Composition for fluorescent labeling, fluorescent probe, injection agent, syringe filling, medical apparatus, medical fiber material, method for producing composition for fluorescent labeling, and method for producing medical fiber material

Abstract

A composition for fluorescent labeling according to the present invention comprises: a compound (A) which is an ICG compound; and a hydroxyl group-containing organic compound (B). This makes it possible to provide, for example, a composition for fluorescent labeling which has excellent compartment identifiability that allows an observation target to be more accurately identified, which has a long light emission time and thus makes it possible to observe the observation target for a long time, and which also reduces a burden on a living body and is excellent in economical efficiency.

Description

Fluorescent labeling composition, fluorescent probe, injectable agent, syringe filling material, medical device, medical fiber material, method for producing fluorescent labeling composition, and method for producing medical fiber material

[0001] The present invention relates to a fluorescent labeling composition, a fluorescent probe, an injectable agent, a syringe filling material, a medical device, a medical fiber material, a method for producing a fluorescent labeling composition, and a method for producing a medical fiber material.

[0002] In vivo fluorescence imaging is used as a method for visualizing and observing the surface or internal state of biological tissues such as blood vessels, lymphatic vessels, and organs. In vivo fluorescence imaging is a technique in which specific proteins or organelles are labeled (marked) with a fluorescent labeling compound and their fluorescence is visualized using a fluorescence microscope, a camera, or the like. Indocyanine green (ICG), for example, is used as a fluorescent labeling compound for use in in vivo fluorescence imaging.

[0003] In vivo fluorescence imaging using ICG is used clinically, for example, in the field of surgery. For example, ICG is injected into a living body, and then irradiated with excitation light to cause it to emit fluorescence, allowing imaging and monitoring of an observation target, such as a fluorescently enhanced region. This allows for non-invasive observation of the state of blood vessels, lymphatic vessels, organs, etc.

[0004] An example of such a technique for biofluorescence imaging is disclosed in Patent Document 1. Patent Document 1 discloses a multipurpose medical imaging marker containing a rubber agent and a fluorescent dye, in which ICG is used as the fluorescent dye.

[0005] On the other hand, for example, Patent Document 2 discloses a method for producing ICG-containing particles, which aims to encapsulate a large amount of ICG in the form of a monomer in the particles. The production method includes a step of mixing ICG, particles, and a solution containing 1 mM to 10 M of a chaotropic agent.

[0006] Furthermore, examples of fluorescently labeled compounds other than ICG are disclosed in Patent Documents 3 and 4. More specifically, Patent Documents 3 and 4 disclose a thermoplastic resin composition containing a near-infrared fluorescent dye made of an azo-boron complex compound, as a resin composition that emits near-infrared fluorescence when irradiated with excitation light in the near-infrared region and can be detected by a detector.

[0007] JP 2019-167341 A JP 2014-227338 A JP 2015-025105 A International Publication No. 2013 / 180127

[0008] In the technology disclosed in Patent Document 1, dimethyl sulfoxide (DMSO) or the like is used as a solvent for ICG. DMSO is a solvent that is highly irritating to the skin and mucous membranes and has high skin permeability, so it is preferable to avoid its use as much as possible. Furthermore, DMSO is cytotoxic, so it is also preferable to avoid its use as much as possible.

[0009] The technology disclosed in Patent Document 2 aims to encapsulate ICG in liposomes at a high concentration as a monomer without aggregation. However, Patent Document 2 does not consider at all the compartmental discrimination of the fluorescent emission for accurately identifying the observation target, such as a fluorescently-imaging site, or the emission duration for observing the observation target over a long period of time.

[0010] The techniques disclosed in Patent Documents 3 and 4 are undesirable in terms of toxicity because they use an azo-boron complex compound. In addition, because the compound is a novel compound not widely used in clinical settings, mass synthesis is costly and not economical.

[0011] In other words, the above-mentioned biofluorescence imaging using ICG requires excellent compartmental discrimination, allowing accurate identification of the structure, shape, and state of the observation target, such as the fluorescently enhanced region, and a long emission time, allowing for prolonged observation of the observation target. However, when ICG is administered into the body, it is difficult to control the emission range and timing, resulting in insufficient fluorescence, and this requirement has not been fully met. For example, in clinical practice, if fluorescence is insufficient during intravenous injection or administration of ICG, it may be difficult to accurately grasp the state of the surgical field or may require additional intravenous injections of ICG. Furthermore, excessive fluorescence may require the surgeon to wait until the ICG is metabolized and eliminated.

[0012] Furthermore, in biofluorescence imaging, there is a demand for low toxicity, low burden on the living body, and economical efficiency by reducing the manufacturing costs of fluorescently labeled compounds.

[0013] However, a technology that meets all of these requirements has not yet been developed.

[0014] The present invention has been made in view of the current situation, and aims to provide a fluorescent labeling composition, a fluorescent probe, an injectable agent, a syringe filler, a medical instrument, a medical fiber material, a method for producing a fluorescent labeling composition, and a method for producing a medical fiber material that have excellent compartment discrimination properties that allow for more accurate discrimination of the object of observation, have a long light emission time that allows the object of observation to be observed over a long period of time, and are economical with little burden on the living body.

[0015] A fluorescent labeling composition according to one aspect of the present invention contains a compound (A) represented by the following formula (1) and a hydroxyl group-containing organic compound (B). (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0016] A fluorescent probe according to another aspect of the present invention contains the above-mentioned fluorescent labeling composition.

[0017] A further aspect of the present invention provides an injectable agent for labeling a target substance present on a mucous membrane or on the skin, which contains the above-described fluorescent labeling composition.

[0018] A syringe filling according to yet another aspect of the present invention includes the above-mentioned fluorescent labeling composition and a syringe filled with the fluorescent labeling composition.

[0019] A medical device according to yet another aspect of the present invention contains the above-mentioned fluorescent labeling composition.

[0020] A medical fiber material according to yet another aspect of the present invention comprises a fiber material containing a compound (A) represented by the following formula (1) and a hydroxyl group-containing organic compound (B): (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0021] A method for producing a fluorescent labeling composition according to still another aspect of the present invention includes a mixing step of mixing a compound (A) represented by the following formula (1) with a hydroxyl group-containing organic compound (B): (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0022] A method for producing a medical fiber material according to yet another aspect of the present invention includes an impregnation step of impregnating or spraying a fiber material containing a hydroxyl group-containing organic compound (B) with a compound (A) represented by the following formula (1), and a mordant step of fixing the compound (A) to the fiber material using a mordant. (In the formula, R １ and R ２each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0023] According to the present invention, it is possible to provide a fluorescent labeling composition, a fluorescent probe, an injectable agent, a syringe filler, a medical instrument, a medical fiber material, a method for producing a fluorescent labeling composition, and a method for producing a medical fiber material, which have excellent compartment discrimination properties that allow for more accurate discrimination of the object of observation, have a long light emission time that allows for long-term observation of the object of observation, and are economical with little burden on the living body.

[0024] It is an explanatory diagram schematically showing the state in which each stock solution is placed in a container. It is an explanatory diagram showing a near-infrared image obtained by irradiating near-infrared light to each container in Fig. 1A. It is an explanatory diagram showing a near-infrared image obtained for the G solution. It is an explanatory diagram showing a near-infrared image obtained for the E solution. It is an explanatory diagram showing a near-infrared image obtained for the N solution. It is an explanatory diagram showing a near-infrared image obtained for the A solution. It is an explanatory diagram schematically showing the state in which each gauze impregnated with a diluent is arranged. It is an explanatory diagram showing a near-infrared image obtained when near-infrared light is irradiated to each gauze in Fig. 6A. It is an explanatory diagram schematically showing an image obtained by placing a gauze impregnated with a diluent of the G solution in the abdominal cavity of a pig and photographing with an endoscope camera. It is an explanatory diagram showing a near-infrared image of the gauze in Fig. 7A. It is an explanatory diagram schematically showing an image obtained by placing a gauze impregnated with a diluent of the E solution in the abdominal cavity and photographing with an endoscope camera. It is an explanatory diagram showing a near-infrared image of the gauze in Fig. 8A. It is an explanatory diagram schematically showing an image obtained by placing a gauze impregnated with a diluent of the N solution in the abdominal cavity and photographing with an endoscope camera. It is an explanatory diagram showing a near-infrared image of the gauze in Fig. 9A. It is an explanatory diagram schematically showing an image obtained by placing a gauze impregnated with a diluent of the A solution in the abdominal cavity and photographing with an endoscope camera. It is an explanatory diagram showing a near-infrared image of the gauze in Fig. 10A. It is a perspective view showing a configuration example of the CV port. It is a cross-sectional view of the CV port. It is an exploded perspective view of the CV port. It is an explanatory diagram schematically showing the state in which each ring obtained by molding an epoxy resin is arranged. It is an explanatory diagram showing a near-infrared image of each ring in Fig. 14A. It is an explanatory diagram showing a near-infrared image of a ring molded by adding a solution with the ICG concentration increased four times compared to each ring in Fig. 14A. It is an explanatory diagram schematically showing the state in which the CV port and the comparison port are arranged. It is an explanatory diagram showing a near-infrared image of the CV port having an index member molded using the G solution. It is an explanatory diagram showing a near-infrared image of the CV port having an index member molded using the E solution. It is an explanatory diagram showing a near-infrared image of the CV port having an index member molded using the N solution. It is an explanatory diagram showing a near-infrared image of the CV port having an index member molded using the A solution.

[0025] Hereinafter, a mode for carrying out the present invention (hereinafter simply referred to as "the present embodiment") will be described in detail. The following present embodiment is an example for explaining the present invention, and is not intended to limit the present invention to the following content. The present invention can be practiced by appropriately modifying it within the scope of its gist. In the following description, when a numerical range is described as AA to BB, the numerical range includes the lower limit AA and the upper limit BB.

