JPH036822B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for manufacturing a urinary catheter, and more particularly to a method for manufacturing a urinary catheter having sustained release performance of antibacterial substances by a dipping method. 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, ensure a smooth urinary tract,
As a result, urinary catheterization using a catheter is adopted to maintain or improve renal function or to prevent urine leakage. The catheter used in this case is particularly called a urinary catheter. Because it is an extremely useful treatment method that allows urinary catheterization and rapid urination, it is frequently used not only in urology but also in fields such as surgery, internal medicine, and obstetrics and gynecology. There is a problem in that once a urinary catheter is placed in the urinary tract, the occurrence of infection is unavoidable. That is, since the urinary catheter is left in the urinary tract for a long period of time, bacteria can enter through the catheter, and symptoms such as urethritis, cystitis, and pyelitis frequently occur. When the conventional open continuous catheterization method (a method of collecting urine in an unsterilized container such as a glass bottle) was performed, infection occurred in 42-80% of cases within 3 days.
It has been reported that infection was established in all cases on the seventh day. For this reason, methods such as cleaning the bladder and injecting disinfectants have been used to prevent urinary tract infections, but they are cumbersome to operate and are inconvenient as they can become a source of new infections. There are many aspects. Chemotherapy, such as the prophylactic administration of antibacterial substances, is also used, but with large doses or depending on the type of antibacterial substance, there are problems with frequent side effects even with small doses, and bacterial replacement occurs once an infection occurs. There is a strong desire for local use of antibacterial substances, to the extent that unplanned chemotherapy is said to be harmful due to problems such as the ease with which antibiotics can develop. Regarding the local use of antibacterial substances, for example, Japanese Patent Publication No. 54-27680 discloses that a coating layer made of polyvinyl alcohol resin is formed on the wall of a urinary catheter, and this layer is impregnated with an antibacterial substance. It has been shown that an antibacterial substance is added to a polyvinyl alcohol resin in advance when forming a coating layer to produce a urinary catheter that releases the antibacterial substance in a sustained manner. However, according to this method, a coating layer is provided afterward on a urinary catheter that has been finished to have a predetermined inner and outer diameter, so there is a drawback that the inner diameter becomes thinner and the outer diameter becomes thicker. Such drawbacks become particularly noticeable when the coating layer is thickened or multiple coating layers are provided for the purpose of sustained release of antibacterial substances over a long period of time. In addition, with this method, it is difficult to easily obtain a urinary catheter that has the characteristic of sustained release of different antibacterial substances from the inner and outer walls of the urinary catheter, which is a characteristic often required from the viewpoint of clinical efficacy. It is. In other words, in order to obtain a catheter with such characteristics, for example, a urinary catheter is immersed in a polyvinyl alcohol resin solution containing a certain type of antibacterial substance, and then the inner and outer walls are coated with a coating containing the same type of antibacterial substance. Complex manufacturing steps are required, such as applying a layer and then spraying the exterior wall with a resin solution containing a different type of antimicrobial substance than previously used. Furthermore, when polyvinyl alcohol-based resin contains antibacterial substances, there is a problem that the speed at which the antibacterial substances are slowly released into the urine during indwelling in the body is too fast, and for these reasons it cannot be used satisfactorily. . In addition, methods such as applying ointments containing antibacterial substances to urinary catheters are actually used, but with this method, the antibacterial substances are washed out by urine and released outside the body in a shorter period of time. Antibacterial ability is no longer recognized. In view of the current situation, the present inventors established a method for easily manufacturing a urinary catheter that can sustainably release the appropriate type and amount of antibacterial substances at an appropriate rate to prevent infection during the period of indwelling in the body. As a result of intensive research with the aim of The present invention has been achieved based on the discovery that a urinary catheter capable of sustained release of antibacterial substances can be obtained that has various favorable properties for preventing the spread of antibacterial substances. That is, in the present invention, when manufacturing a urinary catheter by repeating the step of immersing a dipping type in a dipping liquid serving as a catheter material and then drying and