WO2024028975A1 - Esophagus-cooling agent - Google Patents

Esophagus-cooling agent Download PDF

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Publication number
WO2024028975A1
WO2024028975A1 PCT/JP2022/029643 JP2022029643W WO2024028975A1 WO 2024028975 A1 WO2024028975 A1 WO 2024028975A1 JP 2022029643 W JP2022029643 W JP 2022029643W WO 2024028975 A1 WO2024028975 A1 WO 2024028975A1
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Prior art keywords
cooling agent
esophageal
compound
weight
esophageal cooling
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PCT/JP2022/029643
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French (fr)
Japanese (ja)
Inventor
聡 杣本
邦彦 木内
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三洋化成工業株式会社
国立大学法人神戸大学
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Priority to PCT/JP2022/029643 priority Critical patent/WO2024028975A1/en
Publication of WO2024028975A1 publication Critical patent/WO2024028975A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to an esophageal cooling agent.
  • An object of the present invention is to provide an esophageal cooling agent that enables cooling of the esophagus with a relatively small burden on the patient by a simple means.
  • the present invention provides an esophageal cooling agent comprising a solvent and compound (A),
  • the esophageal cooling agent at 25° C., at least a part of the compound (A) is an undissolved substance that is not dissolved in the solvent,
  • DSC differential scanning calorimetry
  • the esophageal cooling agent of the present invention enables cooling of the esophagus with a relatively small burden on the patient by a simple means.
  • FIG. 1(a), FIG. 1(b), and FIG. 1(c) are diagrams each schematically showing a DSC curve of an esophageal cooling agent.
  • FIG. 2 is a cross-sectional view schematically showing a cross section of the esophagus.
  • FIG. 3 shows the DSC measurement results of the esophageal cooling agent of Example 3.
  • FIG. 4(a) is a photograph showing a state in which a temperature sensor is inserted in evaluation 1 of the cooling effect in the example.
  • FIG. 4(b) is a photograph showing a state in which the esophagus was filled with an esophageal cooling agent in evaluation 1.
  • FIG. 4(c) is a perspective view schematically showing the insertion position of the temperature sensor in the evaluation 1.
  • FIG. 5 is a diagram schematically showing the insertion position of the temperature sensor in evaluation 2 of the cooling effect in the example.
  • the esophageal cooling agent of the present invention contains a solvent and compound (A). Moreover, in the 25° C. esophageal cooling agent, at least a portion of the compound (A) is an undissolved substance that is not dissolved in the solvent.
  • the compound (A) in the present invention is preferably a compound having a polyoxyethylene chain, a compound having a sugar chain, a sugar alcohol, or the like.
  • a compound having a polyoxyethylene chain the following general formula (1): HO-(CH 2 CH 2 O) n -H (1)
  • n is an integer from 40 to 230, preferably from 50 to 220, more preferably from 60 to 211, from the viewpoint of influence on the human body (safety).
  • Examples include compounds represented by (polyethylene glycol), ethylene oxide adducts of compounds having active hydrogen and having 1 to 20 carbon atoms, and the like.
  • Compound (A) represented by general formula (1) can be obtained from the market as PEG-4000N, PEG-6000P, Macrogol 4000, Macrogol 6000SP [manufactured by Sanyo Chemical Industries, Ltd.], etc. .
  • Examples of the compound having 1 to 20 carbon atoms and having active hydrogen in the ethylene oxide adduct of the compound having 1 to 20 carbon atoms having active hydrogen include hydroxyl group-containing compounds (methanol, ethanol, 1,6-hexanediol, glycerin, etc.); Selected from hydroxyl groups, primary or secondary amino groups, carboxyl groups, and mercapto groups of amino group-containing compounds (methylamine, ethylamine, etc.), carboxyl group-containing compounds (succinic acid, etc.), and thiols (ethanethiol, ethanedithiol, etc.) Examples include compounds having at least one type of group.
  • Alkylene oxide other than ethylene oxide may be further added to the compound, and examples of the alkylene oxide include 1,2- or 1,3-propylene oxide, 1,2-, 1,3-, 1,4 - or 2,3-butylene oxide.
  • the total number of additions of ethylene oxide and other alkylene oxides is preferably 40 to 230, more preferably 50 to 220, and particularly preferably 60 to 211.
  • Examples of the compound having a sugar chain include carboxyalkyl (alkyl has 1 to 5 carbon atoms) cellulose (carboxymethyl cellulose, etc.) or a salt thereof (alkali metal salts and alkaline earth metal salts are preferred).
  • Examples of sugar alcohols include erythritol, xylitol, sorbitol, mannitol, maltitol, and lactitol.
  • Compound (A) may be used alone or in combination of two or more.
  • Compound (A) preferably satisfies the following (i) or (ii).
  • the heat of dissolution in water is less than 0 J/g.
  • the melting point is 10 to 50°C.
  • the heat of dissolution in water is less than 0 J/g can be confirmed, for example, by DSC described below.
  • DSC liquid crystal display
  • the DSC curve curves downward in the temperature range where compound (A) dissolves in water. If so, it can be determined that the heat of melting is less than 0 J/g.
  • the melting point of compound (A) is preferably 10 to 300°C, more preferably 10 to 50°C, even more preferably 25 to 50°C, and particularly preferably 30 to 40°C.
  • the melting point of compound (A) can be measured by DSC as described below.
  • the specific heat of compound (A) is preferably 0.8 kJ/kg ⁇ K or more, more preferably 1.0 kJ/kg ⁇ K or more, and 1.5 kJ/kg ⁇ K. It is particularly preferable that it is above.
  • the boiling point of compound (A) is preferably 39° C. or higher from the viewpoint of cooling efficiency.
  • the number average molecular weight (Mn) of compound (A) is preferably 500 to 9,000 from the viewpoint of cooling efficiency.
  • Mn is preferably 3,000 to 9,000.
  • Mn is preferably 500 to 2,000.
  • the number average molecular weight is a value measured using gel permeation chromatography (hereinafter abbreviated as GPC) under the following conditions.
  • GPC gel permeation chromatography
  • Examples of the solvent in the present invention include water, ethanol, and the following general formula (2): HO-(CH 2 CH 2 O) m -H (2) (In the formula, m is an integer from 1 to 39) Compounds represented by the following are preferred.
  • the solvent preferably contains water from the viewpoint of cooling efficiency.
  • Water may be contained in the form of physiological saline; Ringer's solution containing sodium chloride, potassium chloride, and calcium chloride; a buffer solution containing a buffer component, and the like.
  • buffer components include organic acids (such as phosphoric acid) and Good's buffer.
  • the buffer components may be used alone or in combination of two or more.
  • the content of the buffer component in the esophageal cooling agent is preferably 0 to 50 mM, more preferably 0 to 10 mM.
  • the weight proportion of water in the solvent is preferably 50 to 100% by weight, more preferably 70 to 100% by weight, particularly preferably 90 to 100% by weight, based on the weight of the solvent.
  • the content of the compound represented by the general formula (2) is preferably 10% by weight or less, more preferably 5% by weight or less, and 1% by weight or less based on the weight of the esophageal cooling agent. It is more preferable that the amount is at least 0.1% by weight or less, particularly preferably 0.1% by weight or less.
  • the specific heat of the solvent is preferably 0.8 kJ/kg K or more, more preferably 2.0 kJ/kg K or more, and 4.0 kJ/kg K or more. It is particularly preferable.
  • the boiling point of the solvent is preferably 39° C. or higher from the viewpoint of cooling efficiency.
  • the DDSC is negative in the temperature range of 10 to 50°C and in the region where the heat flow is 0 (W/g) or less. An endothermic signal with a value of can be observed.
  • DSC is measured by the following method.
  • ⁇ DSC measurement method> The esophageal cooling agent of the present invention is subjected to DSC using, for example, "DSC Q20" (manufactured by TA instruments) under the following conditions according to JIS K7122-2012.
  • a measurement sample previously cooled to 4°C is heated to 10 to 50°C under the following conditions, and then cooled to 10°C. Thereafter, the measurement sample is heated again under the following conditions and DSC is performed.
  • ⁇ Measurement start temperature 10°C
  • ⁇ Measurement end temperature 50°C
  • Nitrogen gas inflow rate 50mL/min
  • the amount of heat that can be calculated from the area area surrounded by the following lines (I) to (IV) is From the viewpoint of cooling efficiency, it is preferably -4 J/g or less, based on the weight of the esophageal coolant, and from the viewpoint of cooling efficiency, it is more preferably -5 J/g or less, -5.5 J. /g or less is more preferable, and -6J/g or less is particularly preferable.
  • the amount of heat that can be calculated from the area surrounded by lines (I) to (IV) is determined by adjusting the heat of dissolution of compound (A) in the solvent, the weight percentage of undissolved matter of compound (A) contained in the esophageal cooling agent, etc. By doing so, it is possible to adjust to the above-mentioned preferable range.
  • the heat of dissolution in water can be reduced to -4 J/g or less. Can be adjusted.
  • the area area below line (III) is calculated.
  • the sum of the amount of heat (negative value) calculated from the area above the line (III) (positive value) is preferably -4 J/g or less. That is, in the range of 25 to 40° C., the absolute value of the total endothermic amount is preferably 4 J/g or more greater than the absolute value of the total calorific value.
  • the sum of the heat amounts is more preferably -5.5 J/g or less, particularly preferably -6 J/g or less.
  • "Area area below line (III)" and “Area area above line (III)” refer to, for example, the total area of area a3 and area a4, and area b1 in FIG. 1(b), respectively. is the area of
  • the esophageal coolant of the present invention has a kinematic viscosity of 100 to 5,000 mm 2 /s at 25°C.
  • the kinematic viscosity of the esophageal coolant is preferably 100 to 4,500 mm 2 /s from the viewpoint of cooling efficiency.
  • the kinematic viscosity at 39° C. is preferably 5,000 mm 2 /s or less, more preferably 4,500 mm 2 /s or less.
  • the kinematic viscosity of the esophageal coolant is a value measured using an Ubbelohde viscometer in accordance with JIS-Z8803 (2011).
  • the weight percentage of undissolved matter that is not dissolved in the solvent of compound (A) is preferably 1 to 95% by weight based on the weight of the esophageal coolant from the viewpoint of cooling efficiency. It is preferably 5 to 80% by weight, more preferably 10 to 80% by weight, and most preferably 25 to 80% by weight.
  • the difference between the weight of the undissolved compound (A) contained in the esophageal coolant at 25°C and the weight of the undissolved compound (A) contained in the esophageal coolant at 40°C is the difference in cooling efficiency. From this point of view, it is preferably 1 to 95% by weight, more preferably 5 to 80% by weight, particularly preferably 10 to 80% by weight, based on the weight of the esophageal cooling agent at 25°C. Most preferably, it is between 80% and 80% by weight.
  • the "undissolved matter of compound (A) that is not dissolved in the solvent" contained in the 25°C esophageal cooling agent is the dried filtration residue obtained by the following method, and its weight percentage is calculated by the following formula: It can be calculated.
  • suction filtration of esophageal coolant previously cooled at 4°C and then temperature-controlled to 25°C
  • weight W (g) is carried out through cellulose filter paper (particle retention capacity: 1 ⁇ m) with weight W1 (g).
  • the cellulose filter paper carrying the filtration residue is dried for 15 hours, and the total weight W2 (g) of the dried filtration residue and the cellulose filter paper is measured.
  • the weight percentage of compound (A) contained in the filtration residue is preferably 50 to 100% by weight, more preferably 70 to 100% by weight, and more preferably 90 to 100% by weight, based on the weight of the filtration residue. Particularly preferred is 100% by weight. Note that the weight percentage of undissolved matter of compound (A) contained in the esophageal cooling agent at 40°C can be obtained by changing "25°C" in the above calculation method to "40°C".
  • the weight proportion of compound (A) is preferably 30 to 95% by weight, based on the weight of the esophageal cooling agent, from the viewpoint of cooling efficiency, and preferably 50 to 95% by weight. is more preferable, still more preferably 60 to 90% by weight, particularly preferably 70 to 90% by weight.
  • the esophageal cooling agent of the present invention may contain components other than the solvent and compound (A).
