Composition containing TARC and method for improving storage stability of TARC

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

[Technical Field]

[0001] The present invention relates to a composition containing TARC. More specifically, the present invention relates to a composition that allows stable long-term storage of TARC. The present invention also relates to a method and kit for measuring TARC, a method for improving the storage stability of TARC, and an agent for preventing adsorption of TARC. [Background technology]

[0002] Thymus and activation-regulated chemokine (hereinafter sometimes referred to as TARC) is CC chemokine ligand 17 (CCL17), a type of chemokine that has leukocyte migration activity. TARC attracts Th2 cells, a type of lymphocyte, to the lesion site, causing IgE production and eosinophil infiltration and activation. In this way, TARC is thought to exacerbate the symptoms of atopic dermatitis by enhancing the allergic response (Non-Patent Document 1).

[0003] It is considered important to quickly and reliably alleviate inflammation in atopic dermatitis. Compared with serum IgE levels, peripheral blood eosinophil counts, and serum LDH levels, which have been used as indicators of the disease progression of atopic dermatitis, TARC is thought to closely correspond to the severity of atopic dermatitis and more sensitively reflect the disease progression (Non-Patent Document 2). Therefore, by using TARC as a biomarker, it is possible to objectively and quickly grasp the severity and evaluate the effectiveness when selecting or changing a therapeutic drug for atopic dermatitis.

[0004] Quantitation of a target component in a biological sample requires the use of a calibration sample. A calibration sample is a sample containing the target component and is used as an internal standard or a standard (calibrator) for concentration calibration. To obtain accurate quantitative values, a calibration sample that is stable over time and temperature is required. For ease of operation, the calibration sample is preferably in a fluid solution state (hereinafter sometimes referred to as "liquid"). In this case, desirable features of the calibration sample include maintaining biological activity (e.g., antigenicity against specific antibodies, binding activity against specific binding partners possessed by antibodies, lectins, etc., physiological activity possessed by peptide hormones, enzymatic activity, and three-dimensional protein structure supporting each of the above activities), preventing adsorption to containers, and maintaining antiseptic properties.

[0005] Known methods for preserving liquid calibration samples intended for use in immunoassays include a method of stabilizing antigens by adding casein and / or whey protein to the calibration sample (Patent Document 1), a method of stabilizing insulin by adding a bile acid amide derivative (Patent Document 2), and a method of stabilizing soluble interleukin-2 receptor (sIL-2R) by adding a chelating agent (Patent Document 3). Stabilization methods must be considered depending on the properties of the substance to be stabilized, but no detailed studies have been conducted on liquid calibration samples for TARC at present. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent Publication No. 08-005634 [Patent Document 2] Patent Publication No. 08-012593 [Patent Document 3] Patent Publication No. 2010-230660 [Non-patent literature]

[0007] [Non-Patent Document 1] J Allergy Clin Immunol 107:535-541,2001 [Non-patent document 2] Journal of the Japanese Dermatological Association 116(1):27-39, 2006 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a TARC-containing composition that has high storage stability. [Means for solving the problem]

