WO2022009973A1 - Composition containing tarc, and method for improving storage stability of tarc - Google Patents

Composition containing tarc, and method for improving storage stability of tarc Download PDF

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Publication number
WO2022009973A1
WO2022009973A1 PCT/JP2021/025902 JP2021025902W WO2022009973A1 WO 2022009973 A1 WO2022009973 A1 WO 2022009973A1 JP 2021025902 W JP2021025902 W JP 2021025902W WO 2022009973 A1 WO2022009973 A1 WO 2022009973A1
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tarc
surfactant
composition
sodium
type
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PCT/JP2021/025902
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French (fr)
Japanese (ja)
Inventor
建午 藤村
智之 臼井
明子 松本
由香 鈴木
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積水メディカル株式会社
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Priority to JP2022535400A priority Critical patent/JPWO2022009973A1/ja
Publication of WO2022009973A1 publication Critical patent/WO2022009973A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to a composition containing TARC. More specifically, the present invention relates to a composition capable of stably storing TARC for a long period of time.
  • the present invention also relates to a TARC measuring method and kit, a TARC storage stability improving method, and a TARC adsorption inhibitor.
  • Thymus and activated-regulated chemokine (hereinafter, may be referred to as TARC) is a CC chemokine ligand 17 (CCL17), which is a kind of chemokine having a leukocyte migration action.
  • TARC attracts Th2 cells, which are one of the lymphocytes, to the lesion site, causing IgE production and infiltration / activation of eosinophils. By enhancing the allergic reaction in this way, TARC is considered to exacerbate the symptoms of atopic dermatitis (Non-Patent Document 1).
  • TARC is important to promptly and surely sedate the inflammation of atopic dermatitis.
  • TARC is in good agreement with the severity of atopic dermatitis compared to serum IgE levels, peripheral blood eosinophil counts, and serum LDH levels, which have been used as indicators of the pathology of other atopic dermatitis. It is considered to reflect the disease situation more sensitively (Non-Patent Document 2). Therefore, by using TARC as a biomarker, when selecting or changing a therapeutic agent for atopic dermatitis, the severity can be objectively and quickly grasped and the effect can be determined.
  • the calibration sample is a sample containing a component to be measured, which is used for purposes such as an internal standard or a concentration calibration standard (calibrator).
  • a calibration sample that is stable with respect to the passage of time and temperature is required.
  • the calibration sample is preferably in a fluid liquid state (hereinafter, may be referred to as “liquid”) because of its ease of operation.
  • biological activity for example, antigenicity to a specific antibody, binding activity to a specific binding partner possessed by an antibody or lectin, physiological activity possessed by a peptide hormone or the like, enzyme activity).
  • biological activity for example, antigenicity to a specific antibody, binding activity to a specific binding partner possessed by an antibody or lectin, physiological activity possessed by a peptide hormone or the like, enzyme activity.
  • Patent Document 1 As a method for storing the calibration sample in liquid form, which is intended for use in an immunological measurement method, a method for stabilizing an antigen by coexisting casein and / or whey protein in the calibration sample (Patent Document 1).
  • Patent Document 2 A method of stabilizing insulin in the coexistence of a bile acid amide derivative (Patent Document 2) and a method of stabilizing a soluble interleukin-2 receptor (sIL-2R) in the coexistence of a chelating agent are known (Patent Document 3).
  • sIL-2R soluble interleukin-2 receptor
  • An object of the present invention is to provide a TARC-containing composition having high storage stability.
  • the present inventors have attempted to prepare a TARC-containing composition having high storage stability. Then, when TARC is added to a solution containing at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant, the stability of TARC is improved. I found it.
  • the present invention is based on such findings. Specifically, the present invention is as follows. ⁇ 1> A composition containing TARC (Thymus and activation-regulated chemokine). The composition comprising TARC and at least one surfactant selected from the group consisting of cationic and anionic surfactants and in liquid form. ⁇ 2> The composition according to ⁇ 1>, which is a sample solution for calibration for measuring TARC.
  • ⁇ 3> The composition according to ⁇ 1> or ⁇ 2>, which is filled in a storage container.
  • ⁇ 4> The composition according to ⁇ 3>, wherein the storage container is plastic or glass.
  • ⁇ 5> The composition according to any one of ⁇ 1> to ⁇ 4>, wherein the concentration of TARC is 10 pg / mL to 1 ⁇ g / mL with respect to the composition.
  • ⁇ 6> The composition according to any one of ⁇ 1> to ⁇ 5>, wherein the concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the composition.
  • the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
  • composition according to any one of ⁇ 1> to ⁇ 6> wherein the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant.
  • the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant.
  • the concentration of TARC is 2000 pg / mL with respect to the composition, the residual rate of TARC after storage at 10 ° C. for 6 hours in a glass container is 55% or more, ⁇ 1> to ⁇ 9.
  • the cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate.
  • ⁇ 13> A TARC measurement kit comprising the composition according to any one of ⁇ 1> to ⁇ 11>.
  • a method for improving the storage stability of TARC which comprises a step of contacting TARC with a solution containing at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant. .. ⁇ 15>
  • the method for improving storage stability of TARC according to ⁇ 14> which comprises a step of adjusting the concentration of TARC to be 10 pg / mL to 1 ⁇ g / mL with respect to the solution.
  • the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
  • the storage stability of TARC according to any one of ⁇ 14> to ⁇ 16>, wherein the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant. How to improve.
  • the cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate.
  • the TARC according to any one of ⁇ 14> to ⁇ 17>, wherein the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or ⁇ -naphthalene sulfonic acid formarin condensate sodium salt.
  • the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or ⁇ -naphthalene sulfonic acid formarin condensate sodium salt.
  • An inhibitor for adsorbing TARC to a container in a solution containing TARC which comprises at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant.
  • the adsorption inhibitor contained as an active ingredient.
  • ⁇ 20> The adsorption inhibitor according to ⁇ 19>, wherein the concentration of TARC in the solution containing TARC is 10 pg / mL to 1 ⁇ g / mL with respect to the solution.
  • the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
  • the cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate.
  • TARC-containing composition having high storage stability, particularly a TARC-containing calibration sample. Therefore, according to the present invention, TARC in a biological sample can be accurately quantified, and the severity of atopic dermatitis can be accurately grasped.
  • TARC means Symus and activated-regulated chemokine (CCL17).
  • TARC is a type of chemokine that has leukocyte migration activity.
  • TARC has the function of attracting Th2 cells, which are one of the lymphocytes, to the lesion site to produce IgE or infiltrate and activate eosinophils.
  • the measurement of TARC can be performed using a known method, for example, an immunological method.
  • Immunological methods include ELISA, enzyme immunoassay, surface plasmon resonance method, latex aggregation immunoassay (LTIA), chemical luminescence immunoassay, electrochemical luminescence immunoassay, fluorescent antibody method, radioimmunoassay, Western blot method, immunochromatography method, high performance liquid chromatography method (HPLC method) and the like can be mentioned.
  • TARC contained in the composition of the present invention a commercially available product may be used, or a product prepared or purified by itself may be used.
  • TARC contained in the composition of the present invention one prepared in vitro may be used, or one extracted from a living body may be used.
  • TARC concentration The concentration of TARC contained in the composition of the present invention is not limited to the following, but is preferably 10 pg / mL to 1 ⁇ g / mL with respect to the composition in consideration of the stability of TARC. It is preferably 50 pg / mL to 500 ng / mL, more preferably 100 pg / mL to 100 ng / mL, and most preferably 100 pg / mL to 50 ng / mL.
  • the anionic surfactant means a surfactant in which the hydrophobic group portion is ionized into negative (negative) ions when dissolved in water.
  • a surfactant having a hydrophilic group that does not ionize when dissolved in water is referred to as a nonionic surfactant, and a surfactant in which the hydrophobic group portion is ionized into a positive (positive) ion is a cation.
  • a surfactant that exhibits the properties of an anionic surfactant in the alkaline region and the properties of a cationic surfactant in the acidic region is referred to as a sex surfactant, and is referred to as an amphoteric surfactant.
  • an alkylamine salt type, a quaternary ammonium salt type and the like are preferable.
  • anionic surfactant cholic acid type, sulfate ester (sulfate) type, carboxylic acid type, sulfonic acid type and the like are preferable.
  • alkylamine salt type of the cationic surfactant examples include amines containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as monododecylamine, monooctadecylamine, dioctadecylamine, and trioctadecylamine, and hydrochloric acid.
  • Inorganic acids such as sulfuric acid or salts with lower carboxylic acids such as acetic acid, lactic acid and citric acid.
  • dodecylamine hydrochloride [CAS number: 929-73-7, manufactured by Tokyo Kasei Kogyo Co., Ltd.]
  • coconut amine acetate [CAS number: 61790-57-6, product name: acetamine 24, Kao Corporation Company-made]
  • stearylamine acetate [CAS number: 2190-04-7, product name: acetamine 86, made by Kao Corporation] and the like.
  • the quaternary ammonium salt type includes ammonium containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as dodecyltrimethylammonium, octadecyltrimethylammonium, hexadecyltrimethylammonium, didecyldimethylammonium, and benzylmethyltetradecylammonium.
  • Examples include salts with chlorine, bromine and the like.
  • lauryltrimethylammonium chloride [CAS number: 112-00-5, product name: Coatamine (registered trademark) 24P, manufactured by Kao Co., Ltd.], dodecyltrimethylammonium bromide [CAS number: 1119-94-4, Tokyo Chemical Industry Co., Ltd.], Octadecyltrimethylammonium chloride [CAS number: 112-03-8, Tokyo Chemical Industry Co., Ltd.], Distearyldimethylammonium chloride [CAS number: 107-64-2, Product name: Coatamine ( Registered trademark) D86P, manufactured by Kao Co., Ltd.] and the like.
  • the cholic acid types of anionic surfactants include sodium deoxycholic acid [CAS number: 302-95-4, manufactured by Fujifilm Wako Co., Ltd.] and sodium cholic acid [CAS number: 361-09-1, Fuji. Film Wako Co., Ltd.] and the like.
  • Examples of the sulfate ester (sulfate) type include higher alcohol sulfate esters such as dodecyl sulfate ester, polyoxyethylene alkyl ether sulfate esters such as polyoxyethylene dodecyl ether sulfate ester, and salts with sodium and ammonium.
  • sodium dodecyl sulfate [CAS number: 151-21-3, manufactured by Sigma-Aldrich], ammonium lauryl sulfate [CAS number: 2235-54-3, Latemul (registered trademark) AD-25, Kao Co., Ltd.
  • Higher alcohol sulfate ester salts such as [manufactured by], polyoxyethylene alkyl ether sulfate ester salts such as polyoxyethylene lauryl ether sulfate sodium [CAS number: 68585-34-2, product name: Emar 20C, manufactured by Kao Co., Ltd.] Can be mentioned.
  • Examples of the carboxylic acid type include dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), and cis-9-octadecenoic acid (oleic acid) having 8 to carbon atoms.
  • Examples thereof include salts of 22 higher fatty acids and the like with alkali metals such as sodium and potassium. Specifically, for example, sodium laurate [CAS number: 629-25-4, manufactured by Fujifilm Wako Co., Ltd.], sodium myristate [CAS number: 822-12-8, manufactured by Fujifilm Wako Co., Ltd.], palmitic acid.
  • sulfonic acid type examples include alkylbenzene sulfonic acid such as dodecylbenzene sulfonic acid, naphthalene sulfonic acid such as dibutylnaphthalene sulfonic acid, formalin condensate of naphthalene sulfonic acid, sulfosuccinic acid such as dioctylsulfosuccinic acid, and salts such as sodium.
  • alkylbenzene sulfonic acid such as dodecylbenzene sulfonic acid
  • naphthalene sulfonic acid such as dibutylnaphthalene sulfonic acid
  • formalin condensate of naphthalene sulfonic acid sulfosuccinic acid
  • sulfosuccinic acid such as dioctylsulfosuccinic acid
  • salts such as sodium.
  • sodium laurylbenzene sulfonate [CAS number: 25155-30-0, manufactured by Fujifilm Wako Co., Ltd.]
  • ⁇ -naphthalene sulfonic acid formarin condensate sodium salt [CAS number: 9084-06-4, product. Name: Demol (registered trademark) RN, manufactured by Kao Co., Ltd.]
  • sodium dioctylsulfosuccinate [CAS number: 577-11-7, product name: Neocol (registered trademark) SW, manufactured by Daiichi Kogyo Co., Ltd.]
  • anionic surfactants or cationic surfactants are handled by various detergent makers and reagent makers, and commercially available products can be purchased and used.
  • anionic surfactants or cationic surfactants may be used alone or in combination of two or more.
  • the cationic or anionic surfactants used in the compositions of the present invention are coconutamine acetate, lauryltrimethylammonium chloride, sodium sulphonate, sodium dodecyl sulfate, sodium lauroylmethylalanine, or ⁇ -.
  • Sodium salt of sodium phthalene sulfonic acid formalin condensate is more preferable.
  • lauryltrimethylammonium chloride, sodium colate, sodium dodecyl sulfate, or sodium lauroylmethylalanine is used
  • lauryltrimethylammonium chloride, coconatamine acetate, or ⁇ is further preferred to use sodium salt of sodium naphthalene sulfonic acid formalin condensate.
  • surfactants it is possible to use other types of surfactants in addition to the anionic surfactants or cationic surfactants as long as the effects of the present invention are not impaired, it is preferable not to use them. ..
  • an anionic surfactant and a cationic surfactant can be used in combination, it is preferable to use only one of them without using them in combination.
  • the order of addition of the cationic surfactant or the anionic surfactant and TARC is not particularly limited as long as the effect of the present invention can be obtained.
  • the concentration of the cationic or anionic surfactant is not limited to the following, but is preferable with respect to the composition in consideration of the stability of TARC. Is 0.00001% by mass to 1% by mass, more preferably 0.0001% by mass to 1% by mass, still more preferably 0.001% by mass to 0.5% by mass, and most preferably 0.001% by mass to 0. It is 1% by mass.
  • the composition of the present invention is preferably filled in a storage container.
  • the material of the storage container is not particularly limited as long as the effects of the present invention can be obtained and can be sealed, but at least a part or all of the contact portion with the composition is a plastic [for example, an olefin resin or a styrene resin.
  • Acrylic resin Acrylic resin, polyester resin, polycarbonate resin, fluororesin, chlorine resin (polyvinyl chloride, etc.), polyamide resin, polyacetal resin, polyphenylene ether resin (modified polyphenylene ether, etc.), polyallylate, polysulfone, Polyimide-based resins, cellulose-based resins (cellulose acetate, etc.), hydrocarbon-based resins (including halogen atom-substituted products), etc.], metals (aluminum, etc.), glass, etc.
  • plastic or glass is preferable from the viewpoint of manufacturing, transporting, and storing the calibration sample, and among the plastics, an olefin resin is preferable, and polypropylene is more preferable.
  • the storage container may be made of a single material or two or more kinds of materials, but is preferably made of a single material.
  • the storage container can include a container body portion and a cap. In this case, the container body portion and the cap may be made of different materials. Further, it is preferable that the storage container, particularly the main body portion, has transparency to the extent that the content liquid can be seen from the outside.
  • the storage container may be of either a hard type or a soft type, and examples thereof include ampoules, vials, soft bags, injection containers, and glass bottles.
  • the storage container is preferably in the form of a plastic eye drop bottle including a container body portion and a cap portion, particularly in the form of a cylindrical eye drop bottle, from the viewpoint of ease of use and stability of TARC.
  • the storage container should be a glass ampoule or a form including a glass container body and a cap, particularly a cylindrical glass container and a form including a rubber cap, for ease of use and TARC. Preferred from the viewpoint of stability.