hardening it multiple times, the dipping liquid is used for at least the first dipping or the final dipping. The gist of the present invention is to provide a method for manufacturing a urinary catheter capable of sustained release of an antibacterial substance, which is characterized by using an immersion liquid containing an antibacterial substance. The immersion type used in the present invention refers to a type used when manufacturing a urinary catheter by the immersion method, and for example, a metal type, ceramic, glass, or slag type is preferably used. The immersion liquid referred to in the present invention refers to the liquid in which the immersion mold is immersed when manufacturing a urinary catheter by the immersion method. In the present invention, as the immersion liquid, liquids, solutions, or suspensions of polymers or monomers constituting compound latexes, silicone compounds, polyurethane elastomers, synthetic diene elastomers, and polyester elastomers are preferably used. The immersion method referred to here means that the immersion mold is immersed in an immersion liquid, the components of the immersion liquid are deposited on the surface of the mold, and then dried or cured after drying, and then the obtained molded product is removed from the mold. Refers to a method of manufacturing a urinary catheter. Furthermore, the term elastomer refers to something that has rubber-like elasticity at around room temperature. Compound latex is a milk-like latex, which is a type of colloid with rubber as a dispersoid, using aqueous solutions of various organic and inorganic substances that flow out when cutting is made on the bark of rubber plants as a dispersion medium. , if necessary, for example, a PH regulator, a vulcanizing agent, a vulcanization accelerator, a vulcanization retarder, a vulcanization accelerator, a softener,
This refers to products containing fillers, anti-aging agents, colorants, etc. Furthermore, a silicone compound refers to a solution or suspension containing a highly polymerized organopolysiloxane mixed with an inorganic filler, a curing agent, etc. Such a silicone compound includes an elastomer called a silicone elastomer. Also includes raw materials. Examples of the organopolysiloxane include dimethylpolysiloxane, methylphenylpolysiloxane, cyanoalkylmethylpolysiloxane, and fluoroalkylmethylsiloxane, but dimethylpolysiloxane is preferably used from the viewpoint of elasticity, strength, and harmlessness to the human body. It will be done. Furthermore, polyurethane is a polymer compound having urethane bonds in the repeating units of its main chain, and is industrially produced mainly by a polyaddition reaction between polyisocyanate and polyol.
Examples of polyisocyanates include triene diisocyanate, xylene diisocyanate, naphthalene diisocyanate, diphenylmethane isocyanate, phelene diisocyanate, ethylene diisocyanate, cyclohexylene diisocyanate, and triphenylmethane triisocyanate. , toluene isocyanate, etc. Examples of polyols include ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, cyclohexanediol, pentaerythritol, glycerin,
Examples include polyols such as 1,1,1-trimethylolpropane, polyether polyols such as polyethylene glycol, polypropylene glycol, polytetramethyl glycol, and polyethylene-polypropylene glycol. In addition, polyols include succinic acid, glutaric acid,
It also includes polyesters having hydroxyl groups at both ends obtained by condensing dicarboxylic acids such as adipic acid, sebacic acid, isophthalic acid, phthalic acid, and terephthalic acid with glycols such as ethylene glycol, propylene glycol, and butylene glycol. 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. In addition, synthetic diene polymers include homopolymers, random copolymers, and random copolymers of dienes such as butadiene, isoprene, 1,3-pentadiene, and chloroprene.
These include block copolymers, graft copolymers, etc., and these polymers are described in detail in "Synthetic Polymers" edited by Murahashi et al. (Asakura Shoten), pages 171-307. Particularly preferred synthetic diene polymers include polyisoprene, polybutadiene, butadiene-acrylonitrile copolymer, butadiene-styrene copolymer, and chloroprene polymer. Moreover, the polyester elastomer is an elastic polyester-polyalkylene oxide copolymer obtained by reacting a polyethylene terephthalate-forming component or a polytetramethylene diterephthalate-forming component with poly(alkylene oxide) glycol. The polyester components of the polyester-polyalkylene oxide copolymer are a polyethylene terephthalate-forming component and a polytetramethylene terephthalate-forming component, and either one can be used alone or the two can be used as a mixture. You can also do that.
Examples of polyethylene terephthalate-forming components include terephthalic acid and ethylene glycol, dimethyl terephthalate and ethylene glycol, bis(2-hydroxyethyl) terephthalate or its initial condensate, and examples of polytetramethylene terephthalate-forming components include, for example. Examples include terephthalic acid and 1,4-butanediol, dimethyl terephthalate and 1,4-butanediol, bis(4-hydroxybutyl)terephthalate or an initial condensate thereof. Examples of the poly(alkylene oxide) glycol used in the production of the polyester-polyalkylene oxide copolymer include poly(ethylene oxide) glycol and poly(1,2-propylene oxide).
