Adhesion-preventive film and method for producing same

Abstract

Provided is an adhesion-preventive film which is hardly broken when folded or rolled. The adhesion-preventive film contains a bioabsorbable polymer compound, has a thickness of 10-500 μm, and has a folding endurance of 10-2,000 times as measured by an MIT tester.

Description

Anti-adhesion film and method for producing the same

[0001] The present invention relates to an anti-adhesion film and a method for producing the same.

[0002] At the time of surgery, in order to prevent adhesion between an organ at the surgical site and other organs when the wound of the organ is healing, an anti-adhesion film that is directly attached to the organ or the like and used is known.

[0003] As the anti-adhesion film, a film made of a bioabsorbable polymer compound is used. For example, in Patent Documents 1 to 4, a film made of a cross-linked product of hyaluronic acid (hereinafter sometimes abbreviated as "HA") and carboxymethyl cellulose (hereinafter sometimes abbreviated as "CMC") is described, and in Patent Document 2, a film made of gelatin is described.

[0004] As described in Patent Documents 1 and 2, the anti-adhesion film is produced by forming a gel containing a bioabsorbable polymer compound into a film and drying it to form a film. Further, in Patent Documents 3 and 4, it is described that in order to increase the strength of the anti-adhesion film, the film may be heat-treated or heat-pressed after drying. Specifically, Patent Document 3 describes heat treatment at 95°C to 105°C for 6 hours to 24 hours, and Patent Document 4 describes that a film that swells but is not easily broken can be obtained by heat-pressing at 150°C for 600 seconds.

[0005] Japanese Patent Application Laid-Open No. Hei 05-508161 International Publication No. WO 2013 / 018864 Japanese Patent Application Laid-Open No. 2012-205928 Japanese Patent Application Laid-Open No. 2020-139117

[0006] Further, when the anti-adhesion film is inserted in a laparoscopic surgery, it is bent or rolled into a cylindrical shape and held by forceps, and after being inserted into the body, it is unfolded (returned to its original shape) and attached to the organ. Therefore, the anti-adhesion film is required to be difficult to crack when bent or rolled. However, as a result of investigations by the present inventors, the anti-adhesion film heat-treated by the methods described in Patent Documents 3 and 4 is likely to crack when bent or rolled during insertion into the body.

[0007] This invention has been made in view of the above problems, and aims to provide an adhesion-preventing film that is less likely to crack when bent or rolled up, and a method for manufacturing the same.

[0008] An embodiment of the present invention for solving the above problems relates to the following adhesion prevention film [1] to [9] and a method for manufacturing the same. [1] An adhesion prevention film containing a bioabsorbable polymer compound, having a thickness of 10 μm or more and 500 μm or less, and having a fold resistance of 10 to 2000 times as measured by an MIT tester under measurement conditions of a temperature of 25°C and a relative humidity of 50%. [2] The adhesion prevention film according to [1], wherein the tensile strength measured at a temperature of 25°C and a relative humidity of 60% is 20.0 MPa or more and 150.0 MPa or less. [3] The adhesion prevention film according to any one of [1] to [2], wherein the loop stiffness is 0.030 N / 10 mm or more and 0.600 N / 10 mm or less. [4] The adhesion strength to a simulated organ after being in close contact with a water-soaked simulated organ for 15 minutes at 25°C is 0.650 N / cm ２ 1.500N / cm or more ２ The anti-adhesion film described in any of the following [1] to [3]. [5] Thermogravimetric analysis (TGA) is performed by heating the film from 30°C to 400°C at a heating rate of 10°C / min in a nitrogen atmosphere, and the mass of the film against the heating temperature is plotted at 0.5°C intervals to obtain a thermogravimetric (TG) curve, and the temperature T ｎ The mass in W ｎ Toshi, T ｎ＋１ Weight change with respect to °C (W) ｎ＋１ -W ｎ The anti-adhesion film according to any one of [1] to [4], wherein the differential curve of the thermogravimetric curve obtained by plotting the curve has peaks with peak tops at least 215°C to 230°C and 270°C to 310°C, respectively. [6] Using a sample solution prepared by adding the film and 1.2 mg of pyrazine to 1.1 mL of deuterated trifluoroacetic acid, the resonance peak of the standard substance pyrazine is normalized to 9.45 ppm. １The film was measured by 1H-NMR. When the integral value of the maximum resonance peak measured in the range of 9.4 to 9.5 ppm is defined as A, and the integral value of the maximum resonance peak measured in the range of 5.0 to 5.2 ppm is defined as B, the adhesion prevention film according to any one of [1] to [5], wherein B / A is 0.10 or less. [7] A step of forming a gel containing a bioabsorbable polymer compound into a film, and drying the formed gel in an atmosphere at 10°C or higher and 70°C or lower and a relative humidity of 25% RH or higher and 95% RH or lower to form a film, and pressing the dried film at a temperature of 25°C or higher and 130°C or lower for a pressing time of 1 minute or longer and 1300 minutes or shorter, the method for producing an adhesion prevention film according to any one of [1] to [6]. [8] The method for producing an adhesion prevention film according to [7], wherein the bioabsorbable polymer compound contains hyaluronic acid or a salt thereof and carboxymethyl cellulose or a salt thereof.

