Composition for fluorescence labeling, fluorescence probe, injection, syringe filler, medical instrument, fiber material for medical use, method for producing composition for fluorescence labeling, and method for producing fiber material for medical use

Abstract

The composition for fluorescence labeling contains a compound (A) that is an ICG-based compound and a hydroxyl group-containing organic compound (B). As a result, it is possible to provide a fluorescence labeling composition or the like which has excellent distinguishing and recognizing properties such that an object to be observed can be recognized more accurately, has a long light emission time, enables the observation of the object to be observed over a long period of time, has little burden on a living body, and has excellent economical efficiency.

Description

Technical Field

[0001] The present invention relates to a fluorescent labeling composition, a fluorescent probe, an injection, a syringe filling, a medical device, a medical fiber raw material, a method for producing the fluorescent labeling composition, and a method for producing the medical fiber raw material. Background Art

[0002] Biofluorescence imaging is used as a technique to visualize the surface or internal state of biological tissues such as blood vessels, lymphatic vessels, and organs. Biofluorescence imaging is a technique that uses fluorescent labeling compounds to label (mark) specific proteins or cell organs and visualizes the fluorescence using a fluorescent microscope or camera. For example, indocyanine green (ICG) is used as a fluorescent labeling compound used in biofluorescence imaging.

[0003] Biofluorescence imaging using ICG is clinically used, for example, in the field of surgery. For example, ICG is injected into a living body and irradiated with excitation light to cause fluorescence, thereby photographing and monitoring the observation object such as the fluorescent imaging site. This allows non-invasive observation of the state of blood vessels, lymphatic vessels, organs, etc.

[0004] An example of such a technology related to biofluorescence imaging is disclosed in Patent Document 1. Patent Document 1 discloses a multi-purpose medical imaging marker containing a rubber agent and a fluorescent dye. 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 for the purpose of including a large amount of ICG in the particles while maintaining a monomer state. The production method includes a step of mixing ICG, particles, and a solution containing a chaotropic agent at a concentration of 1 mM or more and 10 M or less.

[0006] Furthermore, examples of fluorescent labeling compounds other than ICG are disclosed in Patent Documents 3 and 4. More specifically, Patent Documents 3 and 4 disclose a thermoplastic resin composition that emits near-infrared fluorescence by irradiation with excitation light in the near-infrared region and contains a near-infrared fluorescent dye composed of an azo boron complex as a resin composition detectable by a detector.

[0007] Prior Art Literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent Application Publication No. 2019-167341

[0010] Patent Document 2: Japanese Patent Application Publication No. 2014-227338

[0011] Patent Document 3: Japanese Patent Application Publication No. 2015-025105

[0012] Patent Document 4: International Publication No. 2013 / 180127 Summary of the invention

[0013] Problems to be solved by the invention

[0014] In the technology disclosed in Patent Document 1, dimethyl sulfoxide (DMSO) or the like is used as a solvent for ICG. Since DMSO is a solvent that has high irritation to the skin and mucous membranes and high permeability to the skin, it is preferably avoided as much as possible. Furthermore, since DMSO has cytotoxicity, it is also preferably avoided as much as possible in this regard.

[0015] The technology disclosed in Patent Document 2 is directed to containing ICG in a high concentration in liposomes without agglutinating ICG but in a monomeric state. However, Patent Document 2 does not study the distinguishing and identifying properties of fluorescent luminescence for accurately identifying the observation object such as the fluorescent contrast imaging site, or the luminescence time for observing the observation object for a long time.

[0016] The techniques disclosed in Patent Documents 3 and 4 use azoboron complexes, which are not preferred in terms of toxicity. In addition, since they are new compounds not commonly used in clinical practice, large-scale synthesis is expensive and thus economical.

[0017] That is, in the biofluorescence imaging using ICG described above, it is desired to obtain a technology that has excellent distinguishing recognition to the extent that the structure, shape, and state of the observation object such as the fluorescence contrast site can be accurately identified, and the luminescence time is long and the observation object can be observed for a long time. However, when ICG is administered to a living body, it is difficult to control the luminescence range and luminescence timing, and sometimes the fluorescence becomes insufficient, thereby failing to fully meet the above requirements. For example, it is considered that if ICG is intravenously injected in clinical practice or the fluorescence is insufficient when administered, the state of the surgical area cannot be accurately grasped, or further additional intravenous injection of ICG must be performed. In addition, it is also considered that in the case of excess fluorescence, the operator must wait until the ICG is metabolized and disappears.

[0018] Furthermore, in biofluorescence imaging, a technology that is less toxic, less burdensome to the organism, and economically efficient by suppressing the production cost of the fluorescent labeling compound is also desired.

[0019] However, technologies that fully meet these requirements have not yet been developed.

[0020] The present invention has been completed in view of such a current situation, and its purpose is to provide a fluorescent labeling composition, a fluorescent probe, an injection, a syringe filling, a medical device, a medical fiber raw material, a method for producing a fluorescent labeling composition, and a method for producing a medical fiber raw material, which have excellent distinguishing and identifying properties to the extent that the observation object can be identified more accurately, have a long luminescence time, can observe the observation object for a long time, and thus have less burden on the living body and are economical.

[0021] Methods for solving problems

[0022] 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).

[0023] [Chemical formula 1]

[0024]

[0025] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0026] A fluorescent probe according to another aspect of the present invention includes the above-mentioned fluorescent labeling composition.

[0027] The injection according to another aspect of the present invention is a labeling injection for labeling an object present on a mucous membrane or skin, and contains the above-mentioned fluorescent labeling composition.

[0028] A syringe filling material according to another aspect of the present invention includes: the fluorescent labeling composition described above; and a syringe filled with the fluorescent labeling composition.

[0029] A medical device according to another aspect of the present invention includes the above-mentioned fluorescent labeling composition.

[0030] A medical fiber material according to another aspect of the present invention comprises a compound (A) represented by the following formula (1) and a fiber material containing a hydroxyl group-containing organic compound (B).

[0031] [Chemical formula 2]

[0032]

[0033] (In the chemical formula, R1 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0034] A method for producing a fluorescent labeling composition according to another aspect of the present invention includes a mixing step of mixing a compound (A) represented by the following formula (1) and a hydroxyl group-containing organic compound (B).

[0035] [Chemical formula 3]

[0036]

[0037] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0038] Another aspect of the present invention relates to a method for producing a medical fiber raw material, comprising: an impregnation step of impregnating a solution containing a compound (A) represented by the following formula (1) into a fiber raw material containing a hydroxyl-containing organic compound (B), or spraying the fiber raw material containing a hydroxyl-containing organic compound (B) with a sprayer; and a mordant step of fixing the compound (A) in the fiber raw material using a mordant.

[0039] [Chemical formula 4]

[0040]

[0041] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0042] Effects of the Invention

[0043] According to the present invention, there can be provided a fluorescent labeling composition, a fluorescent probe, an injection, a syringe filling, a medical device, a medical fiber raw material, a method for producing a fluorescent labeling composition, and a method for producing a medical fiber raw material, which have excellent distinguishing and identifying properties to the extent that the observation object can be identified more accurately, have a long luminescence time, can observe the observation object for a long time, and thus have less burden on the biological body and are economically excellent. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1A This is an explanatory diagram schematically showing a state where various stock solutions are placed and arranged in a container.

[0045] Figure 1B To express Figure 1A An explanatory diagram of a near-infrared image obtained by irradiating each container with near-infrared light.

[0046] Figure 2 This is an explanatory diagram showing a near-infrared image obtained for solution G.

[0047] Figure 3 This is an explanatory diagram showing a near-infrared image obtained for Solution E.

[0048] Figure 4 It is an explanatory diagram showing a near-infrared image obtained for the N solution.

[0049] Figure 5 This is an explanatory diagram showing a near-infrared image obtained for solution A.

[0050] Fig. 6A This is an explanatory diagram schematically showing a state in which gauze soaked in a diluent is arranged.

[0051] Figure 6B To express Fig. 6A An explanatory diagram of near-infrared images obtained when each gauze is irradiated with near-infrared light.

[0052] Fig. 7A This is an explanatory diagram schematically showing an image obtained by placing gauze soaked in a diluted solution of G solution in the abdominal cavity of a pig and photographing the image with an endoscopic camera.

[0053] Figure 7B To express Fig. 7A An illustration of a near-infrared image of gauze.

[0054] Fig. 8A This is an explanatory diagram schematically showing an image obtained by placing gauze soaked in a diluted E solution in the abdominal cavity and photographing the image with an endoscopic camera.

[0055] Figure 8B To express Fig. 8A An illustration of a near-infrared image of gauze.

[0056] Fig.9A This is an explanatory diagram schematically showing an image obtained by placing gauze soaked in a diluted N solution in the abdominal cavity and photographing the image with an endoscopic camera.

[0057] Fig. 9B To express Fig.9A An illustration of a near-infrared image of gauze.

[0058] Fig. 10A This is an explanatory diagram schematically showing an image obtained by placing gauze soaked in a diluted solution of solution A in the abdominal cavity and photographing the image with an endoscopic camera.

[0059] Fig. 10B To express Fig. 10A An illustration of a near-infrared image of gauze.

[0060] Fig.11 It is a perspective view showing a structural example of a CV infusion port.

[0061] Fig.12 This is a cross-sectional view of the above-mentioned CV infusion port.

[0062] Fig.13 This is an exploded perspective view of the above-mentioned CV infusion port.

[0063] Fig.14A This is an explanatory diagram schematically showing a state in which rings obtained by molding an epoxy resin are arranged.

[0064] Fig. 14B To express Fig.14A Illustration of the near-infrared images of each ring.

[0065] Fig.15 To express Fig.14A An illustration of a near-infrared image of a ring formed by a solution with an ICG concentration increased fourfold is added for comparison of the rings.

[0066] Fig.16A This is an explanatory diagram schematically showing a state where the above-mentioned CV infusion port and the comparative infusion port are arranged in parallel.

[0067] Fig. 16B This is an explanatory diagram showing a near-infrared image of the CV port having an indicator member molded using a G solution.

[0068] Fig.17 This is an explanatory diagram showing a near-infrared image of the CV port having an indicator member molded using the E solution.

[0069] Fig.18 It is an explanatory diagram showing a near-infrared image of the CV port having an indicator member molded using N solution.