[0009] The present inventors attempted to create a TARC-containing composition with high storage stability. They found that the stability of TARC improved when TARC was added to a solution containing at least one surfactant selected from the group consisting of cationic surfactants and anionic surfactants. The present invention is based on this finding. Specifically, the present invention is as follows. <1> A composition comprising TARC (Thymus and activation-regulated chemokine), The composition comprises TARC and at least one surfactant selected from the group consisting of cationic surfactants and anionic surfactants, and is in a liquid form. <2> A calibration sample solution for measuring TARC. <1> The composition described in <3> Filled into storage containers, <1> or <2> The composition described in <4> The storage container is plastic or glass. <3> The composition described in <5> The concentration of TARC in the composition is 10 pg / mL to 1 μg / mL. <1> ~ <4> The composition according to any one of the preceding claims. <6> The concentration of the surfactant is 0.00001% by mass to 1% by mass relative to the composition. <1> ~ <5> The composition according to any one of the preceding claims. <7> the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant; The anionic surfactant is a cholic acid type, sulfate type, carboxylic acid type, or sulfonic acid type anionic surfactant; <1> ~ <6> The composition according to any one of the preceding claims. <8> When the TARC concentration in the composition is 500 pg / mL, the residual rate of TARC after storage in a plastic container at 37°C for 28 days is 80% or more. <1> ~ <7> The composition according to any one of the preceding claims. <9> When the TARC concentration in the composition is 500 pg / mL, the residual rate of TARC after storage in a plastic container at 4°C for 28 days is 90% or more. <1> ~ <8> The composition according to any one of the preceding claims. <10> When the TARC concentration in the composition is 2000 pg / mL, the TARC remaining rate after storage in a glass container at 10°C for 6 hours is 55% or more. <1> ~ <9> The composition according to any one of the preceding claims. <11> the cationic surfactant is lauryltrimethylammonium chloride or coconutamine acetate; The anionic surfactant is sodium cholate, sodium lauryl sulfate, sodium lauroylmethylalanine, or sodium salt of β-naphthalenesulfonic acid formalin condensate; <1> ~ <10> The composition according to any one of the preceding claims. <12> <1> ~ <11> A method for measuring TARC using the composition described in any one of the above. <13> <1> ~ <11> A kit for measuring TARC, comprising the composition according to any one of the above. <14> A method for improving the storage stability of TARC, comprising the step of contacting TARC with a solution containing at least one surfactant selected from the group consisting of cationic surfactants and anionic surfactants. <15> adjusting the concentration of the TARC in the solution to 10 pg / mL to 1 μg / mL; <14> 2. A method for improving the storage stability of TARC according to claim 1. <16> The concentration of the surfactant is 0.00001% by mass to 1% by mass with respect to the solution. <14> or <15> 2. A method for improving the storage stability of TARC according to claim 1. <17> the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant; The anionic surfactant is a cholic acid type, sulfate type, carboxylic acid type, or sulfonic acid type anionic surfactant; <14> ~ <16> 2. A method for improving the storage stability of TARC according to any one of the preceding claims. <18> the cationic surfactant is lauryltrimethylammonium chloride or coconutamine acetate; The anionic surfactant is sodium cholate, sodium lauryl sulfate, sodium lauroylmethylalanine, or sodium salt of β-naphthalenesulfonic acid formalin condensate; <14> ~ <17> 2. A method for improving the storage stability of TARC according to any one of the preceding claims. <19> An agent for preventing adsorption of TARC to a container in a solution containing TARC, the agent containing at least one surfactant selected from the group consisting of cationic surfactants and anionic surfactants as an active ingredient. <20> The concentration of TARC in the solution containing TARC is 10 pg / mL to 1 μg / mL relative to the solution. <19> The adsorption inhibitor according to claim 1. <21> The surfactant is used so that the concentration thereof is 0.00001% by mass to 1% by mass relative to the solution. <19> or <20> The adsorption inhibitor according to claim 1. <22> the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant; The anionic surfactant is a cholic acid type, sulfate type, carboxylic acid type, or sulfonic acid type anionic surfactant; <19> ~ <21> The adsorption inhibitor according to any one of the preceding claims. <23> the cationic surfactant is lauryltrimethylammonium chloride or coconutamine acetate; The anionic surfactant is sodium cholate, sodium lauryl sulfate, sodium lauroylmethylalanine, or sodium salt of β-naphthalenesulfonic acid formalin condensate; <19> ~ <22> The adsorption inhibitor according to any one of the preceding claims. [Effects of the Invention]

[0010] According to the present invention, a TARC-containing composition, particularly a TARC-containing calibration sample, having high storage stability can be provided, which allows accurate quantification of TARC in a biological sample and accurate assessment of the severity of atopic dermatitis. DETAILED DESCRIPTION OF THE INVENTION

[0011] (TARC) As used herein, "TARC" stands for thymus and activation-regulated chemokine (CCL17). TARC is a type of chemokine that acts to chemotactically leukocytes. TARC attracts Th2 cells, a type of lymphocyte, to the lesion site, and induces IgE production or eosinophil infiltration and activation. Using TARC as a biomarker makes it possible to objectively and quickly grasp the severity of atopic dermatitis when selecting or changing therapeutic agents.

[0012] TARC can be measured using known techniques, such as immunological techniques, including ELISA, enzyme-linked immunosorbent assay, surface plasmon resonance, latex agglutination immunoassay (LTIA), chemiluminescent immunoassay, electrochemiluminescent immunoassay, fluorescent antibody technique, radioimmunoassay, Western blotting, immunochromatography, and high-performance liquid chromatography (HPLC).

[0013] The TARC contained in the composition of the present invention may be a commercially available product, or may be prepared or purified by oneself.The TARC contained in the composition of the present invention may be prepared in vitro or extracted from a living body.

[0014] (TARC concentration) The concentration of TARC contained in the composition of the present invention is not limited to the following, but taking into consideration the stability of TARC, it is preferably 10 pg / mL to 1 μg / mL, more preferably 50 pg / mL to 500 ng / mL, even more preferably 100 pg / mL to 100 ng / mL, and most preferably 100 pg / mL to 50 ng / mL of the composition.

[0015] (cationic surfactants and anionic surfactants) In this specification, an anionic surfactant refers to a surfactant whose hydrophobic group is ionized into a negative ion when dissolved in water. In this specification, a surfactant having a hydrophilic group that does not ionize when dissolved in water is called a nonionic surfactant, a surfactant whose hydrophobic group is ionized into a positive ion is called a cationic surfactant, and a surfactant that exhibits the properties of an anionic surfactant in the alkaline range and the properties of a cationic surfactant in the acidic range is called an amphoteric surfactant.

[0016] Preferred cationic surfactants are alkylamine salts, quaternary ammonium salts, etc. Preferred anionic surfactants are cholic acid, sulfate, carboxylic acid, sulfonic acid, etc.