[0009] According to the present invention, there are provided an adhesion prevention film that is difficult to crack when bent or rolled, and a method for producing the same.

[0010] 1. Adhesion prevention film One embodiment of the present invention relates to an adhesion prevention film that is directly attached to an organ or the like for preventing adhesion between the organ at the surgical site and other organs when the wound of the organ at the surgical site recovers during surgery.

[0011] 1-1. Characteristics of the adhesion prevention film The adhesion prevention film has a fold resistance number measured by an MIT tester of 10 or more and 2000 or less, preferably 50 or more and 2000 or less, more preferably 80 or more and 2000 or less, still more preferably 80 or more and 1500 or less, particularly preferably 90 or more and 1100 or less, and most preferably 100 or more and 1100 or less. The larger the fold resistance number, the higher the fold resistance, indicating that the adhesion prevention film is difficult to crack when bent or rolled.

[0012] The number of folds the film can withstand is measured according to the method specified in JIS P 8115:2001. Specifically, a 10 mm x 110 mm sample of the anti-adhesion film is cut to include the intersection of the diagonals of the film. An MIT folding resistance tester (MIT-D, manufactured by Toyo Seiki Seisakusho Co., Ltd.) is used to fix both ends of the sample with a spring load clamp and a bending clamp, and the number of back-and-forth folds until breakage is measured. However, if it is difficult to cut the film to the above dimensions, the dimensions of the sample can be adjusted as appropriate. The measurement conditions are: temperature 25°C, relative humidity 50% RH, bending speed 175 times per minute, bending angle 90°, load 2.5 N, and the bending surface of the bending clamp has a radius of curvature of 0.38 mm and an opening width of 0.5 mm. Measurements are performed with n=3, and the average value of the obtained values ​​is taken as the number of folds the anti-adhesion film can withstand.

[0013] The adhesion prevention film preferably has a swelling rate of 110% to 500% by volume when immersed in pH 6.0 phosphate buffer for 15 minutes, more preferably 170% to 450%, even more preferably 200% to 420%, particularly preferably 200% to 320%, and most preferably 200% to 260%. When the swelling rate is 500% by volume or less, it is less likely to compress other organs when applied to the surface of an organ.

[0014] The adhesion prevention film swells appropriately when wet. Therefore, when the adhesion prevention film is applied to organs after surgery, it swells due to the body's moisture and conforms to the surface shape of the organ. This allows the adhesion prevention film to adhere tightly to the organ surface without gaps. The higher the swelling rate, the easier it is for the film to deform to conform to the shape of the organ, making it less likely for gaps to form between the film and the organ. By adhering tightly to the organ without gaps, it prevents exudate from accumulating in the gap between the adhesion prevention film and the organ, and prevents the exudate from flowing out, thereby suppressing the development of adhesions caused by inflammation triggered by exudate.

[0015] The swelling ratio is measured by the following method. For a square-shaped adhesion prevention film, the film is divided into four divided areas by drawing a line perpendicular to the opposite side from the center of each side. A sample piece is a rectangle of 10 mm × 10 mm cut so as to include the central part of each divided area. Here, the central part of each divided area refers to an area including the intersection point of the diagonals of the quadrilateral defining the divided area. However, when it is difficult to cut out the sample piece by the above method, the cutting method can be appropriately adjusted according to the film dimensions. The rectangular adhesion prevention film (sample piece) for swelling ratio measurement is photographed, the lengths of the four sides are measured from the photographed image, and the arithmetic mean value of the lengths of the four sides is defined as the side length L of the adhesion prevention film before swelling. ０ Let it be.