[0070] Fig.19 This is an explanatory diagram showing a near-infrared image of the CV port having an indicator member molded using solution A. DETAILED DESCRIPTION

[0071] Hereinafter, a method for implementing the present invention (hereinafter referred to as "the present embodiment") is described in detail. The present embodiment below is an example for illustrating the present invention, and is not intended to limit the present invention to the following content. The present invention can be implemented by appropriately deforming within the scope of its main purpose. In addition, in the following description, when the numerical range is recorded as AA to BB, it is assumed that the value of the lower limit AA and the upper limit BB are included in the above numerical range.

[0072] <Fluorescent labeling composition>

[0073] The fluorescent labeling composition involved in this embodiment is a fluorescent labeling composition containing a compound (A) represented by the following formula (1) and a hydroxyl-containing organic compound (B). Compound (A) includes indigo green ("ICG") and its derivatives ("indigo green derivatives", "ICG derivatives"). In addition, in this specification, ICG and ICG derivatives are sometimes collectively referred to as "indigo green compounds" ("ICG compounds"), etc.

[0074] [Chemical formula 5]

[0075]

[0076] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0077] ((A) ingredient: indigo green compound)

[0078] The compound (A) represented by formula (1) contains indocyanine green (ICG). ICG is a compound having a structure represented by the following formula (1a) (CAS No. 3599-32-4), and is a fluorescent organic pigment whose excitation light and fluorescence are both in the near-infrared region. Formula (1a) is 1 and R 2 When all are hydrogen, p is 2, and m and n are both 4.

[0079] [Chemical formula 6]

[0080]

[0081] Although R1 and R2 each independently represent hydrogen, an alkyl group having 1 to 13 carbon atoms, an alkoxy group having 1 to 13 carbon atoms, or a sulfonyl group, they each independently represent preferably 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 still more preferably hydrogen.

[0082] Although p is an integer of 1 to 5, it is preferably 1 to 4, more preferably 2 to 3, and even more preferably 2.

[0083] Although m and n are each independently an integer of 1 to 12, 1 to 8 are preferred, 2 to 6 are more preferred, 3 to 5 are further preferred, and 4 is still more preferred.

[0084] ICG hardly absorbs the excitation energy of wavelengths below 600nm, but absorbs the excitation energy of wavelengths of 650~900nm to emit fluorescence. Therefore, although it is difficult to visually confirm fluorescence in the irradiation of visible light, it is easy to visualize by using a fluorescence microscope or a camera, etc. to receive the fluorescence luminescence that emits light by irradiation of near-infrared light as excitation light. Therefore, in the case of using the fluorescent labeling composition involved in the present embodiment in biological fluorescence imaging in blood, the excitation light of ICG is not absorbed by hemoglobin, etc., which has strong absorption in the visible light region below 600nm. Therefore, the excitation light of ICG can reach the inner deep part of the biological tissue, so that the biological permeability is higher. Therefore, it can be said that ICG is a near-infrared fluorescent organic pigment suitable for the observation of biological tissue, that is, the observation of the state of blood vessels, lymphatic vessels and organs, etc.

[0085] However, ICG has the problem of unstable fluorescence coloration, insufficient fluorescence intensity, or inactivation in a short period of time. Therefore, in clinical situations where identification is required, such as in determining the resection site during surgery, or where long-term and continuous monitoring is required, the existing biofluorescence imaging using ICG is not sufficient and needs to be improved.

[0086] In this regard, according to the present embodiment, since stable fluorescence color development can be obtained by using ICG in combination with a hydroxyl-containing organic compound described later, and sufficient fluorescence intensity can be obtained, excellent discrimination and recognition can be obtained to the extent that the structure of the observation object such as the fluorescent contrast imaging site can be more clearly identified. In addition, since the luminescence time is long, the observation object can be observed for a long time.

[0087] Although the reason for obtaining such an advantage is uncertain, it is speculated as follows. By using ICG and a hydroxyl-containing organic compound in combination, the two can be firmly bonded by the effect of hydrogen bonding, thereby obtaining a stable form. As a result, it is believed that excellent distinguishing recognition and a long luminescence time can be achieved (but the effect of the present embodiment is not limited to this). As the above-mentioned hydrogen bond, for example, the bonding of the hydrogen atom contained in the hydroxyl group possessed by the hydroxyl-containing organic compound and the oxygen atom contained in ICG can be considered.

[0088] In addition, the above description also applies to the use of ICG (see formula (1a)) and ICG derivatives having the same basic structure (in formula (1), R 1 and R 2 In the case where all of them are hydrogen, p is 1, and m and n are both 4).

[0089] In addition, as fluorescent organic pigment, it is preferred to contain only the compound represented by formula (1) (ICG system compound). That is, the fluorescent organic pigment preferably contains only ICG, ICG derivatives or any one of the two. For example, from the viewpoints of toxicity and economy, it is preferred to not contain substantially the azo boron complex disclosed in patent documentation 3 and patent documentation 4. In addition, in this specification, "not containing substantially" or "not being mixed substantially" refers to the situation of not actively adding or mixing the component, and does not exclude the situation of inevitably containing or being mixed. The most preferred form in the case of "not containing substantially" is the situation of zero content.

[0090] ((B) ingredient: hydroxyl-containing organic compound)

[0091] The hydroxyl-containing organic compound (B) is an organic compound containing a hydroxyl group (OH group) as a functional group. As the hydroxyl-containing organic compound (B), for example, an alcohol-containing hydroxyl compound (B1) can be used. In addition, when the above-mentioned ICG-based compound is applied to the medical fiber raw 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 in a part of its components. In addition, since water is an inorganic compound, it is not included in the above-mentioned hydroxyl-containing organic compound (B). Moreover, when the ICG-based compound is applied to the resin material described later, a polymer formed by polymerization of a hydroxyl-containing monomer such as an epoxy resin (B4) can be used.

[0092] ((B1) ingredient: alcohol hydroxyl-containing compound)

[0093] The alcoholic hydroxyl group-containing compound (B1) is not particularly limited, but is preferably a fatty alcohol. As the fatty alcohol, a fatty alcohol having 1 to 10 carbon atoms is more preferred. The fatty alcohol having 1 to 10 carbon atoms has 1 to 5 carbon atoms, and more preferably 1 to 4 carbon atoms.

[0094] Although specific examples of the alcoholic hydroxyl group-containing compound (B1) are not particularly limited, examples thereof include monoalcohols such as methanol, ethanol, isopropanol, and propylene glycol; glycols such as diethylene glycol; triols such as glycerol; and sugar alcohols such as mannitol. Among these alcohols, ethanol, isopropanol, glycerol, etc. are also preferred from the viewpoints of cytotoxicity and tissue barrier properties. In particular, glycerol, etc. are more preferred from the viewpoints of ignitability and safety to the human body.

[0095] The alcoholic hydroxyl group-containing compound (B1) may be used alone or in combination of two or more.

[0096] Although the content of the compound (A) in the fluorescent labeling composition is not particularly limited, it is preferably 0.0000001 to 10 mass %, more preferably 0.0000001 to 1 mass %, further preferably 0.000001 to 1 mass %, and further more preferably 0.000001 to 0.6 mass %. When the fluorescent pigment becomes a certain fixed concentration or more, sometimes there will be a concentration quenching phenomenon in which the fluorescence intensity (quantum yield) decreases. In the present embodiment, by setting the content of the compound (A) to the above range, the concentration quenching phenomenon can be effectively suppressed. As a result, the distinguishing recognition during fluorescence luminescence can be further improved, and the luminescence time can also be further extended (however, the effect of the present embodiment is not limited thereto).

[0097] 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% by mass, more preferably 99 to 99.9999999% by mass, further preferably 99 to 99.999999% by mass, and further more preferably 99.4 to 99.999999% by mass.

[0098] Moreover, as a combination of the content of compound (A) and alcoholic hydroxyl compound (B1), it is preferred that the content of compound (A) is 0.0000001-10% by mass and the content of alcoholic hydroxyl compound (B1) is 1-90% by mass. By setting the content of compound (A) and alcoholic hydroxyl compound (B1) to the above range, the distinguishing recognition during fluorescence luminescence can be further improved, and the luminescence time can also be further extended. In addition, the content of the above-mentioned compound (A) and alcoholic hydroxyl compound (B) is the content when the fluorescent labeling composition is used, and a high concentration of the fluorescent labeling composition can be prepared in advance before use, and the fluorescent labeling composition is diluted to achieve the above content when used.

[0099] In addition, although the content ratio of the alcoholic hydroxyl compound (B1) relative to the total of 100 parts by mass of the compound (A) and the alcoholic hydroxyl compound (B1) is not particularly limited, it 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 compound (B1) to the above range, the distinguishing and identifying property during the fluorescence emission can be further improved, and the emission time can also be further prolonged.

[0100] And, according to the present embodiment, since it is not necessary to use organic solvents such as DMSO and chloroform, there is less burden on the organism. In addition, since commercially available products can also be used as alcohol-containing hydroxy compounds, the economy is excellent. From such a viewpoint, the fluorescent labeling composition involved in the present embodiment is preferably substantially free of DMSO. Similarly, it is preferably substantially free of chloroform. By substantially free of these organic solvents, the above-mentioned advantages can be further improved. Most preferably, the content of DMSO and chloroform is zero.

[0101] The fluorescent labeling composition according to the present embodiment may also contain other additives, etc. As such additives, for example, components added to contrast agents can be considered, specifically, sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate, aminotriazole sodium, aminotriazole sodium meglumine, iohexol, etc.

[0102] Here, an example of the case where the fluorescent labeling composition according to the present embodiment is used clinically will be described.

[0103] When used for angiography, the fluorescent labeling composition as a liquid can be administered into the body by intra-arterial injection or intravenous injection, and angiography can be performed by a fluorescence observation device (camera, etc.) corresponding to the excitation light and fluorescence of the compound (A). That is, after the compound (A) is injected intravenously, the surgical area is irradiated with near-infrared light (excitation light) by using a fluorescence observation device, so that not only visual observation but also fluorescence observation achieved by near-infrared light can be performed. Thus, the state of the surgical area can be accurately grasped.

[0104] For example, a fluorescent labeling composition is administered to the blood, so that it is possible to judge where sufficient blood flow has reached. If the blood flow has reached normally, fluorescence will be emitted in a relatively short time such as a few seconds to a few minutes. That is, when the fluorescence is sufficient, it can be judged that sufficient blood flow has arrived. In addition, compound (A) is strengthened by bonding with blood proteins and emits fluorescence by irradiation with excitation light.