[0026] <Fluorescent Labeling Composition> The fluorescent labeling composition according to this embodiment is a fluorescent labeling composition containing a compound (A) represented by the following formula (1) and a hydroxyl group-containing organic compound (B). Compound (A) includes indocyanine green ("ICG") and its derivatives ("indocyanine green derivatives", "ICG derivatives"). In this specification, ICG and ICG derivatives may be collectively referred to as "indocyanine green-based compounds" ("ICG-based compounds"), etc.

[0027] (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0028] (Component (A): Indocyanine Green Compound) Compound (A) represented by formula (1) includes indocyanine green (ICG). ICG is a compound (CAS No. 3599-32-4) having a structure represented by the following formula (1a), and is a fluorescent organic dye whose excitation light and fluorescence are both in the near-infrared region. Formula (1a) is a compound represented by the formula (1) in which R １ and R ２ are both hydrogen, p is 2, and m and n are both 4.

[0029]

[0030] R １ and R ２each independently represent hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; these are preferably each independently hydrogen, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms, more preferably hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and even more preferably hydrogen.

[0031] p is an integer of 1 to 5, preferably 1 to 4, more preferably 2 or 3, and even more preferably 2.

[0032] m and n are each independently an integer of 1 to 12, preferably 1 to 8, more preferably 2 to 6, even more preferably 3 to 5, and even more preferably 4.

[0033] ICG hardly absorbs excitation energy at wavelengths of 600 nm or less, but absorbs excitation energy at wavelengths of 650 to 900 nm to emit fluorescence. Therefore, while the fluorescence is difficult to visualize when irradiated with visible light, the fluorescence emitted by irradiation with near-infrared light, which is the excitation light, can be easily visualized by receiving it with a fluorescence microscope or camera. Therefore, when the fluorescent labeling composition according to this embodiment is used for biological fluorescence imaging in blood, the ICG excitation light is not absorbed by hemoglobin, which has strong absorption in the visible light range of 600 nm or less. This allows the ICG excitation light to reach deep within biological tissue, resulting in high biological permeability. Therefore, ICG can be said to be a near-infrared fluorescent organic dye suitable for observing biological tissues, i.e., the condition of blood vessels, lymphatic vessels, and organs.

[0034] However, ICG fluorescence can be unstable, insufficient in intensity, and can be deactivated in a short time. Therefore, in clinical situations where compartmental differentiation is required, such as determining the resection site in a surgical procedure, or where continuous monitoring over a long period of time is required, conventional biofluorescence imaging using ICG is insufficient and requires improvement.

[0035] In this regard, according to the present embodiment, by using ICG in combination with a hydroxyl group-containing organic compound described later, stable fluorescent coloring is obtained and sufficient fluorescent intensity is obtained, thereby obtaining excellent compartment discrimination to the extent that the structure of the observation target, such as the fluorescently enhanced region, can be more clearly discriminated. Furthermore, since the emission time is long, the observation target can be observed for a long period of time.

[0036] The reason why such advantages are obtained is not clear, but is presumed to be as follows: By using ICG and a hydroxyl group-containing organic compound in combination, the two can be firmly bonded to each other through the action of hydrogen bonding, thereby forming a stable structure. As a result, it is thought that excellent compartment discrimination ability and a long luminescence time can be achieved (however, the effects of this embodiment are not limited to these). As the above-mentioned hydrogen bond, for example, a bond between a hydrogen atom contained in a hydroxyl group of the hydroxyl group-containing organic compound and an oxygen atom contained in ICG can be considered.

[0037] The above-described circumstances are applicable to ICG derivatives (in formula (1), R １ and R ２ are both hydrogen, p is 1, and m and n are both 4).

[0038] It is preferable that the fluorescent organic dye contains only the compound represented by formula (1) (ICG-based compound). That is, it is preferable that the fluorescent organic dye contains only ICG, an ICG derivative, or both. For example, from the standpoints of toxicity and economy, it is preferable that the dye does not substantially contain azo-boron complex compounds such as those disclosed in Patent Documents 3 and 4. In this specification, "substantially not contained" or "not substantially mixed" means that the component is not actively added or mixed, and does not exclude the inevitable inclusion or mixing. The most desirable form of "substantially not contained" is when the content is zero.

[0039] (Component (B): Hydroxyl-Containing Organic Compound) The hydroxyl-containing organic compound (B) is an organic compound containing a hydroxyl group (OH group) as a functional group. For example, an alcoholic hydroxyl-containing compound (B1) can be used as the hydroxyl-containing organic compound (B). Furthermore, when the above-mentioned ICG-based compound is applied to a medical fiber material described later, cellulose (B2) or silk (B3) can be used as the hydroxyl-containing organic compound (B). Silk (B3) is a protein containing hydroxyl-containing amino acids such as tyrosine and serine as part of its composition. Note that water is an inorganic compound and is therefore not included in the above-mentioned hydroxyl-containing organic compound (B). Furthermore, when the ICG-based compound is applied to a resin material described later, a polymer formed by polymerizing a hydroxyl-containing monomer, such as an epoxy-based resin (B4), can be used.

[0040] (Component (B1): Alcoholic Hydroxyl Group-Containing Compound) The alcoholic hydroxyl group-containing compound (B1) is not particularly limited, but is preferably an aliphatic alcohol. The aliphatic alcohol is more preferably an aliphatic alcohol having 1 to 10 carbon atoms. The carbon number of the aliphatic alcohol having 1 to 10 carbon atoms is more preferably 1 to 5, and even more preferably 1 to 4.

[0041] Specific examples of the alcoholic hydroxyl group-containing compound (B1) include, but are not limited to, monoalcohols such as methanol, ethanol, isopropyl alcohol, and propylene glycol; diols such as diethylene glycol; triols such as glycerin; and sugar alcohols such as mannitol. Among these, ethanol, isopropyl alcohol, and glycerin are preferred from the viewpoints of cytotoxicity and tissue damage. In particular, glycerin is more preferred from the viewpoints of flammability and safety to the human body.

[0042] The alcoholic hydroxyl group-containing compound (B1) may be used alone or in combination of two or more kinds.

[0043] The content of compound (A) in the fluorescent labeling composition is not particularly limited, but is preferably 0.0000001 to 10% by mass, more preferably 0.0000001 to 1% by mass, even more preferably 0.000001 to 1% by mass, and even more preferably 0.000001 to 0.6% by mass. When the fluorescent dye concentration exceeds a certain level, concentration quenching, which reduces the fluorescence intensity (quantum yield), can occur. In this embodiment, by setting the content of compound (A) within the above range, the concentration quenching phenomenon can be effectively suppressed. As a result, the compartment discrimination ability can be further improved when fluorescence is emitted, and the emission time can be further extended (although the effects of this embodiment are not limited to these).

[0044] Furthermore, the content of the alcoholic hydroxyl group-containing compound (B1) in the fluorescent labeling composition is not particularly limited, but is preferably 90 to 99.9999999 mass%, more preferably 99 to 99.9999999 mass%, even more preferably 99 to 99.999999 mass%, and still more preferably 99.4 to 99.999999 mass%.

[0045] The combination of the contents of compound (A) and alcoholic hydroxyl group-containing compound (B1) is preferably such that the content of compound (A) is 0.0000001 to 10% by mass and the content of alcoholic hydroxyl group-containing compound (B1) is 1 to 90% by mass. By setting the contents of compound (A) and alcoholic hydroxyl group-containing compound (B1) within the above ranges, the compartment discrimination ability upon fluorescence emission is further improved and the emission time is further extended. The above contents of compound (A) and alcoholic hydroxyl group-containing compound (B) are the contents at the time of use of the fluorescent labeling composition. Alternatively, a high-concentration fluorescent labeling composition may be prepared before use, and the fluorescent labeling composition may be diluted at the time of use to achieve the above contents.

[0046] The content ratio of the alcoholic hydroxyl group-containing compound (B1) relative to 100 parts by mass of the total of the compound (A) and the alcoholic hydroxyl group-containing compound (B1) is not particularly limited, but is preferably 97 to 99.99998 parts by mass, more preferably 99.96 to 99.9999 parts by mass, and even more preferably 99.4 to 99.9997 parts by mass. By setting the content ratio of the compound (A) and the alcoholic hydroxyl group-containing compound (B1) within the above range, the compartment distinguishability upon fluorescence emission is further improved and the emission time is further extended.

[0047] Furthermore, according to this embodiment, organic solvents such as DMSO and chloroform do not necessarily need to be used, which reduces the burden on the living body. Furthermore, since commercially available products can be used as the alcoholic hydroxyl group-containing compound, it is economically advantageous. From this perspective, it is preferable that the fluorescent labeling composition according to this embodiment substantially does not contain DMSO. Similarly, it is preferable that it substantially does not contain chloroform. By substantially not containing these organic solvents, the above-mentioned advantages can be further improved. Most preferably, the content of DMSO and chloroform is zero.

[0048] The fluorescent labeling composition according to this embodiment may further contain other additive components, etc. Examples of such additive components include components added to contrast agents, and specific examples include sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium amidotrizoate, sodium meglumine amidotrizoate, and iohexol.

[0049] Here, an example of clinical use of the fluorescent labeling composition according to this embodiment will be described. When used for angiography or the like, the liquid fluorescent labeling composition is administered into a living body by intra-arterial or intravenous injection, and can be imaged using a fluorescence observation device (camera, etc.) compatible with the excitation light and fluorescence of compound (A). That is, after intravenous injection of compound (A), near-infrared light (excitation light) is irradiated onto the surgical field using the fluorescence observation device, allowing for both visual observation and fluorescence observation using near-infrared light. This allows for accurate understanding of the state of the surgical field.