  • Components other than compound (A) include additives such as antioxidants.
  • the type and content of components other than the solvent and compound (A) are determined so that the amount of heat calculated from the area surrounded by the lines (I) to (IV) and the kinematic viscosity of the esophageal coolant will be the desired values. You can select it as appropriate.
  • Components other than compound (A) are preferably soluble or miscible in the solvent.
  • the esophageal cooling agent of the present invention preferably has a turbidity of 0.1 or more, more preferably 2 or more, as measured by the following method.
  • the method for producing the esophageal cooling agent of the present invention is not particularly limited, and for example, it can be produced by mixing compound (A) and a solvent at 20 to 30°C.
  • a method for cooling the esophagus using the esophageal cooling agent of the present invention includes a method of filling the esophageal cooling agent into the esophagus.
  • Methods for filling the esophagus include direct oral administration (swallowing), or inserting a gastric tube into the esophagus (preferably using a balloon during insertion; the gastric tube described above has the function of a balloon). Examples include a method of injecting the drug through a gastric tube. Among these, direct oral administration is preferred because it is simple and causes relatively little burden on the patient.
  • the filling amount of the esophageal cooling agent is preferably 5 to 20 ml per time.
  • the temperature of the esophageal cooling agent is preferably adjusted to 1 to 15° C. before filling.
  • the esophageal cooling agent of the present invention exhibits an excellent cooling effect on the esophagus with a simple operation such as having the patient swallow the esophageal cooling agent. Therefore, it is useful as a cooling agent for cooling the esophagus located near the heart in surgeries that perform electrocautery of the heart, and is particularly useful as an esophageal cooling agent (atrial fibrillation) used during catheter ablation treatment for atrial fibrillation. It is useful as an esophageal cooling agent for catheter ablation procedures.
  • FIG. 2 is a cross-sectional view schematically showing a cross section of the esophagus.
  • FIG. 2 shows the adventitia 1, longitudinal muscularis layer 2, orbicularis muscle layer 3, submucosal layer 4, muscularis mucosae 5, lamina intestinal 6, and mucosal epithelium 7 that constitute the esophagus.
  • the method for filling the esophageal coolant of the present invention into the esophagus is as described above.
  • the location of the filled esophageal coolant can be confirmed by using a 3D mapped thermometer, or by adding a contrast agent to the esophageal coolant and performing an image diagnostic test (CT scan, MRI scan, etc.) Examples include methods for checking.
  • An appropriate cooling effect can be achieved by performing the catheter ablation procedure while the esophageal cooling agent remains in the esophagus. Note that if the esophageal coolant flows down from the esophagus during catheter ablation treatment, an esophageal cooling agent may be additionally applied as necessary.
  • the catheter ablation procedure is a 5-30 second procedure at a power of 20-50W.
  • the temperature of the esophagus during treatment can be confirmed by inserting a thermometer with a 3D mapping function into the esophagus through the nose and measuring the temperature at appropriate times.
  • the patient may drink water (approximately 100 to 300 ml) to wash away the esophageal cooling agent remaining in the esophagus.
  • DSC differential scanning calorimetry
  • the amount of heat that can be calculated from the area area surrounded by the following lines (I) to (IV) in the DSC curve with the vertical axis as heat flow (W/g) and the horizontal axis as temperature (°C) is ⁇ 4 J/g or less based on the weight of the esophageal cooling agent according to [1].
  • the weight percentage of undissolved matter of the compound (A) contained in the 25°C esophageal cooling agent is 1 to 95% by weight based on the weight of the esophageal cooling agent [1] to [4].
  • the esophageal cooling agent according to any of the above.
  • the esophageal cooling agent according to any one of [1] to [8], which is an esophageal cooling agent for catheter ablation treatment for atrial fibrillation.
  • Compound (A) was carboxymethyl cellulose sodium [trade name: carboxymethyl cellulose sodium, number average molecular weight: 1,050, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 1.6 kJ /kg ⁇ K, boiling point: 100°C or higher] was mixed with pure water at 25°C to obtain an esophageal cooling agent (A-9) containing 30% by weight of carboxymethylcellulose sodium. This was left standing in a refrigerator at 4°C for 30 minutes.
  • Example 2 was carried out in the same manner as in Example 2, except that the pure water was changed to a mixture of pure water and ethanol (95% by weight of pure water, 5% by weight of ethanol), and 70% by weight of PEG-4000N was used. An esophageal cooling agent (A-10) was obtained. This was left standing in a refrigerator at 4°C for 30 minutes.
  • Example 11 As compound (A), sorbitol [manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 2.2 kJ/kg ⁇ K, boiling point: 100°C or more] was used, and polyethylene glycol [trade name: PEG-400, number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd.] and pure water at 25°C, containing 63% by weight of sorbitol, 10% by weight of PEG-400, and 27% by weight of pure water. Esophageal cooling agent (A-11) was obtained. This was left standing in a refrigerator at 4°C for 30 minutes.
  • Comparative example 2 Comparative esophageal coolant (A'-2), polyethylene glycol [trade name: PEG-400, number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: 0 J/g, specific heat: 2.2 kJ/kg ⁇ K, boiling point: 100°C or higher] was left standing in a refrigerator at 4°C for 30 minutes.
  • PEG-400 number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: 0 J/g, specific heat: 2.2 kJ/kg ⁇ K, boiling point: 100°C or higher
  • Compound (A) was polyethylene glycol [trade name: PEG-400, number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: 0 J/g, specific heat: 2.2 kJ/kg K, boiling point Comparative esophageal cooling agents (A'-3) to (A'-7 ) was obtained. These were left standing in a 4°C refrigerator for 30 minutes.
  • Compound (A) was polyethylene glycol [trade name: PEG-4000N, number average molecular weight: 3100, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 2.3 kJ/kg K, Boiling point: 100°C or higher] was mixed with pure water at 25°C to obtain comparative esophageal coolants (A'-8) to (A'-9) containing 10 or 30% by weight of PEG-4000N. These were left standing in a 4°C refrigerator for 30 minutes.
  • Compound (A) was polyethylene glycol [trade name: PEG-6000P, number average molecular weight: 8600, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 2.3 kJ/kg K, Boiling point: 100°C or higher] was mixed with pure water at 25°C to obtain comparative esophageal coolants (A'-10) to (A'-11) containing 10 or 30% by weight of PEG-6000P. These were left standing in a 4°C refrigerator for 30 minutes.
  • kinematic viscosity of esophageal coolant was measured using an Ubbelohde viscometer in accordance with JIS-Z8803 (2011).
  • ⁇ Weight percentage of undissolved matter> At 25°C, a weight W (g) (approximately 5 g) of an esophageal coolant (previously cooled at 4°C and then temperature-controlled at 25°C) was transferred to a cellulose filter paper weighing W1 (g) (particle retention capacity: 1 ⁇ m). ), the filter residue and cellulose filter paper were dried for 15 hours, and their total weight W2 (g) was measured.
  • FIG. 4(a) is a photograph showing a state in which a temperature sensor is inserted in evaluation 1 of the cooling effect in the example.
  • FIG. 4(b) is a photograph showing a state in which the esophagus was filled with an esophageal cooling agent in evaluation 1.
  • FIG. 4(c) is a perspective view schematically showing the insertion position of the temperature sensor in the evaluation 1.
  • a test esophagus a pig's esophagus (approximately 15 cm, Kyoto Meat Market Co., Ltd.
  • FIG. 5 is a diagram schematically showing the insertion position of the temperature sensor in evaluation 2 of the cooling effect in the example.
  • Literature (Arruda MS, et al. Feasibility and safety of using an esophageal protective system to eliminate esophageal thermal inju ry: Implications on atrial-esophageal fistula following AF ablation. J Cardiovasc Electrophysiol. 2009; 20:1272-1278. doi: 10 .. 1111/j.1540-8167.2009.01536.x), the temperature of pig-derived heart tissue and esophageal tissue was controlled in a 37°C water bath. Thereafter, as shown in FIG.
  • the temperature of the temperature sensor (the highest temperature among the four temperature sensors) was measured during the current application time until the temperature rose to 39°C and during the current application time of 8 seconds and 20 seconds. Note that if the temperature did not reach 39°C even after 20 seconds, it was written as "-”. In addition, if the temperature exceeded 40° C. after 8 seconds and before 20 seconds, “interruption” was written in the “Temperature at 20 seconds of current application time (° C.)” column.
  • the esophageal cooling agent of the present invention exhibits an excellent cooling effect on the esophagus by a simple operation such as having the patient swallow the esophageal cooling agent. Therefore, it is useful as a cooling agent for cooling the esophagus located near the heart in surgeries that perform electrocautery of the heart (catheter ablation treatment for atrial fibrillation, etc.). In particular, it is useful as an esophageal cooling agent used in catheter ablation treatment for atrial fibrillation (esophageal cooling agent for catheter ablation treatment for atrial fibrillation).

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Abstract

The purpose of the present invention is to provide an esophagus-cooling agent capable of cooling the esophagus by a simple and easy means with a relatively small burden on a patient. The present invention pertains to an esophagus-cooling agent comprising a solvent and a compound (A). At least a portion of the compound (A) is a non-dissolved material that is not dissolved in the solvent when the esophagus-cooling agent is at 25°C. When differential scanning calorimetry (DSC) is performed on the esophagus-cooling agent in accordance with JIS K7122-2012, an endothermic signal that has a negative DDSC (value obtained by differentiating a heat flow by temperature) in a region where the temperature is in the range of 10-50°C and where the heat flow is at most 0 (W/g) can be observed, and the dynamic viscosity at 25°C is 100-5,000 mm2/s.

Description

食道冷却剤Esophageal cooling agent
　本発明は、食道冷却剤に関する。 The present invention relates to an esophageal cooling agent.
　心房細動に対するカテーテルアブレーション等の手術においては、心臓の電気焼灼が実施される。電気焼灼の際、心臓に近い位置に存在する食道が高温に曝されることになることから、食道の細胞障害（食道潰瘍等）を避けるためには、手術時に食道を冷却する処置が必要となる。
　このような冷却処置として、従来は、食道に管を挿入し、管中に冷却媒体を循環させることで冷却する方法が知られている（特許文献１）。しかし、特許文献１に記載の方法は、管挿入に伴う患者の負担が高く、大掛かりな装置が必要であり、手術の費用も高額となる点で問題であった。 In surgeries such as catheter ablation for atrial fibrillation, electrocautery of the heart is performed. During electrocautery, the esophagus, which is located close to the heart, is exposed to high temperatures, so to avoid cell damage to the esophagus (esophageal ulcer, etc.), it is necessary to cool the esophagus during surgery. Become.
As such a cooling treatment, a conventionally known method is to insert a tube into the esophagus and cool the esophagus by circulating a cooling medium through the tube (Patent Document 1). However, the method described in Patent Document 1 has problems in that the tube insertion imposes a heavy burden on the patient, requires a large-scale device, and increases the cost of the surgery.
特表２０１２－５１９０３３号公報Special Publication No. 2012-519033
　本発明の課題は、簡便な手段により、患者の負担が比較的少ない食道の冷却を可能とする食道冷却剤を提供することにある。 An object of the present invention is to provide an esophageal cooling agent that enables cooling of the esophagus with a relatively small burden on the patient by a simple means.
　本発明者らは、上記の課題を解決すべく鋭意検討した結果、本発明に到達した。
　即ち本発明は、溶媒及び化合物（Ａ）を含む食道冷却剤であって、
２５℃の前記食道冷却剤において、前記化合物（Ａ）の少なくとも一部が、前記溶媒に溶解していない非溶解物であり、
前記食道冷却剤について、ＪＩＳ　Ｋ７１２２－２０１２に準拠して示差走査熱量測定（ＤＳＣ）を行ったときに、１０～５０℃の温度範囲、かつ、熱流が０（Ｗ／ｇ）以下となる領域において、ＤＤＳＣ（熱流を温度で微分した値）が負の値となる吸熱シグナルが観測でき、
２５℃での動粘度が１００～５，０００ｍｍ２／ｓである食道冷却剤である。 The present inventors have arrived at the present invention as a result of intensive studies to solve the above problems.
