JP5466904B2 - Cleaning method for medical equipment - Google Patents

Description

The present invention relates to a biofilm removing agent, and more particularly, biofilm removal for effectively removing biofilm and preventing harm caused by biofilm in various fields involving microorganisms. The present invention relates to a cleaning composition for hard surfaces that effectively removes composite stains of agents and biofilms and other stains.

A biofilm is also called a biofilm or slime, and generally refers to an aqueous system in which microorganisms adhere to and grow on the surface of substances to produce macromolecular substances such as polysaccharides and proteins from within microbial cells to form structures. . When a biofilm is formed, harm caused by microorganisms occurs, causing problems in various industrial fields. For example, when a biofilm is formed in the piping of a food plant, the biofilm peels off and leads to contamination by foreign substances in the product, and causes food poisoning due to microorganism-derived toxins. Furthermore, biofilm formation on the metal surface causes metal corrosion and promotes aging of the equipment.
Furthermore, compared to microorganisms that are dispersed and suspended in an aqueous system, microbial control agents such as bactericides and bacteriostatic agents are often unable to exert sufficient effects on microbial aggregates that have formed biofilms. . For example, in the medical field, in recent years, there have been many reports of nosocomial infections caused by microorganisms remaining in narrow gaps or holes in medical devices such as endoscopes to form biofilms. In the human oral cavity, it is well known that biofilms formed on teeth, so-called dental plaque (plaque), cause caries and periodontal disease, and these problems have been studied for a long time.

Until now, in order to prevent the harm of biofilm, the idea of not allowing bacteria to grow by giving bactericidal or bacteriostatic action to microorganisms, particularly bacteria, has been generally studied. Patent Document 1 describes an antibacterial preparation containing arginine hydrochloride, arginine ethyl ester, arginine glutamic acid or other arginine or a derivative thereof and a compound exhibiting antibacterial activity, but the effect is not yet satisfactory. In addition, this document shows an antibacterial effect on microbial aggregates and is not intended to remove biofilms.
As a method for removing a biofilm, a method using a bactericide, a method using a chelating agent, a method using an enzyme, and the like have been tried. In Patent Document 2, hypochlorite, alkali metal hydroxide and a surfactant are used. A method of using these in combination is disclosed. However, none of the methods has been able to remove the biofilm effectively, and it still remains a big problem.
In other words, when a highly bactericidal agent with immediate effects, such as a highly bactericidal cationic surfactant or hypochlorite, is used, the bactericidal properties are quickly lost due to organic substances in the system or biofilm. Therefore, it is difficult to maintain the effect of reducing the number of bacteria over a long period of time, and when the bactericidal effect is lost, the bacteria grow again. In addition, since the disinfectant does not remove the biofilm, it must act until the microorganisms adhere to the surface and form a biofilm.
As mentioned above, biofilms are formed from various substances such as bacterial cells, polysaccharides and proteins, and it is difficult to completely remove biofilms by decomposing only a part of these compounds. It is done.
Therefore, in the method of removing a biofilm using an enzyme as disclosed in Patent Document 3, although a certain degree of removal effect is recognized, complete removal is difficult and there is no biofilm production suppressing effect. Therefore, the bacteria in the remaining biofilm grow again and produce high-molecular substances such as polysaccharides and proteins. In addition, biofilms are easy to be formed in an environment where microorganisms are likely to multiply, such as bathrooms, kitchens, kitchens, toilet bowls, drainage lectures, drain pipes, etc., but the types of dirt are different in each place. For example, fat and oil stains are mainly used around kitchens, metal soaps in the bathroom, especially fatty acid calcium salts, and inorganic stains in toilet toilets. When biofilm coexists with such dirt and becomes composite dirt, it becomes difficult to remove it with a detergent mainly composed of a normal surfactant, and it is desired to effectively remove these composite dirt. Yes.

JP-A-8-151324 JP 2005-75873 A JP-T-2001-508677

  Accordingly, an object of the present invention is to provide a biofilm remover and a biofilm remover composition that effectively remove microorganisms and biofilms composed of microorganisms in various regions, and composite stains in which biofilms and various stains coexist. It is providing the cleaning composition for hard surfaces and the cleaning composition for medical devices which remove effectively.