[0050] For example, by administering a fluorescent labeling composition into the blood, it is possible to determine the extent to which sufficient blood flow has reached the target area. If blood flow is normal, fluorescence will be emitted in a relatively short time, such as several seconds to several minutes. In other words, if fluorescence emission is sufficient, it can be determined that sufficient blood flow has reached the target area. Compound (A) becomes stronger when it binds to blood proteins, and emits fluorescence when irradiated with excitation light.

[0051] Alternatively, when used for identifying sentinel lymph nodes, the liquid fluorescent labeling composition can be injected subcutaneously near a tumor or in the areola, etc., and imaged using the above-mentioned fluorescence observation device (camera, etc.). In this case, compound (A) becomes toughened by binding to plasma proteins in lymph, and emits fluorescence when irradiated with excitation light.

[0052] When used for angiography, sentinel lymph node identification, and the like as described above, the fluorescent labeling composition is preferably a liquid (25°C, relative humidity 50%) from the viewpoint of preventing the composition from being injected into the body in an undissolved state. When the fluorescent labeling composition is a liquid, it may be stored as a highly concentrated solution (e.g., a concentrated solution) and diluted before use. The dilution ratio in this case may be set so that the diluted solution has the above-mentioned suitable concentration and content. The concentrated solution and diluted solution can be prepared, for example, using a vial of distilled water provided with commercially available compound (A).

[0053] Furthermore, the fluorescent labeling composition can also be used clinically as an infusion, as described below. The infusion will be described later, but it may be a liquid. Furthermore, the infusion may be in a gel or semi-solid form in order to provide a certain degree of viscosity or shape retention. To obtain a gel or semi-solid form, for example, at least one component (D) selected from the group consisting of sodium alginate and sodium hyaluronate may be blended.

[0054] (Component (C): Resin) When the fluorescent labeling composition according to this embodiment is used as various materials for medical devices and the like, it is preferable that the fluorescent labeling composition further contains a resin (C). For example, by using the fluorescent labeling composition as a molding material for medical devices such as stents, tubes, catheters, clips, fluorescent color-producing portions around the septum of subcutaneously implantable ports, filaments for 3D printers, and resin fiber materials, it is possible to cause such medical devices to emit fluorescence. Details of medical devices will be described later.

[0055] Conventionally, it has been thought that ICG is difficult to melt-knead into a resin due to its low heat resistance and water solubility. However, the present inventors have found that by using the above-mentioned compound (A) in combination with the alcoholic hydroxyl group-containing compound (B1), compound (A) can be melt-kneaded into a resin (C) to an extent that it can be used as a molding material.

[0056] Considering that ICG is water-soluble, it is desirable to use a material for resin (C) that does not undergo hydrolysis and has a melting point lower than that of ICG (approximately 230°C). For example, it is preferable to use at least one selected from the group consisting of polyurethane resins, olefin resins, epoxy resins, vinyl chloride resins, fluorine-based resins, polycarbonate resins, polyamide resins, ABS resins, acrylic resins, and silicone resins. These resins are easily available and have high stability, making them suitable as molding materials for medical devices and the like. They are also suitable in that they do not adversely affect the fluorescent properties of compound (A).

[0057] A polyurethane resin is a suitable resin. In this case, it is more preferable to use a high-boiling organic solvent (e.g., glycerin) as the alcoholic hydroxyl group-containing compound (B1) than a low-boiling organic solvent, in order to effectively prevent the compound (A) from leaching out under high temperature and humidity.

[0058] Examples of olefin resins include polyethylene and polypropylene.

[0059] The epoxy resin (B4) is represented by the following structural formula: The epoxy resin (B4) does not necessarily require the alcoholic hydroxyl group-containing compound (B1) because the hydroxyl groups contained in the epoxy resin itself act as a toughening factor for ICG. Therefore, the epoxy resin (B4) has significantly stronger fluorescent activity than other resins. Examples include epoxy resins obtained by glycidyl etherifying bisphenol A, bisphenol F, or novolac; epoxy resins obtained by adding propylene oxide, ethylene oxide, or polyalkylene glycol to bisphenol A and then glycidyl etherifying the resulting resin; aliphatic epoxy resins; alicyclic epoxy resins; and polyether epoxy resins. Furthermore, since the epoxy resin (B4) can be used to coat metals, it is suitable as a material for attaching to the tips of surgical instruments such as various forceps or scissors.

[0060] Examples of vinyl chloride resins include vinyl chloride homopolymers, vinyl chloride-vinyl acetate copolymers, vinyl chloride-ethylene copolymers, vinyl chloride-propylene copolymers, vinyl chloride-styrene copolymers, vinyl chloride-vinylidene chloride copolymers, vinyl chloride-acrylic acid ester copolymers, vinyl chloride-maleic acid ester copolymers, vinyl chloride-methacrylic acid ester copolymers, and vinyl chloride-acrylonitrile copolymers.

[0061] Examples of fluorine-based resins include polytetrafluoroethylene, tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-fluoroalkyl vinyl ether-fluoroolefin copolymer, ethylene-tetrafluoroethylene copolymer, and ethylene-trichlorofluoroethylene copolymer.

[0062] Examples of polycarbonate resins include aromatic polycarbonate resins, aliphatic polycarbonate resins, and aromatic-aliphatic polycarbonate resins, each of which contains bisphenol A or the like as a polymerization component.

[0063] Examples of polyamide resins include polytetramethylene adipamide (nylon 46), polytetramethylene sebacamide (nylon 410), polypentamethylene adipamide (nylon 56), polypentamethylene sebacamide (nylon 510), polycaproamide (nylon 6), polyhexamethylene adipamide (nylon 66), polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide (nylon 612), and polydecamethylene adipamide. (Nylon 106), polydecamethylene sebacamide (Nylon 1010), polydecamethylene dodecamide (Nylon 1012), polyundecane amide (Nylon 11), polyundecamethylene adipamide (Nylon 116), polydodecanamide (Nylon 12), polyxylene adipamide (Nylon XD6), polyxylene sebacamide (Nylon XD10), polymeta-xylylene adipamide (Nylon MXD6), polypara-xylylene adipamide (Nylon PX D6), polytetramethylene terephthalamide (nylon 4T), polypentamethylene terephthalamide (nylon 5T), polyhexamethylene terephthalamide (nylon 6T), polyhexamethylene isophthalamide (nylon 6I), polynonamethylene terephthalamide (nylon 9T), polydecamethylene terephthalamide (nylon 10T), polyundecamethylene terephthalamide (nylon 11T), polydodecamethylene terephthalamide (nylon 1 2T), polytetramethylene isophthalamide (nylon 4I), polybis(3-methyl-4-aminohexyl)methane terephthalamide (nylon PACMT), polybis(3-methyl-4-aminohexyl)methane isophthalamide (nylon PACMI), polybis(3-methyl-4-aminohexyl)methanendodecamide (nylon PACM12), polybis(3-methyl-4-aminohexyl)methane tetradecamide (nylon PACM14), and the like.

[0064] Examples of ABS resins include acrylonitrile butadiene styrene (ABS), acrylonitrile styrene acrylic (ASA), acrylonitrile ethylene styrene (AES), chlorinated polyethylene acrylonitrile styrene (ACS), α-methylstyrene ABS resin, flame-retardant ABS resin (FR-ABS), reinforced ABS resin, and phenylmaleimide ABS resin.

[0065] Examples of acrylic resins include homopolymers such as polymethyl methacrylate (PMMA) and polyethyl methacrylate; and copolymers such as methyl methacrylate-styrene copolymer and methyl methacrylate-α-methylstyrene copolymer.

[0066] Examples of silicone resins include methyl silicone resin, methyl phenyl silicone resin, phenyl silicone resin, epoxy-modified silicone resin, polyester-modified silicone resin, and acrylic-modified silicone resin.

[0067] In addition, since acetal resins may undergo hydrolysis when kneaded with ICG, and may emit harmful substances such as formaldehyde, it is desirable that resin (C) does not contain acetal resins.

[0068] The resin (C) may be used alone or in combination of two or more kinds.

[0069] The content of resin (C) in the fluorescent labeling composition is not particularly limited, but is preferably 80 to 99.99998% by mass, more preferably 85 to 99.9999% by mass, and even more preferably 90 to 99.9997% by mass. By setting the resin content within the above range, it is possible to maintain high levels of compartment identification and luminescence duration through fluorescent emission while achieving strength, processing characteristics, and degradation resistance suitable for a molding material. Furthermore, various experimental results have shown that when the fluorescent labeling composition contains resin (C), a relatively low concentration of compound (A) in the fluorescent labeling composition tends to result in stronger luminescence intensity. However, these characteristics vary depending on the resin.

[0070] When the fluorescent labeling composition is used as a molding material, it is preferable that the fluorescent labeling composition is in a solid or semi-solid state at 25°C and a relative humidity of 50%. A semi-solid state means that the composition has shape retention, such as a paste, unlike a liquid state. When the fluorescent labeling composition is in such a state, the handling properties, measuring accuracy, and uniform dispersion within the molding material are improved compared to when compound (A) is directly mixed. Furthermore, when the fluorescent labeling composition is used as a molding material, it can be made into a masterbatch.

[0071] The fluorescent labeling composition can be made solid or semi-solid by adding the resin (C) or a solid or semi-solid alcoholic hydroxyl group-containing compound (B1). In this case, glycerin or the like is suitable as the alcoholic hydroxyl group-containing compound (B1). Other solid or semi-solid components may also be added.

[0072] <Method for producing a fluorescent labeling composition> The method for producing a fluorescent labeling composition of this embodiment includes a mixing step of mixing the above-described compound (A) with a hydroxyl group-containing organic compound (B). As the hydroxyl group-containing organic compound (B), the above-described alcoholic hydroxyl group-containing compound (B1) can be used. The mixing method in the mixing step is not particularly limited, and a known method can be selected. Suitable mixing conditions can be adopted as appropriate for the mixing step.