That is, the present invention provides an esophageal cooling agent comprising a solvent and compound (A),
In the esophageal cooling agent at 25° C., at least a part of the compound (A) is an undissolved substance that is not dissolved in the solvent,
Regarding the esophageal cooling agent, when performing differential scanning calorimetry (DSC) in accordance with JIS K7122-2012, in the temperature range of 10 to 50 ° C. and in the region where the heat flow is 0 (W / g) or less , an endothermic signal with a negative value of DDSC (value obtained by differentiating heat flow with respect to temperature) can be observed,
It is an esophageal cooling agent with a kinematic viscosity of 100 to 5,000 mm 2 /s at 25°C.
　本発明の食道冷却剤は、簡便な手段により、患者の負担が比較的少ない食道の冷却を可能とする。 The esophageal cooling agent of the present invention enables cooling of the esophagus with a relatively small burden on the patient by a simple means.
図１（ａ）、図１（ｂ）及び図１（ｃ）は、それぞれ食道冷却剤のＤＳＣ曲線を模式的に示す図である。FIG. 1(a), FIG. 1(b), and FIG. 1(c) are diagrams each schematically showing a DSC curve of an esophageal cooling agent. 図２は、食道の断面を模式的に示す断面図である。FIG. 2 is a cross-sectional view schematically showing a cross section of the esophagus. 図３は、実施例３の食道冷却剤のＤＳＣ測定結果である。FIG. 3 shows the DSC measurement results of the esophageal cooling agent of Example 3. 図４（ａ）は、実施例における冷却効果の評価１において、温度センサーを挿入した状態を示した写真である。図４（ｂ）は、該評価１において、食道内に食道冷却剤を充填した状態を示した写真である。図４（ｃ）は、該評価１において、温度センサーの挿入位置を模式的に示す斜視図である。FIG. 4(a) is a photograph showing a state in which a temperature sensor is inserted in evaluation 1 of the cooling effect in the example. FIG. 4(b) is a photograph showing a state in which the esophagus was filled with an esophageal cooling agent in evaluation 1. FIG. 4(c) is a perspective view schematically showing the insertion position of the temperature sensor in the evaluation 1. 図５は、実施例における冷却効果の評価２において、温度センサーの挿入位置を模式的に示した図である。FIG. 5 is a diagram schematically showing the insertion position of the temperature sensor in evaluation 2 of the cooling effect in the example.
　本発明の食道冷却剤は、溶媒及び化合物（Ａ）を含有する。また、２５℃の食道冷却剤において、前記化合物（Ａ）の少なくとも一部は、前記溶媒に溶解していない非溶解物である。 The esophageal cooling agent of the present invention contains a solvent and compound (A). Moreover, in the 25° C. esophageal cooling agent, at least a portion of the compound (A) is an undissolved substance that is not dissolved in the solvent.
　本発明における化合物（Ａ）としては、ポリオキシエチレン鎖を有する化合物、糖鎖を有する化合物及び糖アルコール等が好ましい。
　ポリオキシエチレン鎖を有する化合物としては、下記一般式（１）：
ＨＯ－（ＣＨ２ＣＨ２Ｏ）ｎ－Ｈ　　　（１）
（式中、ｎは４０～２３０の整数であり、人体に対する影響（安全性）の観点から、好ましくは５０～２２０であり、更に好ましくは６０～２１１である。）
で表される化合物（ポリエチレングリコール）、活性水素を有する炭素数１～２０の化合物のエチレンオキサイド付加物等が挙げられる。 The compound (A) in the present invention is preferably a compound having a polyoxyethylene chain, a compound having a sugar chain, a sugar alcohol, or the like.
As a compound having a polyoxyethylene chain, the following general formula (1):
HO-(CH 2 CH 2 O) n -H (1)
(In the formula, n is an integer from 40 to 230, preferably from 50 to 220, more preferably from 60 to 211, from the viewpoint of influence on the human body (safety).)
Examples include compounds represented by (polyethylene glycol), ethylene oxide adducts of compounds having active hydrogen and having 1 to 20 carbon atoms, and the like.
　一般式（１）で表される化合物（Ａ）としては、ＰＥＧ－４０００Ｎ、ＰＥＧ－６０００Ｐ、マクロゴール４０００及びマクロゴール６０００ＳＰ［三洋化成工業（株）製］等として、市場から入手することができる。
　活性水素を有する炭素数１～２０の化合物のエチレンオキサイド付加物における活性水素を有する炭素数１～２０の化合物としては、水酸基含有化合物（メタノール、エタノール、１，６－ヘキサンジオール、グリセリン等）、アミノ基含有化合物（メチルアミン、エチルアミン等）、カルボキシル基含有化合物（コハク酸等）及びチオール（エタンチオール、エタンジチオール等）等の水酸基、１級又は２級アミノ基、カルボキシル基及びメルカプト基から選ばれる少なくとも１種の基を有する化合物等が挙げられる。該化合物にはエチレンオキサイド以外のアルキレンオキサイドがさらに付加していてもよく、該アルキレンオキサイドとしては、１，２－又は１，３－プロピレンオキサイド、１，２－、１，３－、１，４－又は２，３－ブチレンオキサイド等を挙げることができる。エチレンオキサイドとそれ以外のアルキレンオキサイドの付加数は、合計４０～２３０であることが好ましく、５０～２２０であることが更に好ましく、６０～２１１であることが特に好ましい。 Compound (A) represented by general formula (1) can be obtained from the market as PEG-4000N, PEG-6000P, Macrogol 4000, Macrogol 6000SP [manufactured by Sanyo Chemical Industries, Ltd.], etc. .
Examples of the compound having 1 to 20 carbon atoms and having active hydrogen in the ethylene oxide adduct of the compound having 1 to 20 carbon atoms having active hydrogen include hydroxyl group-containing compounds (methanol, ethanol, 1,6-hexanediol, glycerin, etc.); Selected from hydroxyl groups, primary or secondary amino groups, carboxyl groups, and mercapto groups of amino group-containing compounds (methylamine, ethylamine, etc.), carboxyl group-containing compounds (succinic acid, etc.), and thiols (ethanethiol, ethanedithiol, etc.) Examples include compounds having at least one type of group. Alkylene oxide other than ethylene oxide may be further added to the compound, and examples of the alkylene oxide include 1,2- or 1,3-propylene oxide, 1,2-, 1,3-, 1,4 - or 2,3-butylene oxide. The total number of additions of ethylene oxide and other alkylene oxides is preferably 40 to 230, more preferably 50 to 220, and particularly preferably 60 to 211.
　糖鎖を有する化合物としては、カルボキシアルキル（アルキルの炭素数は１～５）セルロース（カルボキシメチルセルロース等）又はその塩（アルカリ金属塩及びアルカリ土類金属塩等が好ましい）等が挙げられる。
　糖アルコールとしては、エリスリトール、キシリトール、ソルビトール、マンニトール、マルチトール、及び、ラクチトール等が挙げられる。 Examples of the compound having a sugar chain include carboxyalkyl (alkyl has 1 to 5 carbon atoms) cellulose (carboxymethyl cellulose, etc.) or a salt thereof (alkali metal salts and alkaline earth metal salts are preferred).
Examples of sugar alcohols include erythritol, xylitol, sorbitol, mannitol, maltitol, and lactitol.
　化合物（Ａ）は、１種を単独で用いても、２種以上を併用してもよい。 Compound (A) may be used alone or in combination of two or more.
　化合物（Ａ）は、以下の（ｉ）又は（ｉｉ）を満たすことが好ましい。
（ｉ）水への溶解熱が０Ｊ／ｇ未満である。
（ｉｉ）融点が１０～５０℃である。 Compound (A) preferably satisfies the following (i) or (ii).
(i) The heat of dissolution in water is less than 0 J/g.
(ii) The melting point is 10 to 50°C.
　水への溶解熱が０Ｊ／ｇ未満であることは、例えば、後述のＤＳＣにより確認することができる。例えば、水と化合物（Ａ）の混合物（化合物（Ａ）の非溶解物が存在するもの）について、ＤＳＣを実施し、化合物（Ａ）が水に溶解する温度領域において、ＤＳＣ曲線が下に凸となっていれば、溶解熱が０Ｊ／ｇ未満であると判断できる。 The fact that the heat of dissolution in water is less than 0 J/g can be confirmed, for example, by DSC described below. For example, when DSC is performed on a mixture of water and compound (A) (in which undissolved compound (A) is present), the DSC curve curves downward in the temperature range where compound (A) dissolves in water. If so, it can be determined that the heat of melting is less than 0 J/g.
　化合物（Ａ）の融点は、冷却効率の観点から、１０～３００℃が好ましく、１０～５０℃がより好ましく、２５～５０℃が更に好ましく、３０～４０℃が特に好ましい。
　化合物（Ａ）の融点は、後述するＤＳＣで測定することができる。 From the viewpoint of cooling efficiency, the melting point of compound (A) is preferably 10 to 300°C, more preferably 10 to 50°C, even more preferably 25 to 50°C, and particularly preferably 30 to 40°C.
The melting point of compound (A) can be measured by DSC as described below.
　化合物（Ａ）の比熱は、冷却効率の観点から、０．８ｋＪ／ｋｇ・Ｋ以上であることが好ましく、１．０ｋＪ／ｋｇ・Ｋ以上であることが更に好ましく、１．５ｋＪ／ｋｇ・Ｋ以上であることが特に好ましい。 From the viewpoint of cooling efficiency, the specific heat of compound (A) is preferably 0.8 kJ/kg·K or more, more preferably 1.0 kJ/kg·K or more, and 1.5 kJ/kg·K. It is particularly preferable that it is above.
化合物（Ａ）の沸点は、冷却効率の観点から、３９℃以上であることが好ましい。 The boiling point of compound (A) is preferably 39° C. or higher from the viewpoint of cooling efficiency.
化合物（Ａ）の数平均分子量（Ｍｎ）は、冷却効率の観点から５００～９，０００であることが好ましい。
　化合物（Ａ）がポリオキシエチレン鎖を有する化合物である場合は、Ｍｎは３，０００～９，０００であることが好ましい。
　化合物（Ａ）が糖鎖を有する化合物である場合は、Ｍｎは５００～２，０００であることが好ましい。 The number average molecular weight (Mn) of compound (A) is preferably 500 to 9,000 from the viewpoint of cooling efficiency.
When compound (A) is a compound having a polyoxyethylene chain, Mn is preferably 3,000 to 9,000.
When compound (A) is a compound having a sugar chain, Mn is preferably 500 to 2,000.
　本発明において、該数平均分子量は、ゲルパーミエーションクロマトグラフィー（以降ＧＰＣと略記する）を用いて、以下の条件で測定した値である。
＜化合物（Ａ）がポリオキシエチレン鎖を有する化合物である場合＞
　装置：「ＨＬＣ－８２２０ＧＰＣ」［東ソー（株）製］
　カラム：「Ｇｕａｒｄｃｏｌｕｍｎ　ＰＷａ」＋「ＴＳＫｇｅｌ　ＰＷｘＬ」［いずれも東ソー（株）製］
　試料溶液：０．２５重量％の溶離液
　溶離液：０．５％酢酸ナトリウム水／メタノール＝７０／３０（Ｖｏｌ／Ｖｏｌ）
　溶液注入量：２００μｌ
　流量：１ｍｌ／分
　測定温度：４０℃
　検出装置：屈折率検出器
　基準物質：標準ポリエチレングリコール［メルク社製］
＜化合物（Ａ）が糖鎖を有する化合物である場合＞
　装置：「ＨＬＣ－８３２０ＧＰＣ」［東ソー（株）製］
　カラム：「Ｇｕａｒｄｃｏｌｕｍｎ　α」＋「ＴＳＫｇｅｌ　αーＭ」［いずれも東ソー（株）製］
　試料溶液：０．２５重量％の溶離液
　溶離液：ｔ－ブタノール／水＝２／１（Ｖｏｌ／Ｖｏｌ）
　溶液注入量：１００μｌ
　流量：０．５ｍｌ／分
　測定温度：４０℃
　検出装置：屈折率検出器
　基準物質：ＧＰＣ用標準ポリエーテル（ＴＳＫ　ｓｔａｎｄａｒｄ　ＰＯＬＹ（ＥＴＨＹＬＥＮＥ　ＯＸＩＤＥ））［東ソー（株）製］ In the present invention, the number average molecular weight is a value measured using gel permeation chromatography (hereinafter abbreviated as GPC) under the following conditions.
