EP0121868B1 - Dispositif pour la détection des endotoxines - Google Patents

Dispositif pour la détection des endotoxines Download PDF

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Publication number
EP0121868B1
EP0121868B1 EP84103474A EP84103474A EP0121868B1 EP 0121868 B1 EP0121868 B1 EP 0121868B1 EP 84103474 A EP84103474 A EP 84103474A EP 84103474 A EP84103474 A EP 84103474A EP 0121868 B1 EP0121868 B1 EP 0121868B1
Authority
EP
European Patent Office
Prior art keywords
endotoxin
tube
reaction tube
detecting device
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP84103474A
Other languages
German (de)
English (en)
Other versions
EP0121868A1 (fr
Inventor
Ryozo Numazawa
Akihiro Sakimae
Hisao Onishi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Rayon Co Ltd
Original Assignee
Mitsubishi Rayon Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP4949283U external-priority patent/JPS59154661U/ja
Priority claimed from JP7712583U external-priority patent/JPS59183660U/ja
Priority claimed from JP9742183U external-priority patent/JPS6022200U/ja
Priority claimed from JP10045083U external-priority patent/JPS608875U/ja
Priority claimed from JP20159683U external-priority patent/JPS60109051U/ja
Application filed by Mitsubishi Rayon Co Ltd filed Critical Mitsubishi Rayon Co Ltd
Publication of EP0121868A1 publication Critical patent/EP0121868A1/fr
Application granted granted Critical
Publication of EP0121868B1 publication Critical patent/EP0121868B1/fr
Expired legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • B01L2300/0838—Capillaries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers

Definitions

  • This invention relates to an endotoxin-detecting device.
  • endotoxin is lipopolysaccharide present in a cell wall of Gram-negative bacteria. Even a very small amount of endotoxin causes various physiologic activities such as pyrexia. The pyrexia of a living organism caused by endotoxin has been a serious problem in the medical, pharmaceutical and sanitary fields. In recent years, it has been proposed to carry out an endotoxin detection using an endotoxin reagent composed of either amebocyte lysate extracted from blood cells of a horseshoe crab or a mixture of a color producing agent and proenzyme separated from the amebocyte lysate. This method is commonly referred to as "limulus test" in the trade. This method enables endotoxin to be detected much more quickly in comparison with a conventional endotoxin-detecting method in which a small amount of a specimen liquid is applied to a rabbit to see whether the rabbit is subjected to pyrexia.
  • Such detection devices comprise a reaction container such as a tube holding the above-mentioned endotoxin .reagent.
  • a specimen liquid to be examined must be transferred to the reaction container by the use of an endotoxin-free sampling tube such as a pipette and a syringe. Therefore, the operation of the conventional endotoxin-detecting devices is rather cumbersome, and in addition there is the risk that the specimen liquid may be contaminated by endotoxin during the transfer of the specimen liquid to the reaction container.
  • the present invention comprises an endotoxin-detecting device comprising a transparent reaction tube containing an endotoxin reagent in the freeze-dried form, which is characterized in that said endotoxin reagent is disposed intermediate and spaced from the opposite ends of said reaction tube and is hermetically sealed in said reaction tube, said reaction tube having a diameter between 0.1 and 5 mm.
  • reaction tube is sealed at opposite ends thereof by either a heat sealing or closure members such as caps and plugs.
  • the opposite ends of the reaction tube when in use, are opened, and one of the open ends is dipped in a specimen liquid so that the specimen liquid is drawn into the reaction tube by the capillary action.
  • the specimen liquid so introduced dissolves the endotoxin reagent to form a mixture which is heated to a predetermined temperature to react the reagent with the specimen liquid.
  • the reaction mixture in the reaction tube is gelated, becomes turbid or is colored in proportion to the concentration of the endotoxin contained in the specimen liquid.
  • the reaction tube is of such a diameter that the specimen liquid introduced into the reaction tube is not caused to flow therefrom when it is held horizontally.
  • the reaction tube has a diameter between 0.1 and 5 mm.
  • the reaction tube may be provided at one end thereof with a suction means for positively drawing the specimen liquid into the reaction tube.
  • the reaction tube can be made of any material so long as it has such a transparency that the inside of the reaction tube can be inspected from outside it.
  • the endotoxin reagent is composed of either amebocyte lysate extracted from blood cells of a horseshoe crab or a mixture of a color producing agent and proenzyme separated from the amebocyte lysate.
  • the endotoxin reagent is preferably in the freeze-dried form.
  • a stabilizing agent may be added to the endotoxin agent.
  • An endotoxin-detecting device shown in FIG. 1 comprises a straight reaction tube 1 of a uniform diameter having opposite closed ends, and an endotoxin reagent 2 sealed in the reaction tube 1 and disposed intermediate the opposite ends thereof.
  • the tube 1 is made of a transparent material such as glass, polymethyl methacrylate and polystyrene.
  • the tube 1 has a small diameter of 0.1 to 5 mm.
  • a notch or a line of cut may be formed circumferentially in each of the opposite end portions of the tube 1 to facilitate the removal of these end portions from the tube 1.
  • the tube 1 may have opposite open ends which are sealed by closure members such as plugs and caps, respectively.
  • closure members such as plugs and caps, respectively.
  • One or both of the opposite end portions of the tube 1 may have either smaller or larger diameter that the major portion extending between these opposite end portions.
  • the reaction tube 1 may be formed into a U-shape.
  • the opposite ends of the tube 1 are first removed or cut off so that the tube has opposite open ends. Then, one of these open ends is dipped in a specimen liquid so that the specimen liquid is introduced into the tube 1 by the capillary action. The specimen liquid introduced into the reaction tube 1 dissolves the endotoxin reagent 2 to form a mixture. Then, the tube 1 holding the mixture is placed in a dry warming device to heat the mixture to a predetermined temperature so that the endotoxin reagent 2 is caused to react with the specimen liquid. Then, the tube 1 is tilted to see whether the reaction mixture in the tube 1 is subjected to gelation.
  • the reaction tube 1 is observed to determine whether the reaction mixture in the tube 1 is subjected to turbidity of coloring.
  • the degree of gelation and turbidity of the reaction mixture are proportional to the concentration of endotoxin in the specimen liquid. Thus, the concentration of the endotoxin can be easily determined.
  • the tube 1 serves as both a sampling tube and a reaction tube.
  • the endotoxin-detecting device according to the present invention obviates the need for a separate endotoxin-free sampling tube for taking the specimen liquid. Therefore, with this endotoxin-detecting device, the specimen liquid does not need to be transferred from a sampling tube to a reaction tube, so that the detection of endotoxin can be carried out easily. In addition, the risk of contamination of the specimen liquid by endotoxin can be substantially reduced.
  • the reaction tube 1 is of such a small diameter that it holds a relatively small amount of specimen liquid. Therefore, the amount of the reagent for endotoxin in the tube can be small.
  • FIG. 2 shows a modified endotoxin-detecting device which differs from the endotoxin-detecting device of FIG. 1 in that a transparent tube 1 has a colored portion 3 extending along the length thereof.
  • the colored portion 3 is formed by a color coating applied to a half of the outer circumferential surface of the tube 1 and extending substantially along the entire length thereof.
  • the colored portion has a white color.
  • the colored portion 3 may be provided on one fourths to three fourths of the outer circumferential surface of the tube 1.
  • the colored portion 3 does not necessarily be provided substantially along the entire length thereof, and it may be provided only at the area of the reaction tube 1 where an endotoxin reagent 2 is positioned.