[0105] Alternatively, when used for identification of sentinel lymph nodes, the fluorescent labeling composition is injected as a liquid under the skin near the tumor or in the areola, etc., so that imaging can be performed using the above-mentioned fluorescence observation device (camera, etc.). In this case, compound (A) is strengthened by bonding with plasma proteins in the lymph fluid, and emits fluorescence by irradiation with excitation light.

[0106] As described above, when used in angiography and identification of sentinel lymph nodes, the fluorescent labeling composition is preferably a liquid (25°C, relative humidity of 50%) from the viewpoint of avoiding the injection of the drug into the body in an undissolved state. In the case where the fluorescent labeling composition is a liquid, it can also be stored as a high concentration solution (e.g., a concentrated solution) and diluted for use when used. The dilution ratio at this time can be set to make the diluent the above-mentioned preferred concentration and content. The concentrated solution and the diluent can be prepared, for example, using a tube medicine bottle of distilled water attached to the commercially available compound (A).

[0107] In addition, as described later, the fluorescent labeling composition can also be used clinically as an injection. Although the injection will be described later, it can also be a liquid. In addition, from the viewpoints of imparting certain viscosity or conformability, the injection can also be a gel or semisolid. In the case of being set as a gel or semisolid, for example, as long as at least one ((D) component) selected from (D) sodium alginate and sodium hyaluronate is blended.

[0108] ((C) component: resin)

[0109] When the fluorescent labeling composition involved in this embodiment is used as various materials such as medical instruments, the fluorescent labeling composition preferably further contains a resin (C). For example, by using the fluorescent labeling composition as a molding material of medical instruments such as stents, tubes, catheters, clips, fluorescent color-producing parts around the septum of subcutaneous implantable infusion ports, filaments for 3D printers, and resin fiber materials, such medical instruments can be made to emit fluorescence. In addition, the details of medical instruments will be described later.

[0110] In the past, ICG was considered difficult to melt-knead into resins because of its low heat resistance and water solubility. However, the inventors of the present application have found that by using the above-mentioned compound (A) and the alcoholic hydroxyl group-containing compound (B1) together, the compound (A) can be melt-kneaded into the resin (C) to a degree that it can be used as a molding material.

[0111] As resin (C), in view of the fact that ICG is water-soluble, it is preferred to use a raw material that does not cause hydrolysis and has a melting point lower than the melting point of ICG (about 230°C). For example, it is preferred to contain at least one selected from polyurethane resins, olefin resins, epoxy resins, vinyl chloride resins, fluorine resins, polycarbonate resins, polyamide resins, ABS resins, acrylic resins and silicone resins. Since these resins are easily available resins and have high stability, they are more suitable as molding materials for medical devices, etc. In addition, it is also more suitable in that the fluorescent properties of compound (A) will not be adversely affected.

[0112] Polyurethane resins are suitable resins. In this case, it is more preferable to use a high boiling point organic solvent (such as glycerol) as the alcoholic hydroxyl group-containing compound (B1) rather than a low boiling point organic solvent from the viewpoint of effectively suppressing the melting out of the compound (A) under high temperature and high humidity.

[0113] Examples of the olefin-based resin include polyethylene and polypropylene.

[0114] The epoxy resin (B4) is represented by the following structural formula.

[0115] [Chemical formula 7]

[0116]

[0117] Since the hydroxyl groups contained in the epoxy resin (B4) itself act as the intensity factor of ICG, the alcohol-containing hydroxyl compound (B1) is not necessarily required. Therefore, the epoxy resin (B4) has a very strong fluorescence activity compared with other resins. As examples, epoxy resins obtained by glycidyl etherification of bisphenol A, bisphenol F or novolac; epoxy resins obtained by adding propylene oxide, ethylene oxide or polyalkylene glycol to bisphenol A and glycidyl etherification; aliphatic epoxy resins; alicyclic epoxy resins; polyether epoxy resins, etc. In addition, since the epoxy resin (B4) can be coated on metals, it is more suitable as a raw material installed on the top of various surgical instruments such as forceps or scissors.

[0118] Examples of the vinyl chloride resin 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-acrylate copolymers, vinyl chloride-maleate copolymers, vinyl chloride-methacrylate copolymers, and vinyl chloride-acrylonitrile copolymers.

[0119] Examples of the fluorine-based resin include polytetrafluoroethylene, tetrafluoroethylene-perfluoroalkyl vinyl ether copolymers, tetrafluoroethylene-hexafluoropropylene copolymers, tetrafluoroethylene-fluoroalkyl vinyl ether-fluoroolefin copolymers, ethylene tetrafluoroethylene copolymers, and ethylene-trichlorofluoroethylene copolymers.

[0120] Examples of the polycarbonate-based resins include aromatic polycarbonate resins containing bisphenol A or the like as a polymerization component, aliphatic polycarbonate resins, and aromatic-aliphatic polycarbonate resins.

[0121] Examples of the polyamide resin include polybutylene adipamide (nylon 46), polybutylene sebacamide (nylon 410), polypentamethylene adipate (nylon 56), polypentamethylene sebacamide (nylon 510), polycaproamide (nylon 6), polyhexamethylene adipamide (nylon 66), polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecanoic acid (nylon 612), polyhexamethylene sebacamide (nylon 10 6), polydecanediamine (nylon 1010), polydodecanoylamine (nylon 1012), polyundecanamide (nylon 11), polydecanediamine (nylon 116), polylaurolactam (nylon 12), polymethylenediamine (nylon XD6), polyterephthalamide (nylon XD10), polymethylenediamine (nylon MXD6), polyhexamethyleneterephthalamide (nylon PXD6), Polytetramethylene terephthalamide (nylon 4T), polypentamethylene terephthalamide (nylon 5T), polyhexamethylene terephthalamide (nylon 6T), polyisophthalamide (nylon 6I), polynonamethylene terephthalamide (nylon 9T), polydecamethylene terephthalamide (nylon 10T), polyundemethylene terephthalamide (nylon 11T), polydodecamethylene terephthalamide (nylon 12T), polytetramethylene isophthalimide (nylon 4I), (3-methyl-4-aminohexyl) methyl terephthalamide (nylon PACMT), (3-methyl-4-aminohexyl) methyl isophthalamide (nylon PACMI), polybis(3-methyl-4-aminohexyl) methyl dodecanamide (nylon PACM12), polybis(3-methyl-4-aminoethyl) methane tetradecamide (nylon PACM14), etc.

[0122] As ABS-based resins, for example, acrylonitrile-butadiene-styrene (ABS), acrylonitrile-styrene-acrylic acid (ASA), acrylonitrile-ethylene-styrene (AES), polyvinyl chloride-acrylonitrile-styrene (ACS), α-methylstyrene-based ABS resins, flame-retardant ABS resins (FR-ABS), reinforced ABS resins, phenylmaleimide-based ABS resins, etc. can be listed.

[0123] Examples of acrylic resins include homopolymers (homopolymers) such as polymethyl methacrylate (PMMA) and polyethyl methacrylate; and copolymers (copolymers) such as methyl methacrylate-styrene copolymers and methyl methacrylate-α-methylstyrene copolymers.

[0124] Examples of the silicone resin include methyl silicone resin, methylphenyl silicone resin, phenyl silicone resin, epoxy-modified silicone resin, polyester-modified silicone resin, and acrylic-modified silicone resin.

[0125] In addition, the acetal resin may be hydrolyzed by kneading with ICG, and may discharge harmful substances such as formaldehyde. Therefore, it is preferred that the resin (C) does not contain an acetal resin.

[0126] The resin (C) may be used alone or in combination of two or more.

[0127] Although the content of the resin (C) in the fluorescent labeling composition is not particularly limited, it is preferably 80 to 99.99998 mass %, more preferably 85 to 99.9999 mass %, and further preferably 90 to 99.9997 mass %. By setting the content of the resin to the above range, it is possible to obtain strength, processing characteristics, and degradation resistance suitable as a molding material while maintaining the distinguishing recognition and luminescence time achieved by the fluorescent luminescence at a higher level. In addition, from various experimental structures, it can be known that when the fluorescent labeling composition includes the resin (C), there is also a trend that the concentration of the compound (A) in the fluorescent labeling composition is low to a certain extent, and a stronger luminescence intensity is obtained. However, this characteristic varies from resin to resin.

[0128] When the fluorescent labeling composition is used as a molding material, it is preferred that the fluorescent labeling composition is in a solid or semi-solid state at 25°C and a relative humidity of 50%. Semi-solid refers to a state that is different from a liquid state and has shape retention like a paste. If the fluorescent labeling composition is in such a state, the operability, metering accuracy and uniform dispersion in the molding material can be improved compared to the case where the compound (A) is directly kneaded. In addition, when the fluorescent labeling composition is used as a molding material, it can also be masterbatched.

[0129] As a method for making the fluorescent labeling composition into a solid or semi-solid state, the above-mentioned resin (C) can be mixed, and a solid or semi-solid alcoholic hydroxyl compound (B1) can also be mixed. As the above-mentioned alcoholic hydroxyl compound (B1) in this case, glycerol and the like are more suitable. In addition, other solid or semi-solid components can also be mixed.

[0130] <Method for producing a fluorescent labeling composition>

[0131] The manufacturing method of the fluorescent labeling composition of the present embodiment includes a mixing step of mixing the above-mentioned compound (A) with a hydroxyl-containing organic compound (B). As the hydroxyl-containing organic compound (B), the above-mentioned alcoholic hydroxyl compound (B1) can be used. The mixing method in the mixing step is not particularly limited, and a known method can be selected. Regarding the mixing conditions in the mixing step, suitable conditions can be appropriately adopted.

[0132] In the mixing step, it is preferred to obtain a fluorescent labeling composition containing 0.0000001 to 10% by mass of the compound (A) and 1 to 90% by mass of the alcoholic hydroxyl compound (B1). The mixing step does not necessarily have to be implemented in one stage. It can also be set as a step of first implementing a high-concentration concentrated solution, and then implementing a step of diluting the concentrated solution in a manner such that the concentrated solution is within the above-mentioned concentration range when used. That is, the dilution concentration when used is preferably within the above-mentioned concentration range.

