Submucosal injection material for endoscopy

Abstract

A submucosal injection material for endoscopy that comprises a water-soluble resin having a weight-average molecular weight of 10,000 or more, an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less and water, and that has an electrical conductivity of 500 mS / m or less and an osmotic pressure ratio to physiological saline of 0.7-1.5.

Description

[Technical Field]

[0001] This disclosure relates to a submucosal injection material for endoscopy. [Background technology]

[0002] Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are known treatments for gastrointestinal polyps, early gastric cancer, and early colorectal cancer (see Journal of the Japan Society of Coloproctology 66:941-949, 2013). Furthermore, in EMR or ESD, to facilitate resection, an endoscopic submucosal injection material is injected into the submucosa of the lesion to elevate the mucosa beneath the lesion. Therefore, the endoscopic submucosal injection material requires excellent elevation properties.

[0003] From a safety standpoint, the osmotic pressure of endoscopic submucosal injection materials is adjusted. For example, Japanese Patent Publication No. 2003-201257 discloses an endoscopic submucosal injection material in which the osmotic pressure ratio to physiological saline is adjusted to 0.7 to 1.4. Furthermore, International Publication No. 2013 / 077357 discloses a submucosal injection material for endoscopy containing osmotic pressure adjusting agents such as sugar alcohols. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] In EMR or ESD, a high-frequency knife is used to excise the lesion. However, depending on the endoscopic submucosal injection material used, sparks may occur. Due to the reaction of these sparks, the high-frequency knife may move in an unintended direction, potentially causing the excision of non-lesional tissue. Furthermore, droplets ejected by these sparks may adhere to the endoscope lens, potentially contaminating it. Furthermore, the inventors have found that the submucosal injection material for endoscopes disclosed in Japanese Patent Publication No. 2003-201257 and International Publication No. 2013 / 077357 may cause the aforementioned sparking, making it difficult to perform resection easily, and that there is room for improvement in the ease of resection.

[0005] This disclosure has been made in view of the above circumstances, and the problem it seeks to solve is to provide an endoscopic submucosal injection material that is excellent in safety, ease of resection, and protrusion. [Means for solving the problem]

[0006] The specific means to achieve the objective are as follows: <1> A submucosal injection material for endoscopy, comprising a water-soluble resin with a weight-average molecular weight of 10,000 or more, an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less, and water, having an electrical conductivity of 500 mS / m or less, and an osmotic pressure ratio of 0.7 to 1.5 with respect to physiological saline. <2> The above organic compound comprises one or more compounds selected from the group including glycol compounds, sugar alcohol compounds, monosaccharide compounds, and disaccharide compounds. <1> Submucosal injection material for endoscopy as described above. <3> The above organic compound comprises one or more glycol compounds selected from the group consisting of propylene glycol, triethylene glycol, and polyethylene glycol. <1> or <2> Submucosal injection material for endoscopy as described above. <4> The above organic compound comprises one or more sugar alcohol compounds selected from the group consisting of erythritol, glycerol, sorbitol, and xylitol. <1> or <2> Submucosal injection material for endoscopy as described above. <5> The above organic compound has a molecular weight of 200 or less. <1> ~ <4> Submucosal injection material for endoscopy as described in any one of the following. <6> The above organic compound comprises one or more compounds selected from the group consisting of erythritol, glycerol, sorbitol, glucose, propylene glycol, triethylene glycol, and polyethylene glycol. <1> or <2> Submucosal injection material for endoscopy as described above. <7> The above organic compound has a molecular weight of 100 or less. <1> ~ <6> Submucosal injection material for endoscopy as described in any one of the following. <8> The content of the above organic compound in the submucosal injection material for endoscopy is 1.9% by mass to 9.0% by mass. <1> ~ <7> Submucosal injection material for endoscopy as described in any one of the following. <9> The above water-soluble resin contains one or more compounds selected from the group consisting of protein compounds, polysaccharides, and derivatives thereof. <1> ~ <8> Submucosal injection material for endoscopy as described in any one of the following. <10> The above water-soluble resin contains one or more compounds selected from the group consisting of sodium hyaluronate, xanthan gum, sodium carboxymethylcellulose, locust bean gum, dextran, dextrin, sodium alginate, hydroxyalkylcellulose, sodium carboxymethyldextran, hydrophobized hydroxyalkylcellulose, sodium poly(meth)acrylate, polyvinyl alcohol, gelatin, and casein. <1> ~ <9> Submucosal injection material for endoscopy as described in any one of the following. <11> The content of the above-mentioned water-soluble resin in the submucosal injection material for endoscopy is 0.1% to 1.5% by mass. <1> ~ <10> Submucosal injection material for endoscopy as described in any one of the following. [Effects of the Invention]

[0007] According to this disclosure, it is possible to provide an endoscopic submucosal injection material that is excellent in terms of safety, ease of resection, and protrusion. [Modes for carrying out the invention]

[0008] In this disclosure, the numerical range indicated using "~" includes the numbers before and after "~" as the minimum and maximum values, respectively. In the numerical ranges described step by step in the present disclosure, the upper limit value or the lower limit value described in one numerical range may be replaced with the upper limit value or the lower limit value of the numerical range described in other step-by-step descriptions. Also, in the numerical ranges described in the present disclosure, the upper limit value or the lower limit value of the numerical range may be replaced with the value shown in the examples.