Examples include glycol, poly(trimethylene oxide) glycol, poly(1,2-butylene oxide) glycol, poly(tetramethylene oxide) glycol, poly(pentamethylene oxide) glycol, etc., especially those with an average molecular weight of 500-
4,000 is preferably used. Among the above-mentioned immersion liquids, blended latex and silicone compounds are preferably used in the present invention from the viewpoint that the resulting urinary catheter has better physical properties and a more appropriate sustained release rate. Compounded latex is preferably used because it is suitable for use in various applications, and the heat treatment temperature can be lower than about 100°C. The immersion liquid containing antibacterial substances according to the present invention is
This refers to the above-mentioned immersion liquid containing one or more antibacterial substances. The antibacterial substance may be dissolved, suspended, or uniformly dispersed. The amount of antibacterial substance contained in the dipping solution is arbitrary, but the urinary catheter is usually left in the body for about 4 to 5 weeks at most, and it is sufficient that the antibacterial substance is released slowly during that time. Considering this, it is economically undesirable to contain more than necessary amount, and it may also have an adverse effect on the stability of the antibacterial substance-containing dipping liquid and the physical properties of the urinary catheter after molding. On the other hand, if the amount of antibacterial substances is too small, infection prevention cannot be expected. Therefore, in the present invention, it is preferable to use an antibacterial substance containing 0.1% to less than 40% of the total weight of the antibacterial substance-containing dipping solution. Furthermore, depending on the combination of the dipping liquid and the antibacterial substance, phenomena such as aggregation may occur, so it is necessary to adjust the pH etc. as appropriate. The antibacterial substance referred to in the present invention refers to antibiotics and bactericidal agents. Examples of antibiotics include penicillins such as cloxacillin, cycloxacillin, flucloxacillin, ampicillin, hetacillin, talampicillin, cyclacillin, amoxicillin, pivmecillinum, and piperacillin, cephalolidine, cephaloglycine, cephalexin,
Cephalosporins such as cefazoline, cefapirin, cefrazine, ceftezole, cefoxytin, and cephatridine; aminoglycosides such as streptomycin, kanamycin, fradiomycin, paromomycin, gentamicin, bekanamycin, ribostamycin, dibekacin, amikacin, tobramycin, and spectinomycin; oxytetracycline; , tetracyclines such as tetracycline, dimethylchlortetracycline, methacycline, doxycycline, and minocycline; macrolides such as erythromycin, kitasamycin, oleandomycin, spiramycin, diyosamycin, and midecamycin; lincomycins such as lincomycin and clindamycin. , antigram-positive bacteria such as micamicin, gramicidin S, and gramicidin, polymyxins such as colistin and polymyxin B, antimycobacteria such as biomycin, capreomycin, enviomycin, and cycloserin, amphotericin B, pimaricin, etc. polyene macrolides,
Examples include rifampicin, pyrrolenitrin, mitomycin C, actinomycin, bleomycin, daunorubicin, doxorubicin, neocarzinostatin, but aminoglycosides or polymyxins are preferably used because of their high efficacy against bacteria that cause urinary tract infections. It will be done. Bactericidal agents include pigment preparations such as acrinol and acrylflavin, furan preparations such as nitrofurazone,
Positive soap preparations such as benzalkonium chloride and benzathonium chloride, chlorhexidine, and povidone-iodine are preferably used. In order to manufacture a urinary catheter by the immersion method according to the method of the present invention, basically following the normal immersion method, the immersion mold is immersed in the immersion liquid, then pulled up and dried, and then immersed in the immersion liquid again. The final drying (heat treatment) is performed after repeatedly performing dipping operations to obtain a predetermined wall thickness, but at least the first dipping or final dipping involves dipping that contains an antibacterial substance as a dipping liquid. It is necessary to use a liquid (hereinafter abbreviated as liquid A). The molded urinary catheter thus obtained contains an antibacterial substance in the surface layer that comes into direct contact with urine or the human body.
This is an important factor in increasing the sustained release amount of antibacterial substances immediately after indwelling and preventing infections that often occur immediately after indwelling. Therefore, the urinary catheter manufactured by the method of the present invention has ideal characteristics as a urinary catheter capable of sustained release of antibacterial substances. In other words, the same urinary catheter is left in the body for about 3 to 7 days in most cases, and for about 3 weeks at the longest, after which it is often replaced with a new catheter. The urinary catheter manufactured by the method described above is capable of gradually releasing an amount of antibacterial substance effective in preventing infection into the urine over such a period of time. There are no particular restrictions regarding the immersion times other than the first and final time, but the order of immersion in Solution A and immersion in an immersion solution that does not contain antibacterial substances (hereinafter abbreviated as Solution B) and By appropriately selecting the number of times of dipping, urinary catheters with characteristics that meet various clinical purposes can be easily manufactured in a series of operations in the normal dipping method, and this is achieved by the present invention. This is a major advantage of this manufacturing method.