<When compound (A) is a compound having a polyoxyethylene chain>
Equipment: “HLC-8220GPC” [manufactured by Tosoh Corporation]
Column: “Guardcolumn PWa” + “TSKgel PWxL” [both manufactured by Tosoh Corporation]
Sample solution: 0.25% by weight eluent Eluent: 0.5% sodium acetate water/methanol = 70/30 (Vol/Vol)
Solution injection volume: 200μl
Flow rate: 1ml/min Measurement temperature: 40℃
Detection device: Refractive index detector Reference material: Standard polyethylene glycol [Merck & Co., Ltd.]
<When compound (A) is a compound having a sugar chain>
Equipment: “HLC-8320GPC” [manufactured by Tosoh Corporation]
Column: “Guardcolumn α” + “TSKgel α-M” [both manufactured by Tosoh Corporation]
Sample solution: 0.25% by weight eluent Eluent: t-butanol/water = 2/1 (Vol/Vol)
Solution injection volume: 100μl
Flow rate: 0.5ml/min Measurement temperature: 40℃
Detection device: Refractive index detector Reference material: Standard polyether for GPC (TSK standard POLY (ETHYLENE OXIDE)) [manufactured by Tosoh Corporation]
本発明における溶媒としては、水、エタノール、下記一般式（２）：
ＨＯ－（ＣＨ２ＣＨ２Ｏ）ｍ－Ｈ　　　（２）
（式中、ｍは、１～３９の整数）
で表される化合物等が好ましい。 Examples of the solvent in the present invention include water, ethanol, and the following general formula (2):
HO-(CH 2 CH 2 O) m -H (2)
(In the formula, m is an integer from 1 to 39)
Compounds represented by the following are preferred.
　溶媒は、冷却効率の観点から、水を含有することが好ましい。
　水は、生理食塩水；塩化ナトリウム、塩化カリウム及び塩化カルシウムを含有するリンゲル液；緩衝成分を含有する緩衝液等の形態で含まれていてもよい。
緩衝成分としては、有機酸（リン酸等）及びグッドバッファー等が挙げられる。緩衝成分は、１種を単独で用いても２種以上を併用してもよい。食道冷却剤中の緩衝成分の含有量は、０～５０ｍＭであることが好ましく、更に好ましくは０～１０ｍＭである。 The solvent preferably contains water from the viewpoint of cooling efficiency.
Water may be contained in the form of physiological saline; Ringer's solution containing sodium chloride, potassium chloride, and calcium chloride; a buffer solution containing a buffer component, and the like.
Examples of buffer components include organic acids (such as phosphoric acid) and Good's buffer. The buffer components may be used alone or in combination of two or more. The content of the buffer component in the esophageal cooling agent is preferably 0 to 50 mM, more preferably 0 to 10 mM.
　溶媒中の水の重量割合は、溶媒の重量を基準として、５０～１００重量％であることが好ましく、７０～１００重量％であることが更に好ましく、９０～１００重量％であることが特に好ましい。
　前記一般式（２）で表される化合物の含有量は、食道冷却剤の重量を基準として１０重量％以下であることが好ましく、５重量％以下であることがより好ましく、１重量％以下であることが更に好ましく、０．１重量％以下であることが特に好ましい。 The weight proportion of water in the solvent is preferably 50 to 100% by weight, more preferably 70 to 100% by weight, particularly preferably 90 to 100% by weight, based on the weight of the solvent. .
The content of the compound represented by the general formula (2) is preferably 10% by weight or less, more preferably 5% by weight or less, and 1% by weight or less based on the weight of the esophageal cooling agent. It is more preferable that the amount is at least 0.1% by weight or less, particularly preferably 0.1% by weight or less.
　溶媒の比熱は、冷却効率の観点から、０．８ｋＪ／ｋｇ・Ｋ以上であることが好ましく、２．０ｋＪ／ｋｇ・Ｋ以上であることが更に好ましく、４．０ｋＪ／ｋｇ・Ｋ以上であることが特に好ましい。
　溶媒の沸点は、冷却効率の観点から、３９℃以上であることが好ましい。 From the viewpoint of cooling efficiency, the specific heat of the solvent is preferably 0.8 kJ/kg K or more, more preferably 2.0 kJ/kg K or more, and 4.0 kJ/kg K or more. It is particularly preferable.
The boiling point of the solvent is preferably 39° C. or higher from the viewpoint of cooling efficiency.
　本発明の食道冷却剤について、ＪＩＳ　Ｋ７１２２－２０１２に準拠してＤＳＣを行ったときに、１０～５０℃の温度範囲、かつ、熱流が０（Ｗ／ｇ）以下となる領域において、ＤＤＳＣが負の値となる吸熱シグナルが観測できる。 When the esophageal cooling agent of the present invention is subjected to DSC in accordance with JIS K7122-2012, the DDSC is negative in the temperature range of 10 to 50°C and in the region where the heat flow is 0 (W/g) or less. An endothermic signal with a value of can be observed.
　ＤＳＣは、以下の方法で測定する。
＜ＤＳＣの測定方法＞
　本発明の食道冷却剤について、例えば「ＤＳＣ　Ｑ２０」（ＴＡ　ｉｎｓｔｒｕｍｅｎｔｓ社製）を用いて、ＪＩＳＫ７１２２－２０１２に準じた以下の条件でＤＳＣを実施する。この際、あらかじめ、４℃に冷却した測定試料を下記の条件で一旦１０～５０℃まで加熱した後、１０℃まで冷却しておく。その後、下記の条件で測定試料を再度加熱してＤＳＣを実施する。
・加熱速度：１０℃／ｍｉｎ
・測定開始温度：１０℃
・測定終了温度：５０℃
・窒素ガスの流入速度：５０ｍＬ／ｍｉｎ DSC is measured by the following method.
<DSC measurement method>
The esophageal cooling agent of the present invention is subjected to DSC using, for example, "DSC Q20" (manufactured by TA instruments) under the following conditions according to JIS K7122-2012. At this time, a measurement sample previously cooled to 4°C is heated to 10 to 50°C under the following conditions, and then cooled to 10°C. Thereafter, the measurement sample is heated again under the following conditions and DSC is performed.
・Heating rate: 10℃/min
・Measurement start temperature: 10℃
・Measurement end temperature: 50℃
・Nitrogen gas inflow rate: 50mL/min
　また、前記ＤＳＣに基づき、縦軸を熱流（Ｗ／ｇ）、横軸を温度（℃）としたＤＳＣ曲線において、以下の線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量は、冷却効率の観点から、前記食道冷却剤の重量を基準として、－４Ｊ／ｇ以下であることが好ましく、冷却効率の観点から、－５Ｊ／ｇ以下であることがより好ましく、－５．５Ｊ／ｇ以下であることが更に好ましく、－６Ｊ／ｇ以下であることが特に好ましい。
（Ｉ）２５℃における縦軸と平行な直線
（ＩＩ）４０℃における縦軸と平行な直線
（ＩＩＩ）横軸と平行な直線であって、２５～４０℃の温度範囲において前記ＤＳＣ曲線の最も熱流が高くなる点と交差する直線［ただし、２５～４０℃の温度範囲において、ＤＳＣ曲線の熱流が０（Ｗ／ｇ）を超える場合、熱流が０（Ｗ／ｇ）の点と交差する直線。この場合、線（ＩＩＩ）より下のエリア面積を用いて計算する］
（ＩＶ）前記ＤＳＣ曲線
　「線（Ｉ）～（ＩＶ）で囲まれるエリア面積」とは、例えば図１（ａ）では領域ａ１と領域ａ２の面積の合計、図１（ｂ）では領域ａ３と領域ａ４の面積の合計、図１（ｃ）では領域ａ５の面積である。
　線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量は、化合物（Ａ）の溶媒への溶解熱、食道冷却剤が含有する化合物（Ａ）の非溶解物の重量割合等を調整することで、上記の好ましい範囲に調整することができる。例えば、溶媒として水を使用し、水への溶解熱が０Ｊ／ｇ未満の化合物（Ａ）を用い、化合物（Ａ）の非溶解物の重量割合を増加させることで、－４Ｊ／ｇ以下に調整することができる。 Furthermore, based on the above DSC, in the DSC curve where the vertical axis is heat flow (W/g) and the horizontal axis is temperature (℃), the amount of heat that can be calculated from the area area surrounded by the following lines (I) to (IV) is From the viewpoint of cooling efficiency, it is preferably -4 J/g or less, based on the weight of the esophageal coolant, and from the viewpoint of cooling efficiency, it is more preferably -5 J/g or less, -5.5 J. /g or less is more preferable, and -6J/g or less is particularly preferable.
(I) A straight line parallel to the vertical axis at 25°C (II) A straight line parallel to the vertical axis at 40°C (III) A straight line parallel to the horizontal axis, which is the most A straight line that intersects the point where the heat flow is high [However, if the heat flow of the DSC curve exceeds 0 (W/g) in the temperature range of 25 to 40°C, the straight line that intersects the point where the heat flow is 0 (W/g) . In this case, calculate using the area area below line (III)]
(IV) Said DSC curve "Area area surrounded by lines (I) to (IV)" means, for example, the total area of area a1 and area a2 in FIG. 1(a), and area a3 and area in FIG. 1(b). The total area of area a4 is the area of area a5 in FIG. 1(c).
The amount of heat that can be calculated from the area surrounded by lines (I) to (IV) is determined by adjusting the heat of dissolution of compound (A) in the solvent, the weight percentage of undissolved matter of compound (A) contained in the esophageal cooling agent, etc. By doing so, it is possible to adjust to the above-mentioned preferable range. For example, by using water as a solvent, using a compound (A) with a heat of dissolution in water of less than 0 J/g, and increasing the weight proportion of undissolved matter of compound (A), the heat of dissolution in water can be reduced to -4 J/g or less. Can be adjusted.
　また、上記のＤＳＣでの測定時に、２５～４０℃の温度範囲においてＤＳＣ曲線の熱流が０（Ｗ／ｇ）を超える温度帯が存在する場合、線（ＩＩＩ）より下のエリア面積から計算される熱量（負の値）と、線（ＩＩＩ）より上のエリア面積から計算される熱量（正の値）との和が、－４Ｊ／ｇ以下であることが好ましい。すなわち、２５～４０℃の範囲において、全吸熱量の絶対値が全発熱量の絶対値よりも４Ｊ／ｇ以上大きいことが好ましい。当該熱量の和は、－５．５Ｊ／ｇ以下であることが更に好ましく、－６Ｊ／ｇ以下であることが特に好ましい。
　「線（ＩＩＩ）より下のエリア面積」及び「線（ＩＩＩ）より上のエリア面積」とは、例えば図１（ｂ）において、それぞれ、領域ａ３と領域ａ４の面積の合計、及び、領域ｂ１の面積である。 In addition, when measuring with the DSC above, if there is a temperature zone in the temperature range of 25 to 40°C where the heat flow in the DSC curve exceeds 0 (W/g), the area area below line (III) is calculated. The sum of the amount of heat (negative value) calculated from the area above the line (III) (positive value) is preferably -4 J/g or less. That is, in the range of 25 to 40° C., the absolute value of the total endothermic amount is preferably 4 J/g or more greater than the absolute value of the total calorific value. The sum of the heat amounts is more preferably -5.5 J/g or less, particularly preferably -6 J/g or less.