[0009] In the present disclosure, the osmotic pressure is measured using an osmometer in accordance with the 2.47 Osmotic Pressure Measurement Method (Osmolality Measurement Method) of the 17th Revised Japanese Pharmacopoeia (Ministry of Health, Labour and Welfare Notification No. 64, March 7, 2016). As the osmometer, OSMOMAT 300(D) manufactured by Gonotec or a device similar thereto can be used. Note that commercially available physiological saline with an osmotic pressure of 250 mOsmol / kg to 300 mOsmol / kg can be used as the physiological saline. As the commercially available physiological saline, for example, Otsuka Normal Saline Injection (osmotic pressure 288 mOsmol / kg) manufactured by Otsuka Pharmaceutical Co., Ltd. can be used. The osmotic pressure ratio is obtained by dividing the measured osmotic pressure by the osmotic pressure value of the physiological saline.

[0010] In the present disclosure, the electrical conductivity of the submucosal injection material for endoscopy is measured by setting the temperature of the submucosal injection material for endoscopy to 25°C and using a conductivity meter. As the conductivity meter, a pen-type pH / conductivity meter MPC70 (manufactured by AS ONE Corporation) or a device of the same level can be used.

[0011] In the present disclosure, the viscosity of the submucosal injection material for endoscopy is measured by setting the temperature of the submucosal injection material for endoscopy to 25°C and using a rheometer under the condition of a frequency of 100 Hz. As the rheometer, a rheometer (Anton Paar, automatic rheometer MCR102) equipped with a cone-plate type jig (parallel plate, 10 mm Φ) or a device of the same level can be used.

[0012] In the present disclosure, the weight-average molecular weight (Mw) of the water-soluble resin with a weight-average molecular weight of 10,000 or more is a value measured using the following GPC measuring device under the following measurement conditions and converted using the calibration curve of standard polystyrene. For the creation of the calibration curve, a set of 5 samples of standard polystyrene ("PStQuick MP-H" and "PStQuick B", manufactured by Tosoh Corporation) was used. (GPC Measuring Device) · GPC device: High-speed GPC device "HCL-8320GPC", detector is a differential refractometer or UV, manufactured by Tosoh Corporation · Columns: TSKgel SuperHZM-H, TSKgel SuperHZ4000, and TSKgel SuperHZ200 (all manufactured by Tosoh Corporation) were connected in series in this order and used. (Measurement Conditions) · Solvent: N-methylpyrrolidone (NMP) · Column temperature: 40 °C

[0013] In the present disclosure, the molecular weight of the organic compound having two or more hydroxyl groups and a molecular weight of 400 or less is determined from the chemical structure of the compound. However, when the organic compound is a polymer such as an oligomer, it is measured using a GPC measuring device under the above measurement conditions.

[0014] In the present disclosure, "water-soluble resin" refers to a resin having a solubility of 0.1 g or more in 100 g of water at a liquid temperature of 22 °C and a pH of 7.0.

[0015] In the present disclosure, "(meth)acryl" means at least one of an acrylic and a methacrylic group.

[0016] <Submucosal Injectable Material for Endoscope> The submucosal injectable material for endoscope of the present disclosure contains a water-soluble resin with a weight-average molecular weight of 10,000 or more, an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less, and water, has an electrical conductivity of 500 mS / m or less, and an osmotic pressure ratio to physiological saline of 0.7 to 1.5.

[0017] The endoscopic submucosal injection material disclosed herein has excellent resectable properties, safety, and elongation properties. In this disclosure, an endoscopic submucosal injection material having excellent safety refers to an endoscopic submucosal injection material that can suppress cell death caused by dehydration of tissue cells or excessive water uptake by tissue cells when injected into the submucosal layer.