[0016] Dissolve 6.24 g of sodium dihydrogen phosphate dihydrate and 14.33 g of disodium hydrogen phosphate dodecahydrate in 0.2 L of ultrapure water respectively to prepare a 0.2 M solution, mix the respective solutions, and prepare a phosphate buffer solution with a pH of 6.0. Put 5 mL of the obtained phosphate buffer solution into a 10 mL vial, immerse the rectangular adhesion prevention film for swelling ratio measurement in the phosphate buffer solution for 15 minutes, then take out the film from the vial, let it stand at room temperature for 5 seconds and then photograph it, measure the lengths of the four sides from the photographed image, and define the arithmetic mean value of the lengths of the four sides as the side length L of the adhesion prevention film after swelling. Ｓ Let it be. When the outline of the taken-out film cannot be confirmed, it is preferable to photograph after removing the phosphate buffer solution with a tech wipe so that the outline of the film can be confirmed. The ratio of the cubes of the side lengths of the adhesion prevention film before and after swelling (L Ｓ ３ / L ０ ３ ) is defined as the swelling ratio of the adhesion prevention film and expressed as a percentage (volume %) based on volume. The measurement is carried out with n = 3, and the average value of the measured values obtained respectively is defined as the swelling ratio.

[0017] The adhesion prevention film preferably has a tensile strength of 20.0 MPa to 150.0 MPa, more preferably 40.0 MPa to 150.0 MPa, even more preferably 48.0 MPa to 150.0 MPa, particularly preferably 50.0 MPa to 130.0 MPa, very preferably 60.0 MPa to 130.0 MPa, and most preferably 65.0 MPa to 130.0 MPa, measured at a temperature of 25°C and a relative humidity of 60%. The higher the tensile strength, the less likely the film is to be damaged during handling. In addition, if the tensile strength of the film before swelling is high, the tensile strength of the film after swelling can be increased.

[0018] The tensile strength is measured by the following method. The rectangular anti-adhesion film is divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A sample is prepared by cutting the film into strips with a long side of 40 mm and a short side of 10 mm, so as to include the center of each section. Here, the center of each section refers to the area that includes the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut the sample using the above method, the cutting method can be adjusted as appropriate according to the dimensions of the film. The thickness of the sample is measured at the center using a micrometer and this is taken as the sample thickness. The measurement room temperature was set to 25°C and the relative humidity to 60% RH. Using a creep meter (Yamaden Co., Ltd., RHEONERII RE2-33005B), the sample was fixed so that the distance between the grips was 20 mm, and the sample was pulled at a tensile speed of 0.1 mm / second. The tensile strength (MPa) of the adhesion prevention film was defined as the maximum load stress value measured until the adhesion prevention film broke, divided by the cross-sectional area of ​​the sample. The measurement was performed with n=4, and the average of the measured values ​​obtained for each sample was defined as the tensile strength.

[0019] The anti-adhesion film preferably has a loop stiffness of 0.030 N / 10 mm or more and 0.600 N / 10 mm or less, more preferably 0.070 N / 10 mm or more and 0.500 N / 10 mm or less, even more preferably 0.100 N / 10 mm or more and 0.400 N / 10 mm or less, particularly preferably 0.115 N / 10 mm or more and 0.3500 N / 10 mm or less, and most preferably 0.155 N / 10 mm or more and 0.300 N / 10 mm or less. Loop stiffness is the resistance to bending and is an indicator of so-called rigidity. When the loop stiffness of the anti-adhesion film is 0.030 N / 10 mm or more, the film does not sag and easily maintains its shape even when grasped with forceps or the like for insertion into the body. Furthermore, after inserting the bent or rolled anti-adhesion film into the body, it easily returns to its original shape and has excellent unfoldability. When the loop stiffness is 0.600 N / 10 mm or less, the film's flexibility is ensured, making it easy to bend or roll even with small forces. A balance between flexibility and unfoldability is crucial for improving the handling of anti-adhesion films.

