WO1998034119A1

WO1998034119A1 - Treatment for solid surface

Info

Publication number: WO1998034119A1
Application number: PCT/JP1998/000398
Authority: WO
Inventors: Hiroshi Tamura; Shigenori Tanaka
Original assignee: Seikagaku Corporation
Priority date: 1997-01-31
Filing date: 1998-01-30
Publication date: 1998-08-06
Also published as: JP3825812B2

Abstract

1) A method for treating a solid surface, characterized by bringing a treatment containing a chelating agent and/or a surfactant as the active ingredients into contact with a solid surface having a Limulus reactive substance deposited or adsorbed thereon to thereby liberate said substance; 2) a treatment for a solid surface to be used for liberating a Limulus reactive substance from a solid surface having said substance deposited or adsorbed thereon, characterized by containing a chelating agent and/or a surfactant as the active ingredient; 3) the use of a treatment containing a chelating agent and/or a surfactant as the active ingredient for liberating a Limulus reactive substance from a solid surface having said substance deposited or adsorbed thereon; and 4) a method for assaying a Limulus reactive substance, characterized by allowing a Limulus reagent to act on a solution obtained by treating a solid surface having a Limulus reactive substance deposited or adsorbed thereon with a treatment containing a chelating agent and/or a surfactant as the active ingredient. The method enables simple and efficient liberation of a Limulus reactive substance deposited or adsorbed on the surface of a solid, such as a medical device or a container for drugs, in a hygienically safe and inexpensive manner.

Description

Specification

Treatment agent for solid surface

The present invention relates to endotoxin and / or

(1 → 3) — A method for easily and efficiently releasing D-glucan (collectively referred to as “limulus-reactive substance” as defined later), the treating agent used in the method, and the treatment In the measurement of the Limulus reaction by Limulus reaction using the horseshoe crab 'Amebosite' lysate, endotoxin and Z or (1 → 3) -β-Ό were measured from solid surfaces such as medical devices and medical containers. —Easily and efficiently release glucan, endotoxin and Ζ or

(1 → 3) One related to a measurement method that significantly enhances the sensitivity of detecting 3-D-glucan and enables appropriate safety evaluation of medical devices, pharmaceutical containers, and the like. Background art

A method of measuring endotoxin, which is a pyrogen, by using the same factor as horseshoe crab メ amebosite lysate (hereinafter, also simply referred to as lysate) is known. Has also been adopted. This method is based on coagulation of the lysate by trace amounts of endotoxin, but subsequent biochemical elucidation reveals that the reaction consists of the stepwise activation of several coagulation factors. (Fig. 1) (Nakamura Takanori, Journal of Bacteriology, 38, 7 8 1-

8 0 3 (1 9 8 3)). Endotoxin, which triggers this reaction, is an outer membrane component of the cell wall of Gram-negative bacteria, also called lipopolysaccharide (LPS), and has amphiphiles in which hydrophilic sugar chains and hydrophobic lipid A moieties are localized in the molecule. Substance.

Endotoxin has an exothermic effect even in minute amounts in vivo, and is known to have various biological activities (toxicity) such as induction of free ゃ shock and lethal effect of inflammatory cytokines such as TNF and IL-11. Must be avoided as much as possible. FDA is 1

In 1998, guidelines were established for endotoxin testing by the Limulus test as an alternative to the heron pyrogenicity test, but since then this test has been used for drug safety testing. Have become widely applied.

Under normal conditions, endotoxin subunits are known to form large molecular aggregates (aggregates) through hydrophobic and ionic bonds, and to form complex micelles with proteins and lipids. This micelle structure greatly affects the Limulus reaction, and there is a molecular size and the micelle structure showing the maximum activity. Endotoxin, which is amphiphilic, adsorbs to various substances and carriers via its hydrophilic group and hydrophobic group. In particular, plastics have the property of strongly adsorbing under certain conditions. Therefore, the endotoxin adsorbed on the plastic device is not released at all simply by distilled water, but may be released only when it comes into contact with body fluids such as blood. It has been pointed out that there is a risk that endotoxin cannot be accurately detected by the method for detecting endotoxin contamination of instruments. Therefore, even if endotoxin contamination is present, conventional test methods may be compatible, and the application of these medical devices to the human body, especially to immunocompromised patients with reduced immunocompetence, poses a major medical problem. Become.

