WO2003055533A1 - Composition pour l'elimination des endotoxines et procede d'elimination - Google Patents

Composition pour l'elimination des endotoxines et procede d'elimination Download PDF

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Publication number
WO2003055533A1
WO2003055533A1 PCT/JP2002/012768 JP0212768W WO03055533A1 WO 2003055533 A1 WO2003055533 A1 WO 2003055533A1 JP 0212768 W JP0212768 W JP 0212768W WO 03055533 A1 WO03055533 A1 WO 03055533A1
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WIPO (PCT)
Prior art keywords
endotoxin
solution
column
solid surface
ion
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Application number
PCT/JP2002/012768
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English (en)
Japanese (ja)
Inventor
Kenji Kamimura
Minako Toda
Original Assignee
Nihon Medi-Physics 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
Application filed by Nihon Medi-Physics Co., Ltd. filed Critical Nihon Medi-Physics Co., Ltd.
Priority to AU2002349439A priority Critical patent/AU2002349439A1/en
Priority to JP2003556108A priority patent/JP4647911B2/ja
Publication of WO2003055533A1 publication Critical patent/WO2003055533A1/fr
Priority to NO20033772A priority patent/NO20033772L/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases

Definitions

  • the present invention relates to a composition for removing endotoxin and a method for removing endotoxin.
  • the present invention relates to a technique for removing endotoxin using a saccharide, and more particularly to a composition for removing endotoxin containing a saccharide, and a method for removing and extracting endotoxin using the composition, and relates to a medical device and a pharmaceutical manufacturing method.
  • the present invention relates to a technique useful for removing endotoxin from a solid surface such as a device or a pharmaceutical manufacturing device.
  • Endotoxin is a type of lipopolysaccharide that mainly exists in the outer membrane of the cell wall of Gram-negative bacteria, and is a substance generally well known as a pyrogen (Pyrogen).
  • endotoxin can be inactivated by heat treatment at 250 ° C for 30 minutes or more or at 100 ° C for 120 minutes or more, so that glass and metals are decontaminated by such heat treatment. it can.
  • endotoxin is inactivated at 30 ° C in an organic solvent such as ethanol containing sodium hydroxide or dimethyl sulfoxide, so that glass and the like can also be washed by washing with such a medium. Can be removed.
  • an organic solvent such as ethanol containing sodium hydroxide or dimethyl sulfoxide
  • Japanese Patent No. 2884975 discloses a method for efficiently extracting endotoxin adhering or adsorbed on a solid surface of a container, device, or the like, in place of water or saline, instead of albumin, human serum albumin, globulin, and other proteins. A method for extracting endotoxin into a solution by washing a container, equipment, and the like using the solution is described.
  • blood proteins are biological components and are therefore not desirable for washing to remove endotoxin present in medical devices, pharmaceutical manufacturing tools and equipment, and the like.
  • Techniques for washing or removing endotoxins using compositions that are easier to prepare and use include, for example, drugs that have a short shelf life and require frequent production on demand, such as a short half-life It is suitable for producing radiopharmaceuticals using radionuclides.
  • drugs used in diagnostic methods for positron emission tomography hereinafter referred to as PET
  • ultrashort half-life positron-emitting nuclides with a half-life of several hours or less is more important. It is a suitable technique.
  • the present invention is intended to adhere to or adsorb to solid surfaces
  • endotoxin which is a non-living chemical reagent that can be sterilized, and that can remove endotoxin more efficiently than water or saline. Aim.
  • 18 F-FDG 2- [18 F] -Fluoro-2-deoxy-D-glucose
  • 18 F-FDG 2- [18 F] -Fluoro-2-deoxy-D-glucose
  • Hamacher et al. Hamacher, K. eta 1., J Nucle ar Medicine, 27: 235-238, 1986
  • the present inventors have developed a method for removing endotoxin adhering or adsorbing to ion-retardant resin often used in this production method.
  • endotoxin which is not normally removed with water or saline, is very efficiently removed by elution or extraction with a solution containing saccharides as a component.
  • the present inventors have found that the present invention can be used for removing endotoxin adhering or adsorbed on a solid surface, and have completed the present invention.
  • composition for removing endotoxin adhered or adsorbed on a solid surface comprising a saccharide as an active ingredient.
  • endotoxin can be effectively removed by bringing the solution of the removing composition of the present invention into contact with and recovering various solid surfaces, in addition to medical tools and pharmaceutical manufacturing equipment and devices that require endotoxin removal. Can be removed.