[0133] As another step, for example, after the mixing step is performed, a step of heating the mixture (heating step) may be performed.

[0134] <Fluorescent probe>

[0135] The above-mentioned composition for fluorescent labeling can be used appropriately as a fluorescent probe. According to the present embodiment, it can be used as a fluorescent probe of an organic compound type from compound (A). For example, when detecting pathological substances or physiologically active substances in a living body, by making the fluorescent probe present in the living body or in the cell, it is possible to visually confirm and observe their activities in real time and with high precision as changes in fluorescence. As described above, since the composition for fluorescent labeling of the present embodiment will not absorb the excitation light by hemoglobin, etc., it is possible to make the excitation light reach the inner deep part of the living body tissue, so that its state can be visually confirmed and observed. In addition, regarding fluorescent luminescence, since it is excellent in distinguishing recognition and the life span of the composition itself becomes longer, it will continue to emit light for a long time. Due to having such advantages, the composition for fluorescent labeling of the present embodiment is more suitable as a fluorescent probe.

[0136] <Injection>

[0137] The above-mentioned fluorescent labeling composition can be used appropriately as an injection. A preferred form of the injection of the present embodiment is a labeling injection for labeling an object present on a mucosa or skin, and an injection containing the above-mentioned fluorescent labeling composition. The above-mentioned injection is injected into the mucosa or skin where the object is located, and can be labeled by being irradiated with the excitation light of the compound (A).

[0138] The injection involved in the present embodiment can be used appropriately as a clinical application. For example, in various local injections under the mucosa or skin of the excision object part such as a tumor, an injection can be used. For example, in the case of surgical treatment of lesions such as tumors formed on the mucosa or on the skin, an injection is injected under the mucosa or skin around the lesion, and it is made to emit fluorescence by irradiating an excitation light. Thus, the predetermined cutting line (the boundary between the side left and the side of the excision) of the lesion can be accurately identified. In addition, by using the visual observation performed by the physician and the fluorescence observation together, a more appropriate predetermined cutting line can also be determined.

[0139] In the case of an injection, the alcoholic hydroxyl compound (B1) as the hydroxyl-containing organic compound (B) is preferably glycerol or mannitol from the viewpoint of safety to the human body. These compounds may be used alone or in combination of two or more.

[0140] The injection involved in the present embodiment can also contain at least one of sodium alginate and sodium hyaluronate as component (D). The component (D) can also function as a thickener. By making the injection contain component (D), for example, the injection can be injected into the submucosal layer or subcutaneous layer near the lesion, and then the injection part is swollen in a bulging manner. By using the above-mentioned fluorescence observation device (camera, etc.) to observe in this state, the position of the lesion part can be accurately grasped, and the predetermined cutting line of the lesion part can be more accurately identified.

[0141] Furthermore, although the content of the component (D) in the injection of the present embodiment is not particularly limited, it is preferably 0.01 to 10% by mass, more preferably 0.05 to 5% by mass, further preferably 0.05 to 3% by mass, and further more preferably 0.1 to 1% by mass. However, in the case of obtaining sufficient viscosity and local restriction, it is effective even if the injection does not contain the component (D) at all.

[0142] The above-mentioned components and compounding contents related to the injection can of course also be used in the above-mentioned composition for fluorescent labeling.

[0143] <Syringe filling>

[0144] The above-mentioned fluorescent marker composition can be appropriately used as a syringe filler. The syringe filler is formed by pre-filling the fluorescent marker composition of the present embodiment in a syringe (syringe barrel). The syringe filler is also called a prefilled syringe, etc. The material and size shape of the syringe are not particularly limited, and suitable conditions can be selected according to the purpose. The syringe can be made of glass or resin, for example. In addition, it is also possible to fill the fluorescent marker composition in the tube of a local injection needle for submucosal injection and connect the local injection needle to the prefilled syringe.

[0145] In the fluorescent labeling composition, from the viewpoint of suppressing the concentration quenching phenomenon and ensuring sufficient fluorescence luminescence intensity and luminescence time, it is important to properly adjust the content and content ratio of compound (A), hydroxyl-containing organic compound (B), other solvents and added components. However, it is relatively complicated to mix these liquid medicines during surgery. By pre-filling the fluorescent labeling composition prepared in a manner to form an accurate content ratio into a syringe (+ a tube of a local injection needle), the above-mentioned complicated operations can be omitted during surgery. For example, a concentrated solution in which the content ratio of compound (A) and alcohol-containing hydroxyl compound (B1) as a hydroxyl-containing organic compound (B) is within the above-mentioned appropriate range can be pre-filled into a syringe, and diluted and modulated by physiological saline or water for injection when used. In addition, the syringe filler of the present embodiment is not limited to a structure in which the concentrated solution of the fluorescent labeling composition is pre-filled into a syringe. For example, the fluorescent labeling composition can also be filled into a syringe at a concentration (diluent) that can be directly injected, thereby constituting a syringe filler.

[0146] <Medical equipment>

[0147] The above-mentioned fluorescent labeling composition can be used as a molding material to make medical instruments. As such medical instruments, there can be listed fluorescent color-forming parts around the septum of a stent, a tube, a catheter, a clip, a subcutaneous implantable infusion port, filaments for 3D printers, fiber materials made of resin (for example, gauze threads, sutures, etc.), and various forceps or scissors with coatings applied to the top, etc. Surgical instruments, etc. Among these instruments, the medical instrument using the fluorescent labeling composition is also particularly preferably selected from the fluorescent color-forming parts around the septum of a stent, a tube, a catheter, a subcutaneous implantable infusion port, filaments for 3D printers, fiber materials made of resin (for example, medical gauze, sponges, medical sponges, cotton balls, hemostatic tampon, silk thread, sponges, etc.), and various forceps or scissors. Surgical instruments, etc.

[0148] As a medical device, for example, in the case of considering a stent, a fluorescent labeling composition is included in the material constituting the stent. By configuring the stent in vivo and irradiating the stent with near-infrared light as the excitation light of compound (A), the stent can be made to emit fluorescence. In the case where the stent is, for example, a bile duct stent or a ureteral stent, the configuration position of the stent can be accurately grasped by the fluorescence of the stent. Thus, the risk of mistakenly damaging the bile duct or ureter during surgery can be reduced.

[0149] As a medical device, for example, in the case of a tube, the material constituting the tube contains a fluorescent labeling composition. The tube is placed in a living body and near-infrared light as the excitation light of compound (A) is irradiated to the tube, so that the tube can emit fluorescence. For example, in the case of an intestinal obstruction tube, since the configuration position of the tube can be accurately grasped by fluorescence, even in the case of laparoscopic surgery, the site of intestinal obstruction can be more accurately determined.

[0150] As a medical device, for example, in the case of a catheter, the material constituting the catheter includes a fluorescent labeling composition. The catheter is arranged in a living body, and near-infrared light as the excitation light of compound (A) is irradiated to the catheter, so that the catheter can emit fluorescence. For example, in the case of a urinary catheter, since the configuration position of the catheter can be accurately grasped by fluorescence, the risk of mistakenly damaging the urinary catheter during surgery can be avoided.

[0151] As a medical device, for example, in the case of a septum of a subcutaneous implantable infusion port, as shown in Patent Document 4, in a subcutaneous implantable infusion port in which a fluorescent labeling composition is included in the material constituting the septum or the cover portion, the resin containing the drug will directly contact the patient's subcutaneous tissue for a long time, which is not preferred in terms of medical safety. For a septum that is repeatedly punctured by a needle, there is a core-forming problem in which the raw material is slowly scraped off, and the case in which the drug is included also includes concerns about reduced durability, which is also not preferred. In addition, if the cover portion contains a drug to display fluorescence, the luminous range will become too large, and there is a concern that the central septum portion will not become fluorescent negative.

[0152] If the fluorescent labeling composition is built into the cover portion around the septum (if it is located inside the outer surface of the cover portion), the light-emitting portion can identify the position of the septum without contacting the patient's subcutaneous tissue. As the form of the fluorescent labeling composition, as long as it is arranged around the septum, it can be a ring or a collection of points. By arranging such a subcutaneous implantable infusion port in the body and irradiating the infusion port with near-infrared light as the excitation light of the compound (A), the fluorescent labeling composition around the septum can emit fluorescence.

[0153] Thus, even in the case of thick subcutaneous fat such as in obese patients, puncture can be performed on the basis of easily and accurately grasping the configuration position of the septum, thereby reducing puncture errors. Therefore, the risk of incorrect leakage of anticancer agents and other liquid medicines into the subcutaneous tissue due to puncture errors can be reduced. In addition, in order to avoid puncture errors, the size of the infusion port that is unnecessarily easy to enlarge can also be minimized. As a result, the aesthetics of the patient's body wall can be improved. In addition, as a septum and a cover portion, in addition to the fluorescent marker composition, the raw materials that have been used can also be directly used. Therefore, the obstacles and costs related to development can also be minimized.

[0154] Furthermore, by applying the fluorescent labeling composition to filaments for 3D printers, various "luminescent medical devices" can be easily prototyped.

[0155] Although the manufacturing method of the medical device of the present embodiment is not particularly limited, a known method can be used. For example, a manufacturing method including a step of injection molding the fluorescent labeling composition using a metal mold can be used. In addition, extrusion molding, compression molding, hollow molding, calendering molding, blow molding, thermoforming, etc. can also be implemented to manufacture the medical device.

[0156] In addition, as a medical device, for example, in the case of considering a fiber material made of resin, the above-mentioned fiber material is made to include a fluorescent labeling composition. As described above, as a fiber material made of resin, for example, a thread of gauze, a suture thread for surgery, etc. can be cited. For example, about gauze, as shown in patent document 4, it can be considered that a fiber material made of resin including a fluorescent labeling composition is knitted into a part of the cotton cloth constituting the gauze, and the near-infrared ray as the excitation light of compound (A) is irradiated to the above-mentioned gauze, so that the above-mentioned fiber material constituting a part of the above-mentioned gauze is fluorescently luminous. However, only a part of the gauze is luminous, and it is considered that the luminous intensity is insufficient as an index of the search or surgical operation when lost. On the other hand, if the blending rate of the fiber material made of resin is improved, the water absorption will be reduced, so that the function of the original gauze may not be brought into play. Therefore, it is preferred that the cotton cloth constituting the gauze all includes a fluorescent labeling composition.