Furthermore, in the field of surgery and emergency care, daily management of endotoxin is extremely important for understanding the condition of infectious diseases, especially for sepsis, determining the treatment and prognosis, and monitoring postoperatively. This is an essential item for the safety management of dialysate. For this reason, strict attention must be paid to the safety of medical devices whose primary purpose is treatment.

On the other hand, there is known a method of measuring (1 → 3) -3-D-glucan separately from endotoxin using lysate factor G. (1 → 3) -β-Ό-gelcan, which triggers this reaction, is widely distributed in nature as a cell wall component of fungi such as yeasts, mushrooms and molds and higher plants. -Induction of production of cytokins such as 1 and IL-6, activation of complement system via (1-3) -yS-D-glucan receptor, activation of reticular system, antitumor effect, etc. Shows biological activity. In addition, since it may have a synergistic effect of enhancing the action of endotoxin, contamination of (1 → 3)-/ 3-D-glucan in various pharmaceuticals and medical devices is becoming an important medical problem.

Samples to be subjected to the Limulus test based on the medical device standards prescribed by the Pharmaceutical Affairs Law Although various heating temperatures and heating times are described as methods for preparing solutions, most of them use harsh extraction conditions (70 ° C, etc.), and the method is different for each target medical device. Is different. Furthermore, it has been pointed out that in the case of low-concentration endotoxin, in particular, the problem of inactivation of endotoxin accompanying these treatments has been pointed out, and it is necessary to accurately measure the concentration of active endotoxin attached or adsorbed to the device, that is, The problem of difficulty in proper safety assessment (J. Antibact. Antifungal Agents, 19, 561-566 (1991)) was there. An endotoxin measurement method using human serum albumin (HSA) or globulin as an extractant is also known (Japanese Patent Application Laid-Open No. 5-255045), which removes endotoxin from an albumin-globulin solution itself. In addition, the operation of deactivating is complicated, and it is difficult to perform these operations reliably. It is said that there is a risk that human-derived pathogenic microorganisms (HIV, mycoplasma, etc.) may be mixed into the power s' and extractant. Due to problems, it was not a practical method. Furthermore, the extractant is expensive and expensive because it is prepared from precious blood and cannot be said to be an effective use of precious resources.

The present invention relates to a hygienic safe and low-cost method capable of easily and efficiently releasing a Limulus-reactive substance adhered or adsorbed to a solid surface of a medical device, a pharmaceutical container or the like, a treating agent used in the method, And a method for measuring limulus-reactive substances using the same. Disclosure of the invention

The present invention has the following configurations.

1) Contacting a treatment agent containing a chelating agent and Z or a surfactant as an active ingredient with a solid surface to which a Limulus-reactive substance is attached or adsorbed to release a Limulus-reactive substance. Processing method.

2) The method for treating a solid surface as described in 1) above, wherein the Limulus-reactive substance is a substance that activates a C-factor system or a G-factor system of horseshoe crab, amebosite, and lysate. .

3) The substance described in 2) above, wherein the substance that activates the factor C system is endotoxin, and the substance that activates the factor G system is (1 → 3) — — D-glucan. Of solid surface treatment.

4) The method for treating a solid surface according to any one of 1) to 3) above, wherein the surfactant is a nonionic surfactant or an anionic surfactant.

5) The method for treating a solid surface according to 4) above, wherein the nonionic surfactant is selected from polyoxyethylene ethers, polyoxyethylene sorbitans, and polyethylene glycol.

6) The method for treating a solid surface as described in 4) above, wherein the anionic surfactant is an alkyl sulfate.

7) The method for treating a solid surface according to any one of the above 1) to 3), wherein the chelating agent is selected from citric acid, ethylenediaminetetraacetic acid and salts thereof.

8) The solid surface according to any one of 1) to 7) above, wherein the solid surface is a surface selected from a synthetic resin, a natural resin, a synthetic fiber, a natural fiber, a metal, and glass. Processing method.

9) A solid surface which is used to release a limulus-reactive substance from a solid surface to which the limulus-reactive substance is attached or adsorbed, and which comprises a chelating agent and / or a surfactant as an active ingredient. Processing agent.