For example, if the indwelling period is expected to be longer than the normal indwelling period and long-term sustained release is required, the number of immersions in Solution A may be increased; Manufacturing may be performed only by immersion. For example, if you use a method such as using liquid B for immersion one time before the second or final time, and using liquid A for two times before the third or final time, it is possible to It is advantageous to be able to obtain a urinary catheter that has both the performance of a large amount of sustained release and a slow sustained release over a long period of time during the indwelling period. To manufacture a urinary catheter by the method of the present invention, one type of liquid A and one type of liquid B are usually used,
Liquid A minus the antibacterial substance has the same ingredients as liquid B,
Solutions A and B are selected so that they have the same composition.
However, it is also possible to use a plurality of types of liquid A. For example, two types of solutions containing different antibacterial substances can be used, for example, a solution A containing chlorhexidine used for the first immersion and a solution containing fradiomycin sulfate used for the final immersion. The above A liquid can be used. In such a method, for example, an antibacterial substance that is highly irritating to the mucous membrane can be contained in the surface that comes into contact with urine, that is, the inner wall of the catheter, and another antibacterial substance can be contained in the surface that comes into contact with the human body, that is, the outer wall of the catheter. It is also a feature of the present invention that a urinary catheter having such characteristics and having great clinical significance can be easily obtained. It is also possible to use a plurality of types of B liquids, for example, three types of immersion liquids, compounded latex, silicone compound, and urethane compound, can be used as B liquid. Also, liquid A and B
It is also possible to use a completely different solution; for example, a silicone compound containing an antibacterial substance may be used, and a mixed latex may be used as the B solution. Furthermore, the thickness of the multilayer obtained in each immersion can be adjusted by changing the concentration of liquid A or liquid B. In the manufacturing method of the present invention, as in the usual dipping method, a drying or heat treatment step is performed between each dipping and after the final dipping, but there are no particular restrictions on the conditions for drying or heat treatment, and usually It may be carried out at a temperature of 200°C or lower for 1 minute to 24 hours, but since there are many antibacterial substances whose pharmacological activity tends to decrease due to heat, it is preferably carried out at a temperature of 40 to 100°C for 1 minute to 8 hours. The number of repetitions of dipping and drying or heat treatment depends on the desired wall thickness of the catheter, but it is usually 1 to 30 times, preferably 3 to 20 times, until the concentration of the dipping solution is adjusted to reach the desired wall thickness. Adjust. Therefore, it is preferable to adjust the weight of the elastomer component of the dipping liquid to 2 to 80% of the total weight of the dipping liquid. Furthermore, as mentioned above, regarding the layer obtained by immersion in liquid B, which is provided to slow down the sustained release rate, if the layer is too thick, the rate at which the antibacterial substance is released to the outside through that layer will be slow. If the layer is too thick or too thin, the effect of suppressing the speed will be poor, so it is preferable to provide the layer with a thickness of 1 to 70 microns. As described above, according to the production method of the present invention, the sustained release amount, sustained release rate, and sustained release period can be determined as needed through a series of repeated dipping and drying operations more easily than in conventional methods. It is possible to obtain a urinary catheter that is capable of sustained release of antibacterial substances, and it is also easy to finish the urinary catheter to have an inner diameter and an outer diameter that meet predetermined specifications. Here, as an example of sustained release trends, the results obtained for a urinary catheter that sustainedly releases an aminoglycoside antibiotic produced by the method of the present invention are shown below. The urinary catheter was immersed in sterile urine at 37°C and replaced with the same amount of fresh urine every day for 40 days.
We obtained 40 urine samples in which antibiotics were released over a period of 1 day, and measured the amount of antibiotics contained in each sample.The results showed that the amount of antibiotics in the urine on the first day was 1,800 to 42,000 μg. The range is 1,200 to 37,000 μg on the second day, and 770 μg on the third day.
~26,000 μg, 500-20,000 μg on the 4th and 5th days,
250-15,000 μg on days 6-7, and 250-15,000 μg on days 8-10.