"Area area below line (III)" and "Area area above line (III)" refer to, for example, the total area of area a3 and area a4, and area b1 in FIG. 1(b), respectively. is the area of
　本発明の食道冷却剤は、２５℃での動粘度が１００～５，０００ｍｍ２／ｓである。
　食道冷却剤の動粘度が１００ｍｍ２／ｓ未満の場合、及び、５，０００ｍｍ２／ｓを超える場合は、冷却効率が悪化する。
　食道冷却剤の動粘度は、冷却効率の観点から、１００～４，５００ｍｍ２／ｓであることが好ましい。
　また、３９℃での動粘度は、冷却効率の観点から、５，０００ｍｍ２／ｓ以下であることが好ましく、４，５００ｍｍ２／ｓ以下であることが更に好ましい。
　食道冷却剤の動粘度は、ＪＩＳ－Ｚ８８０３（２０１１年）に準拠し、ウベローデ粘度計を用いて測定した値である。 The esophageal coolant of the present invention has a kinematic viscosity of 100 to 5,000 mm 2 /s at 25°C.
When the kinematic viscosity of the esophageal coolant is less than 100 mm 2 /s and when it exceeds 5,000 mm 2 /s, the cooling efficiency deteriorates.
The kinematic viscosity of the esophageal coolant is preferably 100 to 4,500 mm 2 /s from the viewpoint of cooling efficiency.
Further, from the viewpoint of cooling efficiency, the kinematic viscosity at 39° C. is preferably 5,000 mm 2 /s or less, more preferably 4,500 mm 2 /s or less.
The kinematic viscosity of the esophageal coolant is a value measured using an Ubbelohde viscometer in accordance with JIS-Z8803 (2011).
　２５℃の食道冷却剤において、化合物（Ａ）の少なくとも一部は、溶媒に溶解していない非溶解物である。
　２５℃の食道冷却剤において、化合物（Ａ）の溶媒に溶解していない非溶解物の重量割合は、冷却効率の観点から、食道冷却剤の重量を基準として１～９５重量％であることが好ましく、５～８０重量％であることが更に好ましく、１０～８０重量％であることが特に好ましく、２５～８０重量％であることが最も好ましい。 In the esophageal cooling agent at 25° C., at least a portion of compound (A) is an undissolved substance that is not dissolved in the solvent.
In the esophageal coolant at 25°C, the weight percentage of undissolved matter that is not dissolved in the solvent of compound (A) is preferably 1 to 95% by weight based on the weight of the esophageal coolant from the viewpoint of cooling efficiency. It is preferably 5 to 80% by weight, more preferably 10 to 80% by weight, and most preferably 25 to 80% by weight.
　２５℃の食道冷却剤が含有する前記化合物（Ａ）の非溶解物の重量と、４０℃の食道冷却剤が含有する前記化合物（Ａ）の非溶解物の重量との差は、冷却効率の観点から、２５℃の食道冷却剤の重量を基準として１～９５重量％であることが好ましく、５～８０重量％であることが更に好ましく、１０～８０重量％であることが特に好ましく、２５～８０重量％であることが最も好ましい。 The difference between the weight of the undissolved compound (A) contained in the esophageal coolant at 25°C and the weight of the undissolved compound (A) contained in the esophageal coolant at 40°C is the difference in cooling efficiency. From this point of view, it is preferably 1 to 95% by weight, more preferably 5 to 80% by weight, particularly preferably 10 to 80% by weight, based on the weight of the esophageal cooling agent at 25°C. Most preferably, it is between 80% and 80% by weight.
　２５℃の食道冷却剤が含有する「化合物（Ａ）の溶媒に溶解していない非溶解物」とは、下記の方法で得られるろ過残さの乾燥物であり、その重量割合は、下記式により算出することができる。
＜２５℃の食道冷却剤が含有する化合物（Ａ）の非溶解物の重量割合の算出方法＞
　２５℃において、重量Ｗ（ｇ）の食道冷却剤（予め４℃で冷却し、その後２５℃に温度調節したもの）を、重量Ｗ１（ｇ）のセルロースろ紙（粒子保持能：１μｍ）で吸引ろ過したのち、ろ過残さを載せたセルロースろ紙を１５時間乾燥させ、ろ過残さの乾燥物とセルロースろ紙の合計重量Ｗ２（ｇ）を測定する。非溶解物の重量割合は下記式により算出する。
非溶解物の重量割合（％）＝｛（Ｗ２－Ｗ１）／Ｗ｝×１００
　なお、前記のろ過残さ中に、化合物（Ａ）以外の物質が含まれている場合は、ＮＭＲ及び各種クロマトグラフィー（ガスクロマトグラフィー等）等の分析により、化合物（Ａ）の重量割合を算出し、上記の式で得られた値を補正する。
　ろ過残さ中に含まれる化合物（Ａ）の重量割合は、前記のろ過残さの重量を基準として、５０～１００重量％であることが好ましく、７０～１００重量％であることが更に好ましく、９０～１００重量％であることが特に好ましい。
　なお、４０℃の食道冷却剤が含有する化合物（Ａ）の非溶解物の重量割合は、上記の算出方法における「２５℃」を、「４０℃」に変更することにより得られる。 The "undissolved matter of compound (A) that is not dissolved in the solvent" contained in the 25°C esophageal cooling agent is the dried filtration residue obtained by the following method, and its weight percentage is calculated by the following formula: It can be calculated.
<Method for calculating the weight percentage of undissolved matter of compound (A) contained in the esophageal cooling agent at 25°C>
At 25°C, suction filtration of esophageal coolant (previously cooled at 4°C and then temperature-controlled to 25°C) with weight W (g) is carried out through cellulose filter paper (particle retention capacity: 1 μm) with weight W1 (g). Thereafter, the cellulose filter paper carrying the filtration residue is dried for 15 hours, and the total weight W2 (g) of the dried filtration residue and the cellulose filter paper is measured. The weight percentage of undissolved matter is calculated by the following formula.
Weight percentage of undissolved matter (%) = {(W2-W1)/W}×100
In addition, if the above-mentioned filtration residue contains substances other than compound (A), calculate the weight percentage of compound (A) by analysis such as NMR and various chromatography (gas chromatography, etc.). , correct the value obtained by the above formula.
The weight percentage of compound (A) contained in the filtration residue is preferably 50 to 100% by weight, more preferably 70 to 100% by weight, and more preferably 90 to 100% by weight, based on the weight of the filtration residue. Particularly preferred is 100% by weight.
Note that the weight percentage of undissolved matter of compound (A) contained in the esophageal cooling agent at 40°C can be obtained by changing "25°C" in the above calculation method to "40°C".
　本発明の食道冷却剤において、化合物（Ａ）の重量割合は、冷却効率の観点から、食道冷却剤の重量を基準として３０～９５重量％であることが好ましく、５０～９５重量％であることがより好ましく、更に好ましくは６０～９０重量％であり、特に好ましくは７０～９０重量％である。 In the esophageal cooling agent of the present invention, the weight proportion of compound (A) is preferably 30 to 95% by weight, based on the weight of the esophageal cooling agent, from the viewpoint of cooling efficiency, and preferably 50 to 95% by weight. is more preferable, still more preferably 60 to 90% by weight, particularly preferably 70 to 90% by weight.
　本発明の食道冷却剤は、溶媒及び化合物（Ａ）以外の成分を含有してもよい。化合物（Ａ）以外の成分として、酸化防止剤等の添加剤が挙げられる。
溶媒及び化合物（Ａ）以外の成分の種類及び含有量は、前記の線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量及び食道冷却剤の動粘度が所望の値となるように適宜選択すればよい。
　化合物（Ａ）以外の成分は、溶媒に可溶又は混和していることが好ましい。 The esophageal cooling agent of the present invention may contain components other than the solvent and compound (A). Components other than compound (A) include additives such as antioxidants.
The type and content of components other than the solvent and compound (A) are determined so that the amount of heat calculated from the area surrounded by the lines (I) to (IV) and the kinematic viscosity of the esophageal coolant will be the desired values. You can select it as appropriate.
Components other than compound (A) are preferably soluble or miscible in the solvent.
　本発明の食道冷却剤は、冷却効率の観点から、以下の方法で測定した濁度が０．１以上であることが好ましく、２以上であることが更に好ましい。
＜濁度測定方法＞
　紫外可視分光光度計［（株）島津製作所社製、ＵＶ－１７００］により、光路長１ｃｍの石英セルを用いて、２５℃の食道冷却剤の波長６００ｎｍにおける吸光度を測定することで得られた値を濁度とする。 From the viewpoint of cooling efficiency, the esophageal cooling agent of the present invention preferably has a turbidity of 0.1 or more, more preferably 2 or more, as measured by the following method.
<Turbidity measurement method>
Value obtained by measuring the absorbance of the esophageal coolant at 25°C at a wavelength of 600 nm using a quartz cell with an optical path length of 1 cm using a UV-visible spectrophotometer [manufactured by Shimadzu Corporation, UV-1700] Let be the turbidity.
　本発明の食道冷却剤の製造方法は特に限定されず、例えば、化合物（Ａ）及び溶媒を、２０～３０℃で混合することで製造することができる。 The method for producing the esophageal cooling agent of the present invention is not particularly limited, and for example, it can be produced by mixing compound (A) and a solvent at 20 to 30°C.
　本発明の食道冷却剤を使用した食道の冷却方法としては、食道冷却剤を食道内へ充填する方法が挙げられる。食道内への充填方法としては、直接経口投与する（飲み込む）方法や、食道まで胃管を挿入し（挿入の際、バルーンを使用することが好ましく、前記の胃管がバルーンの機能を備えていても良い）、胃管を通して注入する方法等が挙げられる。中でも、簡便かつ患者の負担が比較的少ないことから、直接経口投与する方法が好ましい。
　食道冷却剤の充填量は、１回当たり５～２０ｍｌであることが好ましい。
　食道冷却剤は充填前に１～１５℃に温度調節しておくことが好ましい。 A method for cooling the esophagus using the esophageal cooling agent of the present invention includes a method of filling the esophageal cooling agent into the esophagus. Methods for filling the esophagus include direct oral administration (swallowing), or inserting a gastric tube into the esophagus (preferably using a balloon during insertion; the gastric tube described above has the function of a balloon). Examples include a method of injecting the drug through a gastric tube. Among these, direct oral administration is preferred because it is simple and causes relatively little burden on the patient.
The filling amount of the esophageal cooling agent is preferably 5 to 20 ml per time.
The temperature of the esophageal cooling agent is preferably adjusted to 1 to 15° C. before filling.
　本発明の食道冷却剤は、患者に食道冷却剤を飲み込ませる等の簡便な操作で、食道に対して優れた冷却効果を発揮する。このため、心臓の電気焼灼を実施する手術において、心臓近傍に位置する食道を冷却するための冷却剤として有用であり、特に、心房細動に対するカテーテルアブレーション処置の際に用いる食道冷却剤（心房細動に対するカテーテルアブレーション処置用食道冷却剤）として有用である。 The esophageal cooling agent of the present invention exhibits an excellent cooling effect on the esophagus with a simple operation such as having the patient swallow the esophageal cooling agent. Therefore, it is useful as a cooling agent for cooling the esophagus located near the heart in surgeries that perform electrocautery of the heart, and is particularly useful as an esophageal cooling agent (atrial fibrillation) used during catheter ablation treatment for atrial fibrillation. It is useful as an esophageal cooling agent for catheter ablation procedures.
　以下、本発明の食道冷却剤を、心房細動に対するカテーテルアブレーション処置用食道冷却剤として使用する場合の具体的な方法を記載する。
　図２は、食道の断面を模式的に示す断面図である。
　図２には、食道を構成する外膜１、縦筋層２、輪筋層３、粘膜下層４、粘膜筋板５、粘膜固有層６及び粘膜上皮７を示している。 Hereinafter, a specific method for using the esophageal cooling agent of the present invention as an esophageal cooling agent for catheter ablation treatment for atrial fibrillation will be described.
FIG. 2 is a cross-sectional view schematically showing a cross section of the esophagus.
FIG. 2 shows the adventitia 1, longitudinal muscularis layer 2, orbicularis muscle layer 3, submucosal layer 4, muscularis mucosae 5, lamina propria 6, and mucosal epithelium 7 that constitute the esophagus.