[0020] Loop stiffness is measured by the following method: Divide the rectangular anti-adhesion film into four sections by drawing perpendicular lines from the center of each side to the opposite side. Cut a 10 mm x 40 mm rectangle so that it includes the center of each section to create the sample piece. Here, the center of each section refers to the area including the intersection of the diagonals of the rectangle that defines that section. However, if it is difficult to cut the sample piece using the above method, the cutting method can be adjusted as appropriate to the dimensions of the film. The ends of the rectangular film (sample piece) are joined together in the longitudinal direction and bonded together with double-sided tape for a width of 5 mm from the ends to create a loop shape (teardrop shape) with a loop length of 30 mm to prepare the measurement sample. Measurements are taken at a temperature of 25°C and a relative humidity of approximately 60% RH. A portion (5 mm) attached with double-sided tape is clamped in the chuck of a creep meter (Yamaden Co., Ltd. RHEONERII RE2-33005B). To compress the loop of the sample, the upper indenter (φ30 mm) attached to the creep meter is moved at a speed of 0.5 mm / second in the direction of the loop. The load (N) when compressed 5 mm from the contact point is recorded and defined as the loop stiffness value (N / 10 mm). Measurements are taken with n=4, and the average of the measured values ​​obtained for each measurement is defined as the loop stiffness value.

[0021] The adhesion prevention film was applied to a water-soaked simulated organ, and after 15 minutes, the adhesion strength to the simulated organ was 0.650 N / cm². ２ 1.500N / cm or more ２ The following is preferred: 0.700 N / cm ２ 1.500N / cm or more ２ The following is more preferable: 0.720 N / cm ２ 1.500N / cm or more ２ The following is even more preferable: 0.740 N / cm ２ 1.125N / cm or more ２ The following is particularly preferred: 0.750 N / cm ２ 1.125N / cm or more ２ The following is the most preferable.

[0022] The higher the adhesion strength, the less likely the adhesion prevention film is to peel off the attached organ, and the longer the adhesion prevention effect can be maintained.

[0023] The adhesion strength is measured by the following method. The rectangular anti-adhesion film is divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A measurement sample is prepared by cutting the film into strips with a long side of 50 mm and a short side of 10 mm, so as to include the center of each section. Here, the center of each section refers to the area that includes the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut the sample using the above method, the cutting method can be adjusted as appropriate according to the dimensions of the film. The measurement sample is reinforced by applying mending tape (3M Japan, part number 810-1-18) to the side of the measurement sample opposite to the surface on which the adhesion strength is measured. Next, 0.1 mL of pure water is uniformly sprayed onto a 40 mm x 20 mm area of ​​the adhesion strength measurement surface of the simulated organ (AS ONE Corporation, silicone rubber sheet (3 mm thick), product number 6-611-05). Then, the adhesion prevention film for adhesion strength measurement and the simulated organ are brought into contact for 15 minutes at 25°C, with a 40 mm long side and a 10 mm short side area, so that a 10 mm area of ​​non-adhesion remains on one side of the long side of the sample to be measured. After that, the adhesion strength is measured using a creep meter (Yamaden Co., Ltd., RHEONERII RE2-33005B). In a sample in which the adhesion prevention film and the simulated organ are in close contact, the areas not in contact with the other sample are fixed to a creep meter, and the adhesion prevention film is pulled along its longitudinal direction at 0.05 mm / second. The maximum load value (N) measured during the time until the adhesion prevention film peels off is recorded as the area in which the adhesion prevention film and the simulated organ were in close contact (40 mm × 10 mm = 4.0 cm²). ２ Divide by ) to obtain the adhesion strength (N / cm ２ The following is determined: The measurement is performed with n=4, and the average of the measured values ​​obtained for each measurement is taken as the adhesion strength.

[0024] The adhesion prevention film preferably has peaks with peak tops at least 218°C to 230°C and 270°C to 310°C, respectively, in the differential curve obtained by plotting the mass change (Wn+1-Wn) with respect to Tn+1°C, where Wn is the mass at temperature Tn, in the thermogravimetric curve obtained by thermogravimetric analysis (TGA) in a nitrogen atmosphere. The peak at 218°C to 230°C (hereinafter simply referred to as "TGA differential peak 1," and the temperature of the peak top of TGA differential peak 1 is also referred to as "TGA differential peak temperature 1") is a peak originating from HA, and the peak at 270°C to 310°C (hereinafter simply referred to as "TGA differential peak 2," and the temperature of the peak top of TGA differential peak 2 is also referred to as "TGA differential peak temperature 2") is a peak originating from carboxyl CMC.