[0073] In the mixing step, it is preferable to obtain a fluorescent labeling composition containing 0.0000001 to 10% by mass of compound (A) and 1 to 90% by mass of alcoholic hydroxyl group-containing compound (B1). The mixing step does not necessarily have to be performed in one stage. A step of obtaining a highly concentrated solution may be performed first, followed by a step of diluting the concentrated solution to the concentration range described above at the time of use. In other words, the diluted concentration at the time of use is preferably within the concentration range described above.

[0074] As other steps, for example, a step of heating the mixture (heating step) may be carried out after the mixing step.

[0075] <Fluorescent Probe> The fluorescent labeling composition described above can be suitably used as a fluorescent probe. According to this embodiment, it can be used as an organic compound-type fluorescent probe derived from compound (A). For example, when detecting a pathological substance or a physiologically active substance in a living body, by placing the fluorescent probe in the living body or intracellularly, the behavior of these substances can be visually observed and observed in real time as changes in fluorescence with high accuracy. As described above, the fluorescent labeling composition of this embodiment does not absorb excitation light by hemoglobin or the like, allowing the excitation light to reach deep within biological tissue, thereby enabling visual observation and observation of the tissue's condition. Furthermore, the fluorescent labeling composition has excellent compartment discrimination properties and a long lifespan, allowing the composition to continue emitting light for a long period of time. Due to these advantages, the fluorescent labeling composition of this embodiment is suitable as a fluorescent probe.

[0076] <Injection> The above-described fluorescent labeling composition can be suitably used as an injectable. A suitable aspect of the injectable of this embodiment is a labeling injectable for labeling a target object present on a mucosa or on the skin, which is an injectable containing the above-described fluorescent labeling composition. The injectable is injected under the mucosa or under the skin where the target object is located, and becomes labelable by irradiation with excitation light for compound (A).

[0077] The injectable agent according to this embodiment can be suitably used for clinical applications. For example, the injectable agent can be used for various local injections submucosally or subcutaneously at the site of tumor or other resection. For example, when performing surgical treatment to resect a lesion such as a tumor formed on the mucosa or skin, the injectable agent is injected submucosally or subcutaneously around the lesion, and then irradiated with excitation light to cause fluorescence. This allows accurate identification of the planned resection line (the boundary between the side to be left and the side to be resected). Furthermore, a more appropriate planned resection line can be determined by combining visual observation by a physician with fluorescent observation.

[0078] In the case of an injectable preparation, the alcoholic hydroxyl group-containing compound (B1) as the hydroxyl group-containing organic compound (B) is preferably glycerin or mannitol from the viewpoint of safety for the human body. These may be used alone or in combination of two or more.

[0079] The injectable agent according to this embodiment may contain at least one of sodium alginate and sodium hyaluronate as component (D). This component (D) may also function as a viscosity enhancer. By including component (D) in the injectable agent, for example, the injectable agent can be injected into the submucosal layer or subcutaneous layer near the lesion, causing the injected area to swell and rise. By observing this state with the above-mentioned fluorescence observation device (camera, etc.), the location of the lesion can be accurately determined, and the planned resection line for the lesion can be more accurately identified.

[0080] The content of component (D) in the injectable agent according to this embodiment is not particularly limited, but is preferably 0.01 to 10% by mass, more preferably 0.05 to 5% by mass, even more preferably 0.05 to 3% by mass, and even more preferably 0.1 to 1% by mass of the total of component (D). However, if sufficient viscosity and localized effect are obtained, the injectable agent can be effective even if it does not contain any component (D).

[0081] The ingredients and formulations of the injection agent described above can naturally be adopted for the fluorescent labeling composition described above.

[0082] <Syringe Filling> The fluorescent labeling composition described above can be suitably used as a syringe filling. The syringe filling is configured by pre-filling a syringe (injection barrel) with the fluorescent labeling composition of this embodiment. The syringe filling is also called a pre-filled syringe. The material and dimensions of the syringe are not particularly limited, and suitable conditions can be selected depending on the application. The syringe may be made of, for example, glass or resin. In addition, the fluorescent labeling composition may be filled into the tube of a local injection needle for submucosal injection, and the local injection needle may be connected to the pre-filled syringe.

[0083] In fluorescent labeling compositions, it is important to appropriately adjust the contents and ratios of compound (A), hydroxyl-containing organic compound (B), other solvents, and additives to suppress concentration quenching and ensure sufficient fluorescence emission intensity and duration. However, blending these chemical solutions during surgery is cumbersome. By pre-filling a syringe (plus the tubing of a local injection needle) with a fluorescent labeling composition prepared to achieve the correct content ratio, this tedious process can be avoided during surgery. For example, a concentrated solution containing compound (A) and the alcoholic hydroxyl-containing compound (B1) as the hydroxyl-containing organic compound (B) in the preferred range described above can be filled into the syringe, and then diluted with saline, water for injection, or the like before use. The syringe filling of this embodiment is not limited to a configuration in which a concentrated solution of the fluorescent labeling composition is filled into the syringe. For example, the fluorescent labeling composition may be filled into the syringe at a concentration (diluted solution) that is suitable for injection.

[0084] <Medical Devices> Medical devices can be produced using the above-described fluorescent labeling composition as a molding material. Examples of such medical devices include stents, tubes, catheters, clips, fluorescent color-emitting portions around the septum of subcutaneously implantable ports, 3D printer filaments, resin fiber materials (e.g., gauze thread, suture thread, etc.), and surgical instruments such as various forceps or scissors with a coated tip. Among these, the medical device to which the fluorescent labeling composition is applied is preferably one selected from the group consisting of stents, tubes, catheters, fluorescent color-emitting portions around the septum of subcutaneously implantable ports, 3D printer filaments, resin fiber materials (e.g., medical gauze, sponges, tupelo, cotton balls, tampons, silk thread, sponges, etc.), and surgical instruments such as various forceps or scissors.

[0085] When a medical device is a stent, for example, the fluorescent labeling composition is contained in the material constituting the stent. The stent is placed in a living body and irradiated with near-infrared light, which is the excitation light for compound (A), to cause the stent to emit fluorescence. When the stent is, for example, a bile duct stent or a ureteral stent, the position of the stent can be accurately determined by the fluorescence emitted from the stent. This reduces the risk of accidentally damaging the bile duct or ureter during surgery.

[0086] Considering a medical device such as a tube, the fluorescent labeling composition is contained in the material constituting the tube. The tube is placed in a living body and irradiated with near-infrared light, which is the excitation light for compound (A), to cause the tube to emit fluorescence. For example, in the case of an ileus tube, the position of the tube can be accurately determined by the fluorescence, and therefore the site of an intestinal obstruction or the like can be more accurately identified even in laparoscopic surgery.

[0087] Considering a medical device such as a catheter, the fluorescent labeling composition is contained in the material constituting the catheter. The catheter is placed in a living body and irradiated with near-infrared light, which is the excitation light for compound (A), to cause the catheter to emit fluorescence. For example, in the case of a ureteral catheter, the position of the catheter can be accurately determined by the fluorescence emission, thereby avoiding the risk of accidentally damaging the ureter during surgery.

[0088] Considering a medical device such as a septum for a subcutaneously implantable port, for example, a subcutaneously implantable port in which a fluorescent labeling composition is impregnated into the material constituting the septum or housing, as in Patent Document 4, would result in the drug-containing resin being in direct contact with the patient's subcutaneous tissue for an extended period of time, which is undesirable from a medical safety perspective. Septums that are repeatedly punctured with needles have the problem of coring, in which the material is gradually worn away, and the inclusion of a drug is undesirable due to concerns about reduced durability. Furthermore, impregnating the housing with a drug to produce fluorescence would result in an excessively wide emission range, raising concerns that the central septum would not be fluorescent-negative.

[0089] If the fluorescent labeling composition is incorporated into a housing portion surrounding the septum (if it is located inside the outer surface of the housing portion), it becomes possible to identify the position of the septum without the light-emitting portion coming into contact with the patient's subcutaneous tissue. The fluorescent labeling composition may be in the form of a ring or a collection of spots, as long as it is located around the septum. By placing such a subcutaneously implantable port in a living body and irradiating the port with near-infrared light, which is the excitation light for compound (A), the fluorescent labeling composition around the septum can be made to emit fluorescence.

[0090] This allows the septum to be easily and accurately positioned before puncturing, even in patients with thick subcutaneous fat, such as obese patients, reducing the risk of puncture errors. This reduces the risk of accidental subcutaneous leakage of medicinal liquids, such as anticancer drugs, due to puncture errors. It also minimizes the size of ports, which tend to be unnecessarily large to avoid puncture errors. As a result, the cosmetic appearance of the patient's body wall is improved. Furthermore, conventional materials can be used for the septum and housing, except for the fluorescent labeling composition. This minimizes development barriers and costs.

[0091] Furthermore, by applying the fluorescent labeling composition to 3D printer filaments, it will be possible to easily prototype various "glowing medical devices."

[0092] The method for producing the medical device of the present embodiment described above is not particularly limited, and any known method can be used. For example, a production method including a step of injection molding the fluorescent labeling composition described above using a mold or the like can be used. The medical device may also be produced by extrusion molding, compression molding, blow molding, calendar molding, inflation molding, thermoforming, or the like.

[0093] Furthermore, when considering a medical device, such as a resin fiber material, the fiber material is impregnated with a fluorescent labeling composition. Examples of resin fiber materials include gauze threads and surgical sutures, as described above. For example, as in Patent Document 4, a resin fiber material impregnated with a fluorescent labeling composition can be woven into a portion of the cotton fabric constituting the gauze, and the gauze is irradiated with near-infrared light, which is the excitation light for compound (A), to cause the fiber material constituting the portion of the gauze to fluoresce. However, if only a portion of the gauze emits light, the luminescence intensity may be insufficient to be used as a guide for searching for lost materials or for surgical procedures. On the other hand, increasing the blending ratio of the resin fiber material may reduce water absorption, potentially hindering the gauze's intended function. For this reason, it is desirable to impregnate the entire cotton fabric constituting the gauze with the fluorescent labeling composition.