  Therefore, the present inventor conducted intensive research to obtain a biofilm remover that effectively removes biofilm, and found that a specific amino acid derivative has a biofilm removing action, leading to the completion of the present invention. It was.

（式中、Ｒ¹は炭素数４〜１８の直鎖又は分岐鎖のアルキル又はアルケニル基を示し、Ｘ及びＹは次の式

で示される基から選ばれる基を示し、ｍは１〜５の整数を示す。）
で表わされる塩基性アミノ酸誘導体又はその塩を含有するバイオフィルム除去剤を提供するものである。 That is, the present invention provides the following general formula (1)

(In the formula, R ¹ represents a linear or branched alkyl or alkenyl group having 4 to 18 carbon atoms, and X and Y represent the following formulae:

And m represents an integer of 1 to 5. )
A biofilm removing agent containing the basic amino acid derivative represented by the formula (1) or a salt thereof is provided.

  The present invention also provides a biofilm remover containing an arginine derivative or a salt thereof obtained by reacting arginine or a salt thereof with glycidyl ether.

  Furthermore, the present invention also provides a biofilm remover composition containing any one of the above biofilm removers and one or more selected from the group consisting of other surfactants and chelating agents. is there.

  Moreover, this invention provides the detergent composition for hard surfaces containing the basic amino acid derivative or its salt represented by the said General formula (1), or the said arginine derivative or its salt.

  Furthermore, the present invention is for a hard surface containing the basic amino acid derivative represented by the general formula (1) or a salt thereof, and one or more selected from the group consisting of other surfactants and chelating agents. A cleaning composition is provided.

  Furthermore, this invention provides the cleaning composition for medical devices containing the basic amino acid derivative or its salt represented by the said General formula (1).

  Furthermore, the present invention provides a medical device immersed in the cleaning composition for medical devices, placed in a water stream of the aqueous solution, or brought into contact with the medical device while applying ultrasonic vibration. The present invention provides a method for cleaning a medical device.

  According to the present invention, biofilms composed of microorganisms and microorganism-producing substances can be effectively removed in various regions, and composite dirt in which biofilms and various kinds of dirt coexist can also be effectively removed.

  The biofilm remover of the present invention has the following general formula (1)

(In the formula, R ¹ represents a linear or branched alkyl or alkenyl group having 4 to 18 carbon atoms, and X and Y represent the following formulae:

And m represents an integer of 1 to 5. )
Containing at least one basic amino acid derivative represented by the formula:

The alkyl group or alkenyl group represented by R ¹ may be linear or branched, but has 4 to 18 carbon atoms, preferably 6 to 14 carbon atoms from the viewpoint of the effect of removing a biofilm. Those having 8 to 14 are more preferable, and those having 10 to 14 carbon atoms are more preferable. Specific examples include an n-hexyl group, a 2-ethylhexyl group, an n-octyl group, a decyl group, a dodecyl group, and a myristyl group. The alkyl group or alkenyl group represented by R ¹ may be single or mixed. Moreover, the mixed alkyl composition derived from natural origin, for example, palm oil or palm kernel oil, may be sufficient.
In general formula (1), m represents an integer of 1 to 5, preferably 2 to 4, and more preferably 3. X is preferably —OCH ₂ —CH (—OH) CH ₂ —, and Y is preferably —NH—C (—NH ₂ ) ═NH.
Examples of the salt of the basic amino acid derivative (1) include salts of inorganic acids such as hydrochloride, sulfate and phosphate, and salts of organic acids such as acetate, lactate, citrate and acidic amino acid salt. Preferable examples include hydrochloride, acetate, lactate and citrate.

  The compound represented by the general formula (1) is obtained by reacting a basic amino acid such as arginine, lysine, ortinine, histidine, hydroxyhistidine and the like with a compound such as glycidyl ether, fatty acid chloride, fatty acid anhydride, or epoxyalkane. can get. Preferred is a compound obtained by reacting arginine with a compound such as glycidyl ether, fatty acid chloride, acid anhydride, or epoxyalkane, and more preferably obtained by reacting arginine with glycidyl ether. It is a compound of (2).