10) The solid surface treating agent according to the above item 9), wherein the active ingredient comprises ethylenediaminetetraacetic acid, a salt thereof, and polyethylene glycol.

11) The solid surface treating agent as described in 9) above, wherein the active ingredient comprises polyoxyethylene sorbitan, polyethylene glycol and ethylenediamine tetraacetic acid or a salt thereof.

1 2) Use of a chelating agent and a treating agent containing Z or a surfactant as an active ingredient in a treatment for releasing a limulus-reactive substance from a solid surface to which the limulus-reactive substance is attached or adsorbed.

13) The limulus reagent is allowed to act on the treatment solution obtained by treating the solid surface to which the limulus-reactive substance is attached or adsorbed with a treatment agent containing a chelating agent and / or a surfactant as an active ingredient. Characteristic method for measuring Limulus-reactive substances.

In the present invention, a treatment agent containing a chelating agent and / or a surfactant as an active ingredient A simple and efficient method for treating the surface of medical devices and drug containers of various materials, and attaching and adsorbing the limulus-reactive substance, ie, endotoxin and / or (1 → 3) -β-1D-glucan, to or from the surface of equipment It can be liberated well (hereinafter, the treating agent is also referred to as “the treating agent of the present invention”).

Further, according to the present invention, a Limulus reagent is allowed to act on a treatment solution obtained by treating a solid surface with the treatment agent of the present invention, whereby a Limulus-reactive substance can be accurately measured. The treating agent of the present invention exhibits a long-term stable releasing effect of a Limulus-reactive substance in an aqueous solution.

In the present invention, the term “limulus-reactive substance” means a substance that acts on a lysate component to induce a Limulus reaction, and includes a C-factor system (including at least C-factor, Β-factor and Ζ or a coagulase precursor as a component). ) Activates endotoxin and G factor system (including at least factor G and / or coagulase precursor) (1 → 3) _ — D-glucan.

The lysate is prepared by extracting the horseshoe bonnet (blood cell) by a suitable method such as a homogenizer.

Further, as the Limulus reagent used in the method for measuring a Limulus-reactive substance of the present invention, any reagent can be used as long as it is obtained using a lysate as a raw material. Specific examples of such a Limulus reagent include known methods from Limulus polyphemus, tachypres * tridentatus, tachypleus * gigas, tachypleus (carcinoscorpius), londiki uruda, etc., from the blood lymph of the horseshoe. (For example, normal lysate prepared by J. Biochem., 80, 1011-1021 (1976)), and endotoxin-specific lysate excluding factor G reaction. Endotoxin-specific reagents for the synthetic substrate method prepared by further adding a synthetic substrate to these lysates (Japanese Patent Publication 2-18080, Japanese Patent Publication 3-18080, Obayashi T. et al. (Obayashi T. et. ), Clini. Chim. Acta, 149, 55-65 (1985)) and the reaction of C factor were excluded (1-3) — / 3-—D-glucan-specific rice G 4-285859), and lysates prepared by adding a synthetic substrate to these lysates (1 → 3) — _D-glucan-specific reagent (Japanese Patent Laid-Open No. 4-285859), etc. Is mentioned. In addition, the assay method of the present invention This method has the advantage that it is highly accurate to perform the reaction using a gel reagent, and there is no need to use a coagulant. However, the present invention is not limited to this.A gel-forming Limulus reagent or a turbidimetric Limulus reagent applying a gel-forming reaction Can also be performed.

Therefore, in the assay method of the present invention, by selecting a Limulus reagent specific for endotoxin or specific for (1 → 3) -3-D-glucan, the Limulus reaction 'f biomaterial present on the solid surface can be reduced. It can be identified as endotoxin or (1 → 3) -β-Ώ-glucan.

The treatment agent of the present invention contains at least one or both of a chelating agent and a surfactant as an active ingredient.