[0017] Examples of alkylamine salt-type cationic surfactants include salts of amines containing 1 to 3 alkyl groups having 8 to 22 carbon atoms, such as monododecylamine, monooctadecylamine, dioctadecylamine, and trioctadecylamine, with inorganic acids such as hydrochloric acid and sulfuric acid, or lower carboxylic acids such as acetic acid, lactic acid, and citric acid. Specific examples include dodecylamine hydrochloride [CAS No. 929-73-7, manufactured by Tokyo Chemical Industry Co., Ltd.], coconutamine acetate [CAS No. 61790-57-6, product name: Acetamine 24, manufactured by Kao Corporation], and stearylamine acetate [CAS No. 2190-04-7, product name: Acetamine 86, manufactured by Kao Corporation]. Examples of quaternary ammonium salts include salts of ammonium containing one to three alkyl groups having 8 to 22 carbon atoms, such as dodecyltrimethylammonium, octadecyltrimethylammonium, hexadecyltrimethylammonium, didecyldimethylammonium, and benzylmethyltetradecylammonium, with chlorine, bromine, etc. Specific examples include lauryltrimethylammonium chloride [CAS number: 112-00-5, product name: QUATAMIN (registered trademark) 24P, manufactured by Kao Corporation], dodecyltrimethylammonium bromide [CAS number: 1119-94-4, manufactured by Tokyo Chemical Industry Co., Ltd.], octadecyltrimethylammonium chloride [CAS number: 112-03-8, manufactured by Tokyo Chemical Industry Co., Ltd.], and distearyldimethylammonium chloride [CAS number: 107-64-2, product name: QUATAMIN (registered trademark) D86P, manufactured by Kao Corporation].

[0018] Examples of the cholic acid type anionic surfactant include sodium deoxycholate [CAS number: 302-95-4, manufactured by Fujifilm Wako Co., Ltd.] and sodium cholate [CAS number: 361-09-1, manufactured by Fujifilm Wako Co., Ltd.]. Examples of sulfate types include salts of higher alcohol sulfates such as dodecyl sulfate, and polyoxyethylene alkyl ether sulfates such as polyoxyethylene dodecyl ether sulfate with sodium, ammonium, etc. Specific examples include higher alcohol sulfates such as sodium dodecyl sulfate [CAS number: 151-21-3, Sigma-Aldrich] and ammonium lauryl sulfate [CAS number: 2235-54-3, Latemul (registered trademark) AD-25, Kao Corporation], and polyoxyethylene alkyl ether sulfates such as sodium polyoxyethylene lauryl ether sulfate [CAS number: 68585-34-2, product name: Emal 20C, Kao Corporation]. Examples of the carboxylic acid type include salts of higher fatty acids having 8 to 22 carbon atoms, such as dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), and cis-9-octadecenoic acid (oleic acid), with alkali metals such as sodium and potassium. Specific examples include 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.], sodium palmitate [CAS number: 408-35-5, manufactured by Tokyo Chemical Industry Co., Ltd.], sodium lauroyl sarcosinate [CAS number: 137-16-6, manufactured by Tokyo Chemical Industry Co., Ltd.], sodium polyoxyethylene lauryl ether acetate [CAS number: 33939-64-9, product name: Energicol EC-30, manufactured by Lion Specialty Chemicals Co., Ltd.], and sodium lauroyl methylalanine [CAS number: 21539-58-2, product name: Energicol L-30AN, manufactured by Lion Specialty Chemicals Co., Ltd.]. Examples of sulfonic acid-type compounds include alkylbenzenesulfonic acids such as dodecylbenzenesulfonic acid, naphthalenesulfonic acids such as dibutylnaphthalenesulfonic acid, formalin condensates of naphthalenesulfonic acid, sulfosuccinic acids such as dioctyl sulfosuccinic acid, and salts thereof, such as sodium salts. Specific examples include sodium laurylbenzenesulfonate [CAS No.: 25155-30-0, manufactured by Fujifilm Wako Co., Ltd.], sodium salt of β-naphthalenesulfonic acid formalin condensate [CAS No.: 9084-06-4, product name: Demol (registered trademark) RN, manufactured by Kao Corporation], and sodium dioctyl sulfosuccinate [CAS No.: 577-11-7, product name: Neocol (registered trademark) SW, manufactured by Daiichi Kogyo Co., Ltd.]. These anionic surfactants or cationic surfactants are available from various detergent and reagent manufacturers, and can be purchased as commercial products. These anionic surfactants or cationic surfactants can be used alone or in combination of two or more. The cationic surfactant or anionic surfactant used in the composition of the present invention is preferably coconut amine acetate, lauryl trimethyl ammonium chloride, sodium cholate, sodium dodecyl sulfate, sodium lauroyl methyl alanine, or sodium salt of β-naphthalene sulfonic acid formalin condensate. In particular, in the case of a plastic container, it is more preferable to use lauryl trimethyl ammonium chloride, sodium cholate, sodium dodecyl sulfate, or sodium lauroyl methyl alanine, and in the case of a glass container, it is more preferable to use lauryl trimethyl ammonium chloride, coconut amine acetate, or sodium salt of β-naphthalene sulfonic acid formalin condensate. In addition to the anionic surfactant or cationic surfactant, other types of surfactants may be used within the scope of not impairing the effects of the present invention, but it is preferable not to use them.Furthermore, although anionic surfactants and cationic surfactants may be used in combination, it is preferable to use only one of them without using them in combination.