  • composition The composition of the present invention can be used as a sample solution for calibration in the measurement of TARC.
  • the sample solution for calibration means a sample solution containing a substance to be measured at a constant concentration, which is used for accurate measurement of the substance to be measured, and is used as a standard substance, a calibrator, a control, and a sample solution. Internal standard substances, etc. are applicable.
  • Examples of the form of supplying the composition of the present invention include a form in which TARC and an anionic surfactant or a cationic surfactant are mixed with a solvent and prepared in a solution state in advance.
  • "using a composition” means using a composition in order to accurately measure TARC.
  • a liquid composition containing TARC is used as a sample solution for calibration ( Means to be used as a reference material, calibrator, control, and internal standard material, etc.).
  • the pH of the composition of the present invention is, for example, 4.0 to 9.5, 5.0 to 9.0, 6.0 to 8.5, 6.5 to 8.0, or 7.0 to 8. It is 0.
  • the pH can be adjusted using a pH adjusting reagent well known to those skilled in the art, such as sodium hydroxide or hydrochloric acid.
  • composition of the composition of the present invention is not particularly limited as long as the effect of the present invention is not impaired. If TARC is measured by an immunological measurement method, the effects of the present invention are not impaired, and the reactions constituting the measurement system such as antigen-antibody reaction, labeling reaction for detection with biotin / avidin, and enzyme reaction It does not have to interfere with all or part of it.
  • Various components commonly used in immunological measurement methods such as acetic acid, citric acid, phosphoric acid, PBS (phosphate buffered saline), HEPES, MES, Tris, glycine, boric acid, carbonic acid and good buffer.
  • buffers components that promote antigen-antibody reactions (polymers such as polyethylene glycol and polyvinylpyrrolidone), glycoproteins and peptides (BSA, casein, etc.), amino acids, salts (sodium chloride, potassium chloride, etc.), sugars (sho) Sugar, cyclodextrin, etc.), preservatives (sodium azide, ProClin300, etc.) and the like can be appropriately selected and used according to the purpose. It is preferable to use PBS having a pH of 6.5 to 8.0.
  • improved storage stability means that most of the TARC contained in the solution containing TARC is not decomposed for a long period of time and the structure is not changed. Alternatively, by maintaining the TARC in the solution without adsorbing it, it means that there is no big difference between the initial value of TARC in the solution and the measured value after storage. More specifically, “improvement of storage stability” or “improvement of storage stability” means, for example, 80% or more of TARC contained in a solution containing TARC having a concentration of 10 pg / mL to 1 ⁇ g / mL. In the solution after storage in a plastic container for 28 days at 37 ° C. by being maintained at 37 ° C.
  • TARC for 28 days without decomposition, structural changes or adsorption to the container. It can mean that the measured value of TARC is 80% or more of the initial value.
  • "improvement of storage stability” or “improvement of storage stability” means that, for example, 90% or more of TARC contained in a solution containing TARC having a concentration of 10 pg / mL to 1 ⁇ g / mL is 4 ° C. Measurement of TARC in the solution after storage in a plastic container at 4 ° C. for 28 days at 4 ° C. by being maintained without decomposition, structural changes or adsorption to the container for 28 days. It can mean that the value is 90% or more of the initial value.
  • improved of storage stability or “improvement of storage stability” means that, for example, 55% or more of TARC contained in a solution containing TARC having a concentration of 10 pg / mL to 1 ⁇ g / mL is 10 ° C.
  • the measured value of TARC in the solution after storage in a glass container at 10 ° C. for 6 hours It can mean that it becomes 55% or more of the initial value.
  • the biological sample for measuring TARC is not particularly limited as long as TARC can be measured, but blood, serum, or plasma is preferably used. If necessary, the biological sample may be pretreated.
  • the biological sample is preferably a biological sample taken from a human.
  • the composition of the present invention can be used to easily and accurately measure TARC.
  • the TARC measurement kit include a kit using an immunological method.
  • the TARC measurement kit of the present invention can contain a reagent for measuring the concentration of TARC in a human body by an immunological method. Immunological methods include ELISA, enzyme immunoassay, surface plasmon resonance method, latex aggregation immunoassay (LTIA), chemical luminescence immunoassay, electrochemical luminescence immunoassay, fluorescent antibody method, radioimmunoassay, Western blot method, immunochromatography method, high performance liquid chromatography method (HPLC method) and the like can be mentioned.
  • the TARC measurement kit of the present invention can be used to grasp the severity of atopic dermatitis in determining the treatment method or drug selection of atopic dermatitis and the effect of the treatment.
  • the TARC measurement kit of the present invention may also include an instruction manual or the like.
  • the TARC measurement kit may include any component, such as a buffer, a stabilizer, a sample diluent, a pH regulator, a reaction vessel, and the like.
  • the method for improving the storage stability of TARC of the present invention includes a step of contacting TARC with a solution containing a cationic surfactant or an anionic surfactant.
  • TARC may be added after the cationic or anionic surfactant is added to the solution, or after the TARC is added to the solution, the cationic or anionic surfactant is added. It may be added.
  • the solution is preferably a buffer such as PBS, HEPES, MES, CHES and Tris. It is more preferable to use PBS having a pH of 6.5 to 8.0.
  • the concentration of TARC contained in the solution is not limited to the following, but is preferably 10 pg / mL to 1 ⁇ g / mL in consideration of the stability of TARC. , More preferably 50 pg / mL to 500 ng / mL, still more preferably 100 pg / mL to 100 ng / mL, and most preferably 100 pg / mL to 50 ng / mL.
  • an alkylamine salt type, a quaternary ammonium salt type and the like are preferable.
  • anionic surfactant cholic acid type, sulfate ester (sulfate) type, carboxylic acid type, sulfonic acid type and the like are preferable.
  • alkylamine salt type of the cationic surfactant examples include amines containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as monododecylamine, monooctadecylamine, dioctadecylamine, and trioctadecylamine, and hydrochloric acid.
  • Inorganic acids such as sulfuric acid or salts with lower carboxylic acids such as acetic acid, lactic acid and citric acid.
  • dodecylamine hydrochloride [CAS number: 929-73-7, manufactured by Tokyo Kasei Kogyo Co., Ltd.]
  • coconut amine acetate [CAS number: 61790-57-6, product name: acetamine 24, Kao Corporation Company-made]
  • stearylamine acetate [CAS number: 2190-04-7, product name: acetamine 86, made by Kao Corporation] and the like.
  • the quaternary ammonium salt type includes ammonium containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as dodecyltrimethylammonium, octadecyltrimethylammonium, hexadecyltrimethylammonium, didecyldimethylammonium, and benzylmethyltetradecylammonium. Examples thereof include salts such as chlorine and bromine.
  • lauryltrimethylammonium chloride [CAS number: 112-00-5, product name: Coatamine (registered trademark) 24P, manufactured by Kao Co., Ltd.], dodecyltrimethylammonium bromide [CAS number: 1119-94-4, Tokyo Chemical Industry Co., Ltd.], Octadecyltrimethylammonium chloride [CAS number: 112-03-8, Tokyo Chemical Industry Co., Ltd.], Distearyldimethylammonium chloride [CAS number: 107-64-2, Product name: Coatamine ( Registered trademark) D86P, manufactured by Kao Co., Ltd.] and the like.
  • the cholic acid types of anionic surfactants include sodium deoxycholic acid [CAS number: 302-95-4, manufactured by Fujifilm Wako Co., Ltd.] and sodium cholic acid [CAS number: 361-09-1, Fuji. Film Wako Co., Ltd.] and the like.
  • Examples of the sulfate ester (sulfate) type include higher alcohol sulfate esters such as dodecyl sulfate ester, polyoxyethylene alkyl ether sulfate esters such as polyoxyethylene dodecyl ether sulfate ester, and salts with sodium and ammonium.
  • sodium dodecyl sulfate [CAS number: 151-21-3, manufactured by Sigma-Aldrich], ammonium lauryl sulfate [CAS number: 2235-54-3, Latemul (registered trademark) AD-25, Kao Co., Ltd.
  • Higher alcohol sulfate ester salts such as [manufactured by], polyoxyethylene alkyl ether sulfate ester salts such as polyoxyethylene lauryl ether sulfate sodium [CAS number: 68585-34-2, product name: Emar 20C, manufactured by Kao Co., Ltd.] Can be mentioned.
  • Examples of the carboxylic acid type include dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), and cis-9-octadecenoic acid (oleic acid) having 8 to carbon atoms.
  • Examples thereof include salts of 22 higher fatty acids and the like with alkali metals such as sodium and potassium. Specifically, for example, sodium laurate [CAS number: 629-25-4, manufactured by Fujifilm Wako Co., Ltd.], sodium myristate [CAS number: 822-12-8, manufactured by Fujifilm Wako Co., Ltd.], palmitic acid.
  • sulfonic acid type examples include alkylbenzene sulfonic acid such as dodecylbenzene sulfonic acid, naphthalene sulfonic acid such as dibutylnaphthalene sulfonic acid, formalin condensate of naphthalene sulfonic acid, sulfosuccinic acid such as dioctylsulfosuccinic acid, and salts such as sodium.
  • alkylbenzene sulfonic acid such as dodecylbenzene sulfonic acid
  • naphthalene sulfonic acid such as dibutylnaphthalene sulfonic acid
  • formalin condensate of naphthalene sulfonic acid sulfosuccinic acid
  • sulfosuccinic acid such as dioctylsulfosuccinic acid
  • salts such as sodium.
  • sodium laurylbenzene sulfonate [CAS number: 25155-30-0, manufactured by Fujifilm Wako Co., Ltd.]
  • ⁇ -naphthalene sulfonic acid formarin condensate sodium salt [CAS number: 9084-06-4, product. Name: Demol (registered trademark) RN, manufactured by Kao Co., Ltd.]
  • sodium dioctylsulfosuccinate [CAS number: 577-11-7, product name: Neocol (registered trademark) SW, manufactured by Daiichi Kogyo Co., Ltd.], etc. Be done.
  • the cationic or anionic surfactants used in the compositions of the present invention are coconutamine acetate, lauryltrimethylammonium chloride, sodium sulphonate, sodium dodecyl sulfate, sodium lauroylmethylalanine, or ⁇ -.
  • Sodium salt of sodium phthalene sulfonic acid formalin condensate is more preferable.
  • lauryltrimethylammonium chloride, sodium colate, sodium dodecyl sulfate, or sodium lauroylmethylalanine is used, and in the case of glass containers, lauryltrimethylammonium chloride, coconatamine acetate, or ⁇ .
  • -It is further preferred to use sodium salt of sodium naphthalene sulfonic acid formalin condensate.
  • the concentration of the cationic surfactant or the anionic surfactant is not limited to the following, but the composition is made in consideration of the stability of TARC. On the other hand, it is preferably 0.00001% by mass to 1% by mass, more preferably 0.0001% by mass to 1% by mass, still more preferably 0.001% by mass to 0.5% by mass, and most preferably 0.001. It is from mass% to 0.1% by mass.
  • TARC adsorption inhibitor contains a cationic surfactant or an anionic surfactant.
  • a TARC adsorption inhibitor containing a cationic surfactant or an anionic surfactant may be added before contacting the storage container with the solution containing TARC, and the cationic surfactant as an adsorption inhibitor may be added to the TARC solution.
  • An agent or anionic surfactant may be added and added to the storage container.
  • MEGA-9 Ingredient name: n-Nonanoyl-N-methyl-D-glucamine, Dojin Chemical Laboratory Co., Ltd. Ingredient name: Sodium dodecyl, Fuji Film Wako Co., Ltd. ⁇ SDS component name: sodium lauryl sulfate, Sigma Aldrich Co., Ltd. ⁇ Energol (registered trademark) L-30AN Ingredient name: lauroylmethylalanine sodium, Lion Specialty Chemicals Co., Ltd.
  • Example 1 Storage stability test results in a plastic eye drop bottle >> The storage stability of TARC in plastic eye drop bottles was tested.
  • the test method and evaluation method are as follows. A solution having the following composition was used as the storage solution. ⁇ PBS (pH 7.2) ⁇ 1% by mass BSA -Surfactant (concentration, product name, type are listed in Table 1)
  • TARC liquid preservation solution 0.5 mL was dispensed into plastic eye drop bottles and stored at 37 ° C for 28 days or at 4 ° C for 28 days. TARC concentrations were tested at 500 pg / mL, 2000 pg / mL, and 10000 pg / mL.
  • Measurement method was performed by a latex immunoturbidimetry method using two types of antibodies.
  • the composition of the reagent and the measurement method are shown below. The measurement was performed by a Hitachi automated analyzer using the first reagent and the second reagent.
  • -First reagent 100 mM MOPS-NaOH (pH 7.5) 500 mM NaCl 0.5% BSA ⁇
  • Second reagent Anti-human TARC monoclonal antibody sensitized latex (2 types) 5 mM MOPS-NaOH (pH 7.0)
  • the anti-human TARC monoclonal antibody was obtained by a method well known to those skilled in the art using a commercially available TARC antigen.
  • TARC antigens include CCL17, thymus and activated chemokine (Shenandoah Biotechnology, Inc.), CCL17 / TARC, Human (LifeSpan Biossyence, Inc., Inc., Inc.). Further, a combination of monoclonal antibodies capable of sandwich measurement against the TARC antigen was selected by a method well known to those skilled in the art.
  • the anti-human TARC monoclonal antibody sensitized latex was prepared with reference to the method described in JP-A-2017-18137. First, 120 ⁇ L of the first reagent was added to 2.4 ⁇ L of the liquid storage solution of TARC of each concentration. After heating at 37 ° C.
  • the change in absorbance for 5 minutes was measured at a main wavelength of 570 nm and a sub-wavelength of 800 nm.
  • the amount of change in the measured absorbance was converted to the TARC concentration using a calibration curve obtained by measuring a standard substance having a known concentration.
  • TARC residual rate (%) of the TARC concentration in the liquid storage solution of each TARC after storage at 37 ° C for 28 days or at 4 ° C for 28 days using the following formula. was calculated.
  • TARC residual rate (%) TARC concentration (pg / mL) of each TARC liquid storage solution after storage at 37 ° C for 28 days or 4 ° C for 28 days in an eye drop bottle / TARC concentration of TARC liquid storage solution immediately after preparation (TARC concentration) pg / mL) x 100
  • the surfactants and concentrations used under each condition are shown in Table 1, and the evaluation results are shown in Tables 2 and 3.
  • the TARC residual rate (%) was calculated based on the average value of the three experiments.
  • Condition 6 is a compound shown in Patent Document 2, and has an effect of improving storage stability with respect to insulin, but has a slight effect of improving storage stability with respect to TARC.
  • the residual rate after 28 days was 80% or more for any of the surfactants. .. This is because under conditions 7 to 10, the addition of an anionic surfactant or a cationic surfactant could prevent the adsorption of TARC on the wall surface of the container, or could suppress the structural change of TARC during storage. It was thought that it was a tame.
  • the TARC concentration is 2000 pg / mL and 10000 pg / mL
  • the conditions 1 in which the surfactant is not added the conditions 2 to 5 in which the nonionic surfactant is added, and the condition 6 in which the amphoteric surfactant is added are met.
  • the residual rate was equal to or higher than that.
  • the residual rate after 28 days was 65.7% under the condition 1 in which the surfactant was not added, which was a low result.
  • the residual rate after 28 days was 92.0 to 100.5%, and any of the surfactants
  • the survival rate after 28 days was significantly improved. This is because under conditions 7 to 10, the addition of an anionic surfactant or a cationic surfactant could prevent the adsorption of TARC on the wall surface of the container, or could suppress the structural change of TARC during storage. It was thought that it was a tame. From the above, it was shown that the coexistence of an anionic surfactant or a cationic surfactant and TARC improves the storage stability of TARC during storage of a plastic instillation bottle.