The chelating agent that can be used in the present invention is not particularly limited as long as it is a compound that forms a cyclic structure (chelating ring) by coordination to a metal ion, but the molecule has a plurality of oxygen, nitrogen or iodide in the molecule. However, an organic compound capable of forming a 5- to 6-membered ring structure by coordination is more preferable. Specifically, citrate, ethylenediaminetetraacetic acid (EDTA :), diaminopropanetetraacetic acid (Methy1-EDTA), hydroxyshethylethylenediaminetriacetic acid (EDTA-OH), glycol ether diamine Tetraacetic acid (GEDTA), N, N-bis (2-hydroxybenzyl) ethylendiamine-N, N-diacetic acid (HBED), tri-triacetate (NTA), and ethylene triamine pentaacetic acid (DTPA ) And salts of these compounds (sodium salt, potassium salt, ammonium salt, etc.) and the like, and these can be used alone or in combination. Preferred chelating agents include citric acid, ethylenediaminetetraacetic acid or salts thereof.

As the surfactant used in the treatment agent of the present invention, a nonionic surfactant or an anionic surfactant is preferable.

As the nonionic surfactant, polyoxyethylene ethers, polyoxyethylene sorbitans, polyethylene glycol and the like are preferable, and these are used alone or in combination. Further, these nonionic surfactants are particularly effective when used in combination with a chelating agent, for example, ethylenediaminetetraacetic acid or a salt thereof. The polyoxyethylene ethers that can be used in the present invention include Trioxy-based polyoxyethylene mono-p-tert-octyl (or isooctyl). Phenyl) phenyl ether (polymerization degree: 8 to 40), polyoxyethylene carboxy (or isooctyl) phenyl ether (polymerization degree: 8 to 40), polyquinethylene: p-nonylphenyl ether (polymerization) Degree 10 to 20) and polyoxyethylene dodecyl ether (polymerization degree 10 to 29) as the Brij series, and these are used alone or in combination. Examples of polyoxyethylene sorbitan include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene ether monostearate (Tween series), etc. These can be used alone or in combination. In addition, polyethylene glycol (PEG) is a polymer of ethylene glycol with an average molecular weight of

2,000 to 20,000, preferably 20,000 to 20,000, more preferably 4,000 to 20,000 These can be used alone or in combination.

Examples of the anionic surfactant that can be used in the present invention include alkyl sulfates, cholate salts, and dequincholate salts (preferably, alkali metal salts such as sodium), and the like. Specific examples include sodium dodecyl sulfate (SDS).

The solid surface to be treated according to the present invention includes any material that requires confirmation or quantification of the presence or absence of a Limulus-reactive substance, and includes a vacuum blood collection tube, a syringe, an infusion connection tube, and a hollow fiber type. Examples include surfaces of medical devices such as module membranes for artificial dialysis, module membranes for plasma exchange, blood circuits and the like, but are not limited thereto, and include, for example, surfaces of food and beverage containers and the like. Therefore, the material for the solid surface includes any material as long as the material cannot be used due to dissolution, deformation or the like with the treatment agent of the present invention. The treatment liquid from which the limulus-reactive substance has been released according to the present invention is strongly checked for its presence or amount by subjecting it to the Limulus reaction, and is discarded or generalized without subjecting the treatment liquid to the Limulus reaction. I can't wait to say that it can be transferred to water treatment facilities. That is, the present invention may have only a function as a cleaning agent for simply removing a limulus-reactive substance that has a harmful effect on a human body or the like from a solid surface.

Specific examples of solid surface materials include synthetic resins, natural resins, synthetic fibers, and natural fibers. Examples include fiber, metal, glass and the like, which may be used alone or in combination. For example, synthetic resins composed of polypropylene, polystyrene, polyethylene, polyvinyl chloride, phenol resin, melamine resin, urea resin, gen-based rubber, olefin-based rubber, polyurethane rubber, silicone rubber, fluorine rubber, polysulfide rubber, etc. Synthetic fiber; natural resin such as gum arabic, cashmere rubber, ammonia rubber, natural rubber

Natural fibers such as cotton, kapok, flax, ramie, manila hemp, wool, mohair, silk, asbestos; metals such as stainless steel copper, silver, gold, platinum, iron, nickel, chromium; soft iron glass, potash glass, hard secondary Hard primary, tungsten, glass, quartz glass, and the like.