[0019] In the composition of the present invention, the order of addition of the cationic surfactant or anionic surfactant and TARC is not particularly limited, as long as the effects of the present invention can be obtained.

[0020] (Concentration of surfactant) In the composition of the present invention, the concentration of the cationic surfactant or anionic surfactant is, but is not limited to, preferably 0.00001 to 1% by mass, more preferably 0.0001 to 1% by mass, even more preferably 0.001 to 0.5% by mass, and most preferably 0.001 to 0.1% by mass, based on the composition, taking into consideration the stability of TARC.

[0021] (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 it can achieve the effects of the present invention and can be sealed. However, at least a portion or all of the portion that comes into contact with the composition may be made of plastic (e.g., olefin-based resins, styrene-based resins, acrylic-based resins, polyester-based resins, polycarbonate-based resins, fluororesins, chlorine-based resins (e.g., polyvinyl chloride), polyamide-based resins, polyacetal-based resins, polyphenylene ether-based resins (e.g., modified polyphenylene ether), polyarylate, polysulfone, polyimide-based resins, cellulose-based resins (e.g., cellulose acetate), hydrocarbon-based resins (including halogen-substituted products), etc.), metal (e.g., aluminum), glass, etc. Among these, plastic or glass is preferred from the viewpoints of production, transportation, and storage of calibration samples. Among plastics, olefin-based resins are preferred, and polypropylene is more preferred.

[0022] The storage container may be made of a single material or two or more materials, but is preferably made of a single material. The storage container may include a container body and a cap. In this case, the container body and the cap may be made of different materials. Furthermore, the storage container, particularly the body, is preferably transparent enough to allow the content liquid to be seen from the outside. The storage container may be in the form of either a hard or soft type, such as an ampoule, a vial, a soft bag, an injection-type container, or a glass bottle. From the viewpoint of ease of use and stability of TARC, the storage container is preferably in the form of a plastic eye dropper bottle, particularly a cylindrical eye dropper bottle, including a container body and a cap. Furthermore, from the viewpoint of ease of use and stability of TARC, the storage container is preferably in the form of a glass ampoule, or a glass container body and cap, particularly a cylindrical glass container and a rubber cap.

[0023] (composition) The composition of the present invention can be used as a calibration sample solution in the measurement of TARC. In this specification, the term "calibration sample solution" refers to a sample solution containing a target substance at a certain concentration, which is used to accurately measure the target substance, and includes a standard substance, a calibrator, a control, and an internal standard substance. The composition of the present invention can be supplied in a pre-liquid state, in which TARC and an anionic surfactant or a cationic surfactant are mixed in a solvent. In the TARC measurement method, "using a composition" means using a composition to accurately measure TARC, for example, using a liquid composition containing TARC as a calibration sample solution (standard substance, calibrator, control, internal standard substance, etc.).

[0024] 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 8.0. 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.

[0025] The composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention. When TARC is measured by an immunological assay, it is sufficient that the composition does not impair the effects of the present invention and does not interfere with all or part of the reactions that constitute the assay system, such as antigen-antibody reactions, labeling reactions for biotin-avidin detection, and enzymatic reactions. Various components commonly used in immunological assays, such as various buffers such as acetic acid, citric acid, phosphoric acid, PBS (phosphate-buffered saline), HEPES, MES, Tris, glycine, boric acid, carbonate, and Good's buffer, 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 (sucrose, cyclodextrin, etc.), and preservatives (sodium azide, ProClin 300, etc.), can be appropriately selected and used depending on the purpose. PBS with a pH of 6.5 to 8.0 is preferably used.

[0026] As used herein, "improved storage stability" or "improved storage stability" means that most of the TARC contained in a solution containing TARC is maintained for a long period of time without being decomposed, changing its structure, or being adsorbed to the container, so that there is no significant difference between the initial value of TARC in the solution and the measured value after storage. More specifically, "improved storage stability" or "improved storage stability" can mean, for example, that 80% or more of the TARC contained in a solution containing TARC at a concentration of 10 pg / mL to 1 μg / mL is maintained without being decomposed, changing in structure, or being adsorbed to the container for 28 days at 37°C, such that the measured value of TARC in the solution after storage in a plastic container at 37°C for 28 days is 80% or more of the initial value. Furthermore, "improved storage stability" or "improved storage stability" can mean, for example, that 90% or more of the TARC contained in a solution containing TARC at a concentration of 10 pg / mL to 1 μg / mL is maintained without being decomposed, changing in structure, or being adsorbed to the container for 28 days at 4°C, such that the measured value of TARC in the solution after storage in a plastic container at 4°C for 28 days is 90% or more of the initial value. Furthermore, "improved storage stability" or "improved storage stability" can mean, for example, that 55% or more of the TARC contained in a solution containing TARC at a concentration of 10 pg / mL to 1 μg / mL is maintained without being decomposed, changing in structure, or being adsorbed to the container for 6 hours at 10°C, so that the measured value of TARC in the solution after storage in a glass container at 10°C for 6 hours is 55% or more of the initial value.