  • the colored portion 3 may be formed by a colored film adhesively bonded to the outer circumferential surface of the reaction tube 1. Further, the colored coating or the colored film may be applied to the inner circumferential surface of the tube 1. The color of the colored portion 3 may be other than a white color so long as it is opaque.
  • a specimen liquid is introduced into the reaction tube 1 in the same manner as described above for the endotoxin-detecting device of FIG. 1.
  • the colored portion 3 the gelation and coloring of the reaction mixture of the reagent 2 and the specimen liquid can be easily observed with the naked eye if they develop.
  • FIG. 3 shows another modified endotoxin-detecting device which differs from the endotoxin-detecting device of FIG. 1 in that a reaction tube 1 has an open end to which a suction member 4 is attached.
  • the suction member 4 is in the form of a bulb and is made of an elastic material such as rubber and a synthetic resin.
  • the suction member 4 is snugly fitted on the open end of the reaction tube 1 in an air-tight manner and is fixed thereto.
  • the suction member 4 may be formed integrally with the reaction tube 1.
  • the closed end of the reaction tube 1 is first removed, and the suction member 4 is squeezed by fingers. Then, the end of the tube 1 remote from the suction member 4 is dipped in a specimen liquid, and the pressure on the suction member 4 is reduced or released so that the specimen liquid is drawn into the reaction tube 1 by suction. Then, the gelation and coloring of the reaction mixture of an endotoxin reagent 2 and the specimen liquid are observed in the same manner as described above for the endotoxin-detecting device of FIG. 1 to determine the concentration of endotoxin contained in the specimen liquid.
  • the suction member 4 the liquid specimen can be introduced into the tube 1 easily and positively.
  • the suction member 4 may be of any shape so long as it can draw the specimen liquid into the reaction tube 1 by suction. Also, the tube 1 may have a colored portion for facilitating the observation of the reaction mixture in the tube 1, as described above for the endotoxin-detecting device of FIG. 2.
  • FIG. 4 shows a further modified endotoxin-detecting device which differs from the endotoxin-detecting device of FIG. 1 in that a reaction tube 1 is provided with a graduated scale 5.
  • a notch or a line 6 of cut is formed circumferentially in each of the opposite end portions of the tube 1 to facilitate the removal of the opposite end portions from the tube 1.
  • the graduated scale 5 comprises a pair of lines each formed circumferentially around the reaction tube 1 and disposed intermediate an endotoxin reagent 2 and a respective one of the notches 6.
  • a plurality of scale lines 5 may be provided on the tube 1 between the reagent 2 and a respective one of the notches 6.
  • the scale lines 5 may be replaced by dots.
  • the reaction tube 1 may have regions of a transparent color which replace the scale lines 5. Further, although the reagent 2 is received in the tube 1 at a central portion thereof, the reagent may be disposed at any position between the opposite scale lines 6.
  • the opposite ends of the tube 1 are broken off from the reaction tube 1 at the respective notches 3.
  • one of the opened ends of the reaction tube 1 is dipped in a specimen liquid to draw it into the tube 1 up to the scale line 5 by the capillary action.
  • the gelation and turbidity of a reaction mixture of the reagent 2 and the specimen liquid are observed to determine the concentration of endotoxin in the specimen liquid.
  • the reaction tube 1 may have a colored portion for facilitating the observation of the reaction mixture in the tube 1, as described above for the endotoxin-detecting device of FIG. 2. Also, the reaction tube 1 may be provided at one end with a suction member for positively drawing the specimen liquid into the tube 1, as described above for the endotoxin-detecting device of FIG. 3.
  • FIG. 5 shows a still further modified endotoxin-detecting device which differs from the endotoxin-detecting device of FIG. 1 in that a reaction tube 1 has opposite open ends and in that the reaction tube 1 is hermetically sealed in a membrane container 7.
  • the membrane container 7 comprises a pair of identical rectangular films 7a and 7b between which the tube 1 is sandwiched, the films 7a and 7b being hermetically sealed or bonded together along their entire peripheral margins by either heat-sealing or a suitable adhesive, thereby providing a peripheral sealed portion 8.
  • a triangular notch 9 is formed in the peripheral sealed portion 8 for facilitating the tearing of the membrane container 7 when in use.
  • the notch 9 may be replaced by a slit.
  • Each of the films 7a and 7b comprises a film impermeable to moisture, such as a laminated aluminum film incorporating a polymer, a polyvinylidene film, a polyolefin film and an ethylene vinyl chloride copolymer film.
  • the membrane container 7 may be made of a single square film folded in two, with three open sides of the folded film being sealed.
  • the membrane container 7 may be made of a film tube with opposite open ends being sealed, in which case a fused portion is formed on the membrane container in which fused portion the notch 9 is provided.
  • the membrane container 7 may be vacuum sealed.
  • a desiccant may be contained in the membrane container 7 together with the reaction tube 1.
  • a plurality of reaction tubes 1 may be sealed in the membrane container 7 as shown in FIG. 7.
  • the membrane container 7 obviates the need for directly closing the opposite open ends of the reaction tube 1 by either heat-sealing or closure members such as caps and plugs after an endotoxin reagent 2 is filled in the tube 1. Therefore, the risk of contamination of the reaction tube 1 by endotoxin when sealing the tube 1 can be substantially reduced.
  • the inner and outer surfaces of the membrane container 7 can be preserved in an endotoxin-free condition. And, in the case where a plurality of reaction tubes 1 are sealed, much time and labor can be saved.
  • the reaction tube 1 may have a colored portion for facilitating the observation of the reaction mixture in the tube 1, as described above for the endotoxin-detecting device of FIG. 2. Also, the reaction tube 1 may be provided at one end with a suction member for positively drawing the specimen liquid into the tube 1, as described above for the endotoxin-detecting device of FIG. 3. Further, the tube 1 may be provided with a graduated scale for introducing a constant amount of the specimen liquid into the tube 1, as described above for the endotoxin-detecting device of FIG. 4.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