[0094] Furthermore, when a suture contains a fluorescent labeling composition, the suture emits fluorescence when irradiated with near-infrared light, which is the excitation light for compound (A). However, because resin sutures are non-absorbent (not absorbed by the body), the drug-containing fibers are in semi-permanent contact with the patient's tissue, which is undesirable from a medical safety perspective. Furthermore, in the method of fluorescently coloring the needle, the needle is removed from the body, but the resin adheres to the needle, which may impair its sharpness. Therefore, for example, in a "needle-attached suture" with a needle attached to the tip, if an epoxy resin containing compound (A) is used as the adhesive connecting the needle and the thread, it becomes possible to find the lost needle without the above-mentioned problems.

[0095] According to this embodiment, such a resin fiber material can be suitably used in a wide range of fields, not limited to its intended use in the medical field (medical applications), as a luminous fiber, a luminous material, etc. Furthermore, since the fiber material is made of a resin, the compound (A) can be uniformly dispersed and blended in the resin, and the entire material can emit fluorescent light uniformly.

[0096] As a method for producing a resin fiber material, the fluorescent labeling composition of this embodiment (e.g., compound (A) + hydroxyl group-containing organic compound (B)) may be kneaded into a resin and then spun into thread, or compound (A) alone may be kneaded into a resin and then spun into thread.

[0097] <Medical Fiber Material> The medical fiber material of this embodiment comprises a fiber material containing the above-mentioned compound (A) and a hydroxyl group-containing organic compound (B), and is capable of emitting light when irradiated with excitation light from the compound (A). When the above-mentioned medical fiber material is irradiated with excitation light from the compound (A), fluorescent light is obtained from the medical fiber material, and this fluorescent light has excellent compartment discrimination and a long emission time. From the viewpoint of easily and reliably exhibiting the effects, the hydroxyl group-containing organic compound (B) contained in the fiber material preferably contains cellulose (B2), and may also contain fibers made of animal protein such as silk (B3).

[0098] The structural formula of cellulose (B2) is shown below.

[0099] The structural formula of silk (B3) is shown below. In the above structural formula, n = 2. G represents glycine, A represents alanine, S represents serine, and T represents tyrosine.

[0100] The structural formula of serine is:

[0101] The structural formula of tyrosine is:

[0102] Specific examples of such medical fiber materials include, but are not limited to, medical gauze, sponges, Zuppel, cotton balls, tampons, silk thread, and the like, as well as the fiber materials that make up these. For example, when the medical fiber material according to this embodiment is used as medical gauze, it can contribute to preventing the gauze from being left inside the body during clinical procedures such as surgical operations. An example of how to use such medical gauze is described below.

[0103] Conventionally, surgical gauze (X-ray gauze) woven with contrast threads that have X-ray contrast media mixed in has been used as a measure to prevent gauze from being left inside the body. If X-ray gauze is left inside the body, the contrast threads will be visible in an X-ray, making it possible to identify the location of the gauze.

[0104] However, because the contrast threads in X-ray gauze appear thin and white in X-ray images, they are difficult to see if they overlap with bone, and there is a possibility that they may be overlooked even in X-ray images. In this regard, the medical gauze according to this embodiment clearly identifies the entire gauze by emitting green or blue fluorescence, making it easy to check the gauze despite the simple method. Furthermore, because it uses near-infrared light instead of X-rays, it is possible to reduce the radiation exposure dose to patients and staff, making it highly safe.

[0105] The reason why the medical gauze according to this embodiment can achieve excellent compartment discrimination and a long luminescence time is thought to be that the compound (A) and the hydroxyl groups of the cellulose (B2), which is the hydroxyl group-containing organic compound (B) contained in the gauze, are strongly bonded to each other through hydrogen bonding, resulting in a stable structure (however, the function of this embodiment is not limited to this). Therefore, during surgery, the gauze can be placed at the target site for ablation in advance, and the fluorescence of this gauze can be used as an indicator, allowing the operation to proceed efficiently.

[0106] The gauze used may contain a hydroxyl group-containing organic compound (B) (e.g., cellulose (B2)), and other materials, dimensions, and shapes are not particularly limited. For example, the gauze used may be square gauze used as surgical gauze (operating gauze), or may be cut gauze, folded gauze, wide gauze, or the like to be applied to a wound or injured area. The gauze used may also be sterilized using ethylene oxide gas (EOG) or an autoclave.

[0107] The amount of compound (A) added is not particularly limited, but it is preferable to control the amount to a certain level, for example, from the viewpoint of accurately determining the amount of bleeding during a surgical operation. ２The amount of compound (A) added per gauze is preferably 0.001 to 10 g, more preferably 0.01 to 5 g, and even more preferably 0.1 to 3 g. Even if blood adheres to the gauze, the visibility of the fluorescence is not hindered, and the luminescence is further enhanced by the binding of ICG to proteins in the blood.

[0108] The medical fiber material according to this embodiment may further contain the alcoholic hydroxyl group-containing compound (B1) described above. The medical fiber material may also contain other additive components, including water, instead of or in addition to the alcoholic hydroxyl group-containing compound (B1).

[0109] The medical fiber material according to this embodiment may further contain a mordant. By using the mordant, the compound (A) can be fixed to the gauze together with the dye. Examples of the mordant that can be used include alum and iron oxide.

[0110] So far, we have described an example of the use of the medical fiber material according to this embodiment as medical gauze, but the medical fiber material according to this embodiment is not limited to this use. For example, when the medical fiber material is used as a sponge, a tupelo, a cotton ball, a tampon, a (needle-attached) silk thread, or the fiber material that constitutes these, it can be made to fluoresce during use, just like medical gauze. The (needle-attached) silk thread may be used as a target during, for example, a second-stage surgery. If the (needle-attached) silk thread fluoresces, the target can be easily identified, making it extremely useful for such second-stage surgery.

[0111] <Method for manufacturing a medical fiber material> The method for manufacturing a medical fiber material according to this embodiment includes an impregnation step and a mordant step. In the impregnation step, a solution containing the compound (A) is impregnated into a fiber material containing a hydroxyl group-containing organic compound (B). In the mordant step, the compound (A) is fixed to the fiber material using a mordant.

[0112] The fiber material is not particularly limited, as long as it contains a hydroxyl-containing organic compound (B) and can be impregnated with a solution containing compound (A). In this case, the hydroxyl-containing organic compound (B) preferably includes cellulose (B2) or silk (B3). As described above, silk (B3) is a protein containing hydroxyl-containing amino acids as a component. Examples of such fiber materials include medical gauze, sponges, tupels, cotton balls, tampons, silk thread (with needles), etc., and the fiber materials that make up these. For example, the solution may be directly impregnated into medical gauze, sponges, tupels, cotton balls, tampons, silk thread (with needles), etc., or the solution may be impregnated into the fiber materials that make up medical gauze, sponges, tupels, cotton balls, tampons, silk thread (with needles), etc. In addition to the other fiber materials described herein, fiber materials commonly used in the medical and other fields can also be used. The impregnation process may be performed by spraying. In other words, impregnation here refers to soaking the fiber material in the solution, but the impregnation may be achieved by immersing the fiber material in the solution, or by spraying the solution onto the fiber material.

[0113] For example, when impregnating a fibrous material such as gauze with the above solution, the impregnation step may involve impregnating the fibrous material with a solution containing at least compound (A) and an alcoholic hydroxyl group-containing compound (B1) as the hydroxyl group-containing organic compound (B). In this case, the alcoholic hydroxyl group-containing compound (B1) can be used as a solvent for compound (A). The impregnation conditions are not particularly limited, and suitable conditions can be selected taking into account the properties and dimensions of the fibrous material. For example, the impregnation time is preferably 1 minute to 3 days at room temperature and humidity, and it is preferable to shield the material from light during impregnation. As mentioned above, impregnation may also be performed by spraying.

[0114] The solution used in the method for producing a medical fiber material may be a composition containing the compound (A), the alcoholic hydroxyl group-containing compound (B1), and water. Note that the solution does not necessarily need to contain the alcoholic hydroxyl group-containing compound (B1). Therefore, the solution may contain only the compound (A) and water.

[0115] When the alcoholic hydroxyl group-containing compound (B1) is used, for example, a low-boiling or volatile alcoholic hydroxyl group-containing compound such as methanol, ethanol, or isopropyl alcohol may be used, or a high-boiling alcoholic hydroxyl group-containing compound such as glycerin may be used.

[0116] When a low-boiling or volatile alcoholic hydroxyl group-containing compound is used as the alcoholic hydroxyl group-containing compound (B1), when gauze is impregnated with the fluorescent labeling composition, compound (A) is supported on the gauze, and then alcoholic hydroxyl group-containing compound (B1) is volatilized or removed, and compound (A) is supported on the gauze.

[0117] When a high-boiling alcoholic hydroxyl group-containing compound is used as the alcoholic hydroxyl group-containing compound (B1), after the gauze is impregnated with the above solution and the compound (A) is supported on the gauze, the alcoholic hydroxyl group-containing compound (B1) is not removed and is supported on the gauze together with the compound (A).

[0118] In this embodiment, among the alcoholic hydroxyl group-containing compounds (B1), a low-boiling point or volatile alcoholic hydroxyl group-containing compound is preferred, ethanol or isopropyl alcohol is more preferred, and ethanol is even more preferred. By using such a component as the alcoholic hydroxyl group-containing compound (B1), it is possible to achieve a simple and economical method in which only the compound (A) is supported on the medical gauze.

[0119] In this embodiment, the mordant process is, for example, a process of dyeing the gauze with the compound (A) using a mordant. The dyeing process may be pre-mordant, post-mordant, or simultaneous mordant, but from the viewpoint of dyeing the gauze with the compound (A), post-mordant is preferred. The mordant may be any of those described above. The mordant conditions are not particularly limited.