[0025] The TGA differential peak temperature 1 is between 215°C and 230°C, preferably between 221°C and 230°C, and more preferably between 223°C and 230°C. The TGA differential peak temperature 2 is between 270°C and 310°C, preferably between 280°C and 310°C, more preferably between 290°C and 310°C, even more preferably between 295°C and 310°C, and particularly preferably between 297°C and 305°C. When strong crosslinking is formed during the manufacturing of the adhesion prevention film, these peaks, especially TGA differential peak 2, shift to the high-temperature side. When this strong crosslinking structure is formed, it can absorb water and swell sufficiently while reducing the permeability to cells and other materials.

[0026] Thermogravimetric analysis (TGA) of the film is performed using a simultaneous thermal analyzer (Mettler Toledo TGA / DSC2). A 10 mg sample cut from the anti-adhesion film is placed in an alumina pan and heated from 30°C to 400°C at a rate of 10°C / min under a nitrogen stream, and the mass of the sample as a function of the heating temperature is measured. The sample is taken by dividing the rectangular anti-adhesion film into four sections by drawing perpendicular lines from the center of each side to the opposite side, and taking a sample that includes the center of each section. Here, the center of each section refers to the region including the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut the sample using the above method, the sampling method can be appropriately adjusted according to the dimensions of the film. A thermogravimetric (TG) curve is obtained by plotting the mass of the film as a function of the heating temperature at 0.5°C intervals, and the temperature T ｎ The mass in W ｎ Toshi, T ｎ＋１ (W) ｎ＋１ -W ｎ The graph is plotted to obtain a thermogravimetric differential curve. Measurements are performed with n=3, and the average of the TGA differential peak temperature 1 and TGA differential peak temperature 2 obtained for each measurement is taken as the measured value.

[0027] Adhesion prevention films are preferable because they can suppress adhesion formation by reducing the permeability of cells and other tissues, thereby preventing cells involved in the adhesion formation process from moving across the film. Therefore, it is preferable to maintain a state of low cell permeability, i.e., maintain barrier properties, after the adhesion prevention film has been attached to an organ. As described above, adhesion prevention films with a strong cross-linked structure can extend the time for which barrier properties are maintained (barrier time).

[0028] The adhesion prevention film preferably has a barrier time of 25 hours to 200 hours, more preferably 25 hours to 150 hours, even more preferably 30 hours to 120 hours, particularly preferably 40 hours to 120 hours, and most preferably 50 hours to 120 hours.

[0029] The barrier time is measured by the following method. The rectangular anti-adhesion film is divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A sample piece is prepared by cutting the film into a 13 mm x 13 mm rectangle that includes the center of each section. Here, the center of each section refers to the area that includes the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut out the sample piece using the above method, the cutting method can be adjusted as appropriate according to the dimensions of the film. The film on the bottom of the 6-well plate cell culture insert (hereinafter sometimes abbreviated as "CCI") is peeled off. A nylon mesh with a mesh size of 108 μm (manufactured by AS ONE, part number 3-3069-15) is attached with adhesive to the opening on the bottom created by peeling off the bottom film, and then the sample piece is placed on the nylon mesh so that it is at the center of the opening. Next, cut a silicone rubber sheet (manufactured by AS ONE, product number 6-611-04, 2 mm thick) into a disc shape with a diameter of 25 mm, make a hole with a diameter of 10 mm in the center of the disc, and place the silicone rubber sheet on top of the sample piece while firmly pressing it with tweezers to ensure there are no gaps.

[0030] 6.24 g of sodium dihydrogen phosphate dihydrate and 14.33 g of disodium hydrogen phosphate dodecahydrate are dissolved in 0.2 L of ultrapure water to prepare 0.2 M solutions. Then, the two solutions are mixed to a pH of 8.0 to prepare a 0.2 M phosphate buffer solution. 1 g of blue dextran (Sigma-Aldrich, weight-average molecular weight 500,000) is dissolved in 100 mL of the 0.2 M phosphate buffer solution to prepare the test solution.