  • a solid surface from which endotoxin is to be removed is brought into contact with a solution of the composition to remove endotoxin attached or adsorbed on the solid surface.
  • a method for removing endotoxin is provided.
  • the method for bringing the solution of the removing composition of the present invention into contact with the solid surface may be appropriately selected according to the type of the solid surface. For example, a solid surface may be immersed in the solution, the solid surface may be washed with the solution, or the solution may be impregnated in a sterilized cloth with an appropriate method, and the solid surface may be wiped with the cloth.
  • the endotoxin adhering or adsorbed to the solid surface of a medical device, a pharmaceutical manufacturing tool or device, etc. by performing the above-described immersion, washing, wiping operations, etc. using the solution of the composition of the present invention, Since the endotoxin can be transferred into a solution and the endotoxin can be eluted or extracted into the solution, the composition of the present invention is useful for obtaining a detection liquid when detecting and measuring the degree of endotoxin contamination on the solid surface. is there.
  • a solid surface to which endotoxin is attached or adsorbed is brought into contact with a solution of the composition, and the endotoxin containing endotoxin detached or desorbed from the solid surface is contained.
  • a method for extracting endotoxin which comprises obtaining a composition.
  • the saccharide used in the composition of the present invention includes a monosaccharide or an oligosaccharide or a derivative thereof. These saccharides may be salts or hydrates thereof.
  • the saccharide may be either the D-form or the L-form.
  • the monosaccharide is generally preferably hexose.
  • the monosaccharide is generally preferably hexose.
  • glucose, galactose, mannose, fructose, etc. glucosamine, galactosamine, glucosamine hydrochloride, galactosamine hydrochloride, N— Amino sugars such as acetylglycosamine and N-acetylgalactosamine, derivatives and salts thereof.
  • Oligosaccharides include disaccharides to hexasaccharides in size, preferably disaccharides such as maltose, sucrose and lactose.
  • disaccharides such as maltose, sucrose and lactose.
  • particularly preferred saccharides are glucose, glucosamine hydrochloride, N-acetyl-D-galactosamine and maltose, most preferably glucose.
  • the removal composition of the present invention is prepared as a solution dissolved in an appropriate solvent.
  • it may be provided in the form of a solution previously dissolved in a solvent, or may be provided in a lyophilized form so that it can be used after being dissolved in a solvent at the time of use.
  • the composition of the present invention may be provided as a kit in which a freeze-dried product and a solvent are combined.
  • the solvent is not particularly limited as long as it is physiologically, pharmaceutically or chemically acceptable.
  • water physiological saline, electrolyte compositions such as Ringer's solution, injection solutions, and various buffer solutions Is mentioned.
  • Buffers include phosphate buffer, citrate buffer, etc., as well as fluoric acid, phosphoric acid, boric acid, citric acid, succinic acid, tartaric acid, lactic acid, acetic acid, ammonium chloride, carbonic acid, tris (hydroxymethyl ) Buffers composed of aminomethane and their salts.
  • composition of the present invention can contain various physiologically, pharmaceutically or chemically acceptable additives as necessary.
  • additives include various pH adjusting agents such as acids and bases, various buffer solutions, dextran 10 and dextran 40, dextrin, cyclodextrin, sodium lactate, various amino acids, methanol, ethanol, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, tetrahydrofuran and the like can be mentioned.
  • the concentration of the saccharide in the solution depends on the type of the saccharide and the solvent, etc., or the degree of endotoxin attachment or adsorption on the solid surface, and cannot be necessarily constant. It is about 1 to 15 g / 100 ml (hereinafter referred to as w / v%), preferably about 0.5 to 10 w / v%. If the concentration is too low, the effect of removing endotoxin decreases, and if the concentration is too high, a large amount of washing solution is required to wash saccharides remaining after the removal operation, and the operation becomes complicated.
  • the solution of the composition of the present invention can be prepared by dissolving a saccharide together with an additive as necessary in a solvent. However, due to its properties, it must be prepared without endotoxin or inactivated. Endotoxin is removed from the composition of the present invention. Examples of the method include removing endotoxin from a saccharide solution using an ultrafiltration membrane or endotoxin adsorbent, or preparing a saccharide solution using water from which endotoxin has been removed in advance using an ultrafiltration membrane. And the like.
