JPH0327213B2 - - 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. 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 catheterization using a catheter is used to ensure a smooth urinary tract, thereby promoting the maintenance or improvement of intellectual function or preventing 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 urinary catheters are left in the urinary tract for long periods of time, bacteria can enter through the catheters, frequently causing symptoms such as urethritis, cystitis, and cystitis. 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 to 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, with this method, it is difficult to obtain sustained release over a long period of time, and there are also problems with the adhesion between the coating layer and the catheter.
Furthermore, the problems of durability during long-term indwelling and the elasticity required when indwelling in the body have not been sufficiently resolved, and for these reasons they are not 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 addition, a method of injecting diluted antibacterial solution directly into the bladder using a so-called three-way catheter (rinsing method) is also used as a local treatment, but because it is cumbersome to handle, some urinary The current situation is that it has only been adopted in the region, and is not used in other territory areas. The entry routes for bacteria include retrograde migration between the urinary catheter and the urinary tract mucosa (extraluminal route), entry from the joint between the urinary catheter and the conduit (including procedures such as cleaning), and entry from the urine storage area. There is retrograde movement within the conduit and urinary catheter (intraluminal route). In the case of invasion through the extraluminal route, bacteria resident in the urethra quickly ascend along the wall of the urinary catheter and reach the bladder neck early after placement. Against such infections, the antibacterial substances present on the wall of the urinary catheter can exert an antibacterial function because they can come into direct contact with bacteria. However, bacteria that enter the urine via the intraluminal route, such as through the urinary collector, or that fall or enter the urinary collector, multiply in the collected urine, and the reflux of urine reaches the bladder as air bubbles rise. reach In fact, in static experiments, it has been confirmed that bacteria can travel upstream in the urine like a carp climbing a waterfall. In case of invasion from such a route, the antibacterial substances present on the wall of the urinary catheter may not be able to come into direct contact with the bacteria, so there is a high possibility that bacteria that cannot be affected by the antibacterial function will remain. The ability to prevent infection is not sufficient. In order to have the ability to prevent infection from all entry routes, antibacterial substances must not only exist on the wall of the urinary catheter, but also gradually leave the wall and diffuse into the urine. It is necessary to come into contact with bacteria that float upward. In this case, the speed at which the antibacterial substance leaves the wall surface becomes an issue. As mentioned above, when methods such as adsorbing antibacterial substances on a urinary catheter or applying ointment containing antibacterial substances are carried out, the antibacterial substances are easily washed away by urine and flow out of the body, resulting in a very short period of time. In time, it ceases to exist on walls and in urine. This means that the ability to prevent infection is lost after being left in the body for an extremely short period of time. Therefore, it is important to control the rate at which antibacterial substances leave the wall surface and to maintain the concentration of antibacterial substances in urine above an effective concentration over a long period of time in order to prevent infection. In view of these current circumstances, the present inventors have developed a conductor that can continuously release an appropriate type and amount of antibacterial substances at an appropriate rate during the period of indwelling in the body, and that has excellent elasticity, flexibility, and durability. As a result of intensive research aimed at establishing a method for manufacturing urinary catheters, we found that when a liquid made of an elastomer material similar to the material that makes up urinary catheters and an antibacterial substance is added to them, it is possible to prevent urinary tract infections. The inventors have discovered that it is possible to obtain a urinary catheter that has both sustained release of antibacterial substances over a long period of time suitable for use in the body, as well as durability and elasticity that are suitable for indwelling in the body, and have thus arrived at the present invention. That is, the present invention provides a urinary catheter made from an elastomer raw material selected from the group consisting of a compounded latex, a silicone resin compound, and a polyurethane compound, and an elastomer of the same type as that used in the manufacture of the urinary catheter. After applying a liquid consisting of a raw material liquid and an antibacterial substance,
This is a method for manufacturing an antibacterial substance sustained release urinary catheter, which is characterized by subjecting the urinary catheter to heat treatment and providing a coating layer containing an antibacterial substance on the inner or outer wall of the urinary catheter. The elastomer referred to in the present invention is one that has rubber-like elasticity at around room temperature, and the elastomer raw material is the elastomer component mixed with plasticizers, fillers, colorants, stabilizers, curing agents, etc. as necessary. It means something that can be used for molding as is. 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, silicone-based compounds refer to solutions or suspensions made by blending organopolysiloxane with a high degree of polymerization with inorganic fillers, curing agents, etc. Such silicone-based compounds are also called silicone elastomers. This also includes raw materials for elastomers. Examples of organone polysiloxanes 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, the term "polyurethane compound" refers to a compound whose main component is a mixture of polyisocyanate and polyol, which constitute a polyurethane elastomer having urethane bonds in the repeating units of the main chain. Examples of polyisocyanates include toluene diisocyanate, xylene diisocyanate, naphthalene diisocyanate, diphenylmethane isocyanate, phenylene diisocyanate, ethylene diisocyanate, cyclohexylene diisocyanate, and triphenylmethane triisocyanate. Examples include toluene isocyanate and toluene isocyanate. Examples of polyols include polyols such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, cyclohexanediol, pentaerythritol, glycerin, 1,1,1-trimethylolpropane, polyethylene glycol, polypropylene glycol, polytetramethyl glycol, and polyethylene glycol. Examples include polyether-polyols such as 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. The liquid consisting of an elastomer raw material and an antibacterial substance as used in the present invention refers to a liquid containing one or more antibacterial substances in the above-mentioned elastomer raw material. The antibacterial substance may be dissolved, suspended, or uniformly dispersed. The amount of antibacterial substances contained in the fluid is arbitrary, but the urinary catheter is usually left in the body for 4 to 5 days at most.