  • Example 2 Storage stability test results in glass vials >> The storage stability of TARC in glass vials was tested. The test method and evaluation method are as follows. A solution having the following composition was used as the storage solution. ⁇ PBS (pH 7.2) ⁇ 1% by mass BSA -Surfactant (concentration, product name, type are listed in Table 4)
  • TARC liquid preservation solution 0.5 mL was dispensed into a glass container and stored at 10 ° C. for 6 hours. As a control, a sample before dispensing in a glass container was also used for measurement. TARC concentrations were tested at 2000 pg / mL and 10000 pg / mL.
  • TARC Residual Rate (%) was calculated using the following formula for the TARC concentration of each TARC liquid storage solution after storage at 10 ° C. for 6 hours.
  • TARC residual rate (%) TARC concentration of each TARC liquid storage solution after storage in a glass container at 10 ° C. for 6 hours (pg / mL) / TARC concentration of TARC liquid storage solution before dispensing in a glass container (pg / mL) ⁇ 100
  • the surfactants and concentrations used under each condition are shown in Table 4, and the evaluation results are shown in Table 5.
  • the TARC residual rate (%) was calculated based on the average value of the three experiments.
  • the residual rate after 6 hours was 42.7% under the condition 1 in which the surfactant was not added, which was a low result.
  • the residual rate after 6 hours was 48.6 to 52.5%, which was hardly improved.
  • the residual rate after 6 hours was improved with any of the surfactants, and particularly under condition 12, 93.7%. It was greatly improved.
  • TARC-containing composition having high storage stability, particularly a TARC-containing calibration sample.

Abstract

The purpose of the present invention is to provide a TARC-containing composition having high storage stability.　The above-mentioned problem can be solved by a composition that contains thymus and activation-regulated chemokine (TARC), said composition being a liquid and containing TARC and one or more surfactants selected from the group consisting of cationic surfactants and anionic surfactants.

Description

ＴＡＲＣを含有する組成物、及びＴＡＲＣの保存安定性向上方法A composition containing TARC and a method for improving the storage stability of TARC.
　本発明は、ＴＡＲＣを含有する組成物に関する。より詳細には、本発明は、ＴＡＲＣを安定に長期間保存することが可能な組成物に関する。本発明は、ＴＡＲＣの測定方法及びキット、ＴＡＲＣの保存安定性向上方法、並びにＴＡＲＣの吸着防止剤にも関する。 The present invention relates to a composition containing TARC. More specifically, the present invention relates to a composition capable of stably storing TARC for a long period of time. The present invention also relates to a TARC measuring method and kit, a TARC storage stability improving method, and a TARC adsorption inhibitor.
　Ｔｈｙｍｕｓ　ａｎｄ　ａｃｔｉｖａｔｉｏｎ－ｒｅｇｕｌａｔｅｄ　ｃｈｅｍｏｋｉｎｅ（以下、ＴＡＲＣと称することがある）は、Ｃ－Ｃケモカイン　リガンド１７（ＣＣＬ１７）であり、白血球遊走作用を持つケモカインの一種である。ＴＡＲＣは、リンパ球の１つであるＴｈ２細胞を病変局所に引き寄せて、ＩｇＥ産生や好酸球の浸潤・活性化を引き起こす。このようにして、アレルギー反応を亢進させることで、ＴＡＲＣはアトピー性皮膚炎の症状を増悪させると考えられている（非特許文献１）。 Thymus and activated-regulated chemokine (hereinafter, may be referred to as TARC) is a CC chemokine ligand 17 (CCL17), which is a kind of chemokine having a leukocyte migration action. TARC attracts Th2 cells, which are one of the lymphocytes, to the lesion site, causing IgE production and infiltration / activation of eosinophils. By enhancing the allergic reaction in this way, TARC is considered to exacerbate the symptoms of atopic dermatitis (Non-Patent Document 1).
　アトピー性皮膚炎の炎症に対しては、速やかにかつ確実に鎮静させることが重要とされている。ＴＡＲＣは、他のアトピー性皮膚炎の病勢を示す指標として用いられてきた血清ＩｇＥ値、末梢血好酸球数、血清ＬＤＨ値と比較して、アトピー性皮膚炎の重症度によく一致し、病勢をより鋭敏に反映すると考えられている（非特許文献２）。したがって、ＴＡＲＣをバイオマーカーとして使用することで、アトピー性皮膚炎に対する治療薬を選択又は変更する際に、客観的に且つ迅速に重症度を把握し、効果を判定することができる。 It is important to promptly and surely sedate the inflammation of atopic dermatitis. TARC is in good agreement with the severity of atopic dermatitis compared to serum IgE levels, peripheral blood eosinophil counts, and serum LDH levels, which have been used as indicators of the pathology of other atopic dermatitis. It is considered to reflect the disease situation more sensitively (Non-Patent Document 2). Therefore, by using TARC as a biomarker, when selecting or changing a therapeutic agent for atopic dermatitis, the severity can be objectively and quickly grasped and the effect can be determined.
　生体試料中の測定対象成分の定量を行うには、校正用試料を用いる必要がある。校正用試料は、内部標準又は濃度校正用基準（キャリブレータ）等の用途で用いられる、測定対象成分を含む試料である。正確な定量値を得るためには、時間経過や温度に対して安定した校正用試料が求められる。校正用試料は、操作の簡便さから、流動性のある溶液の状態（以下、「液状」ということがある）であることが好ましい。この場合に校正用試料に望まれる事項としては、生物学的活性（例えば、特異抗体に対する抗原性、抗体やレクチンなどが有する特異的結合相手に対する結合活性、ペプチドホルモンなどが有する生理活性、酵素活性、前記各活性を支持するためのタンパク質としての立体構造など）の維持、容器への吸着防止、防腐能力の維持などが挙げられる。 It is necessary to use a calibration sample in order to quantify the components to be measured in the biological sample. The calibration sample is a sample containing a component to be measured, which is used for purposes such as an internal standard or a concentration calibration standard (calibrator). In order to obtain an accurate quantitative value, a calibration sample that is stable with respect to the passage of time and temperature is required. The calibration sample is preferably in a fluid liquid state (hereinafter, may be referred to as “liquid”) because of its ease of operation. In this case, what is desired of the calibration sample is biological activity (for example, antigenicity to a specific antibody, binding activity to a specific binding partner possessed by an antibody or lectin, physiological activity possessed by a peptide hormone or the like, enzyme activity). , Maintenance of three-dimensional structure as a protein to support each of the above activities), prevention of adsorption to a container, maintenance of antiseptic ability, and the like.
　免疫学的測定方法での使用を意図した、校正用試料の液状での保存方法としては、校正用試料にカゼイン及び／又はホエイ蛋白を共存させて抗原を安定化する方法（特許文献１）、胆汁酸アミド誘導体を共存させてインスリンを安定化する方法（特許文献２）、キレート剤を共存させて可溶性インターロイキン－２受容体（ｓＩＬ－２Ｒ）を安定化する方法（特許文献３）が知られている。安定化対象物質の性質に応じて安定化方法を検討する必要があるが、ＴＡＲＣに関しては、液状の校正用試料についての詳細な検討はなされていないのが現状である。 As a method for storing the calibration sample in liquid form, which is intended for use in an immunological measurement method, a method for stabilizing an antigen by coexisting casein and / or whey protein in the calibration sample (Patent Document 1). A method of stabilizing insulin in the coexistence of a bile acid amide derivative (Patent Document 2) and a method of stabilizing a soluble interleukin-2 receptor (sIL-2R) in the coexistence of a chelating agent are known (Patent Document 3). Has been done. It is necessary to study the stabilization method according to the properties of the substance to be stabilized, but at present, no detailed study has been made on the liquid calibration sample for TARC.
特開平０８－００５６３４Japanese Patent Application Laid-Open No. 08-005634 特開平０８－０１２５９３Japanese Patent Application Laid-Open No. 08-012593 特開２０１０－２３０６６０JP-A-2010-230660
　本発明の目的は、保存安定性の高いＴＡＲＣ含有組成物を提供することである。 An object of the present invention is to provide a TARC-containing composition having high storage stability.
　本発明者らは、保存安定性の高いＴＡＲＣ含有組成物を作製しようと試みた。そして、陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤を含む溶液にＴＡＲＣを添加した場合に、ＴＡＲＣの安定性が向上することを見出した。本発明は、このような知見に基づくものである。
　具体的に、本発明は以下のとおりである。
＜１＞ＴＡＲＣ（Ｔｈｙｍｕｓ　ａｎｄ　ａｃｔｉｖａｔｉｏｎ－ｒｅｇｕｌａｔｅｄ　ｃｈｅｍｏｋｉｎｅ）を含む組成物であって、
　ＴＡＲＣ、並びに陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤を含み、そして液状である、前記組成物。
＜２＞ＴＡＲＣを測定するための校正用試料溶液である、＜１＞に記載の組成物。
＜３＞保存容器に充填されている、＜１＞又は＜２＞に記載の組成物。
＜４＞保存容器が、プラスチック又はガラスである、＜３＞に記載の組成物。
＜５＞ＴＡＲＣの濃度が、前記組成物に対して、１０ｐｇ／ｍＬ～１μｇ／ｍＬである、＜１＞～＜４＞のいずれかに記載の組成物。
＜６＞前記界面活性剤の濃度が、前記組成物に対して、０．００００１質量％～１質量％である、＜１＞～＜５＞のいずれかに記載の組成物。
＜７＞陽イオン性界面活性剤が、アルキルアミン塩型又は第四級アンモニウム塩型陽イオン性界面活性剤であり、
陰イオン性界面活性剤が、コール酸型、サルフェート型、カルボン酸型、又はスルホン酸型陰イオン性界面活性剤である、＜１＞～＜６＞のいずれかに記載の組成物。
＜８＞ＴＡＲＣの濃度が、前記組成物に対して５００ｐｇ／ｍＬの場合に、３７℃で２８日間、プラスチック容器において保存した後のＴＡＲＣの残存率が、８０％以上である、＜１＞～＜７＞のいずれかに記載の組成物。
＜９＞ＴＡＲＣの濃度が、前記組成物に対して５００ｐｇ／ｍＬの場合に、４℃で２８日間、プラスチック容器において保存した後のＴＡＲＣの残存率が、９０％以上である、＜１＞～＜８＞のいずれかに記載の組成物。
＜１０＞ＴＡＲＣの濃度が、前記組成物に対して２０００ｐｇ／ｍＬの場合に、１０℃で６時間、ガラス容器において保存した後のＴＡＲＣ残存率が５５％以上である、＜１＞～＜９＞のいずれかに記載の組成物。
＜１１＞陽イオン性界面活性剤が、ラウリルトリメチルアンモニウムクロライド又はココナットアミンアセテートであり、
陰イオン性界面活性剤が、コール酸ナトリウム、ラウリル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ―ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩である、＜１＞～＜１０＞のいずれかに記載の組成物。
＜１２＞＜１＞～＜１１＞のいずれかに記載の組成物を使用する、ＴＡＲＣの測定方法。
＜１３＞＜１＞～＜１１＞のいずれかに記載の組成物を含む、ＴＡＲＣの測定キット。
＜１４＞陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤を含む溶液にＴＡＲＣを接触させる工程を含む、ＴＡＲＣの保存安定性向上方法。
＜１５＞前記ＴＡＲＣの濃度が、前記溶液に対して、１０ｐｇ／ｍＬ～１μｇ／ｍＬとなるように調整する工程を含む、＜１４＞に記載のＴＡＲＣの保存安定性向上方法。
＜１６＞前記界面活性剤の濃度が、前記溶液に対して、０．００００１質量％～１質量％である、＜１４＞又は＜１５＞に記載のＴＡＲＣの保存安定性向上方法。
＜１７＞陽イオン性界面活性剤が、アルキルアミン塩型又は第四級アンモニウム塩型陽イオン性界面活性剤であり、
　陰イオン性界面活性剤が、コール酸型、サルフェート型、カルボン酸型、又はスルホン酸型陰イオン性界面活性剤である、＜１４＞～＜１６＞のいずれかに記載のＴＡＲＣの保存安定性向上方法。
＜１８＞陽イオン性界面活性剤が、ラウリルトリメチルアンモニウムクロライド又はココナットアミンアセテートであり、
　陰イオン性界面活性剤が、コール酸ナトリウム、ラウリル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ―ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩である、＜１４＞～＜１７＞のいずれかに記載のＴＡＲＣの保存安定性向上方法。
＜１９＞ＴＡＲＣを含む溶液中のＴＡＲＣの容器への吸着防止剤であって、陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤を有効成分として含有する前記吸着防止剤。
＜２０＞前記ＴＡＲＣを含む溶液中のＴＡＲＣの濃度が、前記溶液に対して、１０ｐｇ／ｍＬ～１μｇ／ｍＬである、＜１９＞に記載の吸着防止剤。
＜２１＞前記界面活性剤の濃度が、前記溶液に対して、０．００００１質量％～１質量％となるように使用する、＜１９＞又は＜２０＞に記載の吸着防止剤。
＜２２＞陽イオン性界面活性剤が、アルキルアミン塩型又は第四級アンモニウム塩型陽イオン性界面活性剤であり、
　陰イオン性界面活性剤が、コール酸型、サルフェート型、カルボン酸型、又はスルホン酸型陰イオン性界面活性剤である、＜１９＞～＜２１＞のいずれかに記載の吸着防止剤。
＜２３＞陽イオン性界面活性剤が、ラウリルトリメチルアンモニウムクロライド又はココナットアミンアセテートであり、
　陰イオン性界面活性剤が、コール酸ナトリウム、ラウリル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ―ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩である、＜１９＞～＜２２＞のいずれかに記載の吸着防止剤。 The present inventors have attempted to prepare a TARC-containing composition having high storage stability. Then, when TARC is added to a solution containing at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant, the stability of TARC is improved. I found it. The present invention is based on such findings.
Specifically, the present invention is as follows.
<1> A composition containing TARC (Thymus and activation-regulated chemokine).
The composition comprising TARC and at least one surfactant selected from the group consisting of cationic and anionic surfactants and in liquid form.
<2> The composition according to <1>, which is a sample solution for calibration for measuring TARC.
<3> The composition according to <1> or <2>, which is filled in a storage container.
<4> The composition according to <3>, wherein the storage container is plastic or glass.
<5> The composition according to any one of <1> to <4>, wherein the concentration of TARC is 10 pg / mL to 1 μg / mL with respect to the composition.
<6> The composition according to any one of <1> to <5>, wherein the concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the composition.
<7> The cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
The composition according to any one of <1> to <6>, wherein the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant.
<8> When the concentration of TARC is 500 pg / mL with respect to the composition, the residual rate of TARC after storage in a plastic container at 37 ° C. for 28 days is 80% or more, <1> to The composition according to any one of <7>.
<9> When the concentration of TARC is 500 pg / mL with respect to the composition, the residual rate of TARC after storage in a plastic container at 4 ° C. for 28 days is 90% or more, <1> to The composition according to any one of <8>.
<10> When the concentration of TARC is 2000 pg / mL with respect to the composition, the residual rate of TARC after storage at 10 ° C. for 6 hours in a glass container is 55% or more, <1> to <9. > The composition according to any one of.
<11> The cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate.
The composition according to any one of <1> to <10>, wherein the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or β-naphthalene sulfonic acid formarin condensate sodium salt. ..
<12> A method for measuring TARC using the composition according to any one of <1> to <11>.
<13> A TARC measurement kit comprising the composition according to any one of <1> to <11>.
<14> A method for improving the storage stability of TARC, which comprises a step of contacting TARC with a solution containing at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant. ..