(R ² represents a linear or branched alkyl or alkenyl group having 4 to 18 carbon atoms.)
These reaction products may contain unreacted products and by-products as long as the bifilm removal performance is not impaired.

  JP-A-9-271655 discloses a cosmetic and a detergent composition containing a basic amino acid derivative or a salt thereof obtained by reacting glycidyl ether with a basic amino acid or a salt thereof. It is hypoallergenic to the skin and mucous membranes, and is used for the purpose of improving the conditioning effect on hair and the like. It is impossible to foresee or infer any removal effect.

  The use amount of the biofilm remover of the present invention can be appropriately determined depending on the application and dosage form, but is usually used in the form of an aqueous solution in the case of acting on the biofilm, and its concentration is cost and handleability. In terms of biofilm removal performance, the concentration of the compound of the general formula (1) is preferably 0.001 to 10% by weight, more preferably 0.002 to 7% by weight, and still more preferably 0.005 to 5% by weight. It is.

  The biofilm remover of the present invention exhibits an effect by bringing an aqueous solution into contact with the surface on which the biofilm is formed. Examples of the method include dipping, coating, or spraying. Further, physical force such as sponge, towel, brush, water flow, etc. may be applied. In addition, the time for which the biofilm remover is allowed to act varies depending on the amount of biofilm that is attached, the concentration at which the biofilm remover acts, the temperature of action, and the presence or absence of physical force, but it usually ranges from a few seconds to several hours. It is a range. In addition, it is desirable that the removed biofilm is immediately rinsed away with running water after the action.

  The biofilm remover composition and the hard surface cleaner composition of the present invention enhance the solubility of the compound represented by the general formula (1), improve the biofilm removal performance, and further enhance the cleaning effect. For the purpose, one or more selected from anionic surfactants, nonionic surfactants, amphoteric surfactants and cationic surfactants other than the compound represented by the general formula (1) can be used in combination.

  Examples of the anionic surfactant include lignin sulfonate, alkylbenzene sulfonate, alkyl sulfonate, polyoxyethylene (hereinafter referred to as POE) alkyl sulfonate, POE alkylphenyl ether sulfonate, and POE alkylphenyl. Ether phosphate ester salt, POE aryl phenyl ether sulfonate, alkyl sulfate ester salt, POE alkyl ether sulfate ester salt, POE aryl phenyl ether phosphate ester salt, naphthalene sulfonate, naphthalene sulfonate formalin condensate, POE tribenzyl Phenyl ether sulfonate, alkyl phosphate, POE alkyl phosphate, POE tribenzyl phenyl ether phosphate ester salt, dialkyl sulfosuccinate, fatty acid salt (soap), P E alkyl ether acetate and the like, it is more preferable to use inter alia alkyl sulfate and POE alkyl ether sulfate or POE alkyl ether acetates.

  Nonionic surfactants include POE alkyl ether, POE alkyl phenyl ether, polyoxypropylene / POE (block or random) alkyl ether, POE aryl phenyl ether, POE styrenated phenyl ether, POE tribenzyl phenyl ether, etc. Polyhydric alcohol derivative type nonionic surfactant such as polyhydric alcohol derivative type nonionic surfactant, (poly) glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, POE sorbitan fatty acid ester, alkyl polyglycoside, fatty acid alkanolamide, etc. Activating agents, etc., among which POE alkyl ether, (poly) glycerin fatty acid ester, alkyl polyglycoside, sorbitan fatty acid ester or POE sorbitan fatty acid ester It is more preferable to use the ether.

  Examples of amphoteric surfactants include alkylcarboxybetaines, alkylsulfobetaines, alkylhydroxysulfobetaines, fatty acid amide betaines, and alkyldimethylamine oxides. Among them, alkyldimethylamine oxides and alkylhydroxysulfobetaines are preferably used.

  Examples of the cationic surfactant include alkyltrimethylammonium salts and dialkyldimethylammonium salts. Among them, alkyltrimethylammonium salts are preferable. As said salt, a halide is preferable and a chloride and a bromide are more preferable.

  Of these surfactants, nonionic surfactants are preferred. Further, these surfactants can be used in combination at any ratio depending on the purpose and the compound of the general formula (1). A preferred ratio is a compound of the general formula (1): other surfactants = 1: 99 to 99: 1 in terms of weight ratio in terms of product stability and cleaning effect, and more preferably 5:95. It is -95: 5, More preferably, it is 10: 90-80: 20.