[0031] The CCI containing the sample piece is placed in a 20 mL mini-cup (manufactured by Maruemu Co., Ltd.) containing 15 mL of 0.2 M phosphate buffer solution. After 20 seconds, 200 μL of the test solution is added to the CCI. The opening of the CCI is covered with a plastic plate to prevent evaporation of the test solution, and the CCI is maintained at 37°C and a relative humidity of approximately 95% RH. After a predetermined time has elapsed, the 0.2 M phosphate buffer solution in the mini-cup is stirred, and approximately 2 mL of the solution is collected. The absorbance of the collected solution at a wavelength of 620 nm is measured using a UV-Vis spectrophotometer (Shimadzu Corporation, UV-2450). ｔ The absorbance at 620 nm can be used as an indicator of the concentration of blue dextran. In addition, the absorbance of the 0.2 M phosphate buffer solution is measured in the same manner and absorbance I ０ The more the barrier properties of the adhesion prevention film decrease, the lower I ｔ The tendency is for I to increase ｔ -I ０ The time at which the value becomes 0.03 is defined as the barrier time of the adhesion prevention film. Measurements are taken with n=3, and the average of the times obtained for each measurement is defined as the barrier time.

[0032] The anti-adhesion film was normalized using a sample solution prepared by adding 1.1 mL of deuterated trifluoroacetic acid, a 10 mm x 10 mm piece of the film, and 1.2 mg of pyrazine, so that the resonance peak of the standard substance, pyrazine, was 9.45 ppm. １ When the film is measured using H-NMR, and the integral value of the maximum resonance peak measured in the range of 9.4 to 9.5 ppm is taken as A, and the integral value of the maximum resonance peak measured in the range of 5.0 to 5.2 ppm is taken as B, it is preferable that B / A is 0.10 or less. １The 1H-NMR spectrum is measured using a nuclear magnetic resonance spectrometer with deuterated trifluoroacetic acid (sometimes abbreviated as "deuterated TFA") as the solvent. The measurement solution is prepared by the following procedure: Divide the rectangular anti-adhesion film into four sections by drawing perpendicular lines from the center of each side to the opposite side. Cut a 10 mm x 10 mm rectangle so that the center of each section is included to obtain the sample piece. Here, the center of each section refers to the area including the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut the sample piece using the above method, the cutting method can be appropriately adjusted according to the dimensions of the film. Place the sample piece in a 5 mL vial, add 1.0 mL of deuterated TFA, and let it stand for 1 hour. Furthermore, 12 mg of pyrazine is placed in a 5 mL vial of a different capacity than the vial mentioned above, and 1.0 mL of heavy TFA is added to the vial. The mixture is then mixed for several seconds using a vortex mixer to prepare a pyrazine solution. 0.1 mL of the obtained pyrazine solution is added to the vial containing the sample piece and mixed for several seconds using a vortex mixer to prepare the measurement solution. The integral value A is set to an integral range of 9.4 to 9.5 ppm, and the integral value B is set to an integral range of 5.0 to 5.2 ppm, and the peak area (integral value) is calculated. The measurement is performed with n=3, and the average value of B / A obtained for each measurement is taken as the measured value. The anti-adhesion film is standardized so that the pyrazine resonance peak is 9.45 ppm. １ The film is measured using 1H-NMR, and the maximum resonance peak intensity measured in the range of 2.5 to 4.0 ppm is defined as I ａ The maximum resonance peak intensity measured in the range of 5.0 to 5.2 ppm is defined as I ｂ In that case, I ｂ / I ａ It is preferable that the value is 0.20 or less. １ The 1H-NMR spectrum was measured using the same method as for determining the B / A ratio, and the measurement was performed with n=3, and the I ratio obtained for each was... ｂ / I ａ The average value will be used as the measured value.

[0033] The resonance peaks in the range of 9.4 to 9.5 ppm are resonance peaks derived from pyrazine, the resonance peaks in the range of 5.0 to 5.2 ppm are peaks indicating polyglycolic acid (PGA), and the resonance peaks in the range of 2.5 to 4.0 ppm are resonance peaks derived from bioabsorbable polymer compounds. Adding PGA to the anti-adhesion film increases the adhesion of the anti-adhesion film to organs, but on the other hand, the anti-adhesion film tends to become more brittle. In contrast, anti-adhesion films with a B / A ratio of 0.10 or less (i.e., no PGA or only a small amount of PGA) are less likely to break when folded or rolled, resulting in better workability during insertion into the body and deployment. A B / A ratio of 0.10 or less is preferable, and 0.05 or less is more preferable. The lower limit of B / A is not limited, but it can be 0.00. ｂ / I ａ It is preferably 0.20 or less, and more preferably 0.10 or less. ｂ / I ａ The lower limit is not restricted, but it can be set to 0.00.