<15> The method for improving storage stability of TARC according to <14>, which comprises a step of adjusting the concentration of TARC to be 10 pg / mL to 1 μg / mL with respect to the solution.
<16> The method for improving storage stability of TARC according to <14> or <15>, wherein the concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the solution.
<17> The cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
The storage stability of TARC according to any one of <14> to <16>, wherein the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant. How to improve.
<18> The cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate.
The TARC according to any one of <14> to <17>, wherein the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or β-naphthalene sulfonic acid formarin condensate sodium salt. How to improve storage stability.
<19> An inhibitor for adsorbing TARC to a container in a solution containing TARC, which comprises at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant. The adsorption inhibitor contained as an active ingredient.
<20> The adsorption inhibitor according to <19>, wherein the concentration of TARC in the solution containing TARC is 10 pg / mL to 1 μg / mL with respect to the solution.
<21> The adsorption inhibitor according to <19> or <20>, which is used so that the concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the solution.
<22> The cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
The adsorption inhibitor according to any one of <19> to <21>, wherein the anionic surfactant is a coli acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant.
<23> The cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate.
The adsorption prevention according to any one of <19> to <22>, wherein the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or β-naphthalene sulfonic acid formarin condensate sodium salt. Agent.
　本発明によれば、保存安定性の高いＴＡＲＣ含有組成物、特に、ＴＡＲＣ含有校正用試料を提供することができる。したがって、本発明によれば、生体試料中のＴＡＲＣを正確に定量することができ、アトピー性皮膚炎の重症度を正確に把握することができる。 According to the present invention, it is possible to provide a TARC-containing composition having high storage stability, particularly a TARC-containing calibration sample. Therefore, according to the present invention, TARC in a biological sample can be accurately quantified, and the severity of atopic dermatitis can be accurately grasped.
（ＴＡＲＣ）
　本明細書において「ＴＡＲＣ」は、Ｔｈｙｍｕｓ　ａｎｄ　ａｃｔｉｖａｔｉｏｎ－ｒｅｇｕｌａｔｅｄ　ｃｈｅｍｏｋｉｎｅ（ＣＣＬ１７）を意味する。ＴＡＲＣは、白血球遊走作用を持つケモカインの一種である。ＴＡＲＣは、リンパ球の１つであるＴｈ２細胞を病変局所に引き寄せて、ＩｇＥ産生又は好酸球の浸潤・活性化する機能を有する。ＴＡＲＣをバイオマーカーとして使用することで、アトピー性皮膚炎に対する治療薬を選択又は変更する際に、客観的に且つ迅速に重症度を把握することができる。 (TARC)
As used herein, "TARC" means Symus and activated-regulated chemokine (CCL17). TARC is a type of chemokine that has leukocyte migration activity. TARC has the function of attracting Th2 cells, which are one of the lymphocytes, to the lesion site to produce IgE or infiltrate and activate eosinophils. By using TARC as a biomarker, the severity can be objectively and quickly grasped when selecting or changing a therapeutic agent for atopic dermatitis.
　ＴＡＲＣの測定は、公知の手法、例えば、免疫学的手法を使用して行うことができる。免疫学的手法としては、ＥＬＩＳＡ、酵素免疫測定法、表面プラズモン共鳴法、ラテックス凝集免疫測定法（ＬＴＩＡ）、化学発光免疫測定法、電気化学発光免疫測定法、蛍光抗体法、放射免疫測定法、ウエスタンブロット法、イムノクロマトグラフィー法、及び高速液体クロマトグラフィー法（ＨＰＬＣ法）等が挙げられる。 The measurement of TARC can be performed using a known method, for example, an immunological method. Immunological methods include ELISA, enzyme immunoassay, surface plasmon resonance method, latex aggregation immunoassay (LTIA), chemical luminescence immunoassay, electrochemical luminescence immunoassay, fluorescent antibody method, radioimmunoassay, Western blot method, immunochromatography method, high performance liquid chromatography method (HPLC method) and the like can be mentioned.
　本発明の組成物に含まれるＴＡＲＣとしては、市販のものを使用してもよく、自ら作製又は精製したものを使用してもよい。本発明の組成物に含まれるＴＡＲＣとしては、インビトロで作製したものを使用してもよく、生体から抽出したものを使用してもよい。 As the TARC contained in the composition of the present invention, a commercially available product may be used, or a product prepared or purified by itself may be used. As the TARC contained in the composition of the present invention, one prepared in vitro may be used, or one extracted from a living body may be used.
（ＴＡＲＣの濃度）
　本発明の組成物に含まれるＴＡＲＣの濃度としては、以下に限定されるものではないが、ＴＡＲＣの安定性を考慮して、組成物に対して、好ましくは１０ｐｇ／ｍＬ～１μｇ／ｍＬ、より好ましくは５０ｐｇ／ｍＬ～５００ｎｇ／ｍＬ、さらに好ましくは１００ｐｇ／ｍＬ～１００ｎｇ／ｍＬ、最も好ましくは１００ｐｇ／ｍＬ～５０ｎｇ／ｍＬである。 (TARC concentration)
The concentration of TARC contained in the composition of the present invention is not limited to the following, but is preferably 10 pg / mL to 1 μg / mL with respect to the composition in consideration of the stability of TARC. It is preferably 50 pg / mL to 500 ng / mL, more preferably 100 pg / mL to 100 ng / mL, and most preferably 100 pg / mL to 50 ng / mL.
（陽イオン性界面活性剤及び陰イオン性界面活性剤）
　本明細書において、陰イオン性界面活性剤とは、水に溶解した時に、疎水基の部分がマイナス（負）イオンに電離する界面活性剤を意味する。本明細書では、水に溶解した時に、イオン化しない親水基を有する界面活性剤を、非イオン性界面活性剤と称し、疎水基の部分がプラス（正）イオンに電離する界面活性剤を陽イオン性界面活性剤と称し、アルカリ性領域では陰イオン性界面活性剤の性質を、酸性領域では陽イオン性界面活性剤の性質を示す界面活性剤を両性界面活性剤と称する。 (Cationic and anionic surfactants)
As used herein, the anionic surfactant means a surfactant in which the hydrophobic group portion is ionized into negative (negative) ions when dissolved in water. In the present specification, a surfactant having a hydrophilic group that does not ionize when dissolved in water is referred to as a nonionic surfactant, and a surfactant in which the hydrophobic group portion is ionized into a positive (positive) ion is a cation. A surfactant that exhibits the properties of an anionic surfactant in the alkaline region and the properties of a cationic surfactant in the acidic region is referred to as a sex surfactant, and is referred to as an amphoteric surfactant.
　陽イオン性界面活性剤としては、アルキルアミン塩型、第四級アンモニウム塩型等が好ましい。陰イオン界面活性剤としては、コール酸型、硫酸エステル（サルフェート）型、カルボン酸型、スルホン酸型などが好ましい。 As the cationic surfactant, an alkylamine salt type, a quaternary ammonium salt type and the like are preferable. As the anionic surfactant, cholic acid type, sulfate ester (sulfate) type, carboxylic acid type, sulfonic acid type and the like are preferable.
　陽イオン性界面活性剤のアルキルアミン塩型としては、例えばモノドデシルアミン、モノオクタデシルアミン、ジオクタデシルアミン、トリオクタデシルアミン等の炭素数８～２２のアルキル基を１～３つ含むアミンと、塩酸、硫酸等の無機酸あるいは酢酸、乳酸、クエン酸等の低級カルボン酸等との塩等が挙げられる。具体的には例えば、ドデシルアミン塩酸塩［ＣＡＳ番号：９２９－７３－７、東京化成工業株式会社製］、ココナットアミンアセテート［ＣＡＳ番号：６１７９０－５７－６、製品名：アセタミン２４、花王株式会社製］、ステアリルアミンアセテート［ＣＡＳ番号：２１９０－０４－７、製品名：アセタミン８６、花王株式会社製］などが挙げられる。
　第四級アンモニウム塩型としては、ドデシルトリメチルアンモニウム、オクタデシルトリメチルアンモニウム、ヘキサデシルトリメチルアンモニウム、ジデシルジメチルアンモニウム、ベンジルメチルテトラデシルアンモニウム等の炭素数８～２２のアルキル基を１～３つ含むアンモニウムと塩素、臭素等との塩等が挙げられる。具体的には例えば、ラウリルトリメチルアンモニウムクロリド［ＣＡＳ番号：１１２－００－５、製品名：コータミン（登録商標）２４Ｐ、花王株式会社製］、ドデシルトリメチルアンモニウムブロミド［ＣＡＳ番号：１１１９－９４－４、東京化成工業株式会社製］、オクタデシルトリメチルアンモニウムクロリド［ＣＡＳ番号：１１２－０３－８、東京化成工業株式会社製］、ジステアリルジメチルアンモニウムクロリド［ＣＡＳ番号：１０７－６４－２、製品名：コータミン（登録商標）Ｄ８６Ｐ、花王株式会社製］などが挙げられる。 Examples of the alkylamine salt type of the cationic surfactant include amines containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as monododecylamine, monooctadecylamine, dioctadecylamine, and trioctadecylamine, and hydrochloric acid. , Inorganic acids such as sulfuric acid or salts with lower carboxylic acids such as acetic acid, lactic acid and citric acid. Specifically, for example, dodecylamine hydrochloride [CAS number: 929-73-7, manufactured by Tokyo Kasei Kogyo Co., Ltd.], coconut amine acetate [CAS number: 61790-57-6, product name: acetamine 24, Kao Corporation Company-made], stearylamine acetate [CAS number: 2190-04-7, product name: acetamine 86, made by Kao Corporation] and the like.
The quaternary ammonium salt type includes ammonium containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as dodecyltrimethylammonium, octadecyltrimethylammonium, hexadecyltrimethylammonium, didecyldimethylammonium, and benzylmethyltetradecylammonium. Examples include salts with chlorine, bromine and the like. Specifically, for example, lauryltrimethylammonium chloride [CAS number: 112-00-5, product name: Coatamine (registered trademark) 24P, manufactured by Kao Co., Ltd.], dodecyltrimethylammonium bromide [CAS number: 1119-94-4, Tokyo Chemical Industry Co., Ltd.], Octadecyltrimethylammonium chloride [CAS number: 112-03-8, Tokyo Chemical Industry Co., Ltd.], Distearyldimethylammonium chloride [CAS number: 107-64-2, Product name: Coatamine ( Registered trademark) D86P, manufactured by Kao Co., Ltd.] and the like.
　陰イオン性界面活性剤のコール酸型としては、デオキシコール酸ナトリウム［ＣＡＳ番号：３０２－９５－４、富士フイルム和光株式会社製］、及びコール酸ナトリウム［ＣＡＳ番号：３６１－０９－１、富士フイルム和光株式会社製］などが挙げられる。
　硫酸エステル（サルフェート）型としては、ドデシル硫酸エステル等の高級アルコール硫酸エステル、ポリオキシエチレンドデシルエーテル硫酸エステル等のポリオキシエチレンアルキルエーテル硫酸エステルと、ナトリウム、アンモニウム等との塩等が挙げられる。具体的には例えば、ドデシル硫酸ナトリウム［ＣＡＳ番号：１５１－２１－３、Ｓｉｇｍａ－Ａｌｄｒｉｃｈ社製］、ラウリル硫酸アンモニウム［ＣＡＳ番号：２２３５－５４－３、ラテムル（登録商標）ＡＤ－２５、花王株式会社製］等の高級アルコール硫酸エステル塩、ポリオキシエチレンラウリルエーテル硫酸ナトリウム［ＣＡＳ番号：６８５８５－３４－２、製品名：エマール２０Ｃ、花王株式会社製］等のポリオキシエチレンアルキルエーテル硫酸エステル塩等が挙げられる。
　カルボン酸型としては、ドデカン酸（ラウリン酸）、テトラデカン酸（ミリスチン酸）、ヘキサデカン酸（パルミチン酸）、オクタデカン酸（ステアリン酸）、ｃｉｓ－９－オクタデセン酸（オレイン酸）等の炭素数８～２２の高級脂肪酸等と、ナトリウム、カリウム等のアルカリ金属等との塩等が挙げられる。具体的には例えば、ラウリン酸ナトリウム［ＣＡＳ番号：６２９－２５－４、富士フイルム和光株式会社製］、ミリスチン酸ナトリウム［ＣＡＳ番号：８２２－１２－８、富士フイルム和光株式会社製］、パルミチン酸ナトリウム［ＣＡＳ番号：４０８－３５－５、東京化成工業株式会社製］、ラウロイルサルコシンナトリウム［ＣＡＳ番号：１３７－１６－６、東京化成工業株式会社製］、ポリオキシエチレンラウリルエーテル酢酸ナトリウム［ＣＡＳ番号：３３９３９－６４－９、製品名：エナジコールＥＣ－３０、ライオン・スペシャリティ・ケミカルズ株式会社製］、及びラウロイルメチルアラニンナトリウム［ＣＡＳ番号：２１５３９－５８－２、製品名：エナジコールＬ－３０ＡＮ、ライオン・スペシャリティ・ケミカルズ株式会社製］などが挙げられる。
　スルホン酸型としては、ドデシルベンゼンスルホン酸等のアルキルベンゼンスルホン酸、ジブチルナフタレンスルホン酸等のナフタレンスルホン酸、ナフタレンスルホン酸のホルマリン縮合物、ジオクチルスルホコハク酸等のスルホコハク酸等と、ナトリウム等の塩等が挙げられる。具体的には例えば、ラウリルベンゼンスルホン酸ナトリウム［ＣＡＳ番号：２５１５５－３０－０、富士フイルム和光株式会社製］、β‐ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩［ＣＡＳ番号：９０８４－０６－４、製品名：デモール（登録商標）ＲＮ、花王株式会社製］、及びジオクチルスルホコハク酸ナトリウム［ＣＡＳ番号：５７７－１１－７、製品名：ネオコール（登録商標）ＳＷ、第一工業株式会社製］などが挙げられる。
　これらの陰イオン性界面活性剤又は陽イオン性界面活性剤は、さまざまな洗剤メーカーや試薬メーカーで取扱いがあり、市販品を購入して使用することができる。また、これらの陰イオン性界面活性剤又は陽イオン性界面活性剤は単独で用いることもでき、２種以上のものを組み合わせて用いることもできる。
　本発明の組成物において使用される陽イオン性界面活性剤又は陰イオン性界面活性剤は、ココナットアミンアセテート、ラウリルトリメチルアンモニウムクロリド、コール酸ナトリウム、ドデシル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ‐ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩がより好ましい。特に、プラスチック容器の場合には、ラウリルトリメチルアンモニウムクロリド、コール酸ナトリウム、ドデシル硫酸ナトリウム、又はラウロイルメチルアラニンナトリウムを使用し、ガラス容器の場合には、ラウリルトリメチルアンモニウムクロリド、ココナットアミンアセテート、又はβ‐ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩を使用することがさらに好ましい。
　本発明の効果を損なわない範囲内で、陰イオン性界面活性剤又は陽イオン性界面活性剤に加えて、他の種類の界面活性剤を使用することも可能であるが、使用しないことが好ましい。また、陰イオン性界面活性剤及び陽イオン性界面活性剤を併用することもできるが、併用せずにいずれか一方のみを使用することが好ましい。 The cholic acid types of anionic surfactants include sodium deoxycholic acid [CAS number: 302-95-4, manufactured by Fujifilm Wako Co., Ltd.] and sodium cholic acid [CAS number: 361-09-1, Fuji. Film Wako Co., Ltd.] and the like.