[0018] The reasons for the above effects are presumed to be as follows, but are not limited to these. The submucosal injection material for endoscopy described herein contains a water-soluble resin with a weight-average molecular weight of 10,000 or more and an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less. It is presumed that this will result in good electrical conductivity and osmotic pressure ratio to physiological saline of the submucosal injection material for endoscopy, thereby improving the ease of resection and safety described above. Furthermore, if the molecular weight of the above-mentioned organic compound exceeds 400, it is necessary to increase the amount of the organic compound added in order to improve the osmotic pressure of the endoscopic submucosal injection material of this disclosure. This tends to cause a step-like difference in the raised portion after the endoscopic submucosal injection material is injected, reducing the ease of resection. The organic compound having two or more hydroxyl groups contained in the endoscopic submucosal injection material of this disclosure has a molecular weight of 400 or less, so the amount added can be reduced, and it is presumed that the reduction in ease of resection caused by the above-mentioned step-like difference can be suppressed. It is presumed that including a water-soluble resin with a weight-average molecular weight of 10,000 or more in the endoscopic submucosal injection material increases its viscosity and improves its ability to rise. Furthermore, it is presumed that the electrical conductivity of the endoscopic submucosal injection material being 500 mS / m or less will suppress the generation of sparks (electrical discharges) when using a high-frequency knife, thereby improving the ease of resection. Furthermore, because the osmotic pressure ratio of the endoscopic submucosal injection material to physiological saline is 0.7 to 1.5, it is presumed that when injected into the submucosal layer of the lesion, the movement of water between the surrounding cells and the endoscopic submucosal injection material can be suppressed, thereby improving safety.

[0019] From the viewpoint of ease of resection, the electrical conductivity of the endoscopic submucosal injection material is preferably 100 mS / m or less, more preferably 50 mS / m or less, even more preferably 10 mS / m or less, and particularly preferably 1 mS / m or less. There is no specific lower limit for electrical conductivity; the lower the better, but it can be, for example, 0.1 mS / m or higher. The electrical conductivity of the submucosal injection material for endoscopy can be adjusted by changing the type and content of a water-soluble resin with a weight-average molecular weight of 10,000 or more and an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less.

[0020] From a safety standpoint, the osmotic pressure ratio of the endoscopic submucosal injection material to physiological saline is more preferably 0.8 to 1.3, and even more preferably 0.9 to 1.1. The osmotic pressure ratio of the endoscopic submucosal injection material to physiological saline can be adjusted by changing the type and content of a water-soluble resin with a weight-average molecular weight of 10,000 or more and an organic compound having two or more hydroxyl groups and a weight-average molecular weight of 400 or less.

[0021] From a safety standpoint, the amount of endotoxin in the submucosal injection material for endoscopy is preferably as low as possible, specifically preferably 50 EU / mL or less. In this disclosure, the amount of endotoxin is measured according to the gelation method of the 17th edition of the Japanese Pharmacopoeia (Ministry of Health, Labour and Welfare Notification No. 64, March 7, 2016). Limulus Color KY Test Wako is used as the endotoxin measurement reagent, and the Japanese Pharmacopoeia Endotoxin Standard is used as the endotoxin standard.

[0022] From the viewpoint of ease of elevation and ease of injection, the viscosity of the endoscopic submucosal injection material at 25°C is preferably 10 mPa·s to 500 mPa·s, and more preferably 50 mPa·s to 200 mPa·s.

[0023] (Water-soluble resin with a weight-average molecular weight of 10,000 or more) The submucosal injection material for endoscopy described herein contains a water-soluble resin with a weight-average molecular weight of 10,000 or more (hereinafter also referred to as a specific water-soluble resin). From the viewpoint of upliftability, the weight-average molecular weight of the specific water-soluble resin is preferably 10,000 or more, and more preferably 100,000 or more. The upper limit of the weight-average molecular weight of the specific water-soluble resin is not particularly limited, but from the viewpoint of easy injection, it is preferably 10,000,000 or less, more preferably 5,000,000 or less, and even more preferably 2,000,000 or less.

[0024] From the viewpoint of ease of excision, safety, and elevation, the specific water-soluble resin preferably contains one or more compounds selected from the group consisting of protein compounds, polysaccharides, and derivatives thereof. A derivative refers to a compound in which part of the structure is modified (change of substituents, introduction of substituents, etc.) while retaining the basic skeleton of the compound.

[0025] Examples of protein compounds include casein, albumin, methylated collagen, hydrolyzed collagen, soluble collagen, gelatin, and synthetic peptides.

[0026] Examples of polysaccharides include hyaluronic acid, sodium hyaluronate, xanthan gum, sodium carboxymethylcellulose, locust bean gum, dextran, dextrin, sodium alginate, hydroxyalkylcellulose (such as hydroxypropyl methylcellulose), sodium carboxymethyldextran, hydrophobized hydroxyalkylcellulose, sodium poly(meth)acrylate, polyvinyl alcohol, gum arabic, tragacanth gum, karaya gum, tamarind gum, guar gum, gellan gum, and sodium chondroitin sulfate.