[0027] (Biological samples for measuring TARC) The biological sample for measuring TARC is not particularly limited as long as it allows measurement of TARC, but blood, serum, or plasma is preferably used. The biological sample may be appropriately pretreated as needed. The biological sample is preferably a biological sample collected from a human.

[0028] (TARC measurement kit) The TARC assay kit of the present invention uses the composition of the present invention, allowing for simple and accurate TARC assay. Examples of the TARC assay kit include kits using immunological techniques. The TARC assay kit of the present invention may contain reagents for measuring the TARC concentration in the human body by immunological techniques. Examples of immunological techniques include ELISA, enzyme-linked immunosorbent assay, surface plasmon resonance, latex agglutination immunoassay (LTIA), chemiluminescent immunoassay, electrochemiluminescent immunoassay, fluorescent antibody assay, radioimmunoassay, Western blotting, immunochromatography, and high-performance liquid chromatography (HPLC). The TARC measurement kit of the present invention can be used to determine the severity of atopic dermatitis when selecting a treatment method or drug for atopic dermatitis and when assessing the effectiveness of the treatment.

[0029] The TARC measurement kit of the present invention may also include instructions for use, etc. The TARC measurement kit may also include optional components such as a buffer, a stabilizer, a sample diluent, a pH adjuster, a reaction vessel, etc.

[0030] (Method for improving storage stability of TARC) The method of the present invention for improving the storage stability of TARC comprises the step of contacting TARC with a solution containing a cationic surfactant or an anionic surfactant. The cationic surfactant or anionic surfactant may be added to the solution, followed by the addition of TARC, or the cationic surfactant or anionic surfactant may be added to the solution after the addition of TARC. The solution is preferably a buffer solution such as PBS, HEPES, MES, CHES, or Tris. It is more preferable to use PBS with a pH of 6.5 to 8.0.

[0031] (TARC concentration) In the method of 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 taking into consideration the stability of TARC, it is preferably 10 pg / mL to 1 μg / mL, more preferably 50 pg / mL to 500 ng / mL, even more preferably 100 pg / mL to 100 ng / mL, and most preferably 100 pg / mL to 50 ng / mL.

[0032] Preferred cationic surfactants are alkylamine salts, quaternary ammonium salts, etc. Preferred anionic surfactants are cholic acid, sulfate, carboxylic acid, sulfonic acid, etc.

[0033] Examples of alkylamine salt-type cationic surfactants include salts of amines containing 1 to 3 alkyl groups having 8 to 22 carbon atoms, such as monododecylamine, monooctadecylamine, dioctadecylamine, and trioctadecylamine, with inorganic acids such as hydrochloric acid and sulfuric acid, or lower carboxylic acids such as acetic acid, lactic acid, and citric acid. Specific examples include dodecylamine hydrochloride [CAS No. 929-73-7, manufactured by Tokyo Chemical Industry Co., Ltd.], coconutamine acetate [CAS No. 61790-57-6, product name: Acetamine 24, manufactured by Kao Corporation], and stearylamine acetate [CAS No. 2190-04-7, product name: Acetamine 86, manufactured by Kao Corporation]. Examples of quaternary ammonium salts include salts of ammonium containing one to three alkyl groups having 8 to 22 carbon atoms, such as dodecyltrimethylammonium, octadecyltrimethylammonium, hexadecyltrimethylammonium, didecyldimethylammonium, and benzylmethyltetradecylammonium, with chlorine, bromine, etc. Specific examples include lauryltrimethylammonium chloride [CAS number: 112-00-5, product name: QUATAMIN (registered trademark) 24P, manufactured by Kao Corporation], dodecyltrimethylammonium bromide [CAS number: 1119-94-4, manufactured by Tokyo Chemical Industry Co., Ltd.], octadecyltrimethylammonium chloride [CAS number: 112-03-8, manufactured by Tokyo Chemical Industry Co., Ltd.], and distearyldimethylammonium chloride [CAS number: 107-64-2, product name: QUATAMIN (registered trademark) D86P, manufactured by Kao Corporation].

