses that silicone is graft-polymerized by impregnating hydrophilic N-vinylpyrrolidone or the like and then irradiating it with radiation.
A method of impregnating the part with benzalcornium chloride, hexachlorophene, iodine, etc. is described. Also,
JP-A-49-34179 and JP-A-49-3418
No. 0 proposes a catheter coated with a polymerized acrylamide monomer or polyvinyl alcohol as a hydrophilic polymer. However, all of these catheters have a coating layer or cover layer made of hydrophilic resin on the outer surface of the catheter, and the antibacterial agent is physically adsorbed to that part, so the common characteristics of these types of catheters are: As a drawback.

(1) Long-term antibacterial activity cannot be obtained because the antibacterial agent elutes and diffuses into the urine early, and (2) body fluids such as urine are absorbed into the hydrophilic coating layer, resulting in a saturated salt concentration. As this occurs, nucleation occurs in the area, and calcium salts and other solids can precipitate, clogging the catheter and forming deposits on the external surface! ! It has been removed.

Based on the technical background described above, the present inventors took advantage of the special properties of silicone rubber to gradually release an antibacterial agent at a concentration above a certain level necessary to prevent urinary tract infections even during long-term indwelling in the body. As a result of extensive research aimed at providing a urinary catheter made of silicone that releases antibacterial agents continuously and does not allow salts to adhere or become clogged, the above objective was achieved by incorporating a specific antibacterial agent into silicone. This is the finding that led to the present invention.

Namely, the present invention is a urinary catheter made of silicone rubber containing a cationic antibacterial agent and capable of releasing an antibacterial agent.

Conventionally, various combinations of active substances dispersed within a polymer matrix structure have been known, but in this case, differences in the physical or chemical properties of the matrix component and filler component and the image components Due to the interaction between the two, it has not always been easy to obtain something with the desired functionality. Rather, it is generally more difficult than the ease of mixing operations, and there are few success stories. However, in the present invention, the cationic antibacterial agent dispersed in the silicone rubber of a urinary catheter made of silicone rubber can be used to absorb relatively high concentrations of salts such as urine and organic waste without losing its properties as silicone rubber. This is based on the discovery that antibacterial agents continue to be released in the urine over a long period of time even when the patient comes into contact with objects or body fluids containing proteins, etc., and that no blockage due to precipitation or deposition of calcium salts, etc. is observed. has not been reported so far. Although it is not clear why a cationic antibacterial agent is uniformly dispersed in a highly hydrophobic matrix such as silicone rubber and yet exhibits sustained release properties over a long period of time.

Usually, cationic antibacterial agents have a relatively large hydrophobic group as well as a hydrophilic cationic group in their molecules.
It is thought that this may have had an advantageous effect on the interaction with the silicone rubber matrix.

To manufacture the antibacterial agent sustained release urinary catheter of the present invention 1
For example, a composition consisting of a compound made by mixing a filler and a vulcanizing agent with raw rubber made of organopolysiloxane with a high degree of polymerization, and a cationic antibacterial agent, or a composition in which additives such as a dispersion accelerator and pigment are further mixed. The composition may be molded. More specifically, for example, fillers, vulcanizing agents, and cationic fungicides may be added and mixed during the mastication stage of raw rubber, and then extrusion molding or compression molding may be performed. Various conventionally known devices and methods can be appropriately employed for mastication and molding.

Examples of organopolysiloxane include dimethylpolysiloxane and methylphenylpolysiloxane.

Methylvinylpolysiloxane, methylphenylpolysiloxane, fluoroalkylmethylborisiloxane, and the like are preferably used. As the filler, fine silica powder is typically used as a reinforcing filler, but for example, calcium carbonate, titanium oxide, zinc oxide, etc. can also be used. Further, as dispersion accelerators for these fillers, for example, silicone resins, alkoxysilanes and siloxanes, hydroxysilanes and siloxanes, organic acid esters, polyhydric alcohols, etc. are used. As the vulcanizing agent, organic peroxides, fatty acids, azone compounds, platinum, palladium, and sulfur are used, but organic peroxides are preferred. Examples of organic peroxides include hensyl peroxide, bis-2,4
-dichlorobenzoyl peroxide, dicumyl peroxide, tert-butyl peroxide, tert-butyl perbenzoate, p-monochlorobenzoyl peroxide, 2,5-dimethyl-2,5-bis(
Tertiary butylperoxy)hexane and the like are preferably used. If the antibacterial agent used in the present invention can withstand the vulcanization temperature, heat-vulcanizing silicone rubber may not be used, but if not, it is preferable to use room-temperature vulcanizing silicone rubber. .