Claims (7)

1. Dispositif de détection d'endotoxines, comprenant un tube de réaction transparent qui contient un réactif à l'endotoxine sous une forme lyophilisée, caractérisé en ce que ledit réactif à l'endotoxine est disposé entre les extrémités opposées dudit tube de réaction et à distance de celles-ci et qu'il est hermétiquement scellé dans ledit tube de réaction, dont le diamètre est compris entre 0,1 et 5 mm.
2. Dispositif de détection d'endotoxines selon la revendication 1, dans lequel ledit tube de réaction présente une paroi phériphérique dont une partie au moins est colorée pour obtenir une portion colorée. ladite portion colorée étant interrompue dans le sens de la périphérie dudit tube de réaction.
3. Dispositif de détection d'endotoxines selon la revendication 1, dans lequel ledit tube de réaction comporte à son extrémité un moyen de succion pour aspirer un échantillon liquide dans ledit tube de réaction.
4. Dispositif détecteur d'endotoxines selon la revendication 1, dans lequel ledit tube de réaction comporte une échelle graduée.
5. Dispositif détecteur d'endotoxines selon la revendication 1, qui comprend en outre un récipient à membrane dans lequel ledit tube de réaction est hermétiquement scellé.
6. Dispositif détecteur d'endotoxines selon la revendication 5, dans lequel plusieurs tubes de réaction sont hermétiquement enfermés dans ledit récipient à membrane.
7. Dispositif détecteur d'endotoxines selon la revendication 5, dans lequel ledit récipient à membrane présente une encoche pratiquée dans une partie centrale de celui-ci pour faciliter le déchirement dudit récipient à membrane.
EP84103474A 1983-04-01 1984-03-29 Dispositif pour la détection des endotoxines Expired EP0121868B1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
JP4949283U JPS59154661U (ja) 1983-04-01 1983-04-01 エンドトキシン検出測定用具
JP49492/83U 1983-04-01
JP7712583U JPS59183660U (ja) 1983-05-23 1983-05-23 エンドトキシン検出測定用具
JP77125/83U 1983-05-23
JP97421/83U 1983-06-24
JP9742183U JPS6022200U (ja) 1983-06-24 1983-06-24 エンドトキシン検出測定用具
JP100450/83U 1983-06-29
JP10045083U JPS608875U (ja) 1983-06-29 1983-06-29 エンドトキシン検出測定用具
JP201596/83U 1983-12-28
JP20159683U JPS60109051U (ja) 1983-12-28 1983-12-28 エンドトキシン検出測定用具

Publications (2)

Publication Number Publication Date
EP0121868A1 EP0121868A1 (fr) 1984-10-17
EP0121868B1 true EP0121868B1 (fr) 1988-06-22

Family

ID=27522803

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84103474A Expired EP0121868B1 (fr) 1983-04-01 1984-03-29 Dispositif pour la détection des endotoxines

Country Status (3)

Country Link
EP (1) EP0121868B1 (fr)
CA (1) CA1236396A (fr)
DE (1) DE3472301D1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK255887D0 (da) * 1987-05-20 1987-05-20 Claus Koch Immunoassay
US5578455A (en) * 1993-03-19 1996-11-26 Tanabe Seiyaku Co., Ltd. Method for determining endotoxin and apparatus therefor
DE602004024769D1 (de) 2003-03-17 2010-02-04 Charles River Lab Inc Methoden und zusammensetzungen für den nachweis mikrobieller verunreinigungen
EP1842069A2 (fr) 2004-12-02 2007-10-10 Charles River Laboratories, Inc. Methodes et compositions pour la detection et/ou la quantification de contaminants bacteriens gram positifs
WO2006076617A2 (fr) 2005-01-13 2006-07-20 Charles River Laboratories, Inc. Procede de classification d'un micro-organisme dans un echantillon biologique
JP7110360B2 (ja) 2017-10-09 2022-08-01 テルモ ビーシーティー バイオテクノロジーズ，エルエルシー 凍結乾燥方法
CN111077307B (zh) * 2018-10-21 2022-08-23 厦门鲎试剂生物科技股份有限公司 一种用革兰氏阴性细菌感染快速检测脓毒病的新方法
JP7495426B2 (ja) 2019-03-14 2024-06-04 テルモ ビーシーティー バイオテクノロジーズ，エルエルシー 凍結乾燥容器用充填治具、システム及び使用方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273557A (en) * 1980-03-31 1981-06-16 Mallinckrodt, Inc. Limulus lysate procedure for determining endotoxins

Also Published As

Publication number Publication date
EP0121868A1 (fr) 1984-10-17
DE3472301D1 (en) 1988-07-28
CA1236396A (fr) 1988-05-10

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