[0034] Examples of the cholic acid type anionic surfactant include sodium deoxycholate [CAS number: 302-95-4, manufactured by Fujifilm Wako Co., Ltd.] and sodium cholate [CAS number: 361-09-1, manufactured by Fujifilm Wako Co., Ltd.]. Examples of sulfate type salts include higher alcohol sulfates such as dodecyl sulfate, and salts of polyoxyethylene alkyl ether sulfates such as polyoxyethylene dodecyl ether sulfate with sodium, ammonium, etc. Specific examples include higher alcohol sulfate salts such as sodium dodecyl sulfate [CAS number: 151-21-3, manufactured by Sigma-Aldrich] and ammonium lauryl sulfate [CAS number: 2235-54-3, Latemul (registered trademark) AD-25, manufactured by Kao Corporation], and polyoxyethylene alkyl ether sulfate salts such as sodium polyoxyethylene lauryl ether sulfate [CAS number: 68585-34-2, product name: Emal 20C, manufactured by Kao Corporation]. Examples of the carboxylic acid type include salts of higher fatty acids having 8 to 22 carbon atoms, such as dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), octadecanoic acid (stearic acid), and cis-9-octadecenoic acid (oleic acid), with alkali metals such as sodium and potassium. Specific examples include 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.], sodium palmitate [CAS number: 408-35-5, manufactured by Tokyo Chemical Industry Co., Ltd.], sodium lauroyl sarcosinate [CAS number: 137-16-6, manufactured by Tokyo Chemical Industry Co., Ltd.], sodium polyoxyethylene lauryl ether acetate [CAS number: 33939-64-9, product name: Energicol EC-30, manufactured by Lion Specialty Chemicals Co., Ltd.], and sodium lauroyl methylalanine [CAS number: 21539-58-2, product name: Energicol L-30AN, manufactured by Lion Specialty Chemicals Co., Ltd.]. Examples of sulfonic acid-type compounds include alkylbenzenesulfonic acids such as dodecylbenzenesulfonic acid, naphthalenesulfonic acids such as dibutylnaphthalenesulfonic acid, formalin condensates of naphthalenesulfonic acid, sulfosuccinic acids such as dioctyl sulfosuccinic acid, and salts thereof, such as sodium salts. Specific examples include sodium laurylbenzenesulfonate [CAS No.: 25155-30-0, manufactured by Fujifilm Wako Co., Ltd.], sodium salt of β-naphthalenesulfonic acid formalin condensate [CAS No.: 9084-06-4, product name: Demol (registered trademark) RN, manufactured by Kao Corporation], and sodium dioctyl sulfosuccinate [CAS No.: 577-11-7, product name: Neocol (registered trademark) SW, manufactured by Daiichi Kogyo Co., Ltd.]. The cationic surfactant or anionic surfactant used in the composition of the present invention is preferably coconut amine acetate, lauryl trimethyl ammonium chloride, sodium cholate, sodium dodecyl sulfate, sodium lauroyl methyl alanine, or sodium salt of β-naphthalene sulfonic acid formalin condensate. In particular, in the case of a plastic container, it is more preferable to use lauryl trimethyl ammonium chloride, sodium cholate, sodium dodecyl sulfate, or sodium lauroyl methyl alanine, and in the case of a glass container, it is more preferable to use lauryl trimethyl ammonium chloride, coconut amine acetate, or sodium salt of β-naphthalene sulfonic acid formalin condensate.

[0035] (Concentration of surfactant) In the method of the present invention for improving the storage stability of TARC, the concentration of the cationic surfactant or anionic surfactant is, but not limited to, preferably 0.00001% by mass to 1% by mass, more preferably 0.0001% by mass to 1% by mass, even more preferably 0.001% by mass to 0.5% by mass, and most preferably 0.001% by mass to 0.1% by mass, relative to the composition, taking into consideration the stability of TARC.

[0036] (TARC adsorption inhibitor) The TARC adsorption inhibitor of the present invention contains a cationic surfactant or an anionic surfactant. The TARC adsorption inhibitor containing a cationic surfactant or an anionic surfactant may be added before contacting the storage container with a solution containing TARC, or the cationic surfactant or anionic surfactant may be added as an adsorption inhibitor to the TARC solution, which is then added to the storage container.

[0037] The present invention will now be described in detail with reference to examples, but these examples are not intended to limit the scope of the present invention. In this specification, unless otherwise specified, % indicates % by mass. The product names, component names, and distributors of the surfactants used in the examples are as follows: Emanon (registered trademark) 1112 Ingredient name: Polyethylene glycol monolaurate, Kao Corporation Brij® 35 Ingredients: Polyoxyethylene lauryl ether, Kishida Chemical Co., Ltd. Triton® X-100 Ingredients: Polyethylene glycol mono-p-isooctylphenyl ether, Kishida Chemical Co., Ltd. MEGA-9 Ingredient name: n-nonanoyl-N-methyl-D-glucamine, Dojindo Laboratories, Ltd. Sodium cholate Ingredients: Sodium cholate, Fujifilm Wako Co., Ltd. SDS Ingredient name: Sodium lauryl sulfate, Sigma Aldrich Co., Ltd. Energical® L-30AN Ingredients: Sodium Lauroyl Methylalanine, Lion Specialty Chemicals Co., Ltd. Demol (registered trademark) RN Ingredient name: β-naphthalenesulfonic acid formalin condensate sodium salt, Kao Corporation Acetamine (registered trademark) 24 Ingredient name: Coconutamine acetate, Kao Corporation ・Cortamin (registered trademark) 24P Ingredient name: Lauryltrimethylammonium chloride, Kao Corporation ·CHAPS Ingredient name: 3-[(3-Cholamidopropyl)dimethylammonio]propanesulfonate, Dojindo Laboratories Co., Ltd. [Example]

[0038] Example 1: Storage stability test results for plastic eye drop bottles The storage stability of TARC in a plastic eye dropper bottle was tested. The test and evaluation methods were as follows: A solution with the following composition was used as the storage solution. PBS (pH 7.2) ·1 mass% BSA Surfactants (concentration, product name, and type are listed in Table 1)

[0039] (1) Storage conditions Each concentration of TARC liquid stock solution was dispensed into a plastic eye dropper bottle in 0.5 mL aliquots and stored at 37°C for 28 days or at 4°C for 28 days. TARC concentrations tested were 500 pg / mL, 2000 pg / mL, and 10000 pg / mL.