  • a sterilized commercially available saccharide solution for example, Japanese Pharmacopoeia Glucose Injection (5 w / v%, 10 w / v%, etc.) can be used as it is, in which case special preparation is required. Not convenient. Further, such a commercially available saccharide solution may be appropriately aseptically diluted using the above-mentioned solvent and used.
  • the composition of the present invention can also be used as an endotoxin detection solution.
  • the solution recovered as described above is used as a sample for measurement by a per se known endotoxin measurement method, for example, the Limulustest method using a blood cell component extract of Limulus aegypti (hereinafter abbreviated as AL solution).
  • AL solution a blood cell component extract of Limulus aegypti
  • the degree of contamination of the solid surface by endotoxin can be accurately measured.
  • AL solution include those extracted from the blood cells of the genus Butogani, such as the genus Limulus (Limus 1 us) and the genus Tachypleus, and are endotoxin or / 1,3-glucan. Those which cause coagulation due to the reaction with can be used.
  • any method for measuring the endotoxin concentration in a sample by the Limulus test method any method commonly used as described in the Japanese Pharmacopoeia can be used without any particular limitation.
  • the solid surface to be subjected to the endotoxin removal or extraction method of the present invention includes: Examples include surfaces of medical equipment, pharmaceutical manufacturing equipment, and pharmaceutical manufacturing equipment.
  • medical devices include disposable injection needles, disposable syringes, disposable blood transfusion devices and infusion devices, disposable blood collection devices, cardiopulmonary bypass devices, medical artificial blood vessels, Includes artificial heart valves, cardiac pacemakers, dialysis artificial kidney devices, and disposable laboratory equipment (sterile pipes, sterile test tubes, sterile pipe tips, etc.) used for endotoxin testing. It is.
  • Pharmaceutical manufacturing equipment and equipment include, for example, purification and separation of resins used for purification and separation of ion exchange resins, reverse osmosis membranes, nanofiltration membranes, ultrafiltration membranes, precision filtration membranes, electrodialysis membranes, etc.
  • the present invention is useful for removing endotoxin from manufacturing equipment and devices for pharmaceuticals requiring short-lived expiration and requiring frequent production according to demand.
  • 2- [18F] This is convenient for effectively removing endotoxin adhering or adsorbed to a device and / or device for synthesizing fluoro-2-dexoxy-D-glucose.
  • the concentration of the saccharide solution is expressed as “w / v%”.
  • a commercially available sterilized disposable device was used for the syringe, stopcock and column. After washing, the glassware was passed through water for injection and sterilized by dry heat at 250 ° C for 90 minutes.
  • a commercially available product was appropriately diluted, or a commercially available special-grade reagent was dissolved in water for injection, and used as an endotoxin removal solution to be passed through an ion-retarding resin in the following Examples. All of these solutions were prepared by aseptic operation.
  • Endotoxin test reagents based on the Japanese Pharmacopoeia were used.
  • Endotoxin standard solution 1000 EU / ml: Endotoxin 100 0
  • Endotoxin test solution (10000 EU / ml) was prepared by adding an appropriate amount of water for endotoxin test to a standard product (standard product of the Japanese Pharmacopoeia) and dissolved, and this was used as a stock solution, diluted appropriately, and used.
  • EU means endotoxin unit.
  • the ion retardation resin used was an ion retardation resin AG11A8 manufactured by Bio-Rad.
  • the column that had been autoclaved 120 ° C, 20 minutes was aseptically packed with the ion-delay resin. Two columns were created.
  • ion-retarding resin (AG11A8) was placed in a beaker, an appropriate amount of water for injection was added to swell, and 0.4 ml of the endotoxin standard solution (10000 EU / ml) prepared as described above was added. This was stored at 4 ° C. with stirring overnight. An appropriate amount of this ion-retarded resin was aseptically packed into a column that had been autoclaved (120 ° C, 20 minutes).
  • column 5 contains 5 ml of water for injection and the other column (hereinafter referred to as column 6). 5 ml of a 1 Ow / v% glucose solution was passed. Each eluate from each column was dispensed in 0.5 ml aliquots into sterile beakers for a total of 10 fractions. These fractions were designated as fraction numbers 1 to 10.
  • fraction number 11 to 25 7.5 ml of a 10 w / v% glucose solution was passed through the columns 5 and 6. Add 0.5 ml of each eluate from each column to a sterile tube. A total of 15 fractions were collected. Each of these fractions was designated fraction number 11 to 25.