Considering that the antibacterial substance should be released slowly for about a week, it is economically undesirable to contain more than necessary, and it also affects the stability of the liquid consisting of the elastomer raw material and the antibacterial substance. This may have an adverse effect on 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, the amount of the antibacterial substance is 0.1% to 40% of the total weight of the liquid consisting of the elastomer raw material and the antibacterial substance.
It is preferable to use one containing less than %. Additionally, depending on the combination of elastomer raw materials and antibacterial substances, phenomena such as aggregation may occur.
It is necessary to adjust the pH etc. accordingly. The antibacterial substance referred to in the present invention refers to an antibacterial substance and a bactericidal agent. Examples of antibacterial substances 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 polyxin B, antimycobacteria such as biomycin, capreomycin, enviomycin, and cycloserine, amphotericin B,
Examples include polyene macrolides such as pimaricin, rifampicin, pyrrolnitrin, mitomycin C, actinomycin, pleomycin, daunorubicin, doxorubicin, and neocarzinostatin, but they are highly effective against bacteria that cause urinary tract infections. Aminoglycosides or polymyxins are preferably used. As the disinfectant, pigment preparations such as acrinol and acrylflavin, furan preparations such as nitrofurazone, positive soap preparations such as benzalkonium chloride and benzathonium chloride, chlorhexidine, povidone-iodine, and the like are preferably used. In order to manufacture a urinary catheter by the method of the present invention, a urinary catheter obtained from an elastomer raw material selected from the group consisting of natural rubber latex, silicone compound, and polyurethane compound is used. A coating layer containing an antibacterial substance is applied to the inner or outer wall of the urinary catheter by applying a liquid consisting of an elastomer raw material similar to that used in Specifically, for example, a method of immersing a natural rubber urinary catheter in a solution consisting of a compounded latex and an antibacterial substance used in the production of natural rubber, pulling it out, and then heat-treating it; A method of applying or spraying the above-mentioned compounded latex on the skin and post-heat treatment, applying a solution consisting of a silicone compound and an antibacterial substance to a silicone urinary catheter, and applying a polyurethane compound and an antibacterial substance to a polyurethane urinary catheter. Examples include a method of dipping, coating, or spraying as described above using a solution consisting of and then heat-treating. There are no particular restrictions on the conditions for heat treatment, and it can usually be carried out at 200℃ for 1 minute to 24 hours, but since there are many antibacterial substances whose pharmacological activity decreases due to heat, it is preferable to heat the treatment at 40 to 100℃. It is carried out at a temperature of 1 minute to 8 hours. Further, in the manufacturing method of the present invention, the application of the liquid consisting of the elastomer raw material and the antibacterial substance as described above may be repeated. In this case, it is possible to sustainably release a larger amount of antibacterial substances over a longer period of time, and if different types of antibacterial substances are used repeatedly, different types of antibacterial substances can be released with a time lag. This makes it possible to provide the antibacterial substance with the characteristic of sustained release. Furthermore, in the production method of the present invention, it is also possible to apply a liquid consisting of an elastomer raw material and an antibacterial substance, and then apply an elastomer raw material that does not contain an antibacterial substance. In this case, it becomes possible to control the sustained release amount and sustained release rate. As described above, in the manufacturing method of the present invention, a coating layer containing an antibacterial substance and a coating layer not containing an antibacterial substance are provided as necessary, and the thickness of the coating layer can be adjusted, and different types of layers can be laminated. By doing so, it is possible to manufacture urinary catheters with various sustained release characteristics. As described above, according to the method of the present invention, it is possible to manufacture a urinary catheter having sustained release properties of antibacterial substances suitable for infection prevention. The urinary catheter manufactured by the method of the present invention is characterized by good elasticity, flexibility, and durability. In other words, the coating layer provided on the inner or outer wall of the urinary catheter is made of the same type of elastomer as the main body, so it has the same elasticity and flexibility as the main body, and it is coated with a resin of a different type from the main body. There is no increase in the hardness or decrease in flexibility of the urinary catheter, which often occurs when In addition, the adhesion between the coating layer and the main body or each coating layer is also good,