[0027] From the viewpoints of ease of excision, safety, and swelling property, among the above, the specific water-soluble resin preferably contains one or more compounds selected from the group consisting of sodium hyaluronate, xanthan gum, sodium carboxymethyl cellulose, locust bean gum, dextran, dextrin, sodium alginate, hydroxyalkyl cellulose, sodium carboxymethyldextran, hydrophobized hydroxyalkyl cellulose, sodium poly(meth)acrylate, polyvinyl alcohol, gelatin, and casein. More preferably, it contains one or more compounds selected from the group consisting of xanthan gum, locust bean gum, hydrophobized hydroxyalkyl cellulose, and sodium poly(meth)acrylate. Even more preferably, it contains hydrophobized hydroxyalkyl cellulose. Note that sodium poly(meth)acrylate may have a crosslinked structure or may not have a crosslinked structure.

[0028] From the viewpoints of ease of excision, safety, swelling property, swelling maintenance property, ease of injection, etc., the above hydrophobized hydroxyalkyl cellulose is preferably represented by the following general formula (1).

[0029]

Chemical formula

[0030] In general formula (1), R 1 , R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, -[CH2CH 2-k (CH3) k O] m H, or -CH2CH(OH)CH2OC j H 2j+1 . Note that the hydrophobized hydroxyalkyl cellulose represented by general formula (1) has at least one -CH2CH(OH)CH2OC j H 2j+1 . Also, when n is 2 or more, two or more Rs1 These may be the same or different.

[0031] C1-C4 alkyl groups may be linear or branched. Examples of C1-C4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl groups.

[0032] The content of an alkyl group having 1 to 4 carbon atoms relative to the mass of the hydrophobized hydroxyalkylcellulose represented by general formula (1) is preferably 10% to 50% by mass.

[0033] -[CH2CH 2-k (CH3) k O] m In H, k represents either 0 or 1. Furthermore, m represents an integer between 1 and 10, preferably between 1 and 5, and more preferably 1.

[0034] -[CH2CH] relative to the mass of hydrophobized hydroxyalkylcellulose represented by general formula (1) 2-k (CH3) k O] m The H content is preferably 3% to 20% by mass.

[0035] -CH2CH(OH)CH2OC j H 2j+1 The integer j in the middle represents an integer between 6 and 26. From the viewpoint of ease of excision, safety, elevation, elevation maintenance, and ease of injection, it is preferable that it represents an integer between 10 and 20, and more preferably an integer between 15 and 18.

[0036] From the viewpoints of ease of excision, safety, elevation, elevation maintenance, and ease of injection, -CH2CH(OH)CH2OC is used in relation to the mass of hydrophobized hydroxyalkylcellulose represented by general formula (1). j H 2j+1The content of is preferably 0.1% to 10% by mass, more preferably 0.2% to 1.0% by mass, and even more preferably 0.3% to 0.6% by mass.

[0037] In general formula (1), n ​​represents an integer between 100 and 100,000, preferably between 100 and 10,000, and more preferably between 2,000 and 4,000.

[0038] The Mw of the hydrophobized hydroxyalkylcellulose represented by general formula (1) is preferably 10,000 to 10,000,000, more preferably 50,000 to 5,000,000, and even more preferably 100,000 to 1,000,000.

[0039] Examples of hydrophobized hydroxyalkylcelluloses that satisfy general formula (1) include palmitoylated hydroxypropyl methylcellulose, margalylated hydroxypropyl methylcellulose, and stearylated hydroxypropyl methylcellulose. From the viewpoints of ease of excision, safety, elevation, elevation maintenance, and ease of injection, hydrophobized hydroxyalkylcellulose satisfying general formula (1) preferably includes stearylated hydroxypropyl methylcellulose.

[0040] The hydrophobized hydroxyalkylcellulose represented by general formula (1) may be manufactured by conventionally known methods or may be commercially available. Commercially available products include Sanjelose® 90L and Sanjelose® 60L from Daido Chemical Industries, Ltd.

[0041] From the viewpoint of ease of excision, safety, and elevation, the content of the specific water-soluble resin relative to the mass of the submucosal injection material for endoscopy is preferably 0.1% to 1.5% by mass, and more preferably 0.3% to 1.3% by mass.

[0042] When the specific water-soluble resin contains hydrophobized hydroxyalkylcellulose, from the viewpoint of ease of excision, safety, and elevation, the content of hydrophobized hydroxyalkylcellulose relative to the mass of the submucosal injection material for endoscopy is preferably 0.1% to 0.5% by mass, and more preferably 0.2% to 0.4% by mass. When the specific water-soluble resin contains one or more compounds selected from the group consisting of sodium hyaluronate, sodium poly(meth)acrylate, xanthan gum, sodium carboxymethylcellulose, locust bean gum, sodium alginate, and sodium carboxymethyl dextran, from the viewpoint of ease of excision, safety, and elevation, the sum of the content of these compounds relative to the mass of the submucosal injection material for endoscopy is preferably 0.1% to 0.9% by mass, and more preferably 0.1% to 0.6% by mass. When the specific water-soluble resin contains one or more compounds selected from the group consisting of dextran, dextrin, hydroxyalkylcellulose, polyvinyl alcohol, gelatin, and casein, from the viewpoint of ease of excision, safety, and elevation, the sum of the content of these compounds relative to the mass of the submucosal injection material for endoscopy is preferably 0.5% to 1.5% by mass, and more preferably 0.8% to 1.3% by mass.