250-10,000 μg, 250-7,500 μg on days 11-14
g, 200 to 5,000 μg on days 15 to 30, and 180 to 3,000 μg on days 31 to 40. As above, 1~
The amount released on the 5th day is high, with a minimum of 500 μg.
250μg up to the 14th day.
The amount above was released, and even on days 31 to 40, the amount released was considered to have the ability to prevent infection. The present invention will be explained in more detail with reference to Examples below. In addition, "parts" in the examples are "parts by weight"
means. Examples 1-5 15 parts of silicone medical grade elastomer base material and 1.5 parts of Catalyst (both Dow Corning MDX4-4210)
was dissolved in 100 parts of trichloroethane to obtain an immersion liquid (hereinafter abbreviated as liquid b). Then this b
Prepare five 100 parts each of dibekacin sulfate, polymyxin B sulfate, fradiomycin sulfate, chlorhexidine, or cyclacillin and mix uniformly. (abbreviated as liquid a) was obtained. The immersion type for urinary catheter is first immersed in liquid A, then pulled out and dried at 80°C for 5 minutes, then immersed in liquid B, pulled out and dried at 80°C for 5 minutes, and then immersed in liquid B again. After repeating the operation of immersion and drying seven times, further immersion in liquid a,
A total of five urinary catheters were obtained, one for each of the five types of a liquid, by pulling the catheter up and finally heat treating it at 60°C for 6 hours. Each of these samples was immersed in test urine at 37°C, and after one day, the urine was tested for antibacterial activity using the cylindrical plate method (disc method) using test bacteria corresponding to each antibacterial substance. The presence of active antibacterial substances in the test urine was confirmed. Furthermore, the same activity test was repeated by replacing the test urine with fresh test urine every day. The results are shown in Table 1.

[Table] Example 6 Part A15 of silicone medical grade elastomer (manufactured by Dow Corning, Q7-2245) consisting of three components: Part A, Part B, and Part C.
After uniformly dispersing 1 part in 100 parts of trichloroethane,
Added 0.05 part Part C and mixed thoroughly. Then, add 0.1 part of Part B to this mixture and mix thoroughly to prepare the immersion liquid (hereinafter referred to as liquid B).
I got it. 0.2 parts of povidone iodine was added to 100 parts of this liquid B and uniformly dispersed to obtain an immersion liquid (hereinafter referred to as liquid A). After repeating dipping and drying in the same manner as in Example 1 using the above solutions a and b, heat treatment was performed at 160° C. for 30 minutes to obtain a urinary catheter.
This one Staphylococcus aureus ATCC6538
When the same activity test as in Example 1 was carried out using -P as the test bacterium, an odor inhibition zone was observed in the test urine on the 25th day. Example 7 Normal tex (total solid content 37.5-41.0wt%,
Dry rubber (34.6 to 37.5 wt%, NH ₃ 0.8 to 1.0 wt%) is concentrated to a rubber content of approximately 60 wt%, and 100 parts are mixed with 3.6 parts of zinc sulfide, 1.8 parts of sulfur, 0.3 parts of stearic acid, and N-cyclohexyl. A blended latex (hereinafter referred to as liquid b) was obtained by uniformly dispersing 0.3 part of 2-benzothiazolesulfenamide. An immersion liquid (hereinafter referred to as liquid A) was obtained by dissolving 35 parts of fradiomycin sulfate in 100 parts of liquid B. The immersion type urinary catheter is first immersed in liquid A, pulled up and dried at 60°C for 10 minutes, immersed in liquid B, pulled out and dried at 60°C for 10 minutes, then immersed in liquid B, After repeating the drying operation 7 times, it was further immersed in liquid A, pulled out, and heated to 60°C.
A urinary catheter was obtained by heat treatment for 8 hours. When this product was used to conduct the same activity test as in Example 3, inhibition circles were also observed in the test urine on the 23rd day. Example 8 Exactly the same as Example 7, except that the same liquids a and b as in example 7 were used, and liquid a was used instead of liquid b for the third immersion and the two previous immersions from the final time. A urinary catheter was obtained. When this product was subjected to the same activity test as in Example 3, inhibition circles were also observed in the test urine on the 29th day.

Claims (1)

[Claims] 1 When manufacturing a urinary catheter by repeating the process of immersing a dipping type in a dipping liquid serving as a catheter material and then drying and hardening it multiple times, at least the first dipping or final dipping contains an antibacterial substance as the dipping liquid. A method for manufacturing an antibacterial substance sustained release urinary catheter characterized by using an immersion liquid.