[0120] Before dyeing with a mordant, a protein treatment step may be performed in which a protein preparation is impregnated into the fiber material. The protein treatment allows compound (A) to be fixed to the gauze together with the dye. Examples of the protein preparation that can be used include milk, soy milk, and skim milk powder.

[0121] Furthermore, in this embodiment, it is preferable to perform a sterilization step as needed. The sterilization conditions are not particularly limited, and any method known as a method for sterilizing medical fiber materials such as medical gauze can be used.

[0122] The tip of a surgical instrument such as various forceps or scissors may be coated with, for example, an epoxy resin containing a fluorescent labeling composition, thereby improving the safety of surgery, since the tip of the instrument, which may be hidden behind an organ, can be visually confirmed during operation.

[0123] As explained above, the fluorescent labeling composition according to this embodiment has excellent compartment discrimination properties, at least to the extent that the structure of the object of observation can be more accurately discriminated, has a long luminescence time, allowing the object of observation to be observed for a long period of time, and furthermore, is economical because it places less strain on the living body.

[0124] In particular, in vivo fluorescence imaging using the fluorescent labeling composition according to this embodiment, compound (A), a near-infrared fluorescent organic dye, is used, and near-infrared light, which has a wavelength longer than visible light, is used as excitation light. Therefore, in vivo fluorescence imaging has the advantage of eliminating the need to detect fluorescence (autofluorescence) from substances contained within biological tissues, resulting in less noise. Furthermore, by using compound (A) in combination with a hydroxyl group-containing organic compound (B) (particularly an alcoholic hydroxyl group-containing compound (B1)), unprecedentedly stable fluorescent coloring and sufficient fluorescence intensity can be achieved.

[0125] In addition, the excitation light is not absorbed by substances in biological tissue such as hemoglobin, and the light can reach deep inside the biological tissue, which has the advantage of making it possible to observe the condition of blood vessels, lymphatic vessels, organs, etc.

[0126] Such a fluorescent labeling composition is also useful as a fluorescent probe, an injectable agent, a syringe filler, a medical device, a medical fiber material, etc., and can exhibit the above-mentioned advantages. Furthermore, the methods for producing the fluorescent labeling composition and the medical fiber material can use readily available materials or components and can be produced by a simple method, so they also have advantages as production methods.

[0127] The fluorescent labeling composition, fluorescent probe, injectable agent, syringe filling material, medical device, and medical fiber material according to the present embodiment have the various advantages described above and are therefore suitable for use in biological fluorescent imaging using an ICG-based compound (compound (A)). For example, in medical settings, they can be applied to angiography, tumor fluorescent imaging, identification of regional lymph nodes including sentinel lymph nodes, marking of surgical targets, marking of organs that should be avoided from damage, prevention of intracorporeal residue, prevention of dissipation, and the like. Furthermore, they are expected to be applied outside of medical settings in fields such as basic medical research, life science, regenerative medicine, various diagnostics, architectural engineering, and entertainment. In other words, the fluorescent labeling composition according to the present embodiment is not limited to medical applications and can be expected to be applicable to a wide range of other applications.

[0128] For example, if a builder wants to mark architectural key locations in a building that the user (owner) does not need to know about, by mixing or applying the fluorescent marking composition described in this embodiment to building materials, the specific location (where the fluorescent marking composition is present) can be identified without the user's knowledge. Furthermore, if "glowing contact lenses" are made using the fluorescent marking composition described in this embodiment, performers wearing the "glowing contact lenses" will not sense the fluorescence, and only viewers will be able to see the light from their eyes (the light emitted by the contact lenses). In other words, the fluorescent marking composition of this embodiment is expected to be applicable to theatrical productions.

[0129] <Verification> [Mixing ICG with Resin] It was verified whether a sheet could be produced by kneading pigment (ICG + solvent) into various resins and then compression molding.

[0130] Five types of resins were prepared: polypropylene (PP), polyvinyl chloride (PVC), low-density polyethylene (LDPE), ethylene-vinyl acetate copolymer (EVA), and thermoplastic polyurethane (TPU). The pigment was a viscous liquid prepared by dissolving four tubes of 25 mg of ICG in 10 ml of glycerol.

[0131] Four different pigment concentrations were prepared: 1 phr, 3 phr, 5 phr, and 7 phr. Note that phr stands for per hundred resin, and is a unit that indicates the ratio of pigment blended when the weight of resin is 100. For example, if Ag of pigment is contained in 100 g of resin, the pigment ratio can be said to be A (phr).

[0132] The kneading procedure was as follows. (Step 1: Pre-kneading) The resin was placed in a preheated mixer and kneaded until plasticized. The mixer used was a Labo Plastomill 4M150 manufactured by Toyo Seiki Seisakusho, Ltd. Note that "Labo Plastomill" is a registered trademark of Toyo Seiki Seisakusho, Ltd. This step was performed for each resin prepared in advance. Kneading was performed for 5 minutes at a temperature set for each resin. The kneading temperatures were specifically as follows: polypropylene: 170°C, polyvinyl chloride: 150°C, low-density polyethylene: 140°C, ethylene-vinyl acetate copolymer resin: 140°C, and thermoplastic polyurethane: 150°C. Note that all kneading temperatures were lower than the melting point of ICG (230°C).

[0133] (Step 2: Pigment Kneading) After confirming that the resin was sufficiently plasticized in step 1, the pigment was added and kneaded. The kneading conditions (time, temperature) were the same as in step 1. Thereafter, the kneaded sample (resin + pigment) was collected.

[0134] (Step 3: Compression Molding) The sample was cut into small pieces with scissors. The cut sample was then sandwiched between a pair of heat-resistant polyimide films, and the sample-containing film was placed between a pair of metal plates (e.g., stainless steel plates). The pair of metal plates containing the sample-containing film was then placed between a pair of spacers. The pair of spacers were then pressed toward each other, and the sample was melt-compressed for 1 minute to the desired thickness, forming a sheet. The compression molding temperature was the same as in steps 1 and 2. After molding, the pair of metal plates were placed on a mounting table and allowed to cool at room temperature with a weight placed on top. Two types of sheet thicknesses were obtained: 1 mm (110 mm long x 110 mm wide) and 0.5 mm (125 mm long x 125 mm wide).

[0135] (Results) It was confirmed that kneading of pigments into resins can be carried out without any problems for all resins. It was also confirmed that kneading can be carried out without any problems regardless of the pigment ratio. From this, it can be concluded that thermal degradation of ICG due to kneading can be suppressed.

[0136] [Testing the gauze] Next, a solution containing ICG was impregnated into the gauze, and then the gauze was irradiated with near-infrared light to test whether the gauze could emit fluorescence. The test process and results are shown below.

[0137] (Preparation of Stock Solutions) First, the following stock solutions were prepared: Solution G, Solution E, Solution N, Solution A, and distilled water. Solution G was prepared by dissolving 25 mg of ICG in 10 ml of glycerol. Solution E was prepared by dissolving 25 mg of ICG in 10 ml of ethanol. Solution N was prepared by dissolving 25 mg of ICG in 10 ml of distilled water. Solution A was prepared by dissolving 25 mg of ICG in 10 ml of 5% BSA solution. BSA stands for bovine serum albumin. Distilled water did not contain ICG and was prepared as a comparison with the ICG-containing stock solutions.

[0138] FIG. 1A is a schematic diagram showing the stock solutions arranged in transparent containers. In FIG. 1A, the containers are arranged in the following order from left to right: G solution, E solution, N solution, A solution, and distilled water. An ICG reference card 1 is placed to the right of the container containing distilled water. The ICG reference card 1 has a light-emitting region 1a. The light-emitting region 1a is an area containing ICG that emits fluorescence when irradiated with excitation light (near-infrared light). Here, the luminescence brightness of the light-emitting region 1a of the ICG reference card 1 is used as a reference to relatively compare and evaluate the presence or absence of luminescence and the brightness of the luminescent portion when irradiated with near-infrared light. In other words, the ICG reference card 1 is used for the relative comparison and evaluation of luminescence brightness.

[0139] Figure 1B shows images (hereinafter also referred to as near-infrared images) of each container irradiated with near-infrared light and photographed with a near-infrared camera (Olympus VISERAELITE II). It can be seen from this figure that the luminescence brightness of solutions G and E was high in their undiluted state.

[0140] Next, each stock solution was diluted 5-fold, 10-fold (×10 １ ), 100 times (×10 ２ ), 1000 times (×10 ３ ), 10,000 times (×10 ４ ) to prepare diluted solutions. The dilution was performed using the solvent of each stock solution. Figure 2 shows a near-infrared image obtained for Solution G. For convenience, the container containing the 5-fold diluted solution is omitted from Figure 2 (the same applies to Figures 3 to 5). Figure 2 shows that Solution G provides good (high) luminescence brightness regardless of the dilution ratio.

[0141] Figure 3 shows a near-infrared image obtained for solution E. As can be seen from this figure, similar to solution G, solution E also exhibits good (high) luminescence brightness regardless of the dilution ratio.

[0142] Figure 4 shows a near-infrared image obtained for the N solution. From this figure, it can be seen that high luminescence brightness is obtained when the N solution is diluted 1000 times, but the luminescence brightness is low at other dilution ratios.

[0143] Figure 5 shows near-infrared images obtained for Solution A. It can be seen from the figure that Solution A exhibits high luminescence brightness over the range of dilution from 10-fold to 10,000-fold, and that especially high luminescence brightness is obtained at 100-fold and 1,000-fold dilutions.