[0043] (Organic compounds having two or more hydroxyl groups and a molecular weight of 400 or less) The submucosal injection material for endoscopy described herein contains an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less (hereinafter also referred to as a specific organic compound). From the viewpoint of ease of excision, the molecular weight of the specific organic compound is preferably 200 or less, and more preferably 100 or less. There is no particular upper limit to the molecular weight of a specific water-soluble resin, but for example, it can be 50 or higher.

[0044] From the viewpoint of ease of excision and safety, it is preferable that the specified organic compound contains one or more compounds selected from the group including glycol compounds, sugar alcohol compounds, monosaccharide compounds, and disaccharide compounds. Examples of glycol compounds include propylene glycol, triethylene glycol, and polyethylene glycol. Examples of sugar alcohol compounds include erythritol, glycerol, sorbitol, and xylitol. Examples of monosaccharide compounds include glucose, mannose, galactose, and fructose. Examples of disaccharide compounds include sucrose, lactose, lactulose, maltose, and trehalose.

[0045] From the viewpoint of ease of excision and safety, it is preferable that the specific organic compound contains one or more compounds selected from the group consisting of erythritol, glycerol, sorbitol, glucose, propylene glycol, triethylene glycol, and polyethylene glycol.

[0046] The content of specific organic compounds relative to the mass of the submucosal injection material for endoscopy is preferably 1.9% to 9.0% by mass, and more preferably 2.1% to 5.7% by mass. By keeping the content of specific organic compounds within the above numerical range, the ease of excision and safety can be further improved.

[0047] (water) Examples of water include deionized water, pure water, and purified water, but among these, pure water or purified water is preferred due to its applicability to submucosal injection materials for endoscopy. Alternatively, purified water containing dispersed or dissolved sodium chloride, organic compounds, etc., may be used.

[0048] The water content relative to the mass of the submucosal injection material for endoscopy is not particularly limited, but can be, for example, 80% to 99.9% by mass.

[0049] (others) The endoscopic submucosal injection material disclosed herein may contain osmotic pressure adjusting agents such as sodium chloride, sodium dihydrogen phosphate, and disodium hydrogen phosphate, coloring agents, contrast agents, fillers, cancer treatment agents, hormones, anti-inflammatory agents, antibiotics, analgesics, antibacterial agents, pH adjusters, and the like.

[0050] (Treatment method) The treatment method disclosed herein involves injecting an endoscopic submucosal injection material into the submucosa of the lesion, causing the mucosa beneath the lesion to rise, and then excising the lesion.

[0051] The injection of endoscopic submucosal injection material into the submucosal layer of the lesion can be performed by conventionally known methods used in EMR or ESD, for example, by using an endoscopic puncture needle. Examples of endoscopic puncture needles include the Super Grip manufactured by Top Co., Ltd.

[0052] The lesion can be excised by conventionally known methods used in EMR or ESD, for example, by using a high-frequency knife. Examples of high-frequency knives include the FlushKnife BT-S DK2620J disposable high-frequency knife manufactured by Fujifilm Corporation. The above-mentioned high-frequency knife can be subjected to vibration using a high-frequency device, such as the ERBE ICC200 manufactured by AMCO. [Examples]

[0053] The above embodiments will be described in detail below with reference to examples, but the above embodiments are not limited to these examples.

[0054] (Examples 1 to 37) A submucosal injection material for endoscopy was prepared by blending a water-soluble resin with a weight-average molecular weight of 10,000 or more (referred to as a specific water-soluble resin in the table), an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less (referred to as a specific organic compound in the table), pure water, etc., in the compositions shown in Tables 1 to 3. In Example 10, the submucosal injection material for endoscopy was prepared, and the amount of endotoxin was measured using Limulus Color KY Test Wako as the endotoxin measurement reagent and the Japanese Pharmacopoeia Endotoxin Standard as the endotoxin standard, according to the gelation method of the 17th edition of the Japanese Pharmacopoeia (Ministry of Health, Labour and Welfare Notification No. 64, March 7, 2016). The result was 0.0005 EU / mL or less (below the detection limit). The viscosity of the endoscopic submucosal injection materials of Example 1 and Example 10 was measured by setting the temperature of the endoscopic submucosal injection material to 25°C and using a rheometer at a frequency of 100 Hz, and the results were 49 mPa·s and 95 mPa·s, respectively. For the rheometer, we used a rheometer (Anton Paar MCR102 automatic rheometer) equipped with a cone-plate type jig (parallel plate, 10mmΦ).