[0157] In addition, when the suture contains a fluorescent labeling composition, the suture is irradiated with near-infrared light as the excitation light of the compound (A) to make the suture fluorescent. However, since the resin suture is a non-absorbent material (because it is not absorbed by the body), the fiber containing the drug will semi-permanently contact the patient's tissue, which is not preferred in terms of medical safety. In addition, in the method of making the needle fluorescent, although the needle is taken out of the body, the resin will adhere to the needle, so the original sharpness may be damaged. Therefore, for example, in a "needle thread" with a needle attached to the top of the suture, if an epoxy resin containing compound (A) is used in the adhesive connecting the needle and the thread, the above-mentioned problems will not arise, and the lost needle can be found.

[0158] According to the present embodiment, such a resin fiber material is not limited to the purpose of use in the medical field (medical use), and can be appropriately applied in a wide range of fields as a luminous fiber, a luminous material, etc. In addition, by making the fiber material a resin material, the compound (A) can be uniformly dispersed and blended in the resin, so that the entire material can be made to emit fluorescent light uniformly.

[0159] In addition, as a method for manufacturing a resin fiber material, the fluorescent labeling composition of this embodiment (for example, compound (A) + hydroxyl-containing organic compound (B)) can be mixed with a resin to make silk, but the compound (A) alone can also be mixed with a resin to make silk.

[0160] <Medical fiber raw materials>

[0161] The medical fiber raw material of the present embodiment comprises the above-mentioned compound (A) and a fiber raw material containing a hydroxyl-containing organic compound (B), and can emit light by being irradiated with the excitation light of the compound (A). When the excitation light of the compound (A) is irradiated to the above-mentioned medical fiber raw material, fluorescent light can be obtained from the medical fiber raw material, and the fluorescent light has excellent distinguishing recognition and a long luminescence time. From the viewpoint of easily and reliably showing the effect, the hydroxyl-containing organic compound (B) contained in the fiber raw material preferably contains cellulose (B2), and in addition, it can also contain fibers composed of animal proteins such as silk (B3).

[0162] Here, the structural formula of cellulose (B2) is shown below.

[0163] [Chemical formula 8]

[0164]

[0165] In addition, the structural formula of silk (B3) is shown below.

[0166] [Chemical formula 9]

[0167]

[0168] In the above structural formula, n = 2. G represents glycine, A represents alanine, S represents serine, and T represents tyrosine.

[0169] The structural formula of serine is shown below.

[0170] [Chemical formula 10]

[0171]

[0172] The structural formula of tyrosine is shown below.

[0173] [Chemical formula 11]

[0174]

[0175] Although specific examples of such medical fiber raw materials are not particularly limited, examples thereof include medical gauze, sponges, medical sponges, cotton balls, hemostatic tampons, silk threads, etc., or fiber raw materials constituting them. For example, when the medical fiber raw materials involved in this embodiment are used as medical gauze, it can help prevent situations such as gauze being forgotten in the body during surgery. Hereinafter, an example of a method of using such medical gauze will be described.

[0176] In the past, as a measure to prevent gauze from being forgotten in the body, surgical gauze (X-ray gauze) with contrast lines kneaded into X-ray contrast agents was used. If the X-ray gauze is left in the body, the contrast lines will be reflected by x-ray photography, so the remaining position of the gauze can be determined.

[0177] However, since the contrast line of the X-ray gauze is presented in the x-ray image in a thin and white manner, it is difficult to visually confirm when overlapping with the skeleton, so that it may be overlooked even if the x-ray image is viewed. In this regard, since the medical gauze involved in the present embodiment can clearly confirm the existence of the gauze as a whole by fluorescent light such as green or blue, although it is a simple method, the confirmation of the gauze is relatively easy. In addition, since near-infrared light is used instead of X-rays, the radiation dose of patients and staff can be reduced, so that safety is higher.

[0178] The reason why the medical gauze involved in the present embodiment can achieve excellent distinguishing recognition and a long luminescence time is that the hydroxyl groups of the compound (A) and the cellulose (B2) as the hydroxyl-containing organic compound (B) contained in the gauze are firmly bonded by the action of hydrogen bonds to obtain a stable form (however, the effect of the present embodiment is not limited to this). Therefore, in surgery, by pre-depositing gauze at the stripping target site and setting the fluorescence of the gauze as an indicator, the operation can be efficiently promoted.

[0179] The gauze used can be any material or size and shape that contains a hydroxyl-containing organic compound (B) (e.g., cellulose (B2)). For example, the gauze used can be a square gauze used as surgical gauze (surgical gauze), or a cut gauze, folded gauze, or wide gauze that is attached to a wound or a wounded part. In addition, the gauze used can also be sterilized by ethylene oxide gas (EOG) or an autoclave.

[0180] Although the amount of compound (A) added is not particularly limited, it is preferably controlled to a fixed amount from the viewpoint of accurately understanding the amount of bleeding during surgery. 2 The amount of compound (A) added to the gauze is preferably 0.001 to 10 g, more preferably 0.01 to 5 g, and further preferably 0.1 to 3 g. In addition, even if blood adheres to the gauze, it will not hinder the visual confirmation of fluorescence, and the luminescence can be further enhanced by bonding of proteins in the blood to ICG.

[0181] The medical fiber raw material according to the present embodiment may further contain the alcoholic hydroxyl compound (B1). In addition, the medical fiber raw material may contain other water-containing additives instead of or in addition to the alcoholic hydroxyl compound (B1).

[0182] The medical fiber material according to the present embodiment may further contain a mordant. By using a mordant, the compound (A) can be fixed to the gauze together with the pigment. As the mordant, alum, iron oxide, etc. can be used.

[0183] So far, although an example of the case where the medical fiber raw material involved in the present embodiment is used as medical gauze has been described, the medical fiber raw material involved in the present embodiment is not limited to the described usage. For example, even when the medical fiber raw material is used as a sponge, a medical sponge, a cotton ball, a hemostatic tampon, a (needle) thread, etc., or a fiber raw material constituting them, it is possible to perform fluorescence when used in the same way as medical gauze. In addition, the above-mentioned (needle) thread is sometimes used as a target during a second-stage operation. If the (needle) thread fluoresces, the above-mentioned target can be easily identified, and therefore, it is very useful when performing such a second-stage operation.

[0184] <Method for producing medical fiber raw materials>

[0185] The method for producing a medical fiber raw material according to the present embodiment includes an impregnation step and a mordant step. In the impregnation step, the fiber raw material containing the hydroxyl-containing organic compound (B) is impregnated in a solution containing the above-mentioned compound (A). In the mordant step, the compound (A) is fixed to the fiber raw material using a mordant.

[0186] The fiber raw material is not particularly limited, as long as it can be impregnated with a solution containing a hydroxyl-containing organic compound (B) and a compound (A). As the hydroxyl-containing organic compound (B) in this case, it is preferably cellulose (B2) or silk (B3). In addition, as mentioned above, silk (B3) is a protein having a hydroxyl-containing amino acid in its structural components. As such a fiber raw material, for example, medical gauze, sponges, medical sponges, cotton balls, tampons, (with needles) silk threads, etc., or fiber raw materials constituting them can be listed. For example, medical gauze, sponges, medical sponges, cotton balls, tampons, (with needles) silk threads, etc. can be directly impregnated in the above solution, or fiber raw materials constituting medical gauze, sponges, medical sponges, cotton balls, tampons, (with needles) silk threads, etc. can be impregnated in the above solution. In addition, in addition to the other fiber materials described in this specification, fiber raw materials commonly used in the medical field and other fields can also be used. In addition, the above-mentioned impregnation process can also be carried out by spraying. That is, although the impregnation here means that the solution is impregnated into the fiber material, the fiber material may be impregnated by immersing the fiber material in the solution or by spraying the solution onto the fiber material with a sprayer.

[0187] For example, when the above solution is impregnated into a fiber raw material such as gauze, in the impregnation step, the fiber raw material is impregnated into a solution containing at least a compound (A) and an alcoholic hydroxyl compound (B1) as a hydroxyl-containing organic compound (B). In this case, the alcoholic hydroxyl compound (B1) can be used as a solvent for the compound (A). The impregnation conditions are not particularly limited, and suitable conditions can be appropriately selected in consideration of the material, size, and shape of the fiber raw material. For example, the impregnation time is preferably 1 minute to 3 days at normal temperature and humidity, and it is preferably shielded from light during the impregnation. In addition, as described above, the impregnation can also be implemented by spraying.

[0188] The solution used in the method for producing a medical fiber raw material may also be a composition comprising compound (A), alcoholic hydroxyl compound (B1) and water. In addition, the solution does not necessarily contain alcoholic hydroxyl compound (B1). Therefore, the solution may also have a structure having only compound (A) and water.

[0189] When the alcoholic hydroxyl group-containing compound (B1) is used, for example, a low-boiling point or volatile alcoholic hydroxyl group-containing compound such as methanol, ethanol, isopropanol, or a high-boiling point alcoholic hydroxyl group-containing compound such as glycerol may be used.

[0190] When a low-boiling point or volatile alcoholic hydroxyl compound is used as the alcoholic hydroxyl compound (B1), when the gauze is immersed in the fluorescent labeling composition, the compound (A) is supported on the gauze, and then the alcoholic hydroxyl compound (B1) is volatilized or removed, so that the compound (A) is supported on the gauze.

[0191] When a high-boiling-point alcoholic hydroxyl compound is used as the alcoholic hydroxyl compound (B1), gauze is immersed in the above solution, and after the compound (A) is supported on the gauze, the alcoholic hydroxyl compound (B1) is not removed but supported on the gauze together with the compound (A).

[0192] In this embodiment, among the above-mentioned alcoholic hydroxyl compound (B1), a low boiling point or volatile alcoholic hydroxyl compound is also preferred, ethanol, isopropanol is more preferred, and ethanol is further preferred. By using such a component as the alcoholic hydroxyl compound (B1), although it is a simple method, it is economically excellent and can be set to a state where only compound (A) is supported on the medical gauze.

[0193] In the present embodiment, as the mordant dyeing process realized by the mordant, for example, a process of dyeing the compound (A) on the gauze by the mordant is implemented. Although the dyeing process can be mordantized first, mordantized later, or mordantized simultaneously, from the viewpoint of dyeing the compound (A) on the gauze, it is preferably mordantized later. As the mordant, the above-mentioned mordant can be used. The mordant conditions are not particularly limited.