　本発明の食道冷却剤の食道内への充填方法は、前述のとおりである。
　充填した食道冷却剤の位置を確認する方法としては、３Ｄマッピングされた温度計を用いて確認する方法、及び、食道冷却剤に造影剤を含有させ画像診断検査（ＣＴ検査及びＭＲＩ検査等）により確認する方法等が挙げられる。
　食道冷却剤が食道内に留まっている時間内に、カテーテルアブレーション処置を実施することで、適切な冷却効果を得ることができる。なお、カテーテルアブレーション処置中に食道から流下した場合は、必要に応じて追加で食道冷却剤を適用してもよい。
　カテーテルアブレーション処置は、２０～５０Ｗの出力における５～３０秒の処置であることが好ましい。
　また、処置の際の食道の温度は、３Ｄマッピング機能のある温度計を、食道内に経鼻で挿入し、適時温度を測定する方法等で確認することができる。
　カテーテルアブレーション処置終了後、麻酔覚醒を確認した上で、必要に応じて、水（１００～３００ｍｌ程度）等を飲み、食道内に残留した食道冷却剤を洗い流しても良い。 The method for filling the esophageal coolant of the present invention into the esophagus is as described above.
The location of the filled esophageal coolant can be confirmed by using a 3D mapped thermometer, or by adding a contrast agent to the esophageal coolant and performing an image diagnostic test (CT scan, MRI scan, etc.) Examples include methods for checking.
An appropriate cooling effect can be achieved by performing the catheter ablation procedure while the esophageal cooling agent remains in the esophagus. Note that if the esophageal coolant flows down from the esophagus during catheter ablation treatment, an esophageal cooling agent may be additionally applied as necessary.
Preferably, the catheter ablation procedure is a 5-30 second procedure at a power of 20-50W.
Furthermore, the temperature of the esophagus during treatment can be confirmed by inserting a thermometer with a 3D mapping function into the esophagus through the nose and measuring the temperature at appropriate times.
After the catheter ablation procedure is completed, after confirming that the patient has woken up from anesthesia, if necessary, the patient may drink water (approximately 100 to 300 ml) to wash away the esophageal cooling agent remaining in the esophagus.
　本明細書には以下の事項が開示されている。 The following matters are disclosed in this specification.
　〔１〕溶媒及び化合物（Ａ）を含む食道冷却剤であって、
２５℃の前記食道冷却剤において、前記化合物（Ａ）の少なくとも一部が、前記溶媒に溶解していない非溶解物であり、
前記食道冷却剤について、ＪＩＳ　Ｋ７１２２－２０１２に準拠して示差走査熱量測定（ＤＳＣ）を行ったときに、１０～５０℃の温度範囲、かつ、熱流が０（Ｗ／ｇ）以下となる領域において、ＤＤＳＣ（熱流を温度で微分した値）が負の値となる吸熱シグナルが観測でき、
２５℃での動粘度が１００～５，０００ｍｍ２／ｓである食道冷却剤。 [1] An esophageal cooling agent containing a solvent and a compound (A),
In the esophageal cooling agent at 25° C., at least a part of the compound (A) is an undissolved substance that is not dissolved in the solvent,
Regarding the esophageal cooling agent, when performing differential scanning calorimetry (DSC) in accordance with JIS K7122-2012, in the temperature range of 10 to 50 ° C. and in the region where the heat flow is 0 (W / g) or less , an endothermic signal with a negative value of DDSC (value obtained by differentiating heat flow with respect to temperature) can be observed,
An esophageal coolant having a kinematic viscosity of 100 to 5,000 mm 2 /s at 25°C.
　〔２〕前記ＤＳＣに基づき、縦軸を熱流（Ｗ／ｇ）、横軸を温度（℃）としたＤＳＣ曲線において、以下の線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量が、前記食道冷却剤の重量を基準として、－４Ｊ／ｇ以下である〔１〕に記載の食道冷却剤。
（Ｉ）２５℃における縦軸と平行な直線
（ＩＩ）４０℃における縦軸と平行な直線
（ＩＩＩ）横軸と平行な直線であって、２５～４０℃の温度範囲において前記ＤＳＣ曲線の最も熱流が高くなる点と交差する直線［ただし、２５～４０℃の温度範囲において、ＤＳＣ曲線の熱流が０（Ｗ／ｇ）を超える場合、熱流が０（Ｗ／ｇ）の点と交差する直線。この場合、線（ＩＩＩ）より下のエリア面積を用いて計算する］
（ＩＶ）前記ＤＳＣ曲線 [2] Based on the above DSC, the amount of heat that can be calculated from the area area surrounded by the following lines (I) to (IV) in the DSC curve with the vertical axis as heat flow (W/g) and the horizontal axis as temperature (°C) is −4 J/g or less based on the weight of the esophageal cooling agent according to [1].
(I) A straight line parallel to the vertical axis at 25°C (II) A straight line parallel to the vertical axis at 40°C (III) A straight line parallel to the horizontal axis, which is the most A straight line that intersects the point where the heat flow is high [However, if the heat flow of the DSC curve exceeds 0 (W/g) in the temperature range of 25 to 40°C, the straight line that intersects the point where the heat flow is 0 (W/g) . In this case, calculate using the area area below line (III)]
(IV) The DSC curve
　〔３〕前記溶媒が水を含有する〔１〕又は〔２〕に記載の食道冷却剤。 [3] The esophageal cooling agent according to [1] or [2], wherein the solvent contains water.
　〔４〕前記化合物（Ａ）が、以下の（ｉ）又は（ｉｉ）を満たす〔１〕～〔３〕のいずれかに記載の食道冷却剤。
（ｉ）水への溶解熱が０Ｊ／ｇ未満である。
（ｉｉ）融点が１０～５０℃である。 [4] The esophageal cooling agent according to any one of [1] to [3], wherein the compound (A) satisfies the following (i) or (ii).
(i) The heat of dissolution in water is less than 0 J/g.
(ii) The melting point is 10 to 50°C.
　〔５〕２５℃の食道冷却剤が含有する前記化合物（Ａ）の非溶解物の重量割合が、前記食道冷却剤の重量を基準として１～９５重量％である〔１〕～〔４〕のいずれかに記載の食道冷却剤。 [5] The weight percentage of undissolved matter of the compound (A) contained in the 25°C esophageal cooling agent is 1 to 95% by weight based on the weight of the esophageal cooling agent [1] to [4]. The esophageal cooling agent according to any of the above.
　〔６〕前記化合物（Ａ）の数平均分子量が５００～９，０００である〔１〕～〔５〕のいずれかに記載の食道冷却剤。 [6] The esophageal cooling agent according to any one of [1] to [5], wherein the compound (A) has a number average molecular weight of 500 to 9,000.
　〔７〕前記化合物（Ａ）の重量割合が、前記食道冷却剤の重量を基準として、５０～９５重量％である〔１〕～〔６〕のいずれかに記載の食道冷却剤。 [7] The esophageal cooling agent according to any one of [1] to [6], wherein the weight proportion of the compound (A) is 50 to 95% by weight based on the weight of the esophageal cooling agent.
　〔８〕前記化合物（Ａ）の比熱が０．８ｋＪ／ｋｇ・Ｋ以上である〔１〕～〔７〕のいずれかに記載の食道冷却剤。 [8] The esophageal cooling agent according to any one of [1] to [7], wherein the specific heat of the compound (A) is 0.8 kJ/kg·K or more.
　〔９〕心房細動に対するカテーテルアブレーション処置用食道冷却剤である〔１〕～〔８〕のいずれかに記載の食道冷却剤。 [9] The esophageal cooling agent according to any one of [1] to [8], which is an esophageal cooling agent for catheter ablation treatment for atrial fibrillation.
　以下本発明を実施例により具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
　尚、以下において「部」は重量部を表す。 EXAMPLES The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.
In addition, "part" represents a weight part below.
＜実施例１～４＞
　化合物（Ａ）としてポリエチレングリコール［商品名：ＰＥＧ－４０００Ｎ、一般式（１）においてｎ＝４０～２３０を満たす化合物の混合物、数平均分子量：３１００、三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ未満、比熱：２．３ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を純水［比熱：４．２ｋＪ／ｋｇ・Ｋ、沸点：１００℃］と２５℃で混合し、ＰＥＧ－４０００Ｎを６５、７０、９０又は９５重量％含有する食道冷却剤（Ａ－１）～（Ａ－４）を得た。これらを４℃の冷蔵庫に３０分間静置した。 <Examples 1 to 4>
Compound (A) was polyethylene glycol [trade name: PEG-4000N, mixture of compounds satisfying n = 40 to 230 in general formula (1), number average molecular weight: 3100, manufactured by Sanyo Chemical Industries, Ltd., dissolved in water. Heat: less than 0 J/g, specific heat: 2.3 kJ/kg K, boiling point: 100°C or higher] is mixed with pure water [specific heat: 4.2 kJ/kg K, boiling point: 100°C] at 25°C, and PEG Esophageal cooling agents (A-1) to (A-4) containing 65, 70, 90 or 95% by weight of -4000N were obtained. These were left standing in a 4°C refrigerator for 30 minutes.
＜実施例５～８＞
　化合物（Ａ）としてポリエチレングリコール［商品名：ＰＥＧ－６０００Ｐ、一般式（１）においてｎ＝４０～２３０を満たす化合物の混合物、数平均分子量：８６００、三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ未満、比熱：２．３ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を純水と２５℃で混合し、ＰＥＧ－６０００Ｐを６０、７０、９０又は９５重量％含有する食道冷却剤（Ａ－５）～（Ａ－８）を得た。これらを４℃の冷蔵庫に３０分間静置した。 <Examples 5 to 8>
Compound (A) was polyethylene glycol [trade name: PEG-6000P, mixture of compounds satisfying n = 40 to 230 in general formula (1), number average molecular weight: 8600, manufactured by Sanyo Chemical Industries, Ltd., dissolved in water. Esophageal cooling containing 60, 70, 90 or 95% by weight of PEG-6000P by mixing heat: less than 0 J/g, specific heat: 2.3 kJ/kg・K, boiling point: 100°C or more] with pure water at 25°C. Agents (A-5) to (A-8) were obtained. These were left standing in a 4°C refrigerator for 30 minutes.
＜実施例９＞
　化合物（Ａ）としてカルボキシメチルセルロースナトリウム［商品名：カルボキシメチルセルロースナトリウム、数平均分子量：１，０５０、富士フイルム和光純薬（株）製、水への溶解熱：０Ｊ／ｇ未満、比熱：１．６ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を純水と２５℃で混合し、カルボキシメチルセルロースナトリウムを３０重量％含有する食道冷却剤（Ａ－９）を得た。これを４℃の冷蔵庫に３０分間静置した。 <Example 9>
Compound (A) was carboxymethyl cellulose sodium [trade name: carboxymethyl cellulose sodium, number average molecular weight: 1,050, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 1.6 kJ /kg·K, boiling point: 100°C or higher] was mixed with pure water at 25°C to obtain an esophageal cooling agent (A-9) containing 30% by weight of carboxymethylcellulose sodium. This was left standing in a refrigerator at 4°C for 30 minutes.
＜実施例１０＞
　実施例２において、純水を、純水とエタノールの混合物（純水９５重量％、エタノール５重量％）に変更した以外は、実施例２と同様に実施して、ＰＥＧ－４０００Ｎを７０重量％含有する食道冷却剤（Ａ－１０）を得た。これを４℃の冷蔵庫に３０分間静置した。 <Example 10>
Example 2 was carried out in the same manner as in Example 2, except that the pure water was changed to a mixture of pure water and ethanol (95% by weight of pure water, 5% by weight of ethanol), and 70% by weight of PEG-4000N was used. An esophageal cooling agent (A-10) was obtained. This was left standing in a refrigerator at 4°C for 30 minutes.
＜実施例１１＞
　化合物（Ａ）としてソルビトール［三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ未満、比熱：２．２ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を、ポリエチレングリコール［商品名：ＰＥＧ－４００、数平均分子量：４００、三洋化成工業（株）製］及び純水と２５℃で混合し、ソルビトールを６３重量％、ＰＥＧ－４００を１０重量％、純水を２７重量％含有する食道冷却剤（Ａ－１１）を得た。これを４℃の冷蔵庫に３０分間静置した。 <Example 11>
As compound (A), sorbitol [manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 2.2 kJ/kg・K, boiling point: 100°C or more] was used, and polyethylene glycol [trade name: PEG-400, number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd.] and pure water at 25°C, containing 63% by weight of sorbitol, 10% by weight of PEG-400, and 27% by weight of pure water. Esophageal cooling agent (A-11) was obtained. This was left standing in a refrigerator at 4°C for 30 minutes.