[0144] (Impregnation into gauze) Next, from each of the diluted solutions prepared above, a diluted solution with the desired dilution ratio (here, distilled water was used, but the solvent of each original solution may also be used) was selected, and the selected diluted solution was impregnated into gauze to obtain a near-infrared image. Here, Sterase (sterilized, 5 cm x 5 cm) manufactured by Hakujuji Co., Ltd. was used as the gauze. Note that "Sterase" is a registered trademark of Hakujuji Co., Ltd.

[0145] Figure 6A is a schematic diagram showing gauzes impregnated with 5x, 10x, 100x, and 1000x diluted solutions of G, E, N, and A solutions, arranged vertically and horizontally. In Figure 6A, gauzes impregnated with G, E, N, and A solutions are arranged from top to bottom, and gauzes impregnated with 5x, 10x, 100x, and 1000x diluted solutions are arranged from left to right. Also in Figure 6A, an ICG reference card 1 is placed to the right of the gauze impregnated with the 1000x diluted solution, and an untreated gauze 2 is placed above the ICG reference card 1. The untreated gauze 2 is simply unimpregnated gauze.

[0146] Figure 6B shows near-infrared images obtained when near-infrared light was irradiated onto each gauze shown in Figure 6A. It can be seen from the figure that high luminescence brightness was obtained for gauzes impregnated with 10- to 1000-fold diluted solutions of Solution G, Solution E, Solution N, and Solution A. In particular, the gauze impregnated with 100-fold diluted solution exhibited the highest luminescence brightness.

[0147] Next, the results of animal experiments using the above-mentioned gauze will be described. Figures 7A, 8A, 9A, and 10A show schematic images of untreated gauze 2 and treated gauze 3 placed in the abdominal cavity of a pig, captured with an endoscopic camera. The treated gauze 3 in Figure 7A was impregnated with a 100-fold diluted solution of G solution. The treated gauze 3 in Figure 8A was impregnated with a 100-fold diluted solution of E solution. The treated gauze 3 in Figure 9A was impregnated with a 100-fold diluted solution of N solution. The treated gauze 3 in Figure 10A was impregnated with a 100-fold diluted solution of A solution.

[0148] Figures 7B, 8B, 9B, and 10B show near-infrared images obtained when near-infrared light was irradiated onto the gauzes shown in Figures 7A, 8A, 9A, and 10A. These figures show that, within the abdominal cavity, each of the treated gauzes 3 emits light with high luminescence intensity when irradiated with near-infrared light.

[0149] [Configuration Example of Subcutaneously Implantable Port] Fig. 11 is a perspective view showing a configuration example of a CV port (central venous port) 10 as a subcutaneously implantable port. Fig. 12 is a cross-sectional view of the CV port 10 of Fig. 10. Fig. 13 is an exploded perspective view of the CV port 10 of Fig. 10. In Fig. 11, the outer shape of the housing portion 12 is shown by a dashed line to clarify the internal configuration of the CV port 10.

[0150] The CV port 10 includes a septum 11, a housing portion 12, and an index member 13. The septum 11 is made of, for example, soft silicone rubber. The septum 11 integrally includes a large-diameter portion 11a and a small-diameter portion 11b. The small-diameter portion 11b has a smaller diameter than the large-diameter portion 11a. The small-diameter portion 11b is located above the large-diameter portion 11a and coaxially with the large-diameter portion 11a. A Huber needle for injecting a medicinal solution is inserted into the septum 11 (for example, the small-diameter portion 11b).

[0151] The housing portion 12 is a cover that holds the septum 11 and holds the septum 11 so that the top surface of the septum 11 (e.g., the small diameter portion 11b) is exposed. The housing portion 12 has an outer housing 12a and an inner housing 12b.

[0152] The outer housing 12a is made of, for example, transparent acrylic resin. When the CV port 10 is implanted subcutaneously in a patient, a portion of the outer surface (e.g., the upper surface) of the outer housing 12a comes into contact with the patient's skin. A screw groove is formed on the inner circumferential surface of the outer housing 12a. The inner housing 12b is a back cover located inside the outer housing 12a. A screw thread is formed on the outer circumferential surface of the inner housing 12b. The inner housing 12b is fixed to the outer housing 12a by screwing the inner housing 12b into the inside of the outer housing 12a while engaging the screw thread with the screw groove.

[0153] A recess 12b1 is formed in the upper part of the inner housing 12b. The large diameter portion 11a of the septum 11 is fitted into the recess 12b1 and is sandwiched between the inner housing 12b and the outer housing 12a from above and below.

[0154] The inner housing 12b is formed with an injection chamber 12b2 for accommodating the medicinal liquid. The injection chamber 12b2 is formed with a smaller diameter than the recess 12b1 and is located below the recess 12b1. The medicinal liquid is injected into the injection chamber 12b2 via a Huber needle inserted through the septum 11 and introduced into a blood vessel or the like via a catheter (not shown) that communicates with the injection chamber 12b2.

[0155] The indicator member 13 is disposed inside the housing portion 12 and outside the septum 11. More specifically, the indicator member 13 is located inside the outer shape of the housing portion 12 (particularly the outer housing 12a). The indicator member 13 is also disposed on the upper surface of the large diameter portion 11a of the septum 11 and is spaced apart in the radial direction from the small diameter portion 11b (see particularly FIG. 12). The indicator member 13 is covered by the outer housing 12a. Therefore, a portion of the outer housing 12a is located between the indicator member 13 and the small diameter portion 11b.

[0156] The indicator member 13 is a ring-shaped member that surrounds the septum 11 (particularly the small diameter portion 11b). The shape of the indicator member 13 is not limited to a ring shape (circular in plan view) and may be other shapes such as a square or elliptical shape. Furthermore, the indicator member 13 does not necessarily have to be formed as a single continuous member in the circumferential direction, and may be, for example, a plurality of indicator members arranged at intervals in the circumferential direction.

[0157] The indicator member 13 contains the fluorescent labeling composition of this embodiment. Specifically, the indicator member 13 is formed by kneading the pigment (ICG + solvent) described above as the fluorescent labeling composition into a resin and then molding the kneaded resin into, for example, a ring shape. When the indicator member 13 contains the fluorescent labeling composition, irradiation with near-infrared light causes the portion of the housing 12 that does not directly contact the patient's subcutaneous tissue, rather than the septum 11 itself, to fluoresce, thereby enabling the septum 11 to be recognized. This eliminates the problem of the drug-containing resin coming into direct contact with the patient's subcutaneous tissue for an extended period of time, thereby ensuring improved safety.

[0158] In particular, since the indicator member 13 has a shape (e.g., a ring shape) that surrounds the septum 11 in a plan view, it is easy to recognize that the septum 11 is present in the area surrounded by the indicator member 13. This makes it easy to insert the Huber needle using the area as an indicator.

[0159] [Verification of the Luminescence Intensity of the Indicator Member] Next, the results of verifying the luminescence intensity of the indicator member 13 are shown below. FIG. 14A schematically shows rings (corresponding to indicator member 13) arranged vertically and horizontally, each of which was formed by mixing G solution, E solution, N solution, and A solution with epoxy resin at ratios of 1 phr, 3 phr, 5 phr, and 10 phr, respectively. In FIG. 14A, from the top to the bottom, rings each formed by mixing G solution, E solution, N solution, and A solution with epoxy resin are arranged. Also, in FIG. 14A, an ICG reference card 1 is placed on the left end, and a negative control 4 is placed above the ICG reference card 1. The negative control 4 is used for comparison with each ring and is composed only of epoxy resin without ICG. In FIG. 14A, the rings are arranged to the right of the ICG reference card 1 and negative control 4 in the order of 1 phr, 3 phr, 5 phr, and 10 phr from left to right.

[0160] Figure 14B shows near-infrared images obtained when near-infrared light was irradiated onto each ring (ICG1v ring) in Figure 14A. The ICG1v ring is a ring molded by mixing the following solutions, G, E, N, and A, with epoxy resin. Specifically, solution G is a solution obtained by dissolving 25 mg of ICG in 10 ml of glycerol. Solution E is a solution obtained by dissolving 25 mg of ICG in 10 ml of ethanol. Solution N is a solution obtained by dissolving 25 mg of ICG in 10 ml of distilled water. Solution A is a solution obtained by dissolving 25 mg of ICG in 10 ml of 5% BSA solution. From this figure, it was found that rings molded using solutions G, E, N, and A all achieved luminescence brightness equivalent to or greater than that of the ICG reference card. It was particularly found that rings containing 3 phr or more achieved higher luminescence brightness.

[0161] Figure 15 shows near-infrared images obtained when each ring (ICG1v ring) in Figure 14A is replaced with an ICG4v ring and irradiated with near-infrared light. The ICG4v ring is a ring molded by mixing the following solutions G, E, N, and A with epoxy resin. Specifically, solution G is a solution obtained by dissolving 100 mg of ICG in 10 ml of glycerol. Solution E is a solution obtained by dissolving 100 mg of ICG in 10 ml of ethanol. Solution N is a solution obtained by dissolving 100 mg of ICG in 10 ml of distilled water. Solution A is a solution obtained by dissolving 100 mg of ICG in 10 ml of 5% BSA solution. It was found that, regardless of whether the ICG4v ring was molded using solution G, solution E, solution N, or solution A, high luminescence brightness was obtained for all rings from 1 phr to 10 phr.

[0162] Furthermore, polishing the surface of each ring tended to result in even higher luminescence intensity in the near-infrared images.

[0163] 16A is a schematic diagram showing a CV port 10 including an index member 13 and a comparison port 10A not including an index member 13, arranged vertically. In FIG. 16A, a negative control 4 is placed on the left side of the CV port 10. An ICG reference card 1 is placed below the negative control 4 (to the left of the comparison port 10A).

[0164] Figure 16B shows near-infrared images obtained when near-infrared light is irradiated onto the CV port 10 and the comparative port 10A in Figure 16A, where the indicator member 13 of the CV port 10 is molded by mixing 10 phr of solution G with epoxy resin. Figures 17 to 19 show near-infrared images of the indicator member 13 of the CV port 10 when 10 phr of solution E, 10 phr of solution N, and 10 phr of solution A are mixed with epoxy resin.