[0034] The adhesion prevention film has a thickness of 10 μm to 500 μm, preferably 10 μm to 100 μm, more preferably 20 μm to 75 μm, and even more preferably 30 μm to 50 μm. The greater the thickness, the stronger the adhesion prevention film is and the less likely it is to decompose in the body, thus providing adhesion prevention effects for a longer period of time. The smaller the thickness, the easier it is to fold or roll the adhesion prevention film and the easier it is to handle by holding it with forceps or the like.

[0035] The thickness of the anti-adhesion film is measured by the following method. Divide the rectangular anti-adhesion film into four sections by drawing perpendicular lines from the center of each side to the opposite side. Cut a 50 mm x 50 mm rectangle so that the center of each section is included, and use this as the sample. Here, the center of each section refers to the area that includes the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut the sample using the above method, the cutting method can be adjusted as appropriate according to the dimensions of the film. After drying the sample at 80°C for 1 hour, cool it in a desiccator and measure its mass. Divide the mass by the area of ​​the film, and then divide it again by the density of the film to obtain the value which is the thickness of the anti-adhesion film. The measurement is performed with n=3, and the average of the values ​​obtained is taken as the thickness.

[0036] The density of the anti-adhesion film is measured in a measurement room maintained at 25°C using the following method. The rectangular anti-adhesion film is divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A 50 mm x 50 mm rectangle is cut into the film so as to include the center of each section, and this rectangle is used as the sample. Here, the center of each section refers to the area including the intersection of the diagonals of the rectangle defining that section. However, if it is difficult to cut the sample using the above method, the cutting method can be appropriately adjusted according to the dimensions of the film. The sample is shredded so that it fits into a 5 mL volumetric flask, dried in air at atmospheric pressure and 80°C for 1 hour, then cooled in a desiccator, and the shredded sample is maintained at 25°C. As a displacement solution for density measurement, corn oil with a density in the range of 0.91 to 0.92 g / mL at 25°C and a 5 mL volumetric flask were stored in a room kept at 25°C beforehand. The temperature of the corn oil and the volumetric flask was maintained at 25°C and used for density measurement. The mass of the volumetric flask was measured and recorded as Wa. Next, the corn oil was added to the mark in the volumetric flask, and after degassing at 10 kPa for 5 minutes, if the bubbles were removed and the liquid level fell below the mark, more corn oil kept at 25°C was added up to the mark, and the mass of the volumetric flask containing the corn oil was measured and recorded as Wd. After the corn oil was drained from the volumetric flask, it was washed and dried, and the volumetric flask was kept at 25°C. The shredded sample was placed in the volumetric flask, and the mass of the volumetric flask containing the adhesion prevention film was measured and recorded as Wb. The corn oil, kept at 25°C, is poured into the volumetric flask containing the shredded sample up to the mark. After degassing at 10 kPa for 10 minutes, if the bubbles have dissipated and the liquid level has fallen below the mark, more corn oil, also kept at 25°C, is poured up to the mark. The mass of the corn oil and the volumetric flask containing the shredded sample is measured and recorded as Wc. The density of the corn oil is determined in accordance with the method for measuring density and specific gravity using a specific gravity bottle as specified in JIS Z 8804:2012. The density of the anti-adhesion film can be determined using formula 1. Measurements are performed with n=3, and the average value obtained is taken as the density of the anti-adhesion film.

[0037]

[0038] 1-2. The material adhesion prevention film is made of a bioabsorbable polymer compound. A bioabsorbable polymer compound is a material that does not lose more than 40% of its mass even when immersed in water at 37°C for 48 hours, but loses more than 40% of its mass when immersed in a 0.2M phosphate buffer (PB) with a pH of 8.0, obtained by mixing a 0.2M sodium dihydrogen phosphate aqueous solution with a 0.2M sodium dihydrogen phosphate aqueous solution to a pH of 8.0, at a liquid temperature of 37°C for 48 hours. Medical films containing bioabsorbable polymer compounds decompose and disappear in the body after a predetermined time has elapsed since being attached to an organ.

[0039] 1-2-1. Bioabsorbable Polymer Compounds Bioabsorbable polymer compounds are, for example, crosslinked polymer compounds (hereinafter also referred to as "crosslinked polymer compounds"). These crosslinked polymer compounds are formed by physically or chemically crosslinking the same or different types of polymer compounds, and are typically gel-like polymer compounds. Crosslinked polymer compounds using HA and CMC have excellent safety.