The biofilm remover and hard surface cleaner composition of the present invention can be used in combination with a chelating agent for the purpose of enhancing the effect. Chelating agents include aminocarboxylic acid derivatives such as nitrilotriacetic acid, ethylenediaminetetraacetic acid, iminodisuccinic acid, aspartic acid diacetic acid, aminomethylglycine diacetic acid and / or their salts, organic acid salts such as citric acid, tartaric acid and gluconic acid Polyacrylic acid and / or salt thereof, polyelectrolyte compound such as polyacrylic acid / maleic acid copolymer and / or salt thereof, phosphoric acid compound such as tripolyphosphate, orthophosphate, pyrophosphate, Phosphonic acid compounds such as 1-hydroxyethane-1,1-diphosphonic acid and / or salt thereof, aminotri (methylenephosphonic acid) and / or salt thereof, ethylenediaminetetra (methylenephosphonic acid) and / or salt thereof, type A Examples include aluminosilicates such as zeolite and B-type zeolite. Nitrilotriacetic acid salts, salts of ethylenediaminetetraacetic acid, tripolyphosphates, 1-hydroxyethane-1,1-diphosphonic acid and / or its salts are preferred.
Further, these chelating agents can be used in combination with the compound of the general formula (1) at an arbitrary ratio depending on the purpose. A preferred ratio is, in terms of washing effect, a weight ratio of the compound of the general formula (1): chelating agent = 1: 99 to 99: 1, and more preferably 5:95 to 95: 5.

  The concentration of the compound of the general formula (1) in the product form of the biofilm remover composition and the hard surface cleaning composition of the present invention can be appropriately determined depending on the use and dosage form, but is difficult to commercialize. From the viewpoint of degree and effect, 0.001 to 80% by weight is preferable, 0.002 to 60% by weight is more preferable, and 0.005 to 40% by weight is more preferable.

  The dosage form of the biofilm remover, biofilm remover composition, and hard surface cleaner composition of the present invention includes a solution dissolved in a solvent such as water, ethanol, isopropanol, or a solid depending on the purpose and purpose. , Gel, emulsified / dispersed, powder, aerosol, etc., and can be selected as appropriate. It is also possible to dilute or use the compound of the general formula (1) and a surfactant and / or a chelating agent in the usage scene.

  The biofilm remover of the present invention is a thickener, a viscosity modifier, a pH adjuster, a solvent, a fragrance, a colorant, an antioxidant, an antiseptic, a fluorescent agent, and an excipient as long as the object of the present invention is not impaired. Agents, soil release agents, bleaching agents, bleach activators, powdering agents, granulating agents, coating agents and the like can be blended.

  The product of the present invention can be used in a wide range of fields where biofilms are a concern. For example, the present invention can be applied to cleaning agents for food production or beverage production plants with a high risk of bacterial contamination, kitchens, kitchens, bathrooms, toilet bowls, drains for kitchens or kitchens, and drain pipes. It can also be applied to cooling water systems such as industrial cooling towers, desalination equipment, pulp and paper manufacturing systems, and circulating water systems such as bathtubs, pools, and artificial ponds. The present invention can also be applied to medical devices in which biofilms are easily formed, for example, cleaning agents such as endoscopes, catheters, and artificial dialysis machines. Furthermore, since it has high safety, it can be used for cleaning agents for the body, dentifrices, oral care agents, denture care agents, contact lens cleaners, and the like.

The medical device cleaning composition of the present invention contains the basic amino acid derivative represented by the above general formula (1) or a salt thereof.
Here, examples of the medical device include medical devices with a high possibility of attachment of body fluids such as an endoscope, a catheter, and an artificial dialysis machine (particularly, an artificial dialysis fluid circuit). Endoscopes here include laryngoscope, bronchoscope, upper gastrointestinal endoscope, small intestine endoscope, large intestine endoscope, thoracoscope, laparoscope, cystoscope, biliary scope, indirect mirror, intravascular An endoscope etc. are mentioned.
In recent years, the application field of these endoscopes has expanded, and the cleaning composition of the present invention is particularly useful for cleaning these endoscopes.