[0055] (Comparative Example 1 and Comparative Example 2) Sodium chloride and pure water were mixed according to the composition shown in Table 4 to prepare a submucosal injection material for endoscopy. The viscosity of the submucosal injection material for endoscopy of Comparative Example 1 was measured at a temperature of 25°C using a rheometer at a frequency of 100 Hz, and was found to be 1 mPa·s.

[0056] (Comparative Example 3) An endoscope submucosal injection material was prepared in the same manner as in Example 1, except that an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less was not used.

[0057] (Comparative Example 4) An endoscopic submucosal injection material was prepared by blending an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less with pure water in the composition shown in Table 4.

[0058] (Comparative Example 5) A submucosal injection material for endoscopy was prepared by blending a water-soluble resin with a weight-average molecular weight of 10,000 or more, an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less, and pure water in the composition shown in Table 4.

[0059] (Comparative Example 6) A submucosal injection material for endoscopy was prepared by blending a water-soluble resin with a weight-average molecular weight of 10,000 or more, an organic compound having two or more hydroxyl groups and a molecular weight exceeding 400, and pure water in the composition shown in Table 4.

[0060] (Comparative Example 7) A submucosal injection material for endoscopy was prepared by blending a water-soluble resin with a weight-average molecular weight of 10,000 or more, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and pure water in the composition shown in Table 4.

[0061] (Comparative Example 8) A submucosal injection material for endoscopy was prepared in the same manner as in Example 1, except that a water-soluble resin with a weight-average molecular weight of 10,000 or more was not used. The viscosity of the endoscopic submucosal injection material of Comparative Example 8 was measured at a temperature of 25°C and using a rheometer at a frequency of 100 Hz, and was found to be 10 mPa·s.

[0062] (Comparative Example 9) A submucosal injection material for endoscopy was prepared in the same manner as in Example 1, except that sodium hyaluronate A (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Mw 1,000,000), a water-soluble resin with a weight-average molecular weight of 10,000 or more, was replaced with sodium hyaluronate B (manufactured by Kewpie Corporation, Hyalonano®, Mw 2,000), a water-soluble resin with a weight-average molecular weight of less than 10,000.

[0063] Details of the various materials listed in Tables 1 to 4 are as follows: <Water-soluble resins with a weight-average molecular weight of 10,000 or more> • Sodium hyaluronate A: Manufactured by Fujifilm Wako Pure Chemical Corporation, Mw 1,000,000 • Xanthan gum: Manufactured by Fujifilm Wako Pure Chemical Corporation • Sodium carboxymethylcellulose: Manufactured by Sigma-Aldrich, Mw 250,000 • Locust bean gum: Manufactured by Fujifilm Wako Pure Chemical Corporation, MW > 10,000 • Dextran: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., dextran 150,000, Mw 150,000 • Dextrin: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., dextrin hydrate, MW>10,000 • Sodium alginate: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., sodium alginate 300-400, Mw 63,000 • Hydroxypropyl methylcellulose: Manufactured by Sigma-Aldrich, Mw 120,000 • Carboxymethyl dextran sodium: Manufactured by Meito Sangyo Co., Ltd., CMD-500, Mw500,000 • Stearylated hydroxypropyl methylcellulose: Manufactured by Daido Chemical Industries, Ltd., Sanjelose (registered trademark) 90L, hydrophobized hydroxyalkyl cellulose satisfying the above general formula (1), Mw 700,000~900,000, -CH2CH(OH)CH2OC j H 2j+1 Content of 0.3% by mass to 0.6% by mass • Sodium polyacrylate: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., degree of polymerization 22,000-70,000 • Cross-linked sodium polyacrylate: Manufactured by Fujifilm Wako Pure Chemical Corporation, Hibiscus Wako 104, MW>10,000 • Polyvinyl alcohol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., saponification degree 78 mol%~82 mol%, MW>10,000 • Gelatin: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., MW>10,000 Casein: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., derived from milk, MW>10,000