＜比較例１＞
　比較用の食道冷却剤（Ａ’－１）である純水を４℃の冷蔵庫に３０分間静置した。 <Comparative example 1>
Pure water, which is a comparative esophageal coolant (A'-1), was left standing in a refrigerator at 4°C for 30 minutes.
＜比較例２＞
　比較用の食道冷却剤（Ａ’－２）であるポリエチレングリコール［商品名：ＰＥＧ－４００、数平均分子量：４００、三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ、比熱：２．２ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を４℃の冷蔵庫に３０分間静置した。 <Comparative example 2>
Comparative esophageal coolant (A'-2), polyethylene glycol [trade name: PEG-400, number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: 0 J/g, specific heat: 2.2 kJ/kg·K, boiling point: 100°C or higher] was left standing in a refrigerator at 4°C for 30 minutes.
＜比較例３～７＞
　化合物（Ａ）としてポリエチレングリコール［商品名：ＰＥＧ－４００、数平均分子量：４００、三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ、比熱：２．２ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を純水と２５℃で混合し、ＰＥＧ－４００を１０、３０、５０、７０又は９０重量％含有する比較用の食道冷却剤（Ａ’－３）～（Ａ’－７）を得た。これらを４℃の冷蔵庫に３０分間静置した。 <Comparative Examples 3 to 7>
Compound (A) was polyethylene glycol [trade name: PEG-400, number average molecular weight: 400, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: 0 J/g, specific heat: 2.2 kJ/kg K, boiling point Comparative esophageal cooling agents (A'-3) to (A'-7 ) was obtained. These were left standing in a 4°C refrigerator for 30 minutes.
＜比較例８～９＞
　化合物（Ａ）としてポリエチレングリコール［商品名：ＰＥＧ－４０００Ｎ、数平均分子量：３１００、三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ未満、比熱：２．３ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を純水と２５℃で混合し、ＰＥＧ－４０００Ｎを１０又は３０重量％含有する比較用の食道冷却剤（Ａ’－８）～（Ａ’－９）を得た。これらを４℃の冷蔵庫に３０分間静置した。 <Comparative Examples 8-9>
Compound (A) was polyethylene glycol [trade name: PEG-4000N, number average molecular weight: 3100, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 2.3 kJ/kg K, Boiling point: 100°C or higher] was mixed with pure water at 25°C to obtain comparative esophageal coolants (A'-8) to (A'-9) containing 10 or 30% by weight of PEG-4000N. These were left standing in a 4°C refrigerator for 30 minutes.
＜比較例１０～１１＞
　化合物（Ａ）としてポリエチレングリコール［商品名：ＰＥＧ－６０００Ｐ、数平均分子量：８６００、三洋化成工業（株）製、水への溶解熱：０Ｊ／ｇ未満、比熱：２．３ｋＪ／ｋｇ・Ｋ、沸点：１００℃以上］を純水と２５℃で混合し、ＰＥＧ－６０００Ｐを１０又は３０重量％含有する比較用の食道冷却剤（Ａ’－１０）～（Ａ’－１１）を得た。これらを４℃の冷蔵庫に３０分間静置した。 <Comparative Examples 10-11>
Compound (A) was polyethylene glycol [trade name: PEG-6000P, number average molecular weight: 8600, manufactured by Sanyo Chemical Industries, Ltd., heat of dissolution in water: less than 0 J/g, specific heat: 2.3 kJ/kg K, Boiling point: 100°C or higher] was mixed with pure water at 25°C to obtain comparative esophageal coolants (A'-10) to (A'-11) containing 10 or 30% by weight of PEG-6000P. These were left standing in a 4°C refrigerator for 30 minutes.
　実施例１～１１で得た食道冷却剤（Ａ－１）～（Ａ－１１）及び比較用の食道冷却剤（Ａ’－１）～（Ａ’－１１）を用いて、以下の方法で各物性を評価した。 Using the esophageal cooling agents (A-1) to (A-11) obtained in Examples 1 to 11 and the comparative esophageal cooling agents (A'-1) to (A'-11), the following method was used. Each physical property was evaluated.
＜線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量＞
　各食道冷却剤について、「ＤＳＣ　Ｑ２０」（ＴＡ　ｉｎｓｔｒｕｍｅｎｔｓ社製）を用いて、ＪＩＳＫ７１２２－２０１２に準じた以下の条件でＤＳＣを実施した。なお、あらかじめ、４℃に冷却した測定試料を下記の条件で一旦１０～５０℃まで加熱し、１０℃まで冷却した後、下記の条件で再度測定試料を加熱してＤＳＣを実施した。
　なお、実施例３のＤＳＣ曲線を図３に示す。
・加熱速度：１０℃／ｍｉｎ
・測定開始温度：１０℃
・測定終了温度：５０℃
・窒素ガスの流入速度：５０ｍＬ／ｍｉｎ
　前記ＤＳＣに基づき、縦軸を熱流（Ｗ／ｇ）、横軸を温度（℃）としたＤＳＣ曲線において、以下の線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量（食道冷却剤の重量を基準とした熱量）を算出した。
（Ｉ）２５℃における縦軸と平行な直線
（ＩＩ）４０℃における縦軸と平行な直線
（ＩＩＩ）横軸と平行な直線であって、２５～４０℃の温度範囲において前記ＤＳＣ曲線の最も熱流が高くなる点と交差する直線
（ＩＶ）前記ＤＳＣ曲線 <The amount of heat that can be calculated from the area surrounded by lines (I) to (IV)>
DSC was performed on each esophageal cooling agent using "DSC Q20" (manufactured by TA instruments) under the following conditions according to JISK7122-2012. Note that a measurement sample cooled to 4°C in advance was once heated to 10 to 50°C under the following conditions, cooled to 10°C, and then heated again under the following conditions to perform DSC.
Note that the DSC curve of Example 3 is shown in FIG.
・Heating rate: 10℃/min
・Measurement start temperature: 10℃
・Measurement end temperature: 50℃
・Nitrogen gas inflow rate: 50mL/min
Based on the above DSC, the amount of heat (esophageal cooling The amount of heat (based on the weight of the agent) was calculated.
(I) A straight line parallel to the vertical axis at 25°C (II) A straight line parallel to the vertical axis at 40°C (III) A straight line parallel to the horizontal axis, which is the most Straight line (IV) that intersects the point where the heat flow becomes high: the DSC curve
＜食道冷却剤の動粘度＞
　食道冷却剤の動粘度は、ＪＩＳ－Ｚ８８０３（２０１１年）に準拠し、ウベローデ粘度計を用いて測定した。 <Kinematic viscosity of esophageal coolant>
The kinematic viscosity of the esophageal coolant was measured using an Ubbelohde viscometer in accordance with JIS-Z8803 (2011).
＜食道冷却剤の濁度＞
　紫外可視分光光度計［（株）島津製作所社製、ＵＶ－１７００］により、光路長１ｃｍの石英セルを用いて、２５℃の食道冷却剤の波長６００ｎｍにおける吸光度を測定することで得られた値を、食道冷却剤の濁度とした。 <Turbidity of esophageal coolant>
Value obtained by measuring the absorbance of the esophageal coolant at 25°C at a wavelength of 600 nm using a quartz cell with an optical path length of 1 cm using a UV-visible spectrophotometer [manufactured by Shimadzu Corporation, UV-1700] was taken as the turbidity of the esophageal coolant.
＜非溶解物の重量割合＞
　２５℃において、重量Ｗ（ｇ）（約５ｇ）の食道冷却剤（予め４℃で冷却し、その後２５℃に温度調節したもの）を、重量Ｗ１（ｇ）のセルロースろ紙（粒子保持能：１μｍ）で吸引ろ過したのち、ろ過残さとセルロースろ紙を１５時間乾燥させ、これらの合計重量Ｗ２（ｇ）を測定した。２５℃の食道冷却剤が含有する非溶解物の重量割合は下記式により算出した。
非溶解物の重量割合（％）＝｛（Ｗ２－Ｗ１）／Ｗ｝×１００
　同様に、４０℃において測定を行い、４０℃の食道冷却剤が含有する非溶解物の重量割合を算出した。 <Weight percentage of undissolved matter>
At 25°C, a weight W (g) (approximately 5 g) of an esophageal coolant (previously cooled at 4°C and then temperature-controlled at 25°C) was transferred to a cellulose filter paper weighing W1 (g) (particle retention capacity: 1 μm). ), the filter residue and cellulose filter paper were dried for 15 hours, and their total weight W2 (g) was measured. The weight percentage of undissolved substances contained in the 25°C esophageal cooling agent was calculated using the following formula.
Weight percentage of undissolved material (%) = {(W2-W1)/W}×100
Similarly, measurement was performed at 40°C, and the weight percentage of undissolved matter contained in the esophageal coolant at 40°C was calculated.
＜冷却効果の評価１＞
　図４（ａ）は、実施例における冷却効果の評価１において、温度センサーを挿入した状態を示した写真である。図４（ｂ）は、該評価１において、食道内に食道冷却剤を充填した状態を示した写真である。図４（ｃ）は、該評価１において、温度センサーの挿入位置を模式的に示す斜視図である。
　試験用の食道として、豚の食道（約１５ｃｍ、京都食肉市場株式会社副生物課）を用い、図４（ｃ）に示す通り、食道の先端から、温度センサー９を豚食道組織中の食道内８、及び、輪筋層３と粘膜下層４との境界にそれぞれ挿入した。シリンジに接続された口鼻用カテーテル（１６Ｆｒ）を用いて、水平に静置した食道内に４℃の食道冷却剤１０ｍｌを充填し、食道の外表面を４００℃で５分間加熱した。加熱により上昇した温度を測定した。 <Evaluation of cooling effect 1>
FIG. 4(a) is a photograph showing a state in which a temperature sensor is inserted in evaluation 1 of the cooling effect in the example. FIG. 4(b) is a photograph showing a state in which the esophagus was filled with an esophageal cooling agent in evaluation 1. FIG. 4(c) is a perspective view schematically showing the insertion position of the temperature sensor in the evaluation 1.
As the test esophagus, a pig's esophagus (approximately 15 cm, Kyoto Meat Market Co., Ltd. By-Products Division) was used, and as shown in Figure 4(c), the temperature sensor 9 was inserted into the esophagus from the tip of the esophagus into the tissue of the pig's esophagus. 8, and the border between the orbicularis muscle layer 3 and the submucosal layer 4, respectively. Using an oronasal catheter (16Fr) connected to a syringe, 10 ml of esophageal cooling agent at 4°C was filled into the horizontally placed esophagus, and the outer surface of the esophagus was heated at 400°C for 5 minutes. The temperature increased by heating was measured.