Examples of the sulfate ester (sulfate) type include higher alcohol sulfate esters such as dodecyl sulfate ester, polyoxyethylene alkyl ether sulfate esters such as polyoxyethylene dodecyl ether sulfate ester, and salts with sodium and ammonium. Specifically, for example, sodium dodecyl sulfate [CAS number: 151-21-3, manufactured by Sigma-Aldrich], ammonium lauryl sulfate [CAS number: 2235-54-3, Latemul (registered trademark) AD-25, Kao Co., Ltd. Higher alcohol sulfate ester salts such as [manufactured by], polyoxyethylene alkyl ether sulfate ester salts such as polyoxyethylene lauryl ether sulfate sodium [CAS number: 68585-34-2, product name: Emar 20C, manufactured by Kao Co., Ltd.] Can be mentioned.
Examples of the carboxylic acid type include dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), and cis-9-octadecenoic acid (oleic acid) having 8 to carbon atoms. Examples thereof include salts of 22 higher fatty acids and the like with alkali metals such as sodium and potassium. Specifically, for example, sodium laurate [CAS number: 629-25-4, manufactured by Fujifilm Wako Co., Ltd.], sodium myristate [CAS number: 822-12-8, manufactured by Fujifilm Wako Co., Ltd.], palmitic acid. Sodium [CAS number: 408-35-5, manufactured by Tokyo Kasei Kogyo Co., Ltd.], sodium lauroyl sarcosine [CAS number: 137-16-6, manufactured by Tokyo Kasei Kogyo Co., Ltd.], sodium polyoxyethylene lauryl ether acetate [CAS number : 33939-64-9, Product Name: Enagicor EC-30, manufactured by Lion Specialty Chemicals Co., Ltd.], and Lauroylmethylalanine Sodium [CAS Number: 21539-58-2, Product Name: Enagicor L-30AN, Lion. Specialty Chemicals Co., Ltd.] and so on.
Examples of the sulfonic acid type include alkylbenzene sulfonic acid such as dodecylbenzene sulfonic acid, naphthalene sulfonic acid such as dibutylnaphthalene sulfonic acid, formalin condensate of naphthalene sulfonic acid, sulfosuccinic acid such as dioctylsulfosuccinic acid, and salts such as sodium. Can be mentioned. Specifically, for example, sodium laurylbenzene sulfonate [CAS number: 25155-30-0, manufactured by Fujifilm Wako Co., Ltd.], β-naphthalene sulfonic acid formarin condensate sodium salt [CAS number: 9084-06-4, product. Name: Demol (registered trademark) RN, manufactured by Kao Co., Ltd.], and sodium dioctylsulfosuccinate [CAS number: 577-11-7, product name: Neocol (registered trademark) SW, manufactured by Daiichi Kogyo Co., Ltd.], etc. Be done.
These anionic surfactants or cationic surfactants are handled by various detergent makers and reagent makers, and commercially available products can be purchased and used. Further, these anionic surfactants or cationic surfactants may be used alone or in combination of two or more.
The cationic or anionic surfactants used in the compositions of the present invention are coconutamine acetate, lauryltrimethylammonium chloride, sodium sulphonate, sodium dodecyl sulfate, sodium lauroylmethylalanine, or β-. Sodium salt of sodium phthalene sulfonic acid formalin condensate is more preferable. In particular, in the case of plastic containers, lauryltrimethylammonium chloride, sodium colate, sodium dodecyl sulfate, or sodium lauroylmethylalanine is used, and in the case of glass containers, lauryltrimethylammonium chloride, coconatamine acetate, or β. -It is further preferred to use sodium salt of sodium naphthalene sulfonic acid formalin condensate.
Although it is possible to use other types of surfactants in addition to the anionic surfactants or cationic surfactants as long as the effects of the present invention are not impaired, it is preferable not to use them. .. Further, although an anionic surfactant and a cationic surfactant can be used in combination, it is preferable to use only one of them without using them in combination.
　本発明の組成物では、本発明の効果が得られる限りにおいて、陽イオン性界面活性剤又は陰イオン性界面活性剤とＴＡＲＣの添加順序は特に限定されない。 In the composition of the present invention, the order of addition of the cationic surfactant or the anionic surfactant and TARC is not particularly limited as long as the effect of the present invention can be obtained.
（界面活性剤の濃度）
　本発明の組成物において、陽イオン性界面活性剤又は陰イオン性界面活性剤の濃度は、以下に限定されるものではないが、ＴＡＲＣの安定性を考慮して、組成物に対して、好ましくは０．００００１質量％～１質量％、より好ましくは０．０００１質量％～１質量％、さらに好ましくは０．００１質量％～０．５質量％、最も好ましくは０．００１質量％～０．１質量％である。 (Concentration of surfactant)
In the composition of the present invention, the concentration of the cationic or anionic surfactant is not limited to the following, but is preferable with respect to the composition in consideration of the stability of TARC. Is 0.00001% by mass to 1% by mass, more preferably 0.0001% by mass to 1% by mass, still more preferably 0.001% by mass to 0.5% by mass, and most preferably 0.001% by mass to 0. It is 1% by mass.
（保存容器）
　本発明の組成物は、好ましくは、保存容器に充填されている。保存容器の材質は、本発明の効果を得ることができ、そして密封ができれば特に限定されないが、少なくとも組成物との接触部分の一部又は全部が、プラスチック［例えば、オレフィン系樹脂、スチレン系樹脂、アクリル系樹脂、ポリエステル系樹脂、ポリカーボネート系樹脂、フッ素樹脂、塩素系樹脂（ポリ塩化ビニルなど）、ポリアミド系樹脂、ポリアセタール系樹脂、ポリフェニレンエーテル系樹脂（変性ポリフェニレンエーテルなど）、ポリアリレート、ポリスルホン、ポリイミド系樹脂、セルロース系樹脂（セルロースアセテートなど）、炭化水素系樹脂（ハロゲン原子置換品を含む）など］、金属（アルミニウムなど）、ガラスなどである。中でも、校正用試料の製造、輸送、保管の観点からプラスチック又はガラスが好ましく、プラスチックの中ではオレフィン系樹脂が好ましく、ポリプロピレンがより好ましい。 (Storage container)
The composition of the present invention is preferably filled in a storage container. The material of the storage container is not particularly limited as long as the effects of the present invention can be obtained and can be sealed, but at least a part or all of the contact portion with the composition is a plastic [for example, an olefin resin or a styrene resin. , Acrylic resin, polyester resin, polycarbonate resin, fluororesin, chlorine resin (polyvinyl chloride, etc.), polyamide resin, polyacetal resin, polyphenylene ether resin (modified polyphenylene ether, etc.), polyallylate, polysulfone, Polyimide-based resins, cellulose-based resins (cellulose acetate, etc.), hydrocarbon-based resins (including halogen atom-substituted products), etc.], metals (aluminum, etc.), glass, etc. Of these, plastic or glass is preferable from the viewpoint of manufacturing, transporting, and storing the calibration sample, and among the plastics, an olefin resin is preferable, and polypropylene is more preferable.
　保存容器は、単独又は２種以上の材質で構成されていてもよいが、単独の材質で構成されていることが好ましい。保存容器は、容器本体部分とキャップとを含むことができる。この場合、容器本体部分とキャップとは異なる材質で構成されていてもよい。また、保存容器、特に本体部分は、外部から内容液が見える程度の透明性を有していることが好ましい。
　保存容器の形態としては、ハードタイプまたはソフトタイプのいずれでもよく、アンプル、バイアル、ソフトバッグ、注射型容器、ガラス瓶などが例示される。保存容器は、容器本体部分とキャップ部分を含む、プラスチック製の点眼瓶の形態、特に円筒形状の点眼瓶の形態であることが、使用しやすさ及びＴＡＲＣの安定性の観点から好ましい。また、保存容器は、ガラス製のアンプル、またはガラス製の容器本体部分とキャップを含む形態、特に円筒形状のガラス容器およびゴム製のキャップを含む形態であることが、使用しやすさ及びＴＡＲＣの安定性の観点から好ましい。 The storage container may be made of a single material or two or more kinds of materials, but is preferably made of a single material. The storage container can include a container body portion and a cap. In this case, the container body portion and the cap may be made of different materials. Further, it is preferable that the storage container, particularly the main body portion, has transparency to the extent that the content liquid can be seen from the outside.
The storage container may be of either a hard type or a soft type, and examples thereof include ampoules, vials, soft bags, injection containers, and glass bottles. The storage container is preferably in the form of a plastic eye drop bottle including a container body portion and a cap portion, particularly in the form of a cylindrical eye drop bottle, from the viewpoint of ease of use and stability of TARC. In addition, the storage container should be a glass ampoule or a form including a glass container body and a cap, particularly a cylindrical glass container and a form including a rubber cap, for ease of use and TARC. Preferred from the viewpoint of stability.
（組成物）
　本発明の組成物は、ＴＡＲＣの測定において、校正用試料溶液として用いることができる。本明細書において、校正用試料溶液とは、測定対象物質の測定を正確に行うために使用する、測定対象物質を一定の濃度で含有する試料溶液を意味し、標準物質、キャリブレーター、コントロール、及び内部標準物質などが該当する。本発明の組成物の供給の形態としては、ＴＡＲＣと陰イオン性界面活性剤又は陽イオン性界面活性剤とを溶媒に混合した、あらかじめ溶液状態にした形態が挙げられる。
　なお、ＴＡＲＣの測定方法において「組成物を使用する」とは、ＴＡＲＣの測定を正確に行うために組成物を使用することを意味し、例えば、ＴＡＲＣを含む液状組成物を校正用試料溶液（標準物質、キャリブレーター、コントロール、及び内部標準物質など）として使用することを意味する。 (Composition)
The composition of the present invention can be used as a sample solution for calibration in the measurement of TARC. In the present specification, the sample solution for calibration means a sample solution containing a substance to be measured at a constant concentration, which is used for accurate measurement of the substance to be measured, and is used as a standard substance, a calibrator, a control, and a sample solution. Internal standard substances, etc. are applicable. Examples of the form of supplying the composition of the present invention include a form in which TARC and an anionic surfactant or a cationic surfactant are mixed with a solvent and prepared in a solution state in advance.
In the method for measuring TARC, "using a composition" means using a composition in order to accurately measure TARC. For example, a liquid composition containing TARC is used as a sample solution for calibration ( Means to be used as a reference material, calibrator, control, and internal standard material, etc.).
　本発明の組成物のｐＨは、例えば、４．０～９．５、５．０～９．０、６．０～８．５、６．５～８．０、又は７．０～８．０である。
　ｐＨの調整は、当業者に周知のｐＨ調整用試薬、例えば水酸化ナトリウム又は塩酸などを用いて行うことができる。 The pH of the composition of the present invention is, for example, 4.0 to 9.5, 5.0 to 9.0, 6.0 to 8.5, 6.5 to 8.0, or 7.0 to 8. It is 0.
The pH can be adjusted using a pH adjusting reagent well known to those skilled in the art, such as sodium hydroxide or hydrochloric acid.
　本発明の組成物の組成は、本発明の効果を損なわないことを限度として特に制限はない。ＴＡＲＣを免疫学的測定方法により測定するのであれば、本発明の効果を損なわず、かつ、抗原抗体反応、ビオチン・アビジンによる検出のための標識反応、酵素反応などの測定系を構成する反応の全部又は一部を妨害しなければよい。免疫学的測定方法において通常使用される各種成分、例えば、酢酸、クエン酸、リン酸、ＰＢＳ（リン酸緩衝生理食塩水）、ＨＥＰＥＳ、ＭＥＳ、Ｔｒｉｓ、グリシン、ホウ酸、炭酸やグッドバッファーなどの各種緩衝液、抗原抗体反応を促進する成分（ポリエチレングリコール、ポリビニルピロリドンなどの高分子など）、糖タンパク質やペプチド（ＢＳＡ、カゼインなど）、アミノ酸、塩類（塩化ナトリウム、塩化カリウムなど）、糖類（ショ糖、シクロデキストリンなど）、防腐剤（アジ化ナトリウム、ＰｒｏＣｌｉｎ３００など）などを目的に応じ、適宜選択して使用することができる。ｐＨが６．５～８．０のＰＢＳを用いることが好ましい。 The composition of the composition of the present invention is not particularly limited as long as the effect of the present invention is not impaired. If TARC is measured by an immunological measurement method, the effects of the present invention are not impaired, and the reactions constituting the measurement system such as antigen-antibody reaction, labeling reaction for detection with biotin / avidin, and enzyme reaction It does not have to interfere with all or part of it. Various components commonly used in immunological measurement methods, such as acetic acid, citric acid, phosphoric acid, PBS (phosphate buffered saline), HEPES, MES, Tris, glycine, boric acid, carbonic acid and good buffer. Various buffers, components that promote antigen-antibody reactions (polymers such as polyethylene glycol and polyvinylpyrrolidone), glycoproteins and peptides (BSA, casein, etc.), amino acids, salts (sodium chloride, potassium chloride, etc.), sugars (sho) Sugar, cyclodextrin, etc.), preservatives (sodium azide, ProClin300, etc.) and the like can be appropriately selected and used according to the purpose. It is preferable to use PBS having a pH of 6.5 to 8.0.
　本明細書において「保存安定性向上」又は「保存安定性が向上する」とは、ＴＡＲＣを含む溶液中に含有されるＴＡＲＣの大部分が長期間分解されずに、構造を変化させずに、又は容器に吸着せずに維持されることにより、当該溶液中のＴＡＲＣの初期値と保存後の測定値とにおいて、大きな差異がなくなることを意味する。
　より具体的には、「保存安定性向上」又は「保存安定性が向上する」とは、例えば、濃度が１０ｐｇ／ｍＬ～１μｇ／ｍＬのＴＡＲＣを含む溶液中に含有されるＴＡＲＣの８０％以上が、３７℃で２８日間の間分解されずに、構造を変化させずに、又は容器に吸着せずに維持されることにより、３７℃で２８日間のプラスチック製容器における保存後の当該溶液中のＴＡＲＣの測定値が、初期値の８０％以上となることを意味することができる。
　また、「保存安定性向上」又は「保存安定性が向上する」とは、例えば、濃度が１０ｐｇ／ｍＬ～１μｇ／ｍＬのＴＡＲＣを含む溶液中に含有されるＴＡＲＣの９０％以上が、４℃で２８日間の間分解されずに、構造を変化させずに、又は容器に吸着せずに維持されることにより、４℃で２８日間のプラスチック製容器における保存後の当該溶液中のＴＡＲＣの測定値が、初期値の９０％以上となることを意味することができる。
　また、「保存安定性向上」又は「保存安定性が向上する」とは、例えば、濃度が１０ｐｇ／ｍＬ～１μｇ／ｍＬのＴＡＲＣを含む溶液中に含有されるＴＡＲＣの５５％以上が、１０℃で６時間分解されずに、構造を変化させずに、又は容器に吸着せずに維持されることにより、１０℃で６時間のガラス製容器における保存後の当該溶液中のＴＡＲＣの測定値が、初期値の５５％以上となることを意味することができる。 As used herein, "improved storage stability" or "improved storage stability" means that most of the TARC contained in the solution containing TARC is not decomposed for a long period of time and the structure is not changed. Alternatively, by maintaining the TARC in the solution without adsorbing it, it means that there is no big difference between the initial value of TARC in the solution and the measured value after storage.
More specifically, "improvement of storage stability" or "improvement of storage stability" means, for example, 80% or more of TARC contained in a solution containing TARC having a concentration of 10 pg / mL to 1 μg / mL. In the solution after storage in a plastic container for 28 days at 37 ° C. by being maintained at 37 ° C. for 28 days without decomposition, structural changes or adsorption to the container. It can mean that the measured value of TARC is 80% or more of the initial value.
Further, "improvement of storage stability" or "improvement of storage stability" means that, for example, 90% or more of TARC contained in a solution containing TARC having a concentration of 10 pg / mL to 1 μg / mL is 4 ° C. Measurement of TARC in the solution after storage in a plastic container at 4 ° C. for 28 days at 4 ° C. by being maintained without decomposition, structural changes or adsorption to the container for 28 days. It can mean that the value is 90% or more of the initial value.