  • the endotoxin concentration was measured for the solutions of fraction numbers 4, 5, 6, 7, 10, 13, 16, 19, 22 and 25 obtained from columns 5 and 6 as described above.
  • the endotoxin test was performed by turbidimetry according to the method of the Japanese Pharmacopoeia.
  • the measured values of the endotoxin test on the eluate were corrected for inhibition. Inhibition correction was performed as follows. An endotoxin standard solution dilution (0.5 EU / ml) was added to each saccharide solution so that the sample solution became 0.25 EU / ml, and the endotoxin concentration of this solution was measured. On the other hand, an endotoxin standard solution diluent (0.5 EUZml) was similarly added to water for injection, and the endotoxin concentration of this solution was measured.
  • Table 3 shows the concentrations (corrected values) of endotoxin contained in fractions 4, 5, 6, 7 and 10 in columns 5 and 6, respectively.
  • Table 4 lists the endotoxins contained in each of fractions 13, 16, 19, 22, and 25 of columns 5 and 6. Indicates the density (value after correction).
  • endotoxin could be more effectively eluted by using a 10 w / v% glucose solution as a solution for removing endotoxin in the ion-retardant resin than by using water for injection.
  • a 10 w / v% glucose solution as a solution for removing endotoxin in the ion-retardant resin than by using water for injection.
  • Example 6 Measurement of Endotoxin Removal Effect in Ion-Retardant Resin Removal Procedure of Endotoxin from Ion-Retardant Resin 1 4 Prepare two ion-retardant resin columns prepared according to Reference Example, and use one column. 5 ml of lw / v% maltose solution for the other column (hereinafter referred to as column 9) and 5 ml of 10 w / v% maltose solution for the other column (hereinafter column 10). was passed. Each eluate from each column was dispensed in 0.5 ml aliquots into sterile beakers for a total of 10 fractions. Each of these fractions was designated fraction number 1 to 10.
  • One column (hereinafter referred to as column 11) contains 5 ml of 1 w / v% N-acetyl-D-galactosamine solution and another column.
  • a column (hereinafter referred to as column 12) was passed with 5 ml of a 10 w / v% N-acetyl-D-galactosamine solution.
  • Each eluate from each column was dispensed in 0.5 ml aliquots into a sterilized beaker for a total of 10 fractions. These fractions were designated as fraction numbers 1 to 10.
  • Ion delay due to lw / v% and 10 w / v% N-acetyl-D-galactosamine solutions Changes in endotoxin concentration during endotoxin removal from resin columns.
  • the endotoxin in the ion-retarding resin column is eluted into each fraction, and the amount of endotoxin varies with the fraction as indicated by the change in endotoxin concentration from fraction 4 to ⁇ .
  • the endotoxin was rapidly removed from the ion-lagging resin column and extracted.
  • endotoxin adhering or adsorbing to a solid surface can be removed using a saccharide solution. Therefore, the endotoxin adhering or adsorbed to the surface can be efficiently removed by bringing the sterilized saccharide solution into contact with the surface of a medical device, a pharmaceutical manufacturing device, or a device.
  • ADVANTAGE OF THE INVENTION According to this invention, it can remove effectively and easily what was difficult to elute or extract with the conventional removal method, Furthermore, complicated post-processing after removal is unnecessary. Useful in the field.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Apparatus For Disinfection Or Sterilisation (AREA)
  • Detergent Compositions (AREA)
  • External Artificial Organs (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur une technique d'élimination d'endotoxines liées ou adsorbées à la surface d'articles solides tels que des instruments médicaux ou des instruments et appareils de fabrication de médicaments, utilisant des réactifs chimiques et stérilisants d'origine non biologique éliminant les endotoxines beaucoup plus efficacement que l'eau ou les solutions salines. L'invention porte en particulier sur des compositions d'élimination d'endotoxines liées ou adsorbées à la surface d'articles solides comportant comme ingrédient actif des saccharides choisis parmi des monosaccharides, des oligosaccharides, ou leurs dérivés, hydrates et sels. L'invention porte également sur un procédé d'élimination des endotoxines de la surface de solides en y appliquant les susdites compositions.
PCT/JP2002/012768 2001-12-26 2002-12-05 Composition pour l'elimination des endotoxines et procede d'elimination WO2003055533A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2002349439A AU2002349439A1 (en) 2001-12-26 2002-12-05 Compositions for eliminating endotoxin and elimination method
JP2003556108A JP4647911B2 (ja) 2001-12-26 2002-12-05 エンドトキシン除去用組成物及び除去方法
NO20033772A NO20033772L (no) 2001-12-26 2003-08-25 Preparater for eliminering av endotoksin samt fremgangsmåte for å gjennomföre elimineringen