[0040] (2)Measurement method Measurement was performed by latex immunoturbidimetry using two types of antibodies. The reagent composition and measurement method are shown below. Measurement was performed using a Hitachi automatic analyzer using the first and second reagents. Daiichi Reagent 100mM MOPS-NaOH (pH 7.5) 500mM NaCl 0.5% BSA Second reagent Anti-human TARC monoclonal antibody sensitized latex (2 types) 5mM MOPS-NaOH (pH 7.0) The anti-human TARC monoclonal antibody was obtained using commercially available TARC antigens by methods well known to those skilled in the art. Commercially available TARC antigens include CCL17, thymus and activation-regulated chemokine (Shenandoah Biotechnology, Inc.), CCL17 / TARC, Human (LifeSpan Bioscientific, Inc.), and Human TARC (CCL17) (Abeomics, Inc.). Furthermore, a combination of monoclonal antibodies capable of sandwich assay against the TARC antigen was selected by methods well known to those skilled in the art. Anti-human TARC monoclonal antibody-sensitized latex was prepared with reference to the method described in JP 2017-181377 A. First, 120 μL of the first reagent was added to 2.4 μL of each TARC liquid stock solution. After heating at 37°C for 5 minutes, 40 μL of the second reagent was added and stirred. The absorbance change over 5 minutes was then measured at a dominant wavelength of 570 nm and a sub-wavelength of 800 nm. The measured absorbance change was converted to TARC concentration using a calibration curve obtained by measuring a standard substance of known concentration.

[0041] (3) Calculation of TARC survival rate (%) The TARC residual rate (%) was calculated using the following formula for the TARC concentration in each TARC liquid preservation solution after storage at 37°C for 28 days or at 4°C for 28 days.

[0042] TARC residual rate (%) = TARC concentration (pg / mL) of each TARC liquid storage solution after storage in an eye dropper bottle for 28 days at 37°C or 28 days at 4°C / TARC concentration (pg / mL) of TARC liquid storage solution immediately after preparation × 100

[0043] (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 three experiments.

[0044] [Table 1]

[0045] [Table 2]

[0046] At a TARC concentration of 500 pg / mL, the residual rate after 28 days was 47.2% under Condition 1, which did not contain any surfactant, and was significantly low. Under Conditions 2 to 6, which contained a fatty acid ester, alcohol, alkylphenol, or sugar amide nonionic surfactant, and Condition 6, which contained an amphoteric surfactant, the residual rate after 28 days was 67.7 to 78.8%, all of which were below 80.0%. In particular, Condition 6, which contained a compound disclosed in Patent Document 2, was effective in improving the storage stability of insulin, but only slightly improved the storage stability of TARC. On the other hand, under Conditions 7 to 10, which contained the anionic or cationic surfactant discovered in this application, the residual rate after 28 days was 80% or higher for all surfactants. This is thought to be due to the addition of an anionic or cationic surfactant under Conditions 7 to 10 preventing TARC from adsorbing to the container wall or suppressing structural changes in TARC during storage. Similarly, when the TARC concentration was 2000 pg / mL or 10000 pg / mL, conditions 7 to 10, in which the anionic or cationic surfactants discovered in the present application were added, showed a residual rate equal to or higher than that of condition 1, in which no surfactant was added, conditions 2 to 5, in which a nonionic surfactant was added, and condition 6, in which an amphoteric surfactant was added.

[0047] [Table 3]

[0048] When the TARC concentration was 500 pg / mL, the residual rate after 28 days was 65.7% under Condition 1, which did not contain a surfactant, a low result. Under Conditions 7 to 10, which contained the anionic or cationic surfactant discovered in the present invention, the residual rate after 28 days was 92.0 to 100.5%, significantly improving the residual rate after 28 days for all surfactants. This is thought to be because the addition of the anionic or cationic surfactant under Conditions 7 to 10 prevented TARC from adsorbing to the container wall or suppressed structural changes in TARC during storage. These results demonstrate that the coexistence of TARC with an anionic or cationic surfactant improves the storage stability of TARC when stored in a plastic eye dropper bottle.

[0049] Example 2: Storage stability test results in glass vials The storage stability of TARC in a glass vial was tested. The test and evaluation methods were as follows: A solution with the following composition was used as the storage solution. PBS (pH 7.2) ·1 mass% BSA Surfactants (concentration, product name, and type are listed in Table 4)

[0050] (1) Storage conditions Each concentration of TARC liquid stock solution was dispensed into a glass container in 0.5 mL aliquots and stored at 10°C for 6 hours. As a control, the samples before dispensing into the glass containers were also measured. TARC concentrations of 2,000 pg / mL and 10,000 pg / mL were tested.