＜冷却効果の評価２＞
　図５は、実施例における冷却効果の評価２において、温度センサーの挿入位置を模式的に示した図である。
　文献（Ａｒｒｕｄａ　Ｍ　Ｓ，　ｅｔ　ａｌ．　Ｆｅａｓｉｂｉｌｉｔｙ　ａｎｄ　ｓａｆｅｔｙ　ｏｆ　ｕｓｉｎｇ　ａｎ　ｅｓｏｐｈａｇｅａｌ　ｐｒｏｔｅｃｔｉｖｅ　ｓｙｓｔｅｍ　ｔｏ　ｅｌｉｍｉｎａｔｅ　ｅｓｏｐｈａｇｅａｌ　ｔｈｅｒｍａｌ　ｉｎｊｕｒｙ：　ｉｍｐｌｉｃａｔｉｏｎｓ　ｏｎ　ａｔｒｉａｌ－ｅｓｏｐｈａｇｅａｌ　ｆｉｓｔｕｌａ　ｆｏｌｌｏｗｉｎｇ　ＡＦ　ａｂｌａｔｉｏｎ．　Ｊ　Ｃａｒｄｉｏｖａｓｃ　Ｅｌｅｃｔｒｏｐｈｙｓｉｏｌ．　２００９；　２０：１２７２－１２７８．　ｄｏｉ：　１０．１１１１／ｊ．１５４０－８１６７．２００９．０１５３６．ｘ）に記載の方法に準拠して、３７℃ウォーターバス内で豚由来心臓組織及び食道組織を温度調節した。
　その後、図５の通り、食道組織１２に、食道外部から１ｍｍ間隔で４本の温度センサー９を挿入し、食道組織を水平に静置した。
　次に、シリンジに接続された口鼻用カテーテル（１６Ｆｒ）を用いて、食道内に４℃の食道冷却剤１３を１０ｍｌ充填し、５分静置した後、アブレーションカテーテル１１［アボット社製、ＴａｃｔｉＣａｔｈイリゲーションカテーテル］で心臓組織１０を加熱した（出力３０Ｗで通電）。３９℃に上昇するまでの通電時間及び通電時間８秒及び２０秒における温度センサーの温度（４つある温度センサーが示した温度の内、最も高い温度）を測定した。
　なお、２０秒を経過後も、３９℃に到達しなかった場合は、「－」と記載した。また、８秒経過後から、２０秒を経過する前に、４０℃を超えた場合は、「通電時間２０秒時点の温度（℃）」の欄は、「中断」と記載した。 <Evaluation of cooling effect 2>
FIG. 5 is a diagram schematically showing the insertion position of the temperature sensor in evaluation 2 of the cooling effect in the example.
Literature (Arruda MS, et al. Feasibility and safety of using an esophageal protective system to eliminate esophageal thermal inju ry: Implications on atrial-esophageal fistula following AF ablation. J Cardiovasc Electrophysiol. 2009; 20:1272-1278. doi: 10 ．． 1111/j.1540-8167.2009.01536.x), the temperature of pig-derived heart tissue and esophageal tissue was controlled in a 37°C water bath.
Thereafter, as shown in FIG. 5, four temperature sensors 9 were inserted into the esophageal tissue 12 from the outside of the esophagus at 1 mm intervals, and the esophageal tissue was left still horizontally.
Next, using an oronasal catheter (16 Fr) connected to the syringe, 10 ml of esophageal cooling agent 13 at 4°C was filled into the esophagus, and after leaving it for 5 minutes, the ablation catheter 11 [manufactured by Abbott, TactiCath Irrigation catheter] was used to heat the heart tissue 10 (current was applied at an output of 30 W). The temperature of the temperature sensor (the highest temperature among the four temperature sensors) was measured during the current application time until the temperature rose to 39°C and during the current application time of 8 seconds and 20 seconds.
Note that if the temperature did not reach 39°C even after 20 seconds, it was written as "-". In addition, if the temperature exceeded 40° C. after 8 seconds and before 20 seconds, “interruption” was written in the “Temperature at 20 seconds of current application time (° C.)” column.
　線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量、食道冷却剤の動粘度、食道冷却剤の濁度、食道冷却剤の非溶解物の重量割合（２５℃、４０℃）、冷却効果の評価１、冷却効果の評価２の結果を表１に示す。また、化合物（Ａ）の融点、比熱及び沸点も合わせて表１に示す。
　なお、各実施例において、１０～５０℃の温度範囲、かつ、熱流が０（Ｗ／ｇ）以下となる領域において、ＤＤＳＣが負の値となる吸熱シグナルが観測された。また、各実施例において、２５～４０℃の温度範囲において、ＤＳＣ曲線の熱流が０（Ｗ／ｇ）を超えることはなかった。 The amount of heat that can be calculated from the area surrounded by lines (I) to (IV), the kinematic viscosity of the esophageal coolant, the turbidity of the esophageal coolant, the weight percentage of undissolved matter in the esophageal coolant (25°C, 40°C), Table 1 shows the results of cooling effect evaluation 1 and cooling effect evaluation 2. Table 1 also shows the melting point, specific heat, and boiling point of compound (A).
In each example, an endothermic signal with a negative value of DDSC was observed in the temperature range of 10 to 50° C. and in a region where the heat flow was 0 (W/g) or less. Further, in each example, the heat flow in the DSC curve did not exceed 0 (W/g) in the temperature range of 25 to 40°C.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　本発明の食道冷却剤は、患者に食道冷却剤を飲み込ませる等の簡便な操作で、食道に対して優れた冷却効果を発揮する。このため、心臓の電気焼灼を実施する手術（心房細動に対するカテーテルアブレーション処置等）において、心臓近傍に位置する食道を冷却する措置のために使用する冷却剤として有用である。
　特に、心房細動に対するカテーテルアブレーション処置の際に用いる食道冷却剤（心房細動に対するカテーテルアブレーション処置用食道冷却剤）として有用である。 The esophageal cooling agent of the present invention exhibits an excellent cooling effect on the esophagus by a simple operation such as having the patient swallow the esophageal cooling agent. Therefore, it is useful as a cooling agent for cooling the esophagus located near the heart in surgeries that perform electrocautery of the heart (catheter ablation treatment for atrial fibrillation, etc.).
In particular, it is useful as an esophageal cooling agent used in catheter ablation treatment for atrial fibrillation (esophageal cooling agent for catheter ablation treatment for atrial fibrillation).
１　外膜
２　縦筋層
３　輪筋層
４　粘膜下層
５　粘膜筋板
６　粘膜固有層
７　粘膜上皮
８　食道内
９　温度センサー
１０　心臓組織
１１　アブレーションカテーテル
１２　食道組織
１３　食道冷却剤 1 Adventitia 2 Longitudinal muscle layer 3 Orbicularis muscle layer 4 Submucosal layer 5 Muscle mucosae 6 Lamina propria mucosa 7 Mucosal epithelium 8 Inner esophagus 9 Temperature sensor 10 Heart tissue 11 Ablation catheter 12 Esophageal tissue 13 Esophageal cooling agent

Claims (9)

  1. 　溶媒及び化合物（Ａ）を含む食道冷却剤であって、
    ２５℃の前記食道冷却剤において、前記化合物（Ａ）の少なくとも一部が、前記溶媒に溶解していない非溶解物であり、
    前記食道冷却剤について、ＪＩＳ　Ｋ７１２２－２０１２に準拠して示差走査熱量測定（ＤＳＣ）を行ったときに、１０～５０℃の温度範囲、かつ、熱流が０（Ｗ／ｇ）以下となる領域において、ＤＤＳＣ（熱流を温度で微分した値）が負の値となる吸熱シグナルが観測でき、
    ２５℃での動粘度が１００～５，０００ｍｍ２／ｓである食道冷却剤。     An esophageal cooling agent comprising a solvent and a compound (A),
    In the esophageal cooling agent at 25° C., at least a part of the compound (A) is an undissolved substance that is not dissolved in the solvent,
    Regarding the esophageal cooling agent, when performing differential scanning calorimetry (DSC) in accordance with JIS K7122-2012, in the temperature range of 10 to 50 ° C. and in the region where the heat flow is 0 (W / g) or less , an endothermic signal with a negative value of DDSC (value obtained by differentiating heat flow with respect to temperature) can be observed,
    An esophageal coolant having a kinematic viscosity of 100 to 5,000 mm 2 /s at 25°C.
  2. 　前記ＤＳＣに基づき、縦軸を熱流（Ｗ／ｇ）、横軸を温度（℃）としたＤＳＣ曲線において、以下の線（Ｉ）～（ＩＶ）で囲まれるエリア面積から計算できる熱量が、前記食道冷却剤の重量を基準として、－４Ｊ／ｇ以下である請求項１に記載の食道冷却剤。
    （Ｉ）２５℃における縦軸と平行な直線
    （ＩＩ）４０℃における縦軸と平行な直線
    （ＩＩＩ）横軸と平行な直線であって、２５～４０℃の温度範囲において前記ＤＳＣ曲線の最も熱流が高くなる点と交差する直線［ただし、２５～４０℃の温度範囲において、ＤＳＣ曲線の熱流が０（Ｗ／ｇ）を超える場合、熱流が０（Ｗ／ｇ）の点と交差する直線。この場合、線（ＩＩＩ）より下のエリア面積を用いて計算する］
    （ＩＶ）前記ＤＳＣ曲線     Based on the DSC, the amount of heat that can be calculated from the area area surrounded by the following lines (I) to (IV) in the DSC curve with the vertical axis as heat flow (W/g) and the horizontal axis as temperature (℃) is as follows. The esophageal cooling agent according to claim 1, which is -4 J/g or less based on the weight of the esophageal cooling agent.
    (I) A straight line parallel to the vertical axis at 25°C (II) A straight line parallel to the vertical axis at 40°C (III) A straight line parallel to the horizontal axis, which is the most A straight line that intersects the point where the heat flow is high [However, if the heat flow of the DSC curve exceeds 0 (W/g) in the temperature range of 25 to 40°C, the straight line that intersects the point where the heat flow is 0 (W/g) . In this case, calculate using the area area below line (III)]
    (IV) The DSC curve
  3. 　前記溶媒が水を含有する請求項２に記載の食道冷却剤。 The esophageal coolant according to claim 2, wherein the solvent contains water.
  4. 　前記化合物（Ａ）が、以下の（ｉ）又は（ｉｉ）を満たす請求項１又は２に記載の食道冷却剤。
    （ｉ）水への溶解熱が０Ｊ／ｇ未満である。
    （ｉｉ）融点が１０～５０℃である。     The esophageal cooling agent according to claim 1 or 2, wherein the compound (A) satisfies the following (i) or (ii).
    (i) The heat of dissolution in water is less than 0 J/g.
    (ii) The melting point is 10 to 50°C.
  5. 　２５℃の食道冷却剤が含有する前記化合物（Ａ）の非溶解物の重量割合が、前記食道冷却剤の重量を基準として１～９５重量％である請求項１又は２に記載の食道冷却剤。 The esophageal cooling agent according to claim 1 or 2, wherein the weight percentage of undissolved matter of the compound (A) contained in the 25° C. esophageal cooling agent is 1 to 95% by weight based on the weight of the esophageal cooling agent. .
  6. 　前記化合物（Ａ）の数平均分子量が５００～９，０００である請求項１又は２に記載の食道冷却剤。 The esophageal cooling agent according to claim 1 or 2, wherein the number average molecular weight of the compound (A) is 500 to 9,000.
  7. 　前記化合物（Ａ）の重量割合が、前記食道冷却剤の重量を基準として、５０～９５重量％である請求項１又は２に記載の食道冷却剤。 The esophageal cooling agent according to claim 1 or 2, wherein the weight proportion of the compound (A) is 50 to 95% by weight based on the weight of the esophageal cooling agent.
  8. 　前記化合物（Ａ）の比熱が０．８ｋＪ／ｋｇ・Ｋ以上である請求項１又は２に記載の食道冷却剤。 The esophageal cooling agent according to claim 1 or 2, wherein the specific heat of the compound (A) is 0.8 kJ/kg·K or more.
  9. 　心房細動に対するカテーテルアブレーション処置用食道冷却剤である請求項１又は２に記載の食道冷却剤。
     

          The esophageal cooling agent according to claim 1 or 2, which is an esophageal cooling agent for catheter ablation treatment for atrial fibrillation.
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JP2006089479A (en) * 2004-09-21 2006-04-06 Mcneil Ppc Inc Medicinal cooling emulsion
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US20190380761A1 (en) * 2017-02-28 2019-12-19 University Of Florida Research Foundation, Inc. Controlling esophageal temperature during cardiac ablation
JP2022112776A (en) * 2021-01-22 2022-08-03 三洋化成工業株式会社 Esophagus cooling agent

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Publication number Priority date Publication date Assignee Title
JP2006089479A (en) * 2004-09-21 2006-04-06 Mcneil Ppc Inc Medicinal cooling emulsion
US20120197245A1 (en) * 2011-02-01 2012-08-02 Channel Medsystems, Inc. Methods and apparatus for cyrogenic treatment of a body cavity or lumen
US20190380761A1 (en) * 2017-02-28 2019-12-19 University Of Florida Research Foundation, Inc. Controlling esophageal temperature during cardiac ablation
JP2022112776A (en) * 2021-01-22 2022-08-03 三洋化成工業株式会社 Esophagus cooling agent

Non-Patent Citations (1)

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Title
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