[0064] <Organic compounds having two or more hydroxyl groups and a molecular weight of 400 or less> Glycerol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., reagent grade, molecular weight 92 • Erythritol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Meso-erythritol, Wako Grade 1, molecular weight 122 • Sorbitol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., D(-) sorbitol, Wako Grade 1, molecular weight 182 Xylitol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Wako Special Grade, Molecular Weight 152 • Propylene glycol: Manufactured by Fujifilm Wako Pure Chemical Corporation, reagent grade, molecular weight 76 Triethylene glycol: Manufactured by Fujifilm Wako Pure Chemical Corporation, molecular weight 150 • Polyethylene glycol 200: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Wako Grade 1, Mw200 (It is an oligomer, and its weight-average molecular weight was measured using a GPC measuring device). • Glucose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., D(+) glucose, reagent grade, molecular weight 180 • Mannose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., D(+) mannose, reagent grade, molecular weight 180 • Galactose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., D(+) galactose, reagent grade, molecular weight 180 • Fructose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., D(-) fructose, reagent grade, molecular weight 180 • Sucrose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., reagent grade, molecular weight 342 Lactose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., lactose hydrate, reagent grade, molecular weight 342 • Maltose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., maltose hydrate, reagent grade, molecular weight 342 • Trehalose: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., reagent grade, molecular weight 342 • Mannitol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., D(-) mannitol, reagent grade, molecular weight 342

[0065] <Other> • Polyethylene glycol 600: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Wako Grade 1, Mw600 • Sodium dihydrogen phosphate: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Wako Special Grade. • Disodium hydrogen phosphate: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Wako Special Grade • Sodium chloride: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., reagent grade. • Sodium hyaluronate B: Manufactured by Kewpie Corporation, Hyalonano®, Mw2,000

[0066] <Conductivity Measurement> The submucosal injection materials for endoscopy prepared in the above examples and comparative examples were brought to 25°C and measured using a pen-type pH / conductivity meter MPC70 (manufactured by AS ONE Corporation). The measurement results are summarized in Tables 1 to 4.

[0067] <Measurement of osmotic pressure ratio relative to physiological saline> The osmotic pressure of the endoscopic submucosal injection materials prepared in the above examples and comparative examples was measured using an osmometer (Gonotec, OSMOMAT300(D)) in accordance with section 2.47, Osmolality Measurement Method (Osmolality Measurement Method), of the 17th Revised Japanese Pharmacopoeia (Ministry of Health, Labour and Welfare Notification No. 64, March 7, 2016). The measured osmolality was divided by the osmolality value of Otsuka Saline Injection to determine the osmolality ratio. The measurement results are summarized in Tables 1 to 4. For the physiological saline solution used, we used Otsuka Saline Injection (manufactured by Otsuka Pharmaceutical Co., Ltd., osmotic pressure 288 mOsmol / kg).

[0068] <Ease of resection assessment> The upper part of the extracted pig stomach (the upper part when the total length is divided into three equal parts) was cut into 5 cm squares to prepare test specimens. Using an endoscopic puncture needle (Super Grip, manufactured by Top Co., Ltd., needle diameter 23G), 2 mL of the endoscopic submucosal injection material prepared in the examples and comparative examples was injected into the submucosal layer of the test specimen, causing the mucosal layer to bulge. The raised mucosal layer was excised using a high-frequency cutting instrument (FlushKnife BT-S DK2620J, disposable high-frequency knife, manufactured by Fujifilm Corporation). During the excision of the mucosal layer, vibration was applied to the high-frequency cutting instrument using a high-frequency device (AMCO ERBE ICC200) set to "Swift Coagulation, effect 4,40W". The number of unidirectional excision movements (swings) required to excise the mucosal layer was measured and evaluated based on the following evaluation criteria. The evaluation results are summarized in Tables 1 to 4. (Evaluation Criteria) A: No sparks occurred, and the number of excision procedures was four or less. B: A small amount of sparking occurred, but the number of excision procedures was more than 4 but less than 7. C: Sparks occurred, but the number of excision operations was between 7 and 9, which was within a range that did not pose a practical problem. D: Sparks occurred, and the number of excision operations was between 9 and 15, which presented practical problems. E: Sparks occurred, and the number of excision operations exceeded 15.

[0069] <Safety Evaluation> The extracted pig small intestine was cut open, washed with physiological saline to remove excess water, and a 3cm x 3cm x 1mm test specimen was prepared. 50 mL each of the endoscopic submucosal injection material prepared in the examples and comparative examples was prepared, and the test specimens were immersed in the endoscopic submucosal injection material for 24 hours at 25°C. After immersion, excess solution was lightly wiped off, the mass of the test specimen was measured, and the rate of change in mass of the test specimen (mass of test specimen after immersion / mass of test specimen before immersion × 100) was calculated and summarized in Tables 1 to 4. Injecting endoscopic submucosal injection materials with a mass change rate of less than 85% into the submucosal layer may cause dehydration of tissue cells, raising safety concerns. Furthermore, injecting endoscopic submucosal injection materials with a mass change rate exceeding 120% into the submucosal layer may lead to cell death due to excessive water uptake by tissue cells, raising safety concerns. Therefore, from a safety standpoint, endoscopic submucosal injection materials with a mass change rate of 85% to 120% are preferred.