The cationic antibacterial agent in the present invention refers to an antibacterial agent having a positive charge and a hydrophobic group in two molecules, and preferred specific examples include biguanide compounds or salts thereof, acridine compounds or salts thereof, quaternary ammonium salt compounds, etc. can be mentioned.

The biguanide compound is the following general formula (1) or (II)
) or (III).

NHNH 111 1? I? 'NCNIfCN+1 (Cllz). RR'NCNHCIIR' R11
1 RR' NCNtlCNII NHNi1111 NHNH (I) (II) (C1l z ) NIICNHCNH-111 IINH (1) where R is an alkyl group, an aminoalkyl group, a phet+
4%, alkylphenyl group, halogenated phenyl group, hydroxyphenyl group, methoxyphenyl group, carboxylphenyl group, naphthyl group or nitri group, R''
is hydrogen or an alkyl group. Note that 1m and n are positive integers, preferably in the range of 2 to 1°. A preferred example of such a biguanide compound is 1,6-di(
4-chlorophenyl biguanide) hexane, diaminohexyl biguanide, 6-di(aminohexyl biguanide) hexane, polyhexyl biguanide, and the like.

The acridine compound is the acridine compound (IV) below.
Various derivatives are described in "Great Organic Chemistry J, Vol. 16, Af-tei (IV), pp. 286-326 (Asakura Shoten, 1960). Specific examples include 9-aminoacridine, 3,6-diaminoacridine, 6,9-diamino-2-ethoxyacridine, and the like.

The salt of a biguanide compound or an acridine compound refers to a salt formed from these and an inorganic acid or an organic acid.

Examples of non-acid or organic acids include gluconic acid, lactic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, carbonic acid, monobicarbonic acid, citric acid, phosphoric acid, and boric acid.

Examples include formic acid, acetic acid, benzoic acid, and tartaric acid.

The quaternary ammonium salt is represented by the following structural formula (V).

Here, R,, R,, R3 and R+ are an alkyl group, a Hensyl group, a carboxyalkyl group, an alkyl group, a nitro group, a benzyl group substituted with a chlorine atom, etc., a bitroxyalkyl group, an acetoxyalkyl group, an alkylphenoxyalkoxy Such as an alkyl group.

Encyclopedia of che+++1ca
l Technology, Volume 19.

pp. 521-531 (1932, Wiley Int.
ernationalPublication ) +
Co-edited by Nishi, Imai, and Kasai “Surfactant Handbook J737-747
J((1960, Industrial Map';!ri, R.

S+ 5helton et al.+ Journal of
American Chemical Society,
RlR in Vol. 68, pp. 753-759 (1946).
, +1, and various quaternary ammonium salts in which R are combined, among these, benzyldimethyldodecyl ammonium salt I in which R1 is a benzyl group, R2 and R3 are a methyl group, and R9 is a dodecyl group R,
is a benzyl group, R2 and R1 are a methyl group, and R is a tetradecyl group, a benzyldimethyltetradecylammonium salt, R1 is a hensyl group, Rz and R3 are a methyl group, and Rf is a hexadecyl group.A benzyldimethyltetradecylammonium salt in which: +RJ+trimethyltetradecylammonium salt in which R2 and R3 are methyl groups and the former is a tetradecyl group; and (2-(2-p -(LL3.
Benzethonium salts such as 3-tetramethylbutyl)phenoxy)ethoxy)ethyl are preferably used in the present invention. X is usually chloride, bromide,
These include iodide, cytrate, sulfate, bosphate, and borate. Also r R/ + R2+
Polymer-type quaternary ammonium salt compounds in which one of the R3+ RPs is a polymer main chain and these quaternary ammonium salts are incorporated into the side chain are also effective in the present invention.

