JPH0261261B2 - - 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 sustained release performance of antibacterial substances. 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, cystitis, and nephritis. It is being 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. Therefore, in order to fundamentally 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. . Conventionally, regarding drug control release technology in the medical or pharmaceutical field, for example, as described in the review of Kagaku Kogaku, Vol. 45, No. 7, p. 441 (1981), (1) polymers with matrix structure and pores have been used. active substance dispersed within the substance, (2)
There are four types: (3) those that use an osmotic pump using osmotic pressure, and (4) those that coat the outside of the core 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), in which drugs are dispersed within a polymer matrix, is easy to manufacture and has been in practical use in various forms for a long time, but zero-order release is impossible, and Few such examples are known to date. In other words, in (1), an abnormally large amount of release is generally observed in the initial stage, and then,
There was a sudden decrease in the amount released, and there was a tendency for it to gradually decrease thereafter. 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 a disinfectant to have a certain bactericidal effect against various types of bacteria, the so-called minimum (growth)
Minimal Inhibitory Concentration
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.
On the other hand, abnormal release of antibacterial agents exceeding the MIC 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 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 zero-order release could not be achieved in a system in which
Surprisingly, we have discovered that substantially zero-order release can be achieved in a system in which a poorly water-soluble biguanide compound or its salt as an antibacterial agent is dispersed in an organic polymer elastomer, and we have arrived at the present invention. It is something. That is, the present invention relates to an antibacterial agent sustained release urinary catheter whose main component is an organic polymer elastomer, characterized in that the catheter contains a poorly water-soluble piguanide compound or a salt thereof. It is. The present invention can be achieved by simply dispersing a poorly water-soluble biguanide 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 biguanide 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. In other words, the biguanide compound of the present invention is characterized by having a large hydrophobic group in which 2 to 10 methylene groups are connected in addition to a cationic group as a polar group in its chemical structure. It is thought that this may have had an advantageous effect on the interaction with 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 rubber, soft polyvinyl chloride, and the like. Natural rubber here refers to an aqueous solution containing various organic and inorganic substances that flows out when the bark of a rubber plant is cut, and the rubber component is used as a dispersoid. This refers to products containing additives, vulcanization accelerators, softeners, fillers, anti-aging agents, etc. Examples of synthetic rubber include butadiene, isoprene, 1,3-pentadiene, 1,5
Examples include homopolymers of diene monomers such as -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 methylphenylpolysiloxane, 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 hydrochloric acid esters, phosphate esters such as tricresyl phosphate, tricylenyl phosphate, monobutyl dixylenyl phosphate, trioctyl phosphate, methyl acetyl ricinoleate, butylacetyl ricinoleate, etc. Epoxidized vegetable oil made by epoxidizing unsaturated fatty acids such as castor oil derivatives and soybean oil, carbon number 6 or more
Tri- or tetraethylene glycol esters of 10 fatty acids, ethylene glycol derivatives such as butylphthalyl butyl glycolate, average molecular weight, 1000
Examples include low-grade polyester plasticizers with a viscosity of ~3000. 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 biguanide compound in the present invention is represented by the following general formula () or ().