  The medical device cleaning composition may be used by immersing the medical device in the medical device cleaning composition, placing the medical device in a water stream of the aqueous solution, or applying ultrasonic vibration to the aqueous solution. And a medical device are brought into contact with each other. When the medical device cleaning composition is diluted and used, an aqueous solution of 0.2 to 20%, particularly 0.3 to 15% by weight, and more preferably 0.4 to 12% by weight is preferable.

Production Example 1
Production of N- [2-hydroxy-3- (2-ethylhexyl) oxypropyl] -L-arginine hydrochloride Into a 200 mL four-necked flask equipped with a reflux condenser, a dropping funnel, a thermometer and a stirring blade was added L ( (+)-Arginine (9.4 g, 53.7 mmol), water (50.0 g), and ethanol (50.0 g) were added, and the mixture was heated to 78 ° C. with stirring in a nitrogen atmosphere. Next, 10.0 g (53.7 mmol) of 2-ethylhexyl glycidyl ether was added dropwise while maintaining the reaction system at 78 to 80 ° C. Then, after aging at 78-80 ° C. for 4 hours, the temperature was returned to room temperature. Next, 9.8 g (53.7 mmol) of 6 mol / L hydrochloric acid aqueous solution was added for neutralization. Water and ethanol were completely distilled off from the reaction solution under reduced pressure to obtain 21.6 g of a white solid of N- [2-hydroxy-3- (2-ethylhexyl) oxypropyl] -L-arginine hydrochloride. This compound corresponds to Compound 2 in Table 1.
In the same manner, compounds having C10 (isodecyl) and C12 (straight chain) were produced. These compounds correspond to the compounds 3 and 4 in Table 1, respectively.

Example 1
<Biofilm removal ability test>
Pseudomonas aeruginosa NBRC13275, Serratia marcescens NBRC12648, and Staphylococcus epidermidis Klebsiella pneumoniae ATCC13883 (Soybean-Casein Digest Agar) [SCD agar medium: manufactured by Nippon Pharmaceutical Co., Ltd.] ], A very small amount of bacterial mass from a colony formed by pre-culturing at 37 ° C. for 24 hours, and using a sterilized bamboo skewer, 1.5 mL each of Mueller Hinton medium was added to each well. Inoculated into plates. After culturing at 37 ° C. for 24 hours, the culture solution was discarded, and each well was rinsed 5 times with 2 mL of purified water to form and attach a biofilm to the microplate wall. Immediately after adding 2 mL of the compounded product containing the prepared biofilm remover shown in Tables 2 and 3 (present products 1 to 24 and comparative products 1 to 19 as a control) and allowing them to act at room temperature for 10 minutes, The biofilm control agent in each well was discarded. Each well was rinsed twice with 2 mL of purified water, and then 2 mL of 0.1% crystal violet was added to stain the biofilm remaining on the microplate wall. After rinsing the excess staining solution with water, 2 mL of 80% ethanol was added, and the crystal violet stained biofilm was uniformly dissolved, and then the absorbance was measured at 570 nm to obtain a measured value. Similarly, after the well not treated with the biofilm remover was treated with 0.1% crystal violet, the absorbance was measured to obtain an initial value. In addition, 1.5 mL each of Mueller Hinton medium in 24 wells but not inoculated with the bacterial mass was performed in the same manner, and the absorbance was measured to obtain a blank value. Each test was performed five times and the average value was used. The removal rate was calculated by the following formula. Concentrations in the table are shown as effective concentration (% by weight) based on the total amount, and pH was adjusted using potassium hydroxide or hydrochloric acid as necessary.

Removal rate (%) = 100 × [{(initial value−blank value) − (measured value−blank value)} / (initial value−blank value)]

The obtained biofilm removal rates are shown in Tables 2 and 3.
In addition, the compounds 1-5 in a table | surface are shown in following Table 1.

  From the above results, it can be seen that the biofilm can be satisfactorily removed by using the biofilm remover of the present invention.