The treatment agent of the present invention is not particularly limited in its form as long as it contains at least a chelating agent and Z or a surfactant as an active ingredient. And preferably an aqueous solution. Water is usually used as a solvent for the active ingredient, but an organic solvent that does not affect the Limulus reaction can be used in combination with water or alone. Here, when the treatment liquid in which the limulus-reactive substance is released from the solid surface according to the present invention is subjected to the limulus reaction, the solvent must not contain the limulus-reactive substance. When there is no solvent, there is no particular limitation, and the quality of the solvent may be selected according to the purpose.

In the treating agent of the present invention, the concentration of the chelating agent varies depending on the type thereof, but is preferably in the range of 0.1 mM to 20 mM, more preferably in the range of 0.1 mM to 5 mM. The concentration of the surfactant may vary depending on the type of the chelating agent as well as the chelating agent, preferably in the range of 0.001% to 0.5% (weight Z volume), and more preferably 0.000%. It is in the range of 1 to 0.05% (weight Z capacity).

The treating agent of the present invention can also be used in combination with a disinfectant such as sodium hypochlorite. That is, a solid surface can be treated by adding a bactericide to the treating agent of the present invention, or by using a treating agent of the present invention and a bactericide successively. When measuring the Limulus-reactive substance in the treated solution after treating the solid surface, when the germicide is a substance that affects the Limulus reaction, it is preferable to dilute the treatment liquid until the effect is eliminated. When the treating agent of the present invention is brought into contact with a solid surface, the contact temperature is 4 to 50 ° C, particularly preferably 10 to 30 ° C, and the contact time is 5 minutes to 2 hours, particularly 30 minutes to 1 hour. Time ranges are preferred. Here, the method of the contact treatment is not particularly limited, and examples thereof include a shaking treatment, a stirring treatment, and a stationary treatment. The treatment time is appropriately selected depending on the treatment method. According to the present invention, after such treatment, the Limulus-reactive substance adhering or adsorbing to the solid surface is easily and efficiently quantitatively released without impairing its activity, and a treatment liquid containing the substance is obtained. The Limulus reagent is mixed with the Limulus reagent, and the Limulus-reactive substance can be accurately measured by a conventional method. INDUSTRIAL APPLICABILITY According to the present invention, it is possible to carry out a more appropriate safety evaluation test of a medical device, a medical container, and the like, thereby greatly contributing to progress in medical treatment and the like.

Further, by treating an arbitrary solid surface such as a medical device or a pharmaceutical container using the treatment agent of the present invention, a safe solid surface free from or having a very small amount of limulus-reactive substance can be provided. Here, after the treatment of the solid surface with the treating agent of the present invention, the remaining treating agent of the present invention is optionally removed with water or the like to provide a solid surface free of the treating agent of the present invention and the Limulus-reactive substance. can do. Furthermore, the number of times of such treatment with the treatment agent of the present invention can be appropriately selected depending on the purpose. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram for explaining the Limulus reaction. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1

JP Endotoxin (E. c 0 1 i UKT-B, control 891 7) Dilute 10 000 EU / mL to 1.0 EU / mL with distilled water, and add 2 m L is a Falcon tube 209 6 (made of polypropylene, Becton Ditzkinson) and an assist tube No. 5.55.4 7 (made of polystyrene, ASIC Was shaken at room temperature for 3 hours with a micromixer MT (Taitec) and washed thoroughly with distilled water to prepare an endotoxin adsorption tube. Into the tube, distilled water (control), 0.1% human serum albumin (comparative example), and various treating agents of the present invention (containing a chelating agent and / or polyethylene glycol (PEG) # 600) were contained. 2 mL each was added, and the mixture was shaken with a micromixer MT for 1 hour. To 50 L of the treated solution, add 50 L of endotoxin (Seikagaku Corporation), which is an endotoxin-specific limulus reagent, and use Perleader SK601 (Seikagaku Corporation) to produce rice. Tick Atsushi (37 ° C, 30 minutes) was performed, and the endotoxin concentration was calculated automatically. Assuming that the theoretical value of adsorbed endotoxin (the amount added to the amount detected in washing water) was 100%, the endotoxin release effect index (%) in each treatment solution was determined (Table 1). In Table 1, the concentration of the treating agent of the present invention used in combination with the chelating agent and PEG indicates the concentration of each component of the mixed solution. Table 1 Endotoxin release effects of various chelating agents