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JP2001394188 2001-12-26
JP2001-394188 2001-12-26

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WO2003055533A1 true WO2003055533A1 (fr) 2003-07-10

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AU (1) AU2002349439A1 (fr)
NO (1) NO20033772L (fr)
TW (1) TW200301142A (fr)
WO (1) WO2003055533A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019508074A (ja) * 2015-10-02 2019-03-28 エシコン・インコーポレイテッドＥｔｈｉｃｏｎ， Ｉｎｃ． 医療機器及び流体を処理するための方法及びシステム

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WO1995021179A1 (fr) * 1994-02-07 1995-08-10 Qiagen Gmbh Procede de reduction ou d'elimination d'endotoxines
JPH07265691A (ja) * 1994-03-30 1995-10-17 Sunstar Inc エンドトキシン吸着除去剤および除去方法
JPH08252301A (ja) * 1995-03-17 1996-10-01 Shiseido Co Ltd エンドトキシンの除去方法

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JPS6219178A (ja) * 1985-07-19 1987-01-27 東レ株式会社 エンドトキシン除去用材料およびエンドトキシンの除去方法
JPS6356300A (ja) * 1986-04-02 1988-03-10 Dainippon Pharmaceut Co Ltd 核酸またはエンドトキシンの除去剤および除去方法
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WO1995021179A1 (fr) * 1994-02-07 1995-08-10 Qiagen Gmbh Procede de reduction ou d'elimination d'endotoxines
JPH07265691A (ja) * 1994-03-30 1995-10-17 Sunstar Inc エンドトキシン吸着除去剤および除去方法
JPH08252301A (ja) * 1995-03-17 1996-10-01 Shiseido Co Ltd エンドトキシンの除去方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019508074A (ja) * 2015-10-02 2019-03-28 エシコン・インコーポレイテッドＥｔｈｉｃｏｎ， Ｉｎｃ． 医療機器及び流体を処理するための方法及びシステム

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AU2002349439A1 (en) 2003-07-15
JPWO2003055533A1 (ja) 2005-04-28
JP5296016B2 (ja) 2013-09-25
NO20033772L (no) 2003-10-01
JP4647911B2 (ja) 2011-03-09
TW200301142A (en) 2003-07-01
NO20033772D0 (no) 2003-08-25
JP2010284535A (ja) 2010-12-24

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