[0194] Before dyeing by mordant, a protein treatment process can be implemented to infiltrate protein preparation into fiber raw material. By protein treatment, compound (A) can be fixed on gauze together with pigment. As the above-mentioned protein preparation, milk, soy milk, skim milk powder etc. can be used.

[0195] Furthermore, in the present embodiment, it is preferable to carry out a sterilization step as necessary. The sterilization conditions are not particularly limited, and a known method can be adopted as a method for sterilizing medical fiber materials such as medical gauze.

[0196] It is also possible to produce instruments formed by coating the tips of various surgical instruments such as forceps or scissors with epoxy resins containing a fluorescent labeling composition, etc. In this case, since the tip of the instrument hidden behind the internal organs can be visually confirmed while performing the operation, the safety of the operation can be improved.

[0197] As described above, the fluorescent labeling composition involved in this embodiment has excellent distinguishing and identifying properties to the extent that it can more accurately identify the structure of the observation object, and has a long luminescence time, so that the observation object can be observed for a long time, thereby placing less burden on the organism and having excellent economic efficiency.

[0198] In particular, in biofluorescence imaging using the fluorescent labeling composition according to the present embodiment, since the compound (A) is a near-infrared fluorescent organic pigment, near-infrared light having a longer wavelength than visible light is used as the excitation light. Therefore, in biofluorescence imaging, the fluorescence (autofluorescence) of the intrinsic substances from the biological tissues can be not detected, thereby having the advantage of less noise. Moreover, by using it in combination with the hydroxyl-containing organic compound (B) (particularly the alcoholic hydroxyl-containing compound (B1)), it is possible to obtain a stable fluorescence color development and sufficient fluorescence intensity that have not been available in the past.

[0199] Furthermore, since the excitation light is not absorbed by substances in the living tissue such as hemoglobin, the light can reach deep inside the living tissue, and therefore there is an advantage that the state of blood vessels, lymphatic vessels, and organs can be observed.

[0200] Such a fluorescent labeling composition can also be used as a fluorescent probe, an injection, a syringe filling, a medical device, a medical fiber raw material, etc., and can exert the above-mentioned advantages. In addition, the manufacturing method of the fluorescent labeling composition and the medical fiber raw material can use easily available materials or components and can be manufactured by a simple method, so it also has the advantages of being a manufacturing method.

[0201] Since the fluorescent labeling composition, fluorescent probe, injection, syringe filling, medical device and medical fiber raw material involved in the present embodiment have the above-mentioned various advantages, it can be appropriately used in biological fluorescence imaging using ICG-based compounds (compound (A)). For example, in the medical field, it can be applied to angiography, tumor fluorescence imaging, identification of lymph nodes including sentinel lymph nodes, marking of surgical operation targets, marking of organs to be avoided from damage, prevention of retention in the body, and prevention of loss. Moreover, outside the medical field, it can also be expected to be applied to basic medical research, life sciences, regenerative medicine, various diagnoses, construction engineering, entertainment and other fields. That is, the fluorescent labeling composition of the present embodiment is not limited to medical use, and it can also be expected to be applied to a wide range of uses other than this.

[0202] For example, in a building, if the builder wants to mark a location on the building that the user (owner) side does not need to know, if the fluorescent marker composition described in this embodiment is mixed or applied to the building material, the specific location (the location where the fluorescent marker composition exists) can be grasped without the user knowing. In addition, if the fluorescent marker composition described in this embodiment is used to make a "luminous contact lens", the performer wearing the "luminous contact lens" on the eye cannot feel the fluorescence, and only the audience can recognize the light of the eye (the luminescence of the contact lens). That is, the fluorescent marker composition of this embodiment can also be expected to be applied to theatrical performances.

[0203] <Verification>

[0204] [About mixing ICG and resin]

[0205] The pigment (ICG + solvent) was mixed with various resins and then tested whether it could be made into sheets by compression molding.

[0206] As various resins, five kinds of polypropylene (PP), polyvinyl chloride (PVC), low-density polyethylene (LDPE), ethylene-vinyl acetate copolymer resin (EVA) and thermoplastic polyurethane (TPU) were prepared. As pigment, a viscous liquid prepared by mixing 25 mg x 4 portions of ICG in 10 ml of glycerin to dissolve the ICG was used.

[0207] In addition, four samples of the above-mentioned pigment were prepared at 1phr, 3phr, 5phr, and 7phr. In addition, phr is the abbreviation of perhundred resin, which is a unit that indicates the ratio of the pigment when the weight of the resin is set to 100. For example, if Ag pigment is added to 100g of resin, the ratio of the pigment can be said to be A (phr).

[0208] The order of mixing is as follows.

[0209] (Step 1: Pre-mixing and kneading)

[0210] The resin is put into the preheated mixer and kneaded until it is plasticized. As the above-mentioned mixer, Laboplast mill 4M 150 manufactured by Toyo Seiki Seisaku-sho, Ltd. is used. In addition, "Laboplast mill" is a registered trademark of Toyo Seiki Seisaku-sho, Ltd. This process is implemented for each pre-prepared resin. Kneading is carried out for 5 minutes at a temperature set for each resin. The above-mentioned kneading temperatures are specifically, polypropylene: 170°C, polyvinyl chloride: 150°C, low-density polyethylene: 140°C, ethylene-vinyl acetate copolymer resin: 140°C, thermoplastic polyurethane: 150°C. In addition, no matter which kneading temperature is used, it is a lower temperature than the melting point (230°C) of ICG.

[0211] (Step 2: Pigment mixing)

[0212] After confirming that the resin was sufficiently plasticized in step 1, the pigment was added and kneaded. The kneading conditions (time, temperature) at this time were the same as those in step 1. Thereafter, the kneaded sample (resin + pigment) was collected.

[0213] (Process 3: Compression molding)

[0214] The sample is cut into pieces using scissors. Then, the cut sample is sandwiched by a pair of heat-resistant polyimide films, and the film sandwiching the sample is placed between a pair of metal plates (e.g., stainless steel plates). Next, a pair of metal plates including the film sandwiching the sample are placed between a pair of spacers. After that, the pair of spacers are pressed in a direction close to each other, and the sample is melted and compressed for 1 minute until it becomes the desired thickness, thereby forming the sheet. The compression molding temperature is set to be the same as that of steps 1 and 2. After molding, a pair of metal plates are placed on a loading table and cooled at room temperature in a state of being loaded with heavy stones. In addition, as the above-mentioned thickness of the sheet, two types of 1 mm thick (110 mm longitudinally × 110 mm transversely) and 0.5 mm thick (125 mm longitudinally × 125 mm transversely) are obtained.

[0215] (result)

[0216] It was confirmed that the pigment can be kneaded with the resin without any problem for all resins. In addition, it was confirmed that the pigment can be kneaded without any problem regardless of the ratio. It can be concluded that the thermal degradation of ICG caused by kneading can be suppressed.

[0217] 〔Verification of gauze〕

[0218] Next, the gauze was immersed in a solution containing ICG, and then near-infrared light was irradiated to the gauze to verify whether the gauze could be made to emit fluorescence. The process and results of this verification are shown below.

[0219] (Preparation of stock solution)

[0220] First, G solution, E solution, N solution, A solution, and distilled water were prepared as stock solutions. G solution is a solution in which 25 mg of ICG is mixed and dissolved in 10 ml of glycerol. E solution is a solution in which 25 mg of ICG is mixed and dissolved in 10 ml of ethanol. N solution is a solution in which 25 mg of ICG is mixed and dissolved in 10 ml of distilled water. A solution is a solution in which 25 mg of ICG is mixed and dissolved in 10 ml of 5% BSA solution. In addition, BSA is bovine serum albumin. Distilled water does not contain ICG and is prepared as a comparison object with the stock solution containing ICG.

[0221] Figure 1A The schematic diagram shows the state where each stock solution is placed and arranged in a container (transparent container). Figure 1AIn the figure, containers are arranged in the order of G solution, E solution, N solution, A solution, and distilled water from the left side. An ICG reference card 1 is arranged on the right side of the container containing distilled water. The ICG reference card 1 has a luminescent area 1A. The luminescent area 1A is an area containing ICG, which emits fluorescent light when irradiated with excitation light (near-infrared light). Here, the luminescent brightness of the luminescent area 1A of the ICG reference card 1 is used as a reference to relatively compare and evaluate the presence or absence of luminescence when irradiated with near-infrared light and the brightness of the luminescent part. In other words, the ICG reference card 1 is used for relative comparison and evaluation of luminescent brightness.

[0222] Figure 1B The figure shows an image (hereinafter also referred to as a near-infrared image) obtained by irradiating each container with near-infrared light and photographing each container using a near-infrared camera (VISERAELITE II, Olympus Corporation). As can be seen from the figure, in the state of the original solution, the luminescence brightness of the G solution and the E solution is high.

[0223] Next, dilute each stock solution 5-fold and 10-fold (×10 1 ), 100 times (×10 2 ), 1000 times (×10 3 ), 10000 times (×10 4 ). In addition, here, the solvent of each stock solution is used for dilution. Figure 2 represents the near infrared image obtained for solution G. Figure 2 In the figure, for convenience, the container containing the 5-fold diluted solution is omitted and shown (in Figures 3 to 5 (The same is omitted in ). Figure 2 It can be seen that in solution G, good (higher) luminescence brightness can be obtained regardless of the dilution ratio.

[0224] Figure 3 1 shows a near-infrared image obtained for solution E. As can be seen from this figure, solution E, like solution G, can obtain good (high) luminescence brightness regardless of the dilution ratio.

[0225] Figure 4 : represents the near-infrared image obtained for solution N. As can be seen from the figure, in solution N, although a high luminescence brightness can be obtained when the solution is diluted 1000 times, the luminescence brightness is low at other dilution ratios.

[0226] Figure 5: represents the near-infrared image obtained for solution A. As can be seen from the figure, in solution A, high luminescence brightness can be obtained from 10 times dilution to 10000 times dilution, especially at 100 times dilution and 1000 times dilution, higher luminescence brightness can be obtained.