The concentration in parentheses indicates the final concentration of the treating agent at the time of treatment. As shown in Table 1, chelating agents that form a cyclic structure with metal ions all have a significant endotoxin releasing effect from the solid surface,

It was found that the effect was enhanced by the addition of PEG (PEG). Furthermore, the method described in Japanese Patent Application Laid-Open No. H5-25255405 (Method for extracting endotoxin) as a comparative example (human Compared to serum albumin (HSA), the effect is remarkably large, and all of the compounds having chelating action and PEG of the present invention are not human-derived components such as HSA and are contaminated with pathogenic bacteria. Since there is no fear of safety, it is clear that the method is excellent in safety and operability, and inexpensive. Example 2

Distilled water (control), 0.1% 7-globulin (comparative example), and the treating agent of the present invention (containing a surfactant or Z and EDTA-4Na) were added to the endotoxin adsorption tube used in Example 1. 2 mL each was added, and the mixture was shaken with a micromixer MT at room temperature for 1 hour. To 50 L of the treated solution, 50 zL of endosperm was added, and the measurement was performed in the same manner as in Example 1 to calculate the endotoxin concentration. Assuming that the theoretical value of adsorbed endotoxin (addition amount-detection amount in washing water) was 100%, the release effect index (%) of endotoxin in each treatment solution was calculated (Table 2). In Table 2, the concentration of each component of the mixed solution with PEG indicates the concentration after mixing.

Table 2 Endotoxin release effects of various surfactants

The concentration in parentheses indicates the final concentration of the treating agent at the time of treatment.

As shown in Table 2, all surfactants consisting of polyoxetylene ethers or polyethylene sorbitans have significant endotoxin release effects, and these surfactants and also PEG When added, PEG-promoting effect was observed as in the case of the chelating agent. Furthermore, it was confirmed that the effect was further enhanced when PEG and a chelating agent were allowed to coexist. All of these surfactant compounds have no risk of contamination with pathogens as in the case of HS A and 7-glopurine, and therefore, like chelating agents, are excellent in safety and operability and are inexpensive. It is clear that this is a practical method.

Example 3

EDTA-4 Na was added to the endotoxin adsorption tube used in Example 1. And PEG # 600 (0.5 mM, 0.004%, respectively) 21: each and then added using a micromixer MT4. C, 10 and shaking at 25 ° C, 30 ° C, 37 ° C, 50 ° C for 1 hour. To 50 L of the treated solution, 5 OjtL of endosperm was added, and the measurement was carried out in the same manner as in Example 1 to calculate the endotoxin concentration. Assuming that the theoretical value of adsorbed endotoxin (addition amount-detection amount in washing water) was 100%, the release effect index (%) of endotoxin in each treatment solution was calculated (Table 3).

Table 3 Effect of treatment temperature on endotoxin release effect

As shown in Table 3, when the solid surface was treated with the treating agent of the present invention containing a chelating agent and a surfactant as an active ingredient, the control (when treated with distilled water even at 4 ° C) The effect of endotoxin release, which was significantly higher than that of), was found to be further enhanced by increasing the contact temperature above 10 ° C.

Example 4

A mixture of Tween 20, PEG # 600 and EDTA-4 Na (0.01%, 0.04%, 0.5 mM, respectively) was added to each sterilized disposable device and medical device. ) Was added and shaken at room temperature for 1 hour in a micromixer MT. For surgical gloves or infusion sets, 20 OmL of the above treatment solution After shaking at room temperature for 3 hours, 50 L of the treated solution was added to 50 L of the treated solution, and the measurement was carried out in the same manner as in Example 1 using distilled water treatment as a control to calculate the endotoxin concentration. (Table 4). Table 4 Endotoxin concentrations in various sterilized plastic instruments and medical devices

As is evident from Table 4, none of the sterilized plastic instruments and medical devices examined in this study are detected by ordinary distilled water treatment (below the detection limit of the quantitative reagent). It turned out that it could be detected.

Example 5

The same treatment was performed using instruments and medical tools of the same mouth as the product used in Example 4, and the treated solution was subjected to 50 ^^ (1 → 3) — — D-glucan-specific limulus. 5 reagents, Glucose (Seikagaku Corporation) were added.