Even in a urinary catheter, the antibacterial agent continues to be released at a constant rate during the period of indwelling in the body, that is, zero order release (Zer.

Needless to say, order release is preferable. The so-called minimum (inhibitory) concentration of antimicrobial agents (
Minimal Inhibitory Concentration
Abnormal release in excess of 30% is not only economically disadvantageous, but also causes inflammation of the mucous membranes in the urinary tract and bladder as a side effect, which is undesirable. In general, it is difficult to achieve zero-order release when a drug is dispersed within a polymer matrix; however, among the cationic antibacterial agents used in the present invention, the poorly water-soluble antibacterial agent has virtually no zero-order release. It is particularly preferably used to realize the following. Here, poorly water-soluble means 20"
The solubility in 100 g of water at c is o, ooi ~
3. Og, preferably in the range of 0.005 to 2.0 g. If the solubility in water is less than 0.001 g, the local release amount will be low and the efficacy as an antibacterial agent will tend to decrease, while if it exceeds 3.0 g, an abnormally large amount of release will be noticeable at the initial stage. Therefore, there is an iJ orientation that makes it difficult to achieve zero order release. Among the cationic antibacterial agents used in the present invention, examples of poorly water-soluble antibacterial agents that are particularly preferably used include l,6-di(4-chlorophenylbiguanide)hexane hydrochloride, acetate, or sulfate; 6,9-diamino-2-ethoxyacridine lactate or hydrochloride 3,6-diaminoacridine sulfate;
Examples include benzyldimethyltetradecylammonium iodide, benzyldimethyltetradecylammonium bosphate, and benzethonium iodide.

The amount of the cationic antibacterial agent incorporated into the silicone rubber in the present invention varies depending on the type and combination, but is generally 0.1 to 50% by weight based on the silicone rubber.
More preferably 0.5 to 25% by weight is appropriate. In this case, if it is less than 0.1% by weight, the desired antibacterial activity will be sufficiently achieved, whereas if it is more than 50% by weight, the physical properties of the silicone rubber as an elastomer tend to be impaired.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples. Note that "parts" in the two examples mean "parts by weight."

Example 1 100 parts of methylvinyl polysiloxane raw rubber, 25 parts of fumed silica, 0.5 part of bis-2,4-dichlorobenzoyl peroxide and easily water-soluble 1,6 as an antibacterial agent.
- Add 15 parts of gluconate of cy(4-chlorophenylbiguanide)hexane, masticate well with a rubber roll machine, apply to an extrusion molding machine, and heat at 200°C for 2 minutes to obtain an outer diameter of 5 mm.

A tube with an inner diameter of 3 mm and a length of 35 mm was prepared.

This was post-vulcanized at 130°C for one week, and a urinary catheter was then produced using a calligraphy method. The obtained urinary catheter was immersed in 100 ml of test urine at 37°C, and after one day, Bacillus subtilis was added as a test bacterium.
ATCC6633 (Medium NUTRIENT AGAI
An antibacterial activity test was conducted using the 8-cylinder plate method (disk method) using the antibacterial activity test, and the concentration of the antibacterial agent released was determined from a predetermined calibration curve based on the size of the inhibition circle generated there.

Furthermore, the same activity test was repeated up to 14 times by replacing the test urine with fresh test urine every day. The results thus obtained are shown in Table 1.

Furthermore, when this catheter was actually applied clinically to five patients, no urinary tract infection was observed on the gold side even after two weeks of indwelling. Also.

No obstruction of the urinary tract due to solid matter deposited inside the catheter/L4 was observed, and the catheter was removed smoothly without causing any pain to the patient.

Comparative Example 1 A commercially available silicone rubber urinary catheter that does not contain antibacterial agents was clinically applied to 5 patients in the same manner as in Example 1, and 1 patient was treated on the 311st day and 2 patients were treated on the 5th day. and one other patient had a urinary tract infection on the 7th day.