[0227] (Impregnation into gauze)

[0228] Next, a dilution of a desired dilution ratio (here, distilled water was used, but the solvent of each stock solution could also be used) was selected from the prepared dilutions, and gauze was immersed in the selected dilution, thereby obtaining a near-infrared image. Here, Sterase (sterilized, 5 cm×5 cm) produced by White Cross Co., Ltd. was used as gauze. In addition, "Sterase" is a registered trademark of White Cross Co., Ltd.

[0229] Fig. 6A The diagram schematically shows a state where gauze soaked in dilution solutions of 5 times, 10 times, 100 times, and 1000 times respectively for the G solution, the E solution, the N solution, and the A solution are arranged vertically and horizontally. Fig. 6A In the figure, gauze impregnated with G solution, E solution, N solution, and A solution are arranged from the top to the bottom, and gauze impregnated with 5-fold, 10-fold, 100-fold, and 1000-fold dilutions are arranged from the left to the right. Fig. 6A In the embodiment, an ICG reference card 1 is arranged on the right side of the gauze soaked with the 1000-fold dilution solution, and an untreated gauze 2 is arranged on the upper side of the ICG reference card 1. The untreated gauze 2 is a simple gauze that is not soaked.

[0230] Figure 6B Shows the Fig. 6A Near infrared images obtained when each gauze of irradiated with near infrared light. According to the figure, no matter for any of the G solution, E solution, N solution, and A solution, a higher luminous brightness can be obtained in the gauze immersed in the diluent diluted 10 to 1000 times. In particular, it can be seen that the maximum luminous brightness can be obtained in the gauze immersed in the diluent diluted 100 times.

[0231] Next, the results of animal experiments using the above-mentioned gauze will be described. Fig. 7A , Fig. 8A , Fig.9A as well as Fig. 10A The figure schematically shows an image captured by an endoscopic camera after placing a non-treated gauze 2 and a treated gauze 3 in the abdominal cavity of a pig. Fig. 7A The treated gauze 3 was impregnated with a solution obtained by diluting the G solution 100 times. Fig. 8AThe treated gauze 3 was impregnated with a dilution solution obtained by diluting the E solution 100 times. Fig.9A The gauze 3 used was soaked in a solution obtained by diluting the N solution 100 times. Fig. 10A The treated gauze 3 was gauze impregnated with a solution obtained by diluting solution A 100 times.

[0232] Figure 7B , Figure 8B , Fig. 9B as well as Fig. 10B Shows that Fig. 7A , Fig. 8A , Fig.9A as well as Fig. 10A Near infrared images obtained when each gauze is irradiated with near infrared light. According to these figures, it can be seen that in the abdominal cavity, each treated gauze 3 emits light with a high luminous intensity when irradiated with near infrared light.

[0233] [Example of the structure of a subcutaneous implantable infusion port]

[0234] Fig.11 It is a perspective view showing a structural example of a CV infusion port (central venous port) 10 which is a subcutaneously implantable infusion port. Fig.12 10 is a cross-sectional view of the CV infusion port 10 . Fig.13 FIG10 is an exploded perspective view of the CV infusion port 10. Fig.11 In order to make the internal structure of the CV port 10 clear, the outer shape of the cover portion 12 is indicated by a dotted line.

[0235] The CV infusion port 10 includes a septum 11, a cover portion 12, and an indicator 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 coaxially located above the large diameter portion 11a. A curved needle for injecting a drug solution is inserted through the septum 11 (for example, the small diameter portion 11b).

[0236] The cover portion 12 is a cover that holds the spacer 11, and holds the spacer 11 so that the upper surface of the spacer 11 (for example, the small diameter portion 11b) is exposed. Such a cover portion 12 includes an outer cover 12a and an inner cover 12b.

[0237] The outer cover 12a is made of, for example, a transparent acrylic resin. When the CV infusion port 10 is implanted under the patient's skin, a portion of the outer surface of the outer cover 12a (for example, the upper surface) contacts the patient's skin. A thread groove is formed on the inner circumferential surface of the outer cover 12a. The inner cover 12b is a rear cover located on the inner side of the outer cover 12a. A thread is formed on the outer circumferential surface of the inner cover 12b. The inner cover 12b is fixed to the outer cover 12a by screwing the inner cover 12b into the inner side of the outer cover 12a while the thread is engaged with the thread groove.

[0238] A recessed portion 12b1 is formed at an upper portion of the inner housing 12b. The large diameter portion 11a of the spacer 11 is sandwiched by the inner housing 12b and the outer housing 12a from the top and bottom while being fitted into the recessed portion 12b1.

[0239] The inner cover 12b is provided with an injection chamber 12b2 for storing the above-mentioned drug solution. The injection chamber 12b2 is formed to have a smaller diameter than the recessed portion 12b1 and is located at the lower portion of the recessed portion 12b1. The drug solution injected into the injection chamber 12b2 via the curved needle inserted through the septum 11 is introduced into a blood vessel or the like via a catheter (not shown) connected to the injection chamber 12b2.

[0240] The indicator member 13 is arranged inside the housing portion 12 and outside the spacer 11. More specifically, the indicator member 13 is located inside the housing portion 12 (particularly the outer housing 12a). In addition, the indicator member 13 is arranged on the upper surface of the large diameter portion 11a of the spacer 11 and is separated from the small diameter portion 11b in the radial direction (particularly refer to FIG. Fig.12 The indicator member 13 is covered by the outer cover 12a. Therefore, a part of the outer cover 12a is located between the indicator member 13 and the small diameter portion 11b.

[0241] The indicator member 13 is an annular member surrounding the spacer 11 (particularly the small diameter portion 11b). In addition, the shape of the indicator member 13 is not limited to an annular shape (circular when viewed from above), and may be other shapes such as a square shape and an elliptical shape. In addition, the indicator member 13 does not necessarily have to be formed continuously in the circumferential direction, and for example, a plurality of indicator members 13 may be arranged at intervals in the circumferential direction.

[0242] The indicator component 13 has the above-mentioned fluorescent labeling composition of the present embodiment. Specifically, the indicator component 13 mixes the above-mentioned pigment (ICG+solvent) as the fluorescent labeling composition in a resin, and molds the mixed resin into, for example, a ring shape. In the structure in which the indicator component 13 has the fluorescent labeling composition, by irradiation with near-infrared light, it is not the diaphragm 11 itself, but the part (indicator component 13) inside the cover part 12 that is not in direct contact with the patient's subcutaneous tissue that emits fluorescence, thereby enabling the diaphragm 11 to be identified. Therefore, there is no problem of the resin containing the drug being in direct contact with the patient's subcutaneous tissue for a long time, thereby effectively improving safety.

[0243] In particular, since the indicator member 13 is in a shape (for example, annular) surrounding the septum 11 in a plan view, it is easy to recognize that the septum 11 exists in the area surrounded by the indicator member 13. Therefore, it becomes easy to puncture with a curved needle by using the area as an indicator.

[0244] 〔Verification of the luminous intensity of indicator parts〕

[0245] Next, the results of verifying the light emission intensity of the indicator member 13 are shown below. Fig.14A The diagram schematically shows the state in which rings (corresponding to the indicator member 13) formed by mixing G solution, E solution, N solution and A solution into epoxy resin at a ratio of 1 phr, 3 phr, 5 phr and 10 phr, respectively, are arranged vertically and horizontally. Fig.14A In the figure, rings formed by mixing G solution, E solution, N solution, and A solution with epoxy resin are arranged from the top to the bottom. Fig.14A In the example, an ICG reference card 1 is arranged at the left end, and a negative control 4 is arranged on the upper side of the ICG reference card 1. The negative control 4 is used for comparison with each ring and is composed only of epoxy resin that does not contain ICG. Fig.14A In the figure, the rings are arranged on the right side of the ICG standard card 1 and the negative control 4 in the order of 1 phr, 3 phr, 5 phr, and 10 phr from the left side to the right side.

[0246] Fig. 14BThe near-infrared image obtained when irradiating near-infrared light to each ring (ICG1v ring) of Figure 14 is shown. In addition, the ICG1v ring refers to a ring formed by mixing the following G solution, E solution, N solution, and A solution into an epoxy resin. That is, the G solution is a solution in which 25 mg of ICG is mixed into 10 ml of glycerol to dissolve it. The E solution is a solution in which 25 mg of ICG is mixed into 10 ml of ethanol to dissolve it. The N solution is a solution in which 25 mg of ICG is mixed into 10 ml of distilled water to dissolve it. The A solution is a solution in which 25 mg of ICG is mixed into 10 ml of 5% BSA solution to dissolve it. According to the figure, it can be seen that for a ring formed using any one of the G solution, E solution, N solution, and A solution, a luminous brightness equal to or higher than that of the ICG reference card can be obtained. In particular, it can be seen that a higher luminous brightness can be obtained in a ring above 3 phr.

[0247] Fig.15 Shows the Fig.14A The near-infrared image obtained when each ring (ICG1v ring) is replaced with an ICG4v ring and each ring is irradiated with near-infrared light. In addition, the ICG4v ring refers to a ring formed by mixing the following G solution, E solution, N solution, and A solution into an epoxy resin. That is, the G solution is a solution in which 100 mg of ICG is mixed with 10 ml of glycerol to dissolve it. The E solution is a solution in which 100 mg of ICG is mixed with 10 ml of ethanol to dissolve it. The N solution is a solution in which 100 mg of ICG is mixed with 10 ml of distilled water to dissolve it. The A solution is a solution in which 100 mg of ICG is mixed with 10 ml of 5% BSA solution to dissolve it. In the ICG4v ring, it can be seen that when it is formed using any one of the G solution, E solution, N solution, and A solution, a higher luminescence brightness can be obtained in all the rings in the range of 1 phr to 10 phr.

[0248] In addition, if the surface of each ring is polished, there is a tendency that higher luminescence intensity can be obtained in the near-infrared image.

[0249] Fig.16A The CV infusion port 10 including the index member 13 and the comparative infusion port 10A not including the index member 13 are schematically shown in a state where they are arranged vertically. Fig.16A In the embodiment, the negative control 4 is placed on the left side of the CV infusion port 10. Furthermore, the ICG reference card 1 is placed below the negative control 4 (on the left side of the comparison infusion port 10A).

[0250] Fig. 16B Shows the Fig.16AThe near infrared images are obtained when the CV port 10 and the comparative port 10A are irradiated with near infrared light, and the indicator member 13 of the CV port 10 is molded by mixing the G solution with the epoxy resin at a ratio of 10 phr. Figures 17 to 19 The near-infrared images of the indicator member 13 of the CV port 10 are shown when the E solution, the N solution, and the A solution are mixed with epoxy resin at a ratio of 10 phr, 10 phr, and 10 phr, respectively.