A force-intensity assay (37 ° C, 30 minutes) was performed at SK601, and the (1 → 3)-3-D-glucan concentration was automatically calculated and compared with the control treated with distilled water ( (Table 5) o Table 5 Concentrations of (1 → 3) -3-D-glucan in various sterilized plastic instruments and medical devices

As is evident from Table 5, the sterilized plastic devices and medical devices examined in this study have trace amounts of (1 → 3)-/ 3-D-glucan contamination that cannot be detected at all with ordinary distilled water treatment. It has been found that the use of the treating agent according to the present invention may be detected for the first time.

Normally, sample preparation for the exothermic test of medical devices is performed under mild extraction conditions for endotoxin, and extraction under relatively severe conditions for chemical pyrogens. Methods for increasing efficiency are known. Minimum extraction time is 15 minutes at 37 ° C, 1 hour at room temperature (> 18 ° C), or other proven elution conditions for Limulus testing of medical devices according to FDA guidelines. It is stipulated that the conditions are equivalent.

As shown in Example 3, it is clear that even if the plastic appliances were extracted under the above conditions, no extraction effect was observed. In addition, even in the case of using HSA diaglobulin, the effect is extremely inadequate, and there is a risk of contamination with pathogenic microorganisms. Industrial applicability

In view of the above situation, the present invention provides a treating agent for releasing a limulus-reactive substance from a solid surface to which the limulus-reactive substance is attached or adsorbed. According to the present invention, contamination of limulus-reactive substances in sterile instruments and medical devices, particularly potential endotoxins and / or (1 → 3) 13-D strongly bound to materials that cannot be detected by ordinary extraction methods. —The glucan contamination can be grasped more appropriately, and a safe and simple safety evaluation test of the utensil can be performed. As a result, safer medical practices can be achieved, leading to improved medical quality.

Claims

The scope of the claims

1. A solid surface characterized by contacting a treating agent containing a chelating agent and / or a surfactant as an active ingredient with a solid surface to which a Limulus-reactive substance is attached or adsorbed, thereby releasing the Limulus-reactive substance. Processing method.

2. The solid surface treatment according to claim 1, wherein the Limulus-reactive substance is a substance that activates a factor C system or a substance that activates a G factor system of horseshoe crab, amebosite, and lysate. Method.

3. The solid surface according to claim 2, wherein the substance activating the factor C system is endotoxin, and the substance activating the factor G system is (1 → 3) —— D-glucan. Processing method.

4. The method for treating a solid surface according to any one of claims 1 to 3, wherein the surfactant is a nonionic surfactant or an anionic surfactant.

5. The method for treating a solid surface according to claim 4, wherein the nonionic surfactant is selected from polyoxyethylene ethers, polyoxyethylene sorbitans, and polyethylene glycol.

6. The method for treating a solid surface according to claim 4, wherein the anionic surfactant is an alkyl sulfate.

7. The method for treating a solid surface according to any one of claims 1 to 3, wherein the chelating agent is selected from citric acid, ethylenediaminetetraacetic acid and salts thereof.

8. The solid surface according to any one of claims 1 to 7, wherein the solid surface is a surface selected from synthetic resin, natural resin, synthetic fiber, natural fiber, metal and glass. Processing method.

9. A solid surface used to release a Limulus-reactive substance from a solid surface to which the Limulus-reactive substance is attached or adsorbed, and characterized by containing a chelating agent and Z or a surfactant as an active ingredient. Treatment agent.

10. The solid surface treating agent according to claim 9, wherein the active ingredient comprises ethylenediaminetetraacetic acid, a salt thereof, and polyethylene glycol.

1 1. Active ingredients are polyoxyethylene sorbitan and polyethylene glycol 10. The solid surface treating agent according to claim 9, comprising ethylenediaminetetraacetic acid or a salt thereof.

1 2. Use of a chelating agent and a treating agent containing Z or a surfactant as an active ingredient in a treatment for releasing a limulus-reactive substance from a solid surface to which the limulus-reactive substance is attached or adsorbed.

13 3. The limulus reagent is allowed to act on the treatment liquid obtained by treating the solid surface to which the limulus-reactive substance is attached or adsorbed with a treatment agent containing a chelating agent and / or a surfactant as an active ingredient. Limulus-reactive substance measurement method.