[0040] Crosslinked polymer compounds can be, for example, crosslinked anionic polymer compounds. Anionic polymer compounds may be polymer compounds having a repeating structure with anionic groups, or polymer compounds obtained by chemically modifying a polymer compound with anionic substituents. The anionic groups can be carboxyl groups, hydroxyl groups, sulfo groups, etc. The anionic groups may partially form salts with alkali metals such as sodium and potassium, or alkaline earth metals such as calcium or magnesium.

[0041] The anionic polymer compound may be a polysaccharide, a protein, or a synthetic polymer. Of these, polysaccharides and proteins are preferred. Only one type of anionic polymer compound may be used, or two or more types may be used.

[0042] The anionic polymer compounds, which are sugars, may be natural sugars such as pullulan, alginic acid, hyaluronic acid (HA), chondroitinic acid, dextranic acid, and pectin, or they may be sugars having anionic groups introduced by modification, such as carboxymethyl amylose, carboxymethylcellulose (CMC), carboxymethyl dextran, carboxymethyl starch, sulfated cellulose, and sulfated dextran. Of these, alginic acid, hyaluronic acid, carboxymethyl amylose, and carboxymethylcellulose are preferred because they are easy to handle, and hyaluronic acid and carboxymethylcellulose are more preferred.

[0043] Examples of proteins, which are anionic polymer compounds, include gelatin, collagen, albumin, fibrin, and chemically modified versions thereof. Proteins may also be polymers of amino acids having anionic groups (polyamino acids), such as polyglutamic acid and polyaspartic acid. Of these, acid-treated gelatin having carboxyl groups produced by the hydrolysis of acid amides is preferred.

[0044] Crosslinking of polymer compounds may be physical crosslinking, which is formed by introducing cationic substituents into an anionic polymer compound, or chemical crosslinking, which is formed by reacting polymer compounds directly or via other molecules. Crosslinking of polymer compounds can be obtained by subjecting the polymer compound to crosslinking treatments such as ultraviolet treatment, heat treatment, and crosslinking agent treatment. Of these, crosslinking agent treatment is preferred.

[0045] Examples of crosslinking agents used in crosslinking treatment include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and N,cyclohexyl-N'-(2-morpholinoethyl)carbodiimidemethyl-p-toluenesulfonic acid. Treatment with these crosslinking agents allows for chemical crosslinking of polymer compounds and the introduction of cationic groups into anionic polymer compounds. Furthermore, intermolecular interactions between the anionic group of one molecule and the cationic group of another molecule allow for physical crosslinking of the polymer compounds. Of these, EDC is preferred due to its ease of handling.

[0046] Crosslinking with a crosslinking agent can be carried out by dissolving the polymer compound in water or an aqueous medium, adding the crosslinking agent, and stirring. The state of the water or aqueous medium at this time should be adjusted according to the type of crosslinking agent. For example, when using EDC as a crosslinking agent, it is preferable to add an acid such as 0.1 M hydrochloric acid as appropriate to lower the pH of the reaction system (for example, pH 4.0 to 5.5) and dissociate the anionic groups of the anionic polymer compound.

[0047] Crosslinking may occur between multiple different types of polymers. This crosslinking may be chemical crosslinking, which is achieved by reacting these polymers with each other, or it may be physical crosslinking, which is achieved by enhancing intermolecular interactions with a crosslinking agent. For example, from a safety standpoint, a crosslinked polymer compound can be made by combining HA and CMC. That is, it is particularly preferable that the bioabsorbable polymer compound contains constituent parts derived from HA and constituent parts derived from CMC. The ratio of constituent parts derived from HA and constituent parts derived from CMC can be controlled by the content of HA relative to the total mass of HA and CMC used in the reaction. The content of HA relative to the total mass of HA and CMC is preferably 50% by mass or more and 90% by mass or less, more preferably 60% by mass or more and 90% by mass or less, even more preferably 60% by mass or more and 80% by mass or less, and particularly preferably 60% by mass or more and 70% by mass or less.

[0048] 1-2-2. The PGA dispersed particle adhesion prevention film may contain a PGA dispersed particle, which is a particle or aggregate of a polymer mainly composed of constituent units derived from glycolic acid. The PGA dispersed particle is a particle or aggregate