Example 2
<Cleaning test for bath dirt>
A test piece made of polypropylene having a length of 80 mm, a width of 20 mm, and a thickness of 1 mm was installed in the drainage groove of a bath of a family of four. The test piece was taken out after being left for 2 months, and the cleaning power was evaluated as follows. After a cotton cloth of the same size as the test piece containing 3 mL of the cleaning composition shown in Table 3 (the present invention products 10-24 and the comparative products 10-19 as a control) was adhered to the test piece for 5 minutes The state of the soil after rubbing with a sponge was visually evaluated in the following five stages, and the results of the detergency against bath soil, which is an average of 5 times, are shown in Table 3.
5: Very good dirt removal 4: Good dirt removal 3: Unevenness in dirt removal 2: Slight dirt removal degree 1: Almost no dirt removal

Example 3
<Cleaning test for kitchen dirt>
A test piece made of stainless steel 80 mm long × 20 mm wide × 1 mm thick was placed in a drainage ditch of a family of four people's family, left as it was for 2 months, and used as a test piece. The detergency was evaluated as follows. After a cotton cloth of the same size as the test piece containing 3 mL of the cleaning composition shown in Table 3 (the present invention products 10-24 and the comparative products 10-19 as a control) was adhered to the test piece for 5 minutes The state of the soil after rubbing with a sponge was visually evaluated in the following five levels. Table 3 shows the results of washing performance against kitchen soil, which is an average of 5 times.
5: Very good dirt removal 4: Good dirt removal 3: Unevenness in dirt removal 2: Slight dirt removal degree 1: Almost no dirt removal

Example 4: Biofilm removal test in a Teflon (registered trademark) tube Pseudomonas aeruginosa NBRC13275 and Klebsiella pneumoniae ATCC13883 (Soybean-Casein Digest Agar) [SCD agar medium: Nippon Pharma Co., Ltd.] was used for pre-culture at 37 ° C. for 24 hours.
One platinum colony of the obtained bacterial colonies on the agar medium was inoculated, and the Masterflex metering pump system (system model No. 7553-80, manufactured by Cole-Parmer Instrument Company), Head No. 7016-21) was used to circulate a culture solution in which bacteria were suspended in a Teflon (registered trademark) tube (inner diameter 5 mm, outer diameter 7 mm) at a flow rate of 50 to 60 mL / min at 30 ° C. for 48 hours, A biofilm was formed on the inner surface of the Teflon (registered trademark) tube. The culture solution was discarded, and the composition shown in Table 2 was prepared to a concentration of 10% with sterilized purified water. This liquid is circulated at 30 ° C. at a flow rate of 50 to 60 mL / min, and the biofilm adhered in the Teflon (registered trademark) tube before and after the treatment is visually confirmed after being stained with 0.1% crystal violet. did. In the biofilm formation state, 0-10% of the biofilm adhesion of the control was marked with ◎, 10-40% with ◯, 40-80% with Δ, and 80% or more with x.
The results are shown in Table 4.

  From the above results, the biofilm removal effect of the product of the present invention is clear. The Teflon (registered trademark) tube is used for an endoscope application, and it can be seen from the effect that the present invention is excellent in the biofilm removal effect for the endoscope application.

Claims (5)

The following general formula (1)

(In the formula, R ¹ represents a linear or branched alkyl or alkenyl group having 4 to 18 carbon atoms, and X and Y represent the following formulae:

And m represents an integer of 3 . )
The medical device is immersed in an aqueous cleaning agent composition solution containing a basic amino acid derivative represented by the formula (I) or a salt thereof, or the medical device is placed in a water stream of the aqueous solution, or the aqueous solution is subjected to ultrasonic vibration. A method of cleaning medical equipment, where medical equipment is brought into contact with Formula (1), X is _{-OCH 2 -CH (-OH) CH 2} - cleaning method according to claim 1, wherein a is.   The washing method according to claim 1 or 2, wherein the basic amino acid derivative of the general formula (1) or a salt thereof is an arginine derivative or a salt thereof obtained by reacting arginine or a salt thereof with glycidyl ether. The medical device cleaning composition further comprises at least one selected from the group consisting of a surfactant other than the basic amino acid derivative of the general formula (1) or a salt thereof and a chelating agent. The cleaning method according to any one of to 3 . The cleaning method according to any one of claims 1 to 4 , wherein the medical device is an endoscope.