Further, "improvement of storage stability" or "improvement of storage stability" means that, for example, 55% or more of TARC contained in a solution containing TARC having a concentration of 10 pg / mL to 1 μg / mL is 10 ° C. By maintaining the solution without decomposition for 6 hours, without changing the structure, or without adsorbing to the container, the measured value of TARC in the solution after storage in a glass container at 10 ° C. for 6 hours , It can mean that it becomes 55% or more of the initial value.
（ＴＡＲＣの測定を行うための生体試料）
　ＴＡＲＣの測定を行うための生体試料としては、ＴＡＲＣの測定が可能であれば特に限定されることはないが、血液、血清、又は血漿を用いることが好ましい。生体試料には、必要に応じて適宜前処理を実施してもよい。生体試料は、好ましくは、ヒトから採取された生体試料である。 (Biological sample for measuring TARC)
The biological sample for measuring TARC is not particularly limited as long as TARC can be measured, but blood, serum, or plasma is preferably used. If necessary, the biological sample may be pretreated. The biological sample is preferably a biological sample taken from a human.
（ＴＡＲＣの測定キット）
　本発明のＴＡＲＣの測定キットでは、本発明の組成物を使用することにより、ＴＡＲＣの測定を簡便に及び正確に行うことが可能である。ＴＡＲＣの測定キットとしては、例えば免疫学的手法を用いたキットを挙げることができる。本発明のＴＡＲＣの測定キットは、免疫学的手法によりヒト体内のＴＡＲＣの濃度を測定するための試薬を含むことができる。免疫学的手法としては、ＥＬＩＳＡ、酵素免疫測定法、表面プラズモン共鳴法、ラテックス凝集免疫測定法（ＬＴＩＡ）、化学発光免疫測定法、電気化学発光免疫測定法、蛍光抗体法、放射免疫測定法、ウエスタンブロット法、イムノクロマトグラフィー法、及び高速液体クロマトグラフィー法（ＨＰＬＣ法）等が挙げられる。
　本発明のＴＡＲＣの測定キットは、アトピー性皮膚炎の治療方法又は薬の選択、そして治療の効果を判定する際に、アトピー性皮膚炎の重症度を把握するために用いることができる。 (TARC measurement kit)
In the TARC measurement kit of the present invention, the composition of the present invention can be used to easily and accurately measure TARC. Examples of the TARC measurement kit include a kit using an immunological method. The TARC measurement kit of the present invention can contain a reagent for measuring the concentration of TARC in a human body by an immunological method. Immunological methods include ELISA, enzyme immunoassay, surface plasmon resonance method, latex aggregation immunoassay (LTIA), chemical luminescence immunoassay, electrochemical luminescence immunoassay, fluorescent antibody method, radioimmunoassay, Western blot method, immunochromatography method, high performance liquid chromatography method (HPLC method) and the like can be mentioned.
The TARC measurement kit of the present invention can be used to grasp the severity of atopic dermatitis in determining the treatment method or drug selection of atopic dermatitis and the effect of the treatment.
　本発明のＴＡＲＣの測定キットには、他に使用説明書などを含むこともできる。ＴＡＲＣの測定キットは、任意の構成要素、例えば緩衝剤、安定化剤、検体希釈液、ｐＨ調整剤、反応容器等を含んでいてもよい。 The TARC measurement kit of the present invention may also include an instruction manual or the like. The TARC measurement kit may include any component, such as a buffer, a stabilizer, a sample diluent, a pH regulator, a reaction vessel, and the like.
（ＴＡＲＣの保存安定性向上方法）
　本発明のＴＡＲＣの保存安定性向上方法は、陽イオン性界面活性剤又は陰イオン性界面活性剤を含む溶液にＴＡＲＣを接触させる工程を含む。溶液に陽イオン性界面活性剤又は陰イオン性界面活性剤を添加した後に、ＴＡＲＣを添加してもよく、ＴＡＲＣを溶液に添加した後に、陽イオン性界面活性剤又は陰イオン性界面活性剤を添加してもよい。溶液は、ＰＢＳ、ＨＥＰＥＳ、ＭＥＳ、ＣＨＥＳ及びＴｒｉｓ等の緩衝液であることが好ましい。ｐＨが６．５～８．０のＰＢＳを用いることがより好ましい。 (Method for improving storage stability of TARC)
The method for improving the storage stability of TARC of the present invention includes a step of contacting TARC with a solution containing a cationic surfactant or an anionic surfactant. TARC may be added after the cationic or anionic surfactant is added to the solution, or after the TARC is added to the solution, the cationic or anionic surfactant is added. It may be added. The solution is preferably a buffer such as PBS, HEPES, MES, CHES and Tris. It is more preferable to use PBS having a pH of 6.5 to 8.0.
（ＴＡＲＣの濃度）
　本発明のＴＡＲＣの保存安定性向上方法において、溶液に含まれるＴＡＲＣの濃度としては、以下に限定されるものではないが、ＴＡＲＣの安定性を考慮して、好ましくは１０ｐｇ／ｍＬ～１μｇ／ｍＬ、より好ましくは５０ｐｇ／ｍＬ～５００ｎｇ／ｍＬ、さらに好ましくは１００ｐｇ／ｍＬ～１００ｎｇ／ｍＬ、最も好ましくは１００ｐｇ／ｍＬ～５０ｎｇ／ｍＬである。 (TARC concentration)
In the method for improving the storage stability of TARC of the present invention, the concentration of TARC contained in the solution is not limited to the following, but is preferably 10 pg / mL to 1 μg / mL in consideration of the stability of TARC. , More preferably 50 pg / mL to 500 ng / mL, still more preferably 100 pg / mL to 100 ng / mL, and most preferably 100 pg / mL to 50 ng / mL.
　陽イオン性界面活性剤としては、アルキルアミン塩型、第四級アンモニウム塩型等が好ましい。陰イオン界面活性剤としては、コール酸型、硫酸エステル（サルフェート）型、カルボン酸型、スルホン酸型などが好ましい。 As the cationic surfactant, an alkylamine salt type, a quaternary ammonium salt type and the like are preferable. As the anionic surfactant, cholic acid type, sulfate ester (sulfate) type, carboxylic acid type, sulfonic acid type and the like are preferable.
　陽イオン性界面活性剤のアルキルアミン塩型としては、例えばモノドデシルアミン、モノオクタデシルアミン、ジオクタデシルアミン、トリオクタデシルアミン等の炭素数８～２２のアルキル基を１～３つ含むアミンと、塩酸、硫酸等の無機酸あるいは酢酸、乳酸、クエン酸等の低級カルボン酸等との塩等が挙げられる。具体的には例えば、ドデシルアミン塩酸塩　［ＣＡＳ番号：９２９－７３－７、東京化成工業株式会社製］、ココナットアミンアセテート　［ＣＡＳ番号：６１７９０－５７－６、製品名：アセタミン２４、花王株式会社製］、ステアリルアミンアセテート［ＣＡＳ番号：２１９０－０４－７、製品名：アセタミン８６、花王株式会社製］などが挙げられる。
　第四級アンモニウム塩型としては、ドデシルトリメチルアンモニウム、オクタデシルトリメチルアンモニウム、ヘキサデシルトリメチルアンモニウム、ジデシルジメチルアンモニウム、ベンジルメチルテトラデシルアンモニウム等の炭素数８～２２のアルキル基を１～３つ含むアンモニウムと塩素、臭素等の塩等が挙げられる。具体的には例えば、ラウリルトリメチルアンモニウムクロリド［ＣＡＳ番号：１１２－００－５、製品名：コータミン（登録商標）２４Ｐ、花王株式会社製］、ドデシルトリメチルアンモニウムブロミド［ＣＡＳ番号：１１１９－９４－４、東京化成工業株式会社製］、オクタデシルトリメチルアンモニウムクロリド［ＣＡＳ番号：１１２－０３－８、東京化成工業株式会社製］、ジステアリルジメチルアンモニウムクロリド［ＣＡＳ番号：１０７－６４－２、製品名：コータミン（登録商標）Ｄ８６Ｐ、花王株式会社製］などが挙げられる。 Examples of the alkylamine salt type of the cationic surfactant include amines containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as monododecylamine, monooctadecylamine, dioctadecylamine, and trioctadecylamine, and hydrochloric acid. , Inorganic acids such as sulfuric acid or salts with lower carboxylic acids such as acetic acid, lactic acid and citric acid. Specifically, for example, dodecylamine hydrochloride [CAS number: 929-73-7, manufactured by Tokyo Kasei Kogyo Co., Ltd.], coconut amine acetate [CAS number: 61790-57-6, product name: acetamine 24, Kao Corporation Company-made], stearylamine acetate [CAS number: 2190-04-7, product name: acetamine 86, made by Kao Corporation] and the like.
The quaternary ammonium salt type includes ammonium containing 1 to 3 alkyl groups having 8 to 22 carbon atoms such as dodecyltrimethylammonium, octadecyltrimethylammonium, hexadecyltrimethylammonium, didecyldimethylammonium, and benzylmethyltetradecylammonium. Examples thereof include salts such as chlorine and bromine. Specifically, for example, lauryltrimethylammonium chloride [CAS number: 112-00-5, product name: Coatamine (registered trademark) 24P, manufactured by Kao Co., Ltd.], dodecyltrimethylammonium bromide [CAS number: 1119-94-4, Tokyo Chemical Industry Co., Ltd.], Octadecyltrimethylammonium chloride [CAS number: 112-03-8, Tokyo Chemical Industry Co., Ltd.], Distearyldimethylammonium chloride [CAS number: 107-64-2, Product name: Coatamine ( Registered trademark) D86P, manufactured by Kao Co., Ltd.] and the like.
　陰イオン性界面活性剤のコール酸型としては、デオキシコール酸ナトリウム［ＣＡＳ番号：３０２－９５－４、富士フイルム和光株式会社製］、及びコール酸ナトリウム［ＣＡＳ番号：３６１－０９－１、富士フイルム和光株式会社製］などが挙げられる。
　硫酸エステル（サルフェート）型としては、ドデシル硫酸エステル等の高級アルコール硫酸エステル、ポリオキシエチレンドデシルエーテル硫酸エステル等のポリオキシエチレンアルキルエーテル硫酸エステルと、ナトリウム、アンモニウム等との塩等が挙げられる。具体的には例えば、ドデシル硫酸ナトリウム［ＣＡＳ番号：１５１－２１－３、Ｓｉｇｍａ－Ａｌｄｒｉｃｈ社製］　、ラウリル硫酸アンモニウム［ＣＡＳ番号：２２３５－５４－３、ラテムル（登録商標）ＡＤ－２５、花王株式会社製］等の高級アルコール硫酸エステル塩、ポリオキシエチレンラウリルエーテル硫酸ナトリウム［ＣＡＳ番号：６８５８５－３４－２、製品名：エマール２０Ｃ、花王株式会社製］等のポリオキシエチレンアルキルエーテル硫酸エステル塩等が挙げられる。
　カルボン酸型としては、ドデカン酸（ラウリン酸）、テトラデカン酸（ミリスチン酸）、ヘキサデカン酸（パルミチン酸）、オクタデカン酸（ステアリン酸）、ｃｉｓ－９－オクタデセン酸（オレイン酸）等の炭素数８～２２の高級脂肪酸等と、ナトリウム、カリウム等のアルカリ金属等との塩等が挙げられる。具体的には例えば、ラウリン酸ナトリウム［ＣＡＳ番号：６２９－２５－４、富士フイルム和光株式会社製］、ミリスチン酸ナトリウム［ＣＡＳ番号：８２２－１２－８、富士フイルム和光株式会社製］、パルミチン酸ナトリウム［ＣＡＳ番号：４０８－３５－５、東京化成工業株式会社製］、ラウロイルサルコシンナトリウム［ＣＡＳ番号：１３７－１６－６、東京化成工業株式会社製］、ポリオキシエチレンラウリルエーテル酢酸ナトリウム［ＣＡＳ番号：３３９３９－６４－９、製品名：エナジコールＥＣ－３０、ライオン・スペシャリティ・ケミカルズ株式会社製］、及びラウロイルメチルアラニンナトリウム［ＣＡＳ番号：２１５３９－５８－２、製品名：エナジコールＬ－３０ＡＮ、ライオン・スペシャリティ・ケミカルズ株式会社製］などが挙げられる。
　スルホン酸型としては、ドデシルベンゼンスルホン酸等のアルキルベンゼンスルホン酸、ジブチルナフタレンスルホン酸等のナフタレンスルホン酸、ナフタレンスルホン酸のホルマリン縮合物、ジオクチルスルホコハク酸等のスルホコハク酸等と、ナトリウム等の塩等が挙げられる。具体的には例えば、ラウリルベンゼンスルホン酸ナトリウム［ＣＡＳ番号：２５１５５－３０－０、富士フイルム和光株式会社製］、β‐ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩［ＣＡＳ番号：９０８４－０６－４、製品名：デモール（登録商標）ＲＮ、花王株式会社製］、及びジオクチルスルホコハク酸ナトリウム［ＣＡＳ番号：５７７－１１－７、製品名：ネオコール（登録商標）ＳＷ、第一工業株式会社製］などが挙げられる。
　本発明の組成物において使用される陽イオン性界面活性剤又は陰イオン性界面活性剤は、ココナットアミンアセテート、ラウリルトリメチルアンモニウムクロリド、コール酸ナトリウム、ドデシル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ‐ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩がより好ましい。特に、プラスチック容器の場合には、ラウリルトリメチルアンモニウムクロリド、コール酸ナトリウム、ドデシル硫酸ナトリウム、又はラウロイルメチルアラニンナトリウムを使用し、ガラス容器の場合には、ラウリルトリメチルアンモニウムクロリド、ココナットアミンアセテート、又はβ‐ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩を使用することがさらに好ましい。 The cholic acid types of anionic surfactants include sodium deoxycholic acid [CAS number: 302-95-4, manufactured by Fujifilm Wako Co., Ltd.] and sodium cholic acid [CAS number: 361-09-1, Fuji. Film Wako Co., Ltd.] and the like.
Examples of the sulfate ester (sulfate) type include higher alcohol sulfate esters such as dodecyl sulfate ester, polyoxyethylene alkyl ether sulfate esters such as polyoxyethylene dodecyl ether sulfate ester, and salts with sodium and ammonium. Specifically, for example, sodium dodecyl sulfate [CAS number: 151-21-3, manufactured by Sigma-Aldrich], ammonium lauryl sulfate [CAS number: 2235-54-3, Latemul (registered trademark) AD-25, Kao Co., Ltd. Higher alcohol sulfate ester salts such as [manufactured by], polyoxyethylene alkyl ether sulfate ester salts such as polyoxyethylene lauryl ether sulfate sodium [CAS number: 68585-34-2, product name: Emar 20C, manufactured by Kao Co., Ltd.] Can be mentioned.
Examples of the carboxylic acid type include dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), and cis-9-octadecenoic acid (oleic acid) having 8 to carbon atoms. Examples thereof include salts of 22 higher fatty acids and the like with alkali metals such as sodium and potassium. Specifically, for example, sodium laurate [CAS number: 629-25-4, manufactured by Fujifilm Wako Co., Ltd.], sodium myristate [CAS number: 822-12-8, manufactured by Fujifilm Wako Co., Ltd.], palmitic acid. Sodium [CAS number: 408-35-5, manufactured by Tokyo Kasei Kogyo Co., Ltd.], sodium lauroyl sarcosine [CAS number: 137-16-6, manufactured by Tokyo Kasei Kogyo Co., Ltd.], sodium polyoxyethylene lauryl ether acetate [CAS number : 33939-64-9, Product Name: Enagicor EC-30, manufactured by Lion Specialty Chemicals Co., Ltd.], and Lauroylmethylalanine Sodium [CAS Number: 21539-58-2, Product Name: Enagicor L-30AN, Lion. Specialty Chemicals Co., Ltd.] and so on.