[0251] like Fig. 16B as well as Figures 17 to 19 As shown, it can be seen that when the ring-shaped indicator member 13 is molded using any of the G solution, the E solution, the N solution, and the A solution, the luminous brightness equal to or higher than that of the ICG standard card can be obtained.

[0252] <Note>

[0253] The fluorescent labeling composition, fluorescent probe, injection, syringe filling, medical device, medical fiber material, method for producing the fluorescent labeling composition, and method for producing the medical fiber material described in the above embodiment can be expressed as described in the following supplementary notes.

[0254] 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).

[0255] [Chemical formula 12]

[0256]

[0257] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0258] The fluorescent labeling composition according to Supplementary Note (2) is the fluorescent labeling composition according to Supplementary Note (1), wherein the hydroxyl-containing organic compound (B) includes an alcoholic hydroxyl-containing compound (B1).

[0259] 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 a fatty alcohol.

[0260] The fluorescent labeling composition according to Supplement (4) is the fluorescent labeling composition according to Supplement (2) or (3), comprising 0.0000001 to 10% by mass of the compound (A) and 1 to 90% by mass of the alcoholic hydroxyl group-containing compound (B1).

[0261] The fluorescent labeling composition involved in Note (5) is a fluorescent labeling composition described in Note (2) or (3), wherein the fluorescent labeling composition according to claim 2 or 3 contains 97 to 99.99998 parts by mass of the alcoholic hydroxyl compound (B1) relative to a total of 100 parts by mass of the compound (A) and the alcoholic hydroxyl compound (B1).

[0262] 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 contains substantially no dimethyl sulfoxide.

[0263] The fluorescent labeling composition involved in Note (7) is a fluorescent labeling composition described in any one of Notes (1) to (6), which further contains, as resin (C), at least one selected from olefin resins, epoxy resins, vinyl chloride resins, fluorine resins, polycarbonate resins, polyamide resins, ABS resins, acetal resins, acrylic resins and silicone resins.

[0264] 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-based resin.

[0265] The fluorescent labeling composition according to Supplement (9) is the fluorescent labeling composition according to any one of Supplements (1) to (8) which is solid or semisolid at 25° C. and a relative humidity of 50%.

[0266] The fluorescent probe according to Supplement (10) comprises the fluorescent labeling composition according to any one of Supplements (1) to (9).

[0267] The injection according to Supplementary Note (11) is a labeling injection for labeling an object present on a mucous membrane or skin, and contains the fluorescent labeling composition according to any one of Supplementary Notes (1) to (9).

[0268] 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).

[0269] The injection according to Supplementary Note (13) is the injection according to Supplementary Note (12), wherein the total amount of the component (D) is 0.01 to 10% by mass.

[0270] The syringe filling material according to Supplement (14) comprises: the fluorescent labeling composition according to any one of Supplements (1) to (9); and a syringe filled with the fluorescent labeling composition.

[0271] The medical device according to Supplementary Note (15) comprises the fluorescent labeling composition according to any one of Supplementary Notes (1) to (9).

[0272] The medical device involved in note (16) is a medical device recorded in note (15), wherein the medical device is one selected from a stent, a tube, a catheter, a clip, a filament for a 3D printer, and a fiber material made of resin.

[0273] The medical fiber material according to Supplementary Note (17) comprises a compound (A) represented by the following formula (1) and a fiber material containing a hydroxyl group-containing organic compound (B).

[0274] [Chemical formula 13]

[0275]

[0276] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0277] The medical fiber material according to Supplementary Note (18) is the medical fiber material according to Supplementary Note (17), wherein the hydroxyl-containing organic compound (B) includes cellulose (B2).

[0278] 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) and a hydroxyl group-containing organic compound (B).

[0279] [Chemical formula 14]

[0280]

[0281] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0282] The method for producing a fluorescent labeling composition according to Note (20) is, in the method for producing a fluorescent labeling composition according to 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 compound (B1) which is the hydroxyl-containing organic compound (B) are mixed.

[0283] The method for producing the medical fiber raw material according to Supplementary Note (21) comprises:

[0284] An impregnation step of impregnating a solution containing a compound (A) represented by the following formula (1) into a fiber raw material containing a hydroxyl-containing organic compound (B), or spraying the solution into the fiber raw material containing a hydroxyl-containing organic compound (B) with a sprayer;

[0285] The mordant step is to fix the compound (A) to the fiber material using a mordant.

[0286] [Chemical formula 15]

[0287]

[0288] (In the chemical 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 sulfonyl group, p is an integer of 1 to 5, and m and n are each independently an integer of 1 to 12.

[0289] 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-containing organic compound (B) contains cellulose (B2).

[0290] The method for producing a medical fiber raw material according to Supplement (23) is a method for producing a medical fiber raw material according to Supplement (21) or (22), further comprising a protein treatment step, in which a protein preparation is infiltrated into the fiber raw material.

[0291] The medical device involved in note (24) is the medical device described in note (15), wherein the medical device is a subcutaneous implantable infusion port, and the subcutaneous implantable infusion port has: a septum; a cover portion that holds the septum; and an indicator component that is arranged inside the cover portion and outside the septum, and the indicator component has the fluorescent labeling composition.

[0292] The medical device according to Supplementary Note (25) is the medical device according to Supplementary Note (24), wherein the indicator member has a shape surrounding the spacer.

[0293] Although the embodiments of the present invention have been described above, the scope of the present invention is not limited thereto, and the present invention can be implemented by expansion or modification within the scope not departing from the gist of the invention.

[0294] Industrial Applicability

[0295] The present invention can be used, for example, in biofluorescence imaging.

[0296] Explanation of symbols

[0297] 10 CV port (subcutaneous implantable port);

[0298] 11 septum;

[0299] 12: housing portion;

[0300] 13 indicator components.

Claims

1. A composition for fluorescent labeling, wherein: Contains a compound (A) represented by the following formula (1) and a hydroxyl-containing organic compound (B), [Chemical formula 1] In the chemical 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 sulfonyl group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

2. The fluorescent labeling composition according to claim 1, wherein The hydroxyl-containing organic compound (B) includes an alcoholic hydroxyl-containing compound (B1).

3. The fluorescent labeling composition according to claim 2, wherein The alcoholic hydroxyl group-containing compound (B1) includes fatty alcohols.

4. The fluorescent labeling composition according to claim 2, wherein The compound (A) is contained in an amount of 0.0000001 to 10% by mass and the alcoholic hydroxyl group-containing compound (B1) is contained in an amount of 1 to 90% by mass.

5. The fluorescent labeling composition according to claim 2, wherein The alcoholic hydroxyl group-containing compound (B1) is contained in an amount of 97 to 99.99998 parts by mass based on 100 parts by mass of the total of the compound (A) and the alcoholic hydroxyl group-containing compound (B1).

6. The fluorescent labeling composition according to claim 1, wherein Contains substantially no dimethyl sulfoxide.

7. The fluorescent labeling composition according to claim 1, wherein The resin (C) further includes at least one selected from olefin resins, epoxy resins, vinyl chloride resins, fluorine resins, polycarbonate resins, polyamide resins, ABS resins, acetal resins, acrylic resins and silicone resins.

8. The fluorescent labeling composition according to claim 1, wherein Contains polyurethane resin.

9. The fluorescent labeling composition according to claim 1, wherein It is solid or semi-solid at 25°C and 50% relative humidity.

10. A fluorescent probe, wherein: A composition for fluorescent labeling according to claim 1.

11. An injection for marking an object present on a mucous membrane or on the skin, in, A composition for fluorescent labeling according to claim 1.

12. The injection according to claim 11, wherein As the component (D), at least one of sodium alginate and sodium hyaluronate is further contained.

13. The injection according to claim 12, wherein The (D) component is contained in an amount of 0.01 to 10% by mass in total.

14. A syringe filler, comprising: The fluorescent labeling composition according to claim 1; A syringe is filled with the fluorescent labeling composition.

15. A medical device, wherein: A composition for fluorescent labeling according to claim 1.

16. The medical device according to claim 15, wherein: The medical device is one selected from a stent, a tube, a catheter, a clip, a filament for a 3D printer, and a fiber material made of resin.

17. A medical fiber raw material, wherein: A fiber material comprising a compound (A) represented by the following formula (1) and a hydroxyl-containing organic compound (B), [Chemical formula 2] In the chemical 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 sulfonyl group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

18. The medical fiber material according to claim 17, wherein: The hydroxyl-containing organic compound (B) contains cellulose (B2).

19. A method for producing a fluorescent labeling composition, wherein: The method comprises a mixing step in which a compound (A) represented by the following formula (1) and a hydroxyl-containing organic compound (B) are mixed. [Chemical formula 3] In the chemical 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 sulfonyl group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

20. The method for producing a fluorescent labeling composition according to claim 19, wherein: In the mixing step, 0.0000001 to 10% by mass of the compound (A) and 1 to 90% by mass of the alcoholic hydroxy compound (B1) as the hydroxyl group-containing organic compound (B) are mixed.

21. A method for producing a medical fiber raw material, comprising: An impregnation step of impregnating a solution containing a compound (A) represented by the following formula (1) into a fiber raw material containing a hydroxyl-containing organic compound (B), or spraying the solution into the fiber raw material containing a hydroxyl-containing organic compound (B) with a sprayer; a mordant step of fixing the compound (A) in the fiber material using a mordant, [Chemical formula 4] In the chemical 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 sulfonyl group; p is an integer of 1 to 5; and m and n are each independently an integer of 1 to 12.

22. The method for producing a medical fiber material according to claim 21, wherein: The hydroxyl-containing organic compound (B) contains cellulose (B2).

23. The method for producing a medical fiber material according to claim 21, wherein: The method further comprises a protein treatment step in which a protein preparation is infiltrated into the fibrous raw material.

24. The medical device according to claim 15, wherein: The medical device is a subcutaneous implantable infusion port, The subcutaneous implantable infusion port has: septum; A cover portion, which holds the diaphragm; an indicator member disposed inside the housing portion and outside the diaphragm, The indicator member includes the fluorescent labeling composition.

25. The medical device according to claim 24, wherein: The indicator member has a shape surrounding the spacer.

Images