[0165] As shown in Figure 16B and Figures 17 to 19, it was found that when the ring-shaped indicator member 13 was molded using any of the G solution, E solution, N solution, and A solution, a luminescence brightness equivalent to or greater than that of the ICG reference card was obtained.

[0166] <Appendix> The fluorescent labeling composition, fluorescent probe, injectable agent, syringe filling material, medical device, medical fiber material, method for producing a fluorescent labeling composition, and method for producing a medical fiber material described in the present embodiment above can be expressed as described in the appendix below.

[0167] The fluorescent labeling composition according to Supplementary Note (1) contains a compound (A) represented by the following formula (1) and a hydroxyl group-containing organic compound (B). (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0168] The fluorescent labeling composition according to Supplementary Note (2) is the fluorescent labeling composition according to Supplementary Note (1), wherein the hydroxyl group-containing organic compound (B) includes an alcoholic hydroxyl group-containing compound (B1).

[0169] The fluorescent labeling composition according to Supplementary Note (3) is the fluorescent labeling composition according to Supplementary Note (2), wherein the alcoholic hydroxyl group-containing compound (B1) includes an aliphatic alcohol.

[0170] The fluorescent labeling composition according to Supplementary Note (4) is the fluorescent labeling composition according to Supplementary Note (2) or (3), which contains 0.0000001 to 10% by mass of the compound (A) and 1 to 90% by mass of the alcoholic hydroxyl group-containing compound (B1).

[0171] The fluorescent labeling composition according to Supplementary Note (5) is the fluorescent labeling composition according to Supplementary Note (2) or (3), wherein the fluorescent labeling composition according to any one of Claims 2 to 3 contains 97 to 99.99998 parts by mass of the alcoholic hydroxyl group-containing compound (B1) relative to 100 parts by mass in total of the compound (A) and the alcoholic hydroxyl group-containing compound (B1).

[0172] The fluorescent labeling composition according to Supplementary Note (6) is the fluorescent labeling composition according to any one of Supplementary Notes (1) to (5), which is substantially free of dimethyl sulfoxide.

[0173] The fluorescent labeling composition according to Supplementary Note (7) is the fluorescent labeling composition according to any one of Supplementary Notes (1) to (6), further comprising, as resin (C), at least one resin selected from the group consisting of olefin-based resins, epoxy-based resins, vinyl chloride-based resins, fluorine-based resins, polycarbonate-based resins, polyamide-based resins, ABS-based resins, acetal-based resins, acrylic-based resins, and silicone-based resins.

[0174] The fluorescent labeling composition according to Supplementary Note (8) is the fluorescent labeling composition according to any one of Supplementary Notes (1) to (7), further comprising a polyurethane resin.

[0175] The fluorescent labeling composition according to Supplementary Note (9) is the fluorescent labeling composition according to any one of Supplementary Notes (1) to (8), which is in a solid or semi-solid state at 25°C and a relative humidity of 50%.

[0176] The fluorescent probe according to Supplementary Note (10) contains the fluorescent labeling composition according to any one of Supplementary Notes (1) to (9).

[0177] The injectable agent according to Supplementary Note (11) is a labeling injectable agent for labeling an object present on a mucous membrane or on the skin, and contains the fluorescent labeling composition according to any one of Supplementary Note (1) to (9).

[0178] The injection according to Supplementary Note (12) is the injection according to Supplementary Note (11), further comprising at least one of sodium alginate and sodium hyaluronate as component (D).

[0179] The injection agent according to Supplementary Note (13) is the injection agent according to Supplementary Note (12), which contains the component (D) in a total amount of 0.01 to 10% by mass.

[0180] A syringe filling according to Supplementary Note (14) includes the fluorescent labeling composition according to any one of Supplementary Notes (1) to (9) and a syringe filled with the fluorescent labeling composition.

[0181] The medical device according to Supplementary Note (15) contains the fluorescent labeling composition according to any one of Supplementary Notes (1) to (9).

[0182] The medical device according to Supplementary Note (16) is the medical device according to Supplementary Note (15), wherein the medical device is one selected from the group consisting of a stent, a tube, a catheter, a clip, a filament for a 3D printer, and a resin fiber material.

[0183] The medical fiber material according to Supplementary Note (17) includes a fiber material containing a compound (A) represented by the following formula (1) and a hydroxyl group-containing organic compound (B). (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0184] The medical fiber material according to Supplementary Note (18) is the medical fiber material according to Supplementary Note (17), wherein the hydroxyl group-containing organic compound (B) contains cellulose (B2).

[0185] The method for producing a fluorescent labeling composition according to Supplementary Note (19) includes a mixing step of mixing a compound (A) represented by the following formula (1) with a hydroxyl group-containing organic compound (B): (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0186] The method for producing a fluorescent labeling composition according to Supplementary Note (20) is the method for producing a fluorescent labeling composition according to Supplementary Note (19), wherein in the mixing step, 0.0000001 to 10% by mass of the compound (A) and 1 to 90% by mass of an alcoholic hydroxyl group compound (B1) as the hydroxyl group-containing organic compound (B) are mixed.

[0187] The method for producing a medical fiber material according to Supplementary Note (21) includes an impregnation step of impregnating or spraying a solution containing a compound (A) represented by the following formula (1) onto a fiber material containing a hydroxyl group-containing organic compound (B), and a mordant step of fixing the compound (A) to the fiber material using a mordant. (In the formula, R １ and R ２ each independently represents hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

[0188] The method for producing a medical fiber material according to Supplementary Note (22) is the method for producing a medical fiber material according to Supplementary Note (21), wherein the hydroxyl group-containing organic compound (B) contains cellulose (B2).

[0189] The method for producing a medical fiber material according to Supplementary Note (23) is the method for producing a medical fiber material according to Supplementary Note (21) or (22), further comprising a protein treatment step of impregnating the fiber material with a protein preparation.

[0190] The medical device according to Supplementary Note (24) is the medical device according to Supplementary Note (15), wherein the medical device is a subcutaneously implantable port, the subcutaneously implantable port having a septum, a housing portion that holds the septum, and an indicator member that is disposed inside the housing portion and on the outside of the septum, and the indicator member has the fluorescent labeling composition.

[0191] The medical device according to Supplementary Note (25) is the medical device according to Supplementary Note (24), wherein the indicator member has a shape that surrounds the septum.

[0192] Although the embodiments of the present invention have been described above, the scope of the present invention is not limited to these, and the invention can be expanded or modified without departing from the spirit of the invention.

[0193] The present invention can be used, for example, in biological fluorescence imaging.

[0194] 10 CV port (subcutaneously implanted port) 11 septum 12 housing part 13 index member

Claims

1. A compound (A) represented by the following formula (1), A hydroxyl group-containing organic compound (B), The fluorescent labeling composition further comprises, as the resin (C), at least one selected from the group consisting of polyurethane-based resins, olefin-based resins, epoxy-based resins, vinyl chloride-based resins, fluorine-based resins, polycarbonate-based resins, polyamide-based resins, ABS-based resins, acetal-based resins, acrylic-based resins, and silicone-based resins. 【Chemistry 1】 (In the formula, R 1 and R 2 each independently represent a hydrogen atom, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer from 1 to 5; and m and n each independently represent an integer from 1 to 12.)

2. The fluorescent labeling composition described in claim 1, which is solid or semi-solid at 25°C and a relative humidity of 50%.

3. A medical device containing the fluorescent labeling composition described in claim 1 or 2.

4. The medical device is a subcutaneously implantable port, The subcutaneous implantable port comprises: Septum and a housing portion for holding the septum; an indicator member disposed within the housing portion and outside the septum; The medical device of claim 3 , wherein the indicator member comprises the fluorescent labeling composition.

5. The medical device described in claim 4, wherein the indicator member is shaped to surround the septum.

6. The medical device described in claim 3, wherein the medical device is one selected from the group consisting of a stent, a tube, a catheter, a clip, a filament for a 3D printer, and a resin fiber material.

7. A fluorescent probe comprising the fluorescent labeling composition described in claim 1 or 2.

8. A marking injection for marking an object present on a mucous membrane or on the skin, comprising: A compound (A) represented by the following formula (1), A hydroxyl-containing organic compound (B); An injection agent comprising: 【Chemistry 2】 (In the formula, R 1 and R 2 each independently represent a hydrogen atom, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer from 1 to 5; and m and n each independently represent an integer from 1 to 12.)

9. The injection agent according to claim 8, further comprising at least one of sodium alginate and sodium hyaluronate as component (D).

10. The injection agent according to claim 9, containing 0.01 to 10 mass% in total of the (D) component.

11. A syringe filled with an injection agent according to any one of claims 8 to 10.

12. A method for producing the fluorescent labeling composition according to claim 1 or 2, comprising the steps of: a mixing step of mixing the compound (A) and the hydroxyl group-containing organic compound (B); and kneading a pigment obtained by mixing the compound (A) and the hydroxyl group-containing organic compound (B) into the resin (C).

13. The method for producing a fluorescent labeling composition described in claim 12, wherein in the mixing step, 0.0000001 to 10 mass % of the compound (A) is mixed with 1 to 90 mass % of an alcoholic hydroxyl group compound (B1) as the hydroxyl group-containing organic compound (B).

14. An impregnation step of impregnating or spraying a solution containing 0.0000001 to 10 mass % of a compound (A) represented by the following formula (1) onto a fiber material containing a hydroxyl group-containing organic compound (B); A method for producing a medical fiber material, comprising: a light-shielding step of shading light during the impregnation step. 【Chemistry 3】 (In the formula, R 1 and R 2 each independently represent a hydrogen atom, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonate group; p is an integer from 1 to 5; and m and n each independently represent an integer from 1 to 12.)

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