Examples of the sulfonic acid type include alkylbenzene sulfonic acid such as dodecylbenzene sulfonic acid, naphthalene sulfonic acid such as dibutylnaphthalene sulfonic acid, formalin condensate of naphthalene sulfonic acid, sulfosuccinic acid such as dioctylsulfosuccinic acid, and salts such as sodium. Can be mentioned. Specifically, for example, sodium laurylbenzene sulfonate [CAS number: 25155-30-0, manufactured by Fujifilm Wako Co., Ltd.], β-naphthalene sulfonic acid formarin condensate sodium salt [CAS number: 9084-06-4, product. Name: Demol (registered trademark) RN, manufactured by Kao Co., Ltd.], and sodium dioctylsulfosuccinate [CAS number: 577-11-7, product name: Neocol (registered trademark) SW, manufactured by Daiichi Kogyo Co., Ltd.], etc. Be done.
The cationic or anionic surfactants used in the compositions of the present invention are coconutamine acetate, lauryltrimethylammonium chloride, sodium sulphonate, sodium dodecyl sulfate, sodium lauroylmethylalanine, or β-. Sodium salt of sodium phthalene sulfonic acid formalin condensate is more preferable. In particular, in the case of plastic containers, lauryltrimethylammonium chloride, sodium colate, sodium dodecyl sulfate, or sodium lauroylmethylalanine is used, and in the case of glass containers, lauryltrimethylammonium chloride, coconatamine acetate, or β. -It is further preferred to use sodium salt of sodium naphthalene sulfonic acid formalin condensate.
（界面活性剤の濃度）
　本発明のＴＡＲＣの保存安定性向上方法において、陽イオン性界面活性剤又は陰イオン性界面活性剤の濃度は、以下に限定されるものではないが、ＴＡＲＣの安定性を考慮して、組成物に対して、好ましくは０．００００１質量％～１質量％、より好ましくは０．０００１質量％～１質量％、さらに好ましくは０．００１質量％～０．５質量％、最も好ましくは０．００１質量％～０．１質量％である。 (Concentration of surfactant)
In the method for improving the storage stability of TARC of the present invention, the concentration of the cationic surfactant or the anionic surfactant is not limited to the following, but the composition is made in consideration of the stability of TARC. On the other hand, it is preferably 0.00001% by mass to 1% by mass, more preferably 0.0001% by mass to 1% by mass, still more preferably 0.001% by mass to 0.5% by mass, and most preferably 0.001. It is from mass% to 0.1% by mass.
（ＴＡＲＣ吸着防止剤）
　本発明のＴＡＲＣ吸着防止剤は、陽イオン性界面活性剤又は陰イオン性界面活性剤を含む。保存容器にＴＡＲＣを含む溶液を接触させる前に陽イオン性界面活性剤又は陰イオン性界面活性剤を含むＴＡＲＣ吸着防止剤を添加してもよく、ＴＡＲＣ溶液に吸着防止剤として陽イオン性界面活性剤又は陰イオン性界面活性剤を添加しておき、これを保存容器に添加してもよい。 (TARC adsorption inhibitor)
The TARC adsorption inhibitor of the present invention contains a cationic surfactant or an anionic surfactant. A TARC adsorption inhibitor containing a cationic surfactant or an anionic surfactant may be added before contacting the storage container with the solution containing TARC, and the cationic surfactant as an adsorption inhibitor may be added to the TARC solution. An agent or anionic surfactant may be added and added to the storage container.
　次に実施例を挙げて本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。なお、本明細書において特に説明のない限り、％は質量％を示す。なお、実施例で使用した界面活性剤の製品名、成分名および販売元は以下のとおりである。
・エマノーン（登録商標）１１１２　成分名：ポリエチレングリコールモノラウレート、花王株式会社
・Ｂｒｉｊ（登録商標）３５　成分名：ポリオキシエチレンラウリルエーテル、キシダ化学株式会社
・Ｔｒｉｔｏｎ（登録商標）Ｘ－１００　成分名：ポリエチレングリコールモノーｐ－イソオクチルフェニルエーテル、キシダ化学株式会社
・ＭＥＧＡ－９　成分名：ｎ－ノナノイルーＮ－メチルーＤ－グルカミン、株式会社同仁化学研究所
・コール酸ナトリウム　成分名：コール酸ナトリウム、富士フイルム和光株式会社
・ＳＤＳ　成分名：ラウリル硫酸ナトリウム、Ｓｉｇｍａ　Ａｌｄｒｉｃｈ株式会社
・エナジコール（登録商標）Ｌ－３０ＡＮ　成分名：ラウロイルメチルアラニンナトリウム、ライオン・スペシャリティ・ケミカルズ株式会社
・デモール（登録商標）ＲＮ　成分名：β―ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩、花王株式会社
・アセタミン（登録商標）２４　成分名：ココナットアミンアセテート、花王株式会社
・コータミン（登録商標）２４Ｐ　成分名：ラウリルトリメチルアンモニウムクロライド、花王株式会社
・ＣＨＡＰＳ　成分名：３－［（３－Ｃｈｏｌａｍｉｄｏｐｒｏｐｙｌ）ｄｉｍｅｔｈｙｌａｍｍｏｎｉｏ］ｐｒｏｐａｎｅｓｕｌｆｏｎａｔｅ、株式会社同仁化学研究所 Next, the present invention will be specifically described with reference to examples, but these do not limit the scope of the present invention. Unless otherwise specified in the present specification,% indicates mass%. The product names, ingredient names and distributors of the surfactants used in the examples are as follows.
・ Emanon (registered trademark) 1112 Ingredient name: Polyethylene glycol monolaurate, Kao Co., Ltd. ・ Brij (registered trademark) 35 Ingredient name: Polyoxyethylene lauryl ether, Kishida Chemical Co., Ltd. ・ Triton (registered trademark) X-100 Ingredient name : Polyethylene Glycol Monop-isooctyl phenyl ether, Kishida Chemical Co., Ltd. MEGA-9 Ingredient name: n-Nonanoyl-N-methyl-D-glucamine, Dojin Chemical Laboratory Co., Ltd. Ingredient name: Sodium dodecyl, Fuji Film Wako Co., Ltd. ・ SDS component name: sodium lauryl sulfate, Sigma Aldrich Co., Ltd. ・ Energol (registered trademark) L-30AN Ingredient name: lauroylmethylalanine sodium, Lion Specialty Chemicals Co., Ltd. : Β-naphthalene sulfonic acid formarin condensate sodium salt, Kao Co., Ltd.-Acetamine (registered trademark) 24 Ingredient name: Coconatamine acetate, Kao Co., Ltd.-Cotamin (registered trademark) 24P Ingredient name: Lauryltrimethylammonium chloride, Kao stock Company / CHAPS Ingredient name: 3-[(3-Cholamidopropyl) timelylammonio] propanesulfonate, Dojin Chemical Research Institute Co., Ltd.
≪実施例１：プラスチック製点眼瓶における保存安定性試験結果≫
　プラスチック製点眼瓶におけるＴＡＲＣの保存安定性を試験した。試験方法及び評価方法は以下のとおりである。保存液としては以下の組成の溶液を使用した。
・ＰＢＳ（ｐＨ７．２）
・１質量％　ＢＳＡ
・界面活性剤（濃度、製品名、種類は表１に記載） << Example 1: Storage stability test results in a plastic eye drop bottle >>
The storage stability of TARC in plastic eye drop bottles was tested. The test method and evaluation method are as follows. A solution having the following composition was used as the storage solution.
・ PBS (pH 7.2)
・ 1% by mass BSA
-Surfactant (concentration, product name, type are listed in Table 1)
（１）保存条件
　各濃度のＴＡＲＣの液状保存液をプラスチック製点眼瓶に０．５ｍＬずつ分注し、３７℃で２８日、あるいは４℃で２８日間保存した。ＴＡＲＣの濃度は、５００ｐｇ／ｍＬ、２０００ｐｇ／ｍＬ、及び１００００ｐｇ／ｍＬで試験した。 (1) Preservation conditions 0.5 mL of TARC liquid preservation solution of each concentration was dispensed into plastic eye drop bottles and stored at 37 ° C for 28 days or at 4 ° C for 28 days. TARC concentrations were tested at 500 pg / mL, 2000 pg / mL, and 10000 pg / mL.
（２）測定方法
　２種類の抗体を使用するラテックス免疫比濁法により測定した。以下に試薬の組成および測定方法を示す。第一試薬と第二試薬を用い、日立自動分析装置により測定した。
・第一試薬
　１００ｍＭ　ＭＯＰＳ－ＮａＯＨ（ｐＨ７．５）
　５００ｍＭ　ＮａＣｌ
　０．５％　ＢＳＡ　
・第二試薬
　抗ヒトＴＡＲＣモノクローナル抗体感作ラテックス（２種類）
　５ｍＭ　ＭＯＰＳ－ＮａＯＨ（ｐＨ７．０）
　なお、抗ヒトＴＡＲＣモノクローナル抗体は、市販のＴＡＲＣ抗原を使用し、当業者周知の方法にて取得した。市販のＴＡＲＣ抗原には、ＣＣＬ１７，　ｔｈｙｍｕｓ　ａｎｄ　ａｃｔｉｖａｔｉｏｎ　ｒｅｇｕｌａｔｅｄ　ｃｈｅｍｏｋｉｎｅ（Ｓｈｅｎａｎｄｏａｈ　Ｂｉｏｔｅｃｈｎｏｌｏｇｙ，Ｉｎｃ．）、ＣＣＬ１７／ＴＡＲＣ，　Ｈｕｍａｎ（ＬｉｆｅＳｐａｎ　Ｂｉｏｓｓｃｉｅｎｃｅ，Ｉｎｃ．）、Ｈｕｍａｎ　ＴＡＲＣ（ＣＣＬ１７）（Ａｂｅｏｍｉｃｓ，Ｉｎｃ．）があった。さらに、ＴＡＲＣ抗原に対してサンドイッチ測定が可能であるモノクローナル抗体の組み合わせを、当業者周知の方法にて選定した。抗ヒトＴＡＲＣモノクローナル抗体感作ラテックスは、特開２０１７－１８１３７７記載の方法を参考に調製した。
　まず、各濃度のＴＡＲＣの液状保存液２．４μＬに、第一試薬を１２０μＬずつ加えた。３７℃で５分間加温後、第二試薬を４０μＬずつ加えて攪拌した。その後、５分間の吸光度変化を、主波長５７０ｎｍ、副波長８００ｎｍにて測定した。測定された吸光度の変化量を濃度既知の標準物質を測定して得られる検量線を用いてＴＡＲＣ濃度に換算した。 (2) Measurement method Measurement was performed by a latex immunoturbidimetry method using two types of antibodies. The composition of the reagent and the measurement method are shown below. The measurement was performed by a Hitachi automated analyzer using the first reagent and the second reagent.
-First reagent 100 mM MOPS-NaOH (pH 7.5)
500 mM NaCl
0.5% BSA
・ Second reagent Anti-human TARC monoclonal antibody sensitized latex (2 types)
5 mM MOPS-NaOH (pH 7.0)
The anti-human TARC monoclonal antibody was obtained by a method well known to those skilled in the art using a commercially available TARC antigen. Commercially available TARC antigens include CCL17, thymus and activated chemokine (Shenandoah Biotechnology, Inc.), CCL17 / TARC, Human (LifeSpan Biossyence, Inc., Inc., Inc.). Further, a combination of monoclonal antibodies capable of sandwich measurement against the TARC antigen was selected by a method well known to those skilled in the art. The anti-human TARC monoclonal antibody sensitized latex was prepared with reference to the method described in JP-A-2017-18137.
First, 120 μL of the first reagent was added to 2.4 μL of the liquid storage solution of TARC of each concentration. After heating at 37 ° C. for 5 minutes, 40 μL of the second reagent was added and the mixture was stirred. Then, the change in absorbance for 5 minutes was measured at a main wavelength of 570 nm and a sub-wavelength of 800 nm. The amount of change in the measured absorbance was converted to the TARC concentration using a calibration curve obtained by measuring a standard substance having a known concentration.
（３）ＴＡＲＣ残存率（％）の算出
　３７℃で２８日、あるいは４℃で２８日間保存後の各ＴＡＲＣの液状保存液のＴＡＲＣの濃度について、次式を用いて、ＴＡＲＣ残存率（％）を算出した。 (3) Calculation of TARC residual rate (%) The TARC residual rate (%) of the TARC concentration in the liquid storage solution of each TARC after storage at 37 ° C for 28 days or at 4 ° C for 28 days using the following formula. Was calculated.
ＴＡＲＣ残存率（％）＝点眼瓶で３７℃で２８日、あるいは４℃で２８日間保存後の各ＴＡＲＣ液状保存液のＴＡＲＣ濃度（ｐｇ／ｍＬ）／調製直後のＴＡＲＣ液状保存液のＴＡＲＣ濃度（ｐｇ／ｍＬ）×１００ TARC residual rate (%) = TARC concentration (pg / mL) of each TARC liquid storage solution after storage at 37 ° C for 28 days or 4 ° C for 28 days in an eye drop bottle / TARC concentration of TARC liquid storage solution immediately after preparation (TARC concentration) pg / mL) x 100
（４）各条件において使用した界面活性剤、濃度を表１に、評価結果を表２、３に示した。なお、ＴＡＲＣ残存率（％）は３回の実験の平均値を元に算出した。 (4) The surfactants and concentrations used under each condition are shown in Table 1, and the evaluation results are shown in Tables 2 and 3. The TARC residual rate (%) was calculated based on the average value of the three experiments.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　ＴＡＲＣ濃度が５００ｐｇ／ｍＬの場合、界面活性剤を添加していない条件１では、２８日経過後の残存率が４７．２％となり、著しく低い結果となった。脂肪酸エステル型、アルコール型、アルキルフェノール型、又は糖アミド型非イオン性界面活性剤を添加した条件２～６、及び両性界面活性剤を添加した条件６では、２８日経過後の残存率は６７．７～７８．８％と、いずれも８０．０％未満となった。特に条件６は、特許文献２に示された化合物であり、インスリンに対して保存安定性を向上させる効果があったが、ＴＡＲＣに対しては保存安定性向上の効果はわずかしかなかった。一方、本願で見いだされた陰イオン性界面活性剤又は陽イオン性界面活性剤を添加した条件７～１０においては、２８日経過後の残存率はいずれの界面活性剤においても８０％以上となった。これは、条件７～１０では、陰イオン性界面活性剤又は陽イオン性界面活性剤の添加により、容器の壁面へのＴＡＲＣの吸着を防止できたため、または保存中のＴＡＲＣの構造変化を抑制できたためと考えられた。同様に、ＴＡＲＣ濃度が２０００ｐｇ／ｍＬ、１００００ｐｇ／ｍＬの場合も、界面活性剤を添加しない条件１、非イオン性界面活性剤を添加した条件２～５、両性界面活性剤を添加した条件６に対して、本願で見いだされた陰イオン性界面活性剤又は陽イオン性界面活性剤を添加した条件７～１０では、同等以上の残存率を示した。 When the TARC concentration was 500 pg / mL, under condition 1 without the addition of a surfactant, the residual rate after 28 days was 47.2%, which was a remarkably low result. Under conditions 2 to 6 to which a fatty acid ester type, alcohol type, alkylphenol type, or sugar amide type nonionic surfactant was added, and condition 6 to which an amphoteric surfactant was added, the residual rate after 28 days was 67.7. It was ~ 78.8%, which was less than 80.0%. In particular, Condition 6 is a compound shown in Patent Document 2, and has an effect of improving storage stability with respect to insulin, but has a slight effect of improving storage stability with respect to TARC. On the other hand, under the conditions 7 to 10 to which the anionic surfactant or the cationic surfactant found in the present application was added, the residual rate after 28 days was 80% or more for any of the surfactants. .. This is because under conditions 7 to 10, the addition of an anionic surfactant or a cationic surfactant could prevent the adsorption of TARC on the wall surface of the container, or could suppress the structural change of TARC during storage. It was thought that it was a tame. Similarly, when the TARC concentration is 2000 pg / mL and 10000 pg / mL, the conditions 1 in which the surfactant is not added, the conditions 2 to 5 in which the nonionic surfactant is added, and the condition 6 in which the amphoteric surfactant is added are met. On the other hand, under the conditions 7 to 10 to which the anionic surfactant or the cationic surfactant found in the present application was added, the residual rate was equal to or higher than that.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　ＴＡＲＣ濃度が５００ｐｇ／ｍＬの場合、界面活性剤を添加していない条件１では、２８日経過後の残存率が６５．７％となり、低い結果となった。本発明で見いだされた陰イオン性界面活性剤又は陽イオン性界面活性剤を添加した条件７～１０では、２８日経過後の残存率が９２．０～１００．５％となり、いずれの界面活性剤においても、２８日経過後の残存率が大幅に改善された。これは、条件７～１０では、陰イオン性界面活性剤又は陽イオン性界面活性剤の添加により、容器の壁面へのＴＡＲＣの吸着を防止できたため、または保存中のＴＡＲＣの構造変化を抑制できたためと考えられた。
　以上より、陰イオン性界面活性剤又は陽イオン性界面活性剤とＴＡＲＣとを共存させることで、プラスチック製点眼瓶保存時におけるＴＡＲＣの保存安定性が改善することが示された。 When the TARC concentration was 500 pg / mL, the residual rate after 28 days was 65.7% under the condition 1 in which the surfactant was not added, which was a low result. Under the conditions 7 to 10 to which the anionic surfactant or the cationic surfactant found in the present invention was added, the residual rate after 28 days was 92.0 to 100.5%, and any of the surfactants However, the survival rate after 28 days was significantly improved. This is because under conditions 7 to 10, the addition of an anionic surfactant or a cationic surfactant could prevent the adsorption of TARC on the wall surface of the container, or could suppress the structural change of TARC during storage. It was thought that it was a tame.