[0070] <Evaluation of elevation> The upper part of the extracted pig stomach (the upper part when the total length is divided into three equal parts) was cut into 5 cm squares to prepare test specimens. Two mL of the endoscopic submucosal injection material prepared in the examples and comparative examples was injected into the submucosal layer of the test specimen using an endoscopic puncture needle (Super Grip, manufactured by Top Co., Ltd., needle diameter 23G). The height of the mucosal layer elevation was measured 30 minutes after injection and evaluated based on the following evaluation criteria. The evaluation results are summarized in Table 1. The height of the uplift was measured using a camera-equipped laser displacement sensor IX-150 manufactured by Keyence Corporation, and the maximum height of the uplift was determined. (Evaluation Criteria) A: The elevation height was 10 mm or more. B: The elevation height was 8m or more and less than 10mm. C: The elevation height was 5 mm or more and less than 8 mm. D: The elevation height was 2 mm or more and less than 5 mm. E: The elevation height was less than 2 mm.

[0071] [Table 1]

[0072] [Table 2]

[0073] [Table 3]

[0074] [Table 4]

[0075] Tables 1 to 4 show that the endoscopic submucosal injection material prepared in the examples is superior in terms of ease of resection, safety, and protrusion compared to the endoscopic submucosal injection material prepared in the comparative examples. Furthermore, the specific organic compounds used in Examples 33-36 have higher molecular weights compared to the specific organic compounds used in other examples, and are added in larger quantities to the submucosal injection material for endoscopy to adjust osmotic pressure. Due to the increased amount of the above-mentioned specific organic compounds added, steps were created in the raised portion, resulting in inferior excision compared to Example 1, etc.

[0076] The disclosure of Japanese Patent Application No. 2021-100418, filed on 16 June 2021, is incorporated herein by reference in its entirety. All documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually described as being incorporated by reference.

Claims

1. A water-soluble resin which is hydrophobized hydroxyalkylcellulose with a weight-average molecular weight of 10,000 or more, an organic compound having two or more hydroxyl groups and a molecular weight of 400 or less, and water. The electrical conductivity is 500 mS / m or less, and The osmotic pressure ratio to physiological saline is 0.7 to 1.

5. The aforementioned organic compound comprises one or more compounds selected from the group consisting of glycerol, erythritol, sorbitol, xylitol, propylene glycol, triethylene glycol, polyethylene glycol, glucose, mannose, galactose, fructose, sucrose, lactose, maltose, trehalose, and mannitol, and is used as a submucosal injection material for endoscopy.

2. The submucosal injection material for endoscopes according to claim 1, wherein the organic compound comprises one or more glycol compounds selected from the group consisting of propylene glycol, triethylene glycol, and polyethylene glycol.

3. The submucosal injection material for endoscopes according to claim 1, wherein the organic compound comprises one or more sugar alcohol compounds selected from the group consisting of erythritol, glycerol, sorbitol, and xylitol.

4. The submucosal injection material for endoscopy according to claim 1, wherein the molecular weight of the organic compound is 200 or less.

5. The submucosal injection material for endoscopes according to claim 1, wherein the organic compound comprises one or more compounds selected from the group consisting of erythritol, glycerol, sorbitol, glucose, propylene glycol, triethylene glycol, and polyethylene glycol.

6. The submucosal injection material for endoscopy according to claim 1, wherein the molecular weight of the organic compound is 100 or less.

7. The endoscopic submucosal injection material according to any one of claims 1 to 6, wherein the content of the organic compound in the endoscopic submucosal injection material is 1.9% by mass to 9.0% by mass.

8. The submucosal injection material for endoscopy according to any one of claims 1 to 6, wherein the hydrophobic hydroxyalkylcellulose with a weight-average molecular weight of 10,000 or more is represented by the following general formula (1). 【Chemistry 1】 (In the formula, R1, R2, and R3 each independently represent a hydrogen atom, a C1-C4 alkyl group, -[CH2CH2-k(CH3)kO]mH, or -CH2CH(OH)CH2OCjH2j+1) k represents 0 or 1, m represents an integer from 1 to 10, j represents an integer from 6 to 26, and n represents an integer from 100 to 100,000. However, the hydrophobized hydroxyalkylcellulose represented by general formula (1) has at least one -CH₂CH(OH)CH₂OC j H₂j+1, and when n is 2 or more, the two or more R₁, R₂, and R₃ may be the same or different.

9. The submucosal injection material for endoscopy according to claim 8, wherein the hydrophobic hydroxyalkylcellulose having a weight-average molecular weight of 10,000 or more comprises stearylated hydroxypropylmethylcellulose having a weight-average molecular weight of 10,000 or more.

10. The endoscopic submucosal injection material according to any one of claims 1 to 6, wherein the content of the water-soluble resin in the endoscopic submucosal injection material is 0.1% by mass to 1.5% by mass.

Images