【formula】

[Formula] Here, R is an alkyl group, an aminoalkyl group, a phenyl group, an alkylphenyl group, a halogenated phenyl group, a hydroxyphenyl group, a methoxyphenyl group, a carboxyphenyl group, a naphthyl group, or a nitrile group. , R' is hydrogen or an alkyl group. Note that n is a positive integer, preferably in the range of 2 to 10. Preferred specific examples of such biguanide compounds include 1,6-di-(4-chlorophenylbiguanide)hexane, diaminohexylbiguanide, and 1,6-di(aminohexylbiguanide)hexane. Among them, 1,6
-Di-(4-chlorophenylbiguanide)hexane (also known as chlorhexidine) has strong bactericidal activity against a wide range of microorganisms and has low toxicity to the human body, so it is most widely used today in medicine, hygiene, and the food industry. It is one of the sterilizing and disinfecting agents, and is particularly preferably used in the present invention. As mentioned above, biguanide compounds are characterized by having a positive charge and a hydrophobic group within one molecule.
The biguanide group is one of the strongest organic bases, and in the physiological pH range it is almost 100%
It is protonated, and chlorhexidine is usually used as a readily water-soluble gluconate salt. The salt of a biguanide compound in the present invention refers to a salt formed from a biguanide compound and an inorganic or organic acid. Examples of inorganic or organic acids that form poorly water-soluble salts with biguanide compounds include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, carbonic acid, bicarbonate, citric acid, phosphoric acid, boric acid, formic acid, acetic acid, and benzoic acid. Examples include acid, tartaric acid, etc. In the present invention, poorly water-soluble means that 100 g at 20°C
The solubility in distilled water is in the range of 0.001 to 3.0 g, preferably 0.005 to 2.0 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, 3.0g
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 biguanide compound or its salt in the urinary catheter of the present invention varies depending on the purpose, but is preferably from 0.01 to
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. . Furthermore, 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 biguanide compound or its salt; however, when the urinary catheter is indwelled 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 in contact with the urinary tract mucosa, a thin coating layer made only of an organic polymer elastomer that does not contain the above-mentioned antibacterial agents 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 only of an organic polymer elastomer containing no antibacterial agent on the inner surface. Furthermore, in the urinary catheter, an antibacterial agent is placed between the outer surface and the inner surface of the urinary catheter, for example, in the middle, in order to avoid a decrease in mechanical strength due to the elution of the antibacterial agent, such as balloon rupture. It is also preferable to provide a layer consisting only of an organic polymer elastomer containing no elastomer. 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 1,6-di-(4-chlorophenyl biguanide)
30 parts of hexane hydrochloride 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, 0.3 parts of zinc dimethyldithiocarbamate, 1.5 parts of sulfur, 100 parts of natural rubber latex with a solid content concentration of about 50 wt%,
A mixed latex liquid (hereinafter referred to as liquid B) was prepared by adding 3 parts of zinc white and 1.2 parts of stearic acid.
Next, 4 parts of Solution A were added to 100 parts of Solution B to prepare an immersion solution (hereinafter referred to as Solution C). 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 500 ml of test urine at 37°C.
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 same activity test was repeated up to 30 times by replacing the test urine with fresh test urine every day. The results thus obtained are shown in Table 1. Furthermore, when the manufactured urinary catheter was applied clinically to five patients, no urinary tract infection was observed in any of the patients 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 8 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 1,6-di-(4-chlorophenyl biguanide)
Instead of hexane hydrochloride, 1,6-di-(4-
A urinary catheter was obtained in the same manner as in Example 1, except that sulfate of (chlorophenyl biguanide) hexane was used, and the same antibacterial activity test as in Example 1 was conducted. 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 1,
20 parts of acetate of 6-di-(aminohexylbiguanide)hexane was added, thoroughly masticated with a rubber roll machine, and extrusion molded to prepare a urinary catheter. 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 Polytetramethylene glycol with a number average molecular weight of 2400 as a polyol, 4,4'-diphenylmethane diisocyanate as a polyisocyanate,
An immersion solution was prepared by adding 0.5 part of diaminohexyl biguanide phosphate to 100 parts of an 8 wt % dimethylacetamide solution of segmented polyurethane synthesized using ethylenediamine as a quenching agent. Next, in the same manner as in Example 1, the operation of immersing the immersion mold in the above-mentioned immersion liquid, pulling it up and drying it was repeated 7 times.
Finally, a urinary catheter with a dry weight of about 11 g was produced. The same antibacterial activity test as in Example 1 was conducted on the obtained urinary catheter. The results are shown in Table-1. Example 6 A layer of approximately 30μ thick consisting only of liquid B was placed on the inner and outer surfaces of the urinary catheter produced in Example 1.
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)

[Scope of Claims] 1. A urinary catheter mainly composed of an organic polymer elastomer, characterized in that the catheter contains a poorly water-soluble biguanide compound or a salt thereof. urinary catheter. 2. The antibacterial agent sustained release urinary catheter 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 layer made 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 biguanide compound is 1,6-di-(4-chlorophenylbiguanide)hexane.