From the above, it was shown that the coexistence of an anionic surfactant or a cationic surfactant and TARC improves the storage stability of TARC during storage of a plastic instillation bottle.
≪実施例２：ガラスバイアルにおける保存安定性試験結果≫
　ガラスバイアルにおけるＴＡＲＣの保存安定性を試験した。試験方法及び評価方法は以下のとおりである。保存液としては以下の組成の溶液を使用した。
・ＰＢＳ（ｐＨ７．２）
・１質量％　ＢＳＡ
・界面活性剤（濃度、製品名、種類は表４に記載） << Example 2: Storage stability test results in glass vials >>
The storage stability of TARC in glass vials was tested. The test method and evaluation method are as follows. A solution having the following composition was used as the storage solution.
・ PBS (pH 7.2)
・ 1% by mass BSA
-Surfactant (concentration, product name, type are listed in Table 4)
（１）保存条件
　各濃度のＴＡＲＣの液状保存液をガラス容器に０．５ｍＬずつ分注し、１０℃で６時間保存した。対照として、ガラス容器に分注前の試料も測定に供した。ＴＡＲＣの濃度は、２０００ｐｇ／ｍＬ、及び１００００ｐｇ／ｍＬで試験した。 (1) Preservation conditions 0.5 mL of TARC liquid preservation solution of each concentration was dispensed into a glass container and stored at 10 ° C. for 6 hours. As a control, a sample before dispensing in a glass container was also used for measurement. TARC concentrations were tested at 2000 pg / mL and 10000 pg / mL.
（２）測定方法
　実施例１と同一の測定方法で測定した。 (2) Measurement method Measurement was performed by the same measurement method as in Example 1.
（３）ＴＡＲＣ残存率（％）の算出
　１０℃、６時間保存後の各ＴＡＲＣ液状保存液のＴＡＲＣ濃度について、次式を用いて、ＴＡＲＣ残存率（％）を算出した。 (3) Calculation of TARC Residual Rate (%) The TARC residual rate (%) was calculated using the following formula for the TARC concentration of each TARC liquid storage solution after storage at 10 ° C. for 6 hours.
ＴＡＲＣ残存率（％）＝ガラス容器で１０℃、６時間保存後の各ＴＡＲＣ液状保存液のＴＡＲＣ濃度（ｐｇ／ｍＬ）／ガラス容器分注前のＴＡＲＣ液状保存液のＴＡＲＣ濃度（ｐｇ／ｍＬ）×１００ TARC residual rate (%) = TARC concentration of each TARC liquid storage solution after storage in a glass container at 10 ° C. for 6 hours (pg / mL) / TARC concentration of TARC liquid storage solution before dispensing in a glass container (pg / mL) × 100
（４）各条件において使用した界面活性剤、濃度を表４に、評価結果を表５に示した。なお、ＴＡＲＣ残存率（％）は３回の実験の平均値を元に算出した。 (4) The surfactants and concentrations used under each condition are shown in Table 4, and the evaluation results are shown in Table 5. The TARC residual rate (%) was calculated based on the average value of the three experiments.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　ＴＡＲＣ濃度が２０００ｐｇ／ｍＬの場合、界面活性剤を添加していない条件１では、６時間経過後の残存率が４２．７％となり、低い結果となった。非イオン性界面活性剤又は両性界面活性剤を添加した条件２～６では、６時間経過後の残存率は４８．６～５２．５％と、ほとんど改善されなかった。
　陽イオン性界面活性剤又は陰イオン性界面活性剤を添加した条件１０～１２においては、いずれの界面活性剤においても、６時間経過後の残存率が改善され、特に条件１２では９３．７％と大幅に改善された。ＴＡＲＣ濃度が１００００ｐｇ／ｍＬの場合も、陽イオン性界面活性剤又は陰イオン性界面活性剤を添加した条件１０～１２において、２０００ｐｇ／ｍＬと同様に残存率が改善された。特に条件１１、１２では残存率がそれぞれ９３．７％、９６．６％と大幅に改善された。
　以上より、陽イオン性界面活性剤又は陰イオン性界面活性剤とＴＡＲＣとを共存させることで、ガラスバイアル保存時におけるＴＡＲＣの保存安定性が改善することが示された。これは、条件１０～１２では、陽イオン性界面活性剤又は陰イオン性界面活性剤の添加により、容器の壁面へのＴＡＲＣの吸着を防止できたため、または保存中のＴＡＲＣの構造変化を抑制できたためと考えられた。 When the TARC concentration was 2000 pg / mL, the residual rate after 6 hours was 42.7% under the condition 1 in which the surfactant was not added, which was a low result. Under the conditions 2 to 6 to which the nonionic surfactant or the amphoteric surfactant was added, the residual rate after 6 hours was 48.6 to 52.5%, which was hardly improved.
Under conditions 10 to 12 to which a cationic or anionic surfactant was added, the residual rate after 6 hours was improved with any of the surfactants, and particularly under condition 12, 93.7%. It was greatly improved. Even when the TARC concentration was 10000 pg / mL, the residual rate was improved as in 2000 pg / mL under the conditions 10 to 12 in which the cationic surfactant or the anionic surfactant was added. In particular, under conditions 11 and 12, the survival rates were significantly improved to 93.7% and 96.6%, respectively.
From the above, it was shown that the coexistence of a cationic surfactant or an anionic surfactant with TARC improves the storage stability of TARC during storage of glass vials. This is because under conditions 10 to 12, the addition of a cationic or anionic surfactant could prevent the adsorption of TARC on the wall surface of the container, or the structural change of TARC during storage could be suppressed. It was thought that it was a tame.
　本発明によれば、保存安定性の高いＴＡＲＣ含有組成物、特に、ＴＡＲＣ含有校正用試料を提供することができる。  According to the present invention, it is possible to provide a TARC-containing composition having high storage stability, particularly a TARC-containing calibration sample. The

Claims (20)

  1. 　ＴＡＲＣ（Ｔｈｙｍｕｓ　ａｎｄ　ａｃｔｉｖａｔｉｏｎ－ｒｅｇｕｌａｔｅｄ　ｃｈｅｍｏｋｉｎｅ）を含む組成物であって、
    　ＴＡＲＣ、並びに
    陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤
    を含み、そして
    液状である、前記組成物。     A composition comprising TARC (Thymus and activation-regulated chemokine).
    The composition comprising TARC and at least one surfactant selected from the group consisting of cationic and anionic surfactants and in liquid form.
  2. 　ＴＡＲＣを測定するための校正用試料溶液である、請求項１に記載の組成物。 The composition according to claim 1, which is a sample solution for calibration for measuring TARC.
  3. 　保存容器に充填されている、請求項１又は２に記載の組成物。 The composition according to claim 1 or 2, which is filled in a storage container.
  4. 　保存容器が、プラスチック又はガラスである、請求項３に記載の組成物。 The composition according to claim 3, wherein the storage container is plastic or glass.
  5. 　ＴＡＲＣの濃度が、前記組成物に対して、１０ｐｇ／ｍＬ～１μｇ／ｍＬである、請求項１～４のいずれかに記載の組成物。 The composition according to any one of claims 1 to 4, wherein the concentration of TARC is 10 pg / mL to 1 μg / mL with respect to the composition.
  6. 　前記界面活性剤の濃度が、前記組成物に対して、０．００００１質量％～１質量％である、請求項１～５のいずれかに記載の組成物。 The composition according to any one of claims 1 to 5, wherein the concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the composition.
  7. 　陽イオン性界面活性剤が、アルキルアミン塩型又は第四級アンモニウム塩型陽イオン性界面活性剤であり、
    　陰イオン性界面活性剤が、コール酸型、サルフェート型、カルボン酸型、又はスルホン酸型陰イオン性界面活性剤である、請求項１～６のいずれかに記載の組成物。     The cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
    The composition according to any one of claims 1 to 6, wherein the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant.
  8. 　ＴＡＲＣの濃度が、前記組成物に対して５００ｐｇ／ｍＬの場合に、３７℃で２８日間、プラスチック容器において保存した後のＴＡＲＣの残存率が、８０％以上である、請求項１～７のいずれかに記載の組成物。 Any of claims 1 to 7, wherein when the concentration of TARC is 500 pg / mL with respect to the composition, the residual rate of TARC after storage at 37 ° C. for 28 days in a plastic container is 80% or more. The composition described in Crab.
  9. 　ＴＡＲＣの濃度が、前記組成物に対して５００ｐｇ／ｍＬの場合に、４℃で２８日間、プラスチック容器において保存した後のＴＡＲＣの残存率が、９０％以上である、請求項１～８のいずれかに記載の組成物。 Any of claims 1 to 8, wherein when the concentration of TARC is 500 pg / mL with respect to the composition, the residual rate of TARC after storage in a plastic container at 4 ° C. for 28 days is 90% or more. The composition described in Crab.
  10. 　ＴＡＲＣの濃度が、前記組成物に対して２０００ｐｇ／ｍＬの場合に、１０℃で６時間、ガラス容器において保存した後のＴＡＲＣ残存率が５５％以上である、請求項１～９のいずれかに記載の組成物。 According to any one of claims 1 to 9, when the concentration of TARC is 2000 pg / mL with respect to the composition, the residual rate of TARC after storage at 10 ° C. for 6 hours in a glass container is 55% or more. The composition described.
  11. 　陽イオン性界面活性剤が、ラウリルトリメチルアンモニウムクロライド又はココナットアミンアセテートであり、
    陰イオン性界面活性剤が、コール酸ナトリウム、ラウリル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ―ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩である、請求項１～１０のいずれかに記載の組成物。     The cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate,
    The composition according to any one of claims 1 to 10, wherein the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or β-naphthalene sulfonic acid formarin condensate sodium salt.
  12. 　請求項１～１１のいずれかに記載の組成物を使用する、ＴＡＲＣの測定方法。 A method for measuring TARC using the composition according to any one of claims 1 to 11.
  13. 　請求項１～１１のいずれかに記載の組成物を含む、ＴＡＲＣの測定キット。 A TARC measurement kit comprising the composition according to any one of claims 1 to 11.
  14. 　陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤を含む溶液にＴＡＲＣを接触させる工程を含む、ＴＡＲＣの保存安定性向上方法。 A method for improving the storage stability of TARC, which comprises a step of contacting TARC with a solution containing at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant.
  15. 　前記ＴＡＲＣの濃度が、前記溶液に対して、１０ｐｇ／ｍＬ～１μｇ／ｍＬとなるように調整する工程を含む、請求項１４に記載のＴＡＲＣの保存安定性向上方法。 The method for improving storage stability of TARC according to claim 14, further comprising a step of adjusting the concentration of TARC to be 10 pg / mL to 1 μg / mL with respect to the solution.
  16. 　前記界面活性剤の濃度が、前記溶液に対して、０．００００１質量％～１質量％である、請求項１４又は１５に記載のＴＡＲＣの保存安定性向上方法。 The method for improving the storage stability of TARC according to claim 14 or 15, wherein the concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the solution.
  17. 　陽イオン性界面活性剤が、アルキルアミン塩型又は第四級アンモニウム塩型陽イオン性界面活性剤であり、
    　陰イオン性界面活性剤が、コール酸型、サルフェート型、カルボン酸型、又はスルホン酸型陰イオン性界面活性剤である、請求項１４～１６のいずれかに記載のＴＡＲＣの保存安定性向上方法。     The cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
    The method for improving the storage stability of TARC according to any one of claims 14 to 16, wherein the anionic surfactant is a cholic acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant. ..
  18. 　陽イオン性界面活性剤が、ラウリルトリメチルアンモニウムクロライド又はココナットアミンアセテートであり、
    　陰イオン性界面活性剤が、コール酸ナトリウム、ラウリル硫酸ナトリウム、ラウロイルメチルアラニンナトリウム、又はβ―ナフタレンスルホン酸ホルマリン縮合物ナトリウム塩である、請求項１４～１７のいずれかに記載のＴＡＲＣの保存安定性向上方法。     The cationic surfactant is lauryltrimethylammonium chloride or coconatamine acetate,
    The storage stability of TARC according to any one of claims 14 to 17, wherein the anionic surfactant is sodium collate, sodium lauryl sulfate, sodium lauroylmethylalanine, or β-naphthalene sulfonic acid formarin condensate sodium salt. How to improve sex.
  19. 　ＴＡＲＣを含む溶液中のＴＡＲＣの容器への吸着防止剤であって、陽イオン性界面活性剤及び陰イオン性界面活性剤からなる群から選択される少なくとも１つ以上の界面活性剤を有効成分として含有する前記吸着防止剤。  An antiadsorption agent for adsorbing TARC in a solution containing TARC, wherein at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant is used as an active ingredient. The adsorption inhibitor contained. The
  20. 　陽イオン性界面活性剤が、アルキルアミン塩型又は第四級アンモニウム塩型陽イオン性界面活性剤であり、
    　陰イオン性界面活性剤が、コール酸型、サルフェート型、カルボン酸型、又はスルホン酸型陰イオン性界面活性剤である、請求項１９に記載の吸着防止剤。      The cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant.
    The adsorption inhibitor according to claim 19, wherein the anionic surfactant is a cole acid type, a sulfate type, a carboxylic acid type, or a sulfonic acid type anionic surfactant.
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