[0051] (2)Measurement method The measurement was carried out in the same manner as in Example 1.

[0052] (3) Calculation of TARC survival rate (%) The TARC concentration of each TARC liquid preservative solution after storage at 10°C for 6 hours was used to calculate the TARC residual rate (%) using the following formula.

[0053] TARC residual rate (%) = TARC concentration (pg / mL) of each TARC liquid preservative solution after storage in a glass container at 10°C for 6 hours / TARC concentration (pg / mL) of the TARC liquid preservative solution before dispensing into glass containers × 100

[0054] (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 three experiments.

[0055] [Table 4]

[0056] [Table 5]

[0057] When the TARC concentration was 2000 pg / mL, the residual rate after 6 hours was 42.7% under condition 1, where no surfactant was added, which was a low result. Under conditions 2 to 6, where a nonionic surfactant or amphoteric surfactant was added, the residual rate after 6 hours was 48.6 to 52.5%, with little improvement. Under conditions 10 to 12, in which a cationic or anionic surfactant was added, the residual rate after 6 hours was improved for all surfactants, with a particularly significant improvement of 93.7% under condition 12. When the TARC concentration was 10,000 pg / mL, the residual rate was also improved under conditions 10 to 12, in which a cationic or anionic surfactant was added, similar to that at 2,000 pg / mL. In particular, the residual rate was significantly improved to 93.7% and 96.6% under conditions 11 and 12, respectively. These results demonstrate that the coexistence of TARC with a cationic or anionic surfactant improves the storage stability of TARC in glass vials. This is thought to be because, under conditions 10 to 12, the addition of a cationic or anionic surfactant prevented TARC from adsorbing to the container wall or suppressed structural changes of TARC during storage. [Industrial Applicability]

[0058] According to the present invention, it is possible to provide a TARC-containing composition, particularly a TARC-containing calibration sample, that has high storage stability.

Claims

1. A composition comprising TARC (Thymus and activation-regulated chemokine), TARC, and At least one surfactant selected from the group consisting of cationic surfactants and anionic surfactants, the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant, the anionic surfactant is a cholic acid type, sulfate type, carboxylic acid type, or sulfonic acid type anionic surfactant; and The composition is in a liquid form.

2. 10. The composition of claim 1, which is a calibration sample solution for measuring TARC.

3. The composition according to claim 1 or 2, which is filled in a storage container.

4. The composition of claim 3 , wherein the storage container is plastic or glass.

5. The composition according to any one of claims 1 to 4, wherein the concentration of TARC in the composition is 10 pg / mL to 1 µg / mL.

6. 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 based on the composition.

7. 7. The composition according to claim 1, wherein when the concentration of TARC in the composition is 500 pg / mL, the residual rate of TARC after storage in a plastic container at 37°C for 28 days is 80% or more.

8. 8. The composition according to claim 1, wherein when the concentration of TARC in the composition is 500 pg / mL, the residual rate of TARC after storage in a plastic container at 4°C for 28 days is 90% or more.

9. 9. The composition according to claim 1, wherein when the concentration of TARC in the composition is 2000 pg / mL, the residual rate of TARC after storage in a glass container at 10°C for 6 hours is 55% or more.

10. The cationic surfactant is lauryltrimethylammonium chloride or coconut amine acetate, 10. The composition according to claim 1, wherein the anionic surfactant is sodium cholate, sodium lauryl sulfate, sodium lauroylmethylalanine, or sodium salt of β-naphthalenesulfonic acid formalin condensate.

11. A method for measuring TARC, which uses the composition according to any one of claims 1 to 10.

12. A kit for measuring TARC, comprising the composition according to any one of claims 1 to 10.

13. A method for improving the storage stability of a TARC, comprising the step of contacting the TARC with a solution containing at least one surfactant selected from the group consisting of a cationic surfactant and an anionic surfactant, the cationic surfactant is an alkylamine salt type or a quaternary ammonium salt type cationic surfactant, A method for improving the storage stability of TARC, wherein the anionic surfactant is a cholic acid type, sulfate type, carboxylic acid type, or sulfonic acid type anionic surfactant.

14. 14. The method for improving the storage stability of TARC according to claim 13, comprising the step of adjusting the concentration of the TARC in the solution to 10 pg / mL to 1 μg / mL.

15. 15. The method for improving the storage stability of a TARC according to claim 13, wherein the concentration of the surfactant is 0.00001% by mass to 1% by mass relative to the solution.

16. The cationic surfactant is lauryltrimethylammonium chloride or coconut amine acetate, The method for improving the storage stability of TARC according to any one of claims 13 to 15, wherein the anionic surfactant is sodium cholate, sodium lauryl sulfate, sodium lauroylmethylalanine, or sodium salt of β-naphthalenesulfonic acid formalin condensate.

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