Example 2 As an antibacterial agent, poorly water-soluble 1.
A urinary catheter was obtained in the same manner as in Example 1, except that 6-di(4-chlorophenylbiguanide)hexane hydrochloride was used, and the same antibacterial activity test as in Example 1 was conducted. The results obtained are shown in Table-1.

Furthermore, when this catheter was actually applied clinically to five patients, no urinary tract infection was observed on the gold side even after two weeks of indwelling. Furthermore, no obstruction of the urinary tract due to solid matter deposited inside the catheter was observed, and the catheter was removed smoothly without causing any pain to the patient.

Example 3 To 100 parts of methylphenyl silicone raw rubber, 20 parts of fumed silica, 0.2 parts of hensyl peroxide, and 20 parts of lactate of 6,9-diamino-2-ethoxyacridine, which is poorly water-soluble as an antibacterial agent, were added. The material was thoroughly masticated using a rubber roll machine, then rolled in an extrusion molding machine and heated at 200°C for 2 minutes to obtain an outer diameter of 5 mm, an inner diameter of 3 mm, and a length of 3 mm.
A 50 mm tube was made. This was post-vulcanized at 180° C. for 2 days, and a urinary catheter was then produced by a conventional method. When the obtained urinary catheter was subjected to the same antibacterial activity test as in Example 1, the results shown in Table 2-1 were obtained.

Furthermore, when this catheter was actually applied clinically to five patients, no urinary tract infection was observed on the gold side even after 3 weeks of indwelling in the body. Furthermore, no blockage due to solid matter deposited inside the catheter was observed, and the catheter was removed smoothly without causing any pain to the patient.

Example 4 Dimethylpolysiloxane 1oo end-blocked with hydroxyl group
After mixing 10 parts of silica airgel, 2 parts of methyltriethoxysilane, 0.2 parts of dibutyltin dilaurate, and 10 parts of readily water-soluble hensyldimethyltetradecylammonium chloride as an antibacterial agent, immediately poured into a casting mold. , cured at room temperature, inner diameter 3 mm, outer diameter 5 mm,
A tube with a length of 350 mm was created. A urinary catheter was prepared using this in a conventional manner, and an antibacterial activity test was conducted in the same manner as in Example 1, and the results shown in Table 3-1 were obtained.

Furthermore, when this catheter was actually applied clinically to five patients, no urinary tract infection was observed on the gold side even after two weeks of indwelling. Furthermore, no blockage due to solid matter deposited inside the catheter was observed, and the catheter was removed smoothly without causing any pain to the patient.

Example 5 A urinary catheter was obtained in the same manner as in Example 4, except that benzyldimethylhexadecyl ammonium iodide was used instead of benzyldimethyltetradecylammonium chloride, and the same antibacterial activity test as in Example 4 was conducted. The results obtained are shown in Table-1. Furthermore, the results of clinical application to five patients were also good.

Table 1 As is clear from the examples above, the urinary catheter of the present invention has a sustained release property of antibacterial agents, so it can effectively prevent urinary tract infections caused by long-term indwelling in the body. In addition to being suitable for use as a urinary catheter, it can also be applied to a drain tube for draining blood and body fluids remaining in the patient's body after surgery.

Patent applicant: Unitika Co., Ltd.

Claims (5)

[Claims] (1) Antibacterial agent sustained release urinary catheter made of silicone rubber containing a cationic antibacterial agent. (2) The antibacterial agent sustained release urinary catheter according to claim 1, wherein the cationic antibacterial agent is a biguanide compound or a salt thereof. (3) The antibacterial agent sustained release urinary catheter according to claim 1, wherein the cationic antibacterial agent is an acridine compound or a salt thereof. (4) The antibacterial agent sustained release urinary catheter according to claim 1, wherein the cationic antibacterial agent is a quaternary ammonium salt compound. (5) The antibacterial agent sustained release urinary catheter according to claim 1, wherein the cationic antibacterial agent is a poorly water-soluble canon type antibacterial agent.