There is no need to provide an adhesive layer. Therefore, even when left in the body for a long period of time, the layers do not peel off and have excellent durability. The present invention will be described in more detail with reference to Examples above. 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. Next, prepare five 100 parts each of this solution, add 5 parts each of dibekacin sulfate, polymyxin B sulfate, fradiomycin sulfate, chlorhexidine, or cyclacillin and mix uniformly to prepare 5 types of elastomers containing antibacterial substances. I got the raw material. Five silicone urinary catheters (Argyle Silicone Foley Catheter, manufactured by Nippon Shaud Co., Ltd.) were immersed in this material for 2 minutes each, then pulled out and heat treated at 60°C for 6 hours. Got a catheter. 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] Furthermore, even after these five catheters were immersed in test urine for 50 consecutive days, their appearance, elasticity, and flexibility remained the same as those of the material catheters. 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 0.03 part Part C and mixed thoroughly. To this mixture, 0.1 part of Part B was added and thoroughly mixed. To 100 parts of the obtained elastomer raw material, 0.2 part of povidone-iodine was added and uniformly dispersed to obtain an elastomer raw material containing an antibacterial substance. A urinary catheter similar to that used in Example 1 was immersed in this solution in the same manner as in Example 1, then pulled out and heated at 160°C.
Heat treatment was performed for 30 minutes. The obtained urinary catheter
When the same activity test as in Example 1 was carried out using Staphylococcus aureus ATCC6538-P as the test bacterium, an inhibition zone was observed in the test urine on the 21st 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. An antibacterial substance-containing elastomer raw material was obtained by dissolving 20 parts of fradiomycin sulfate into 100 parts of a compounded latex in which 0.3 parts of 2-benzothiazolesulfenamide was uniformly dispersed. This natural rubber urinary catheter [Argyle]
A Foley catheter (manufactured by Nippon Shearwood Co., Ltd.) was immersed for 3 minutes, then pulled out and heat treated at 80°C for 4 hours. When the same activity test as in Example 3 was conducted using the obtained urinary catheter, an inhibition zone was also observed in the test urine on the 26th day. In addition, the urinary catheter of this example and the natural rubber catheter that was the material of this example were immersed in the same test urine for 50 days, then taken out and observed. There were no gender differences. Example 8 The urinary catheter obtained in Example 7 was further immersed in the same mixed latex used in Example 7 for 3 minutes, then taken out and treated at 80°C for 4 hours. When the obtained urinary catheter was subjected to the same activity test as in Example 3, inhibition circles were also observed in the test urine on the 31st day. Moreover, regarding the size of the inhibition circle, compared to that obtained in Example 7, it was smaller from the 1st day to the 18th day, and larger from the 19th day onwards. This indicates that the sustained release rate of antibacterial substances can be controlled by modifying the manufacturing method. Example 9 A urinary catheter was obtained in exactly the same manner as in Example 7, except that the same amount of water was added to the mixed latex as the mixed latex, and then the same treatment as in Example 8 was carried out. Regarding the obtained catheter
Inhibition circles were allowed until the 21st day.

Claims (1)

[Claims] 1. A urinary catheter made from an elastomer raw material selected from the group consisting of compound latex, silicone compound, and polyurethane compound, and an elastomer raw material of the same type as that used in the manufacture of the urinary catheter and an antibacterial substance. 1. A method for manufacturing an antibacterial substance sustained release urinary catheter, which comprises applying a liquid to the urinary catheter, followed by heat treatment, and providing a coating layer containing an antibacterial substance on the inner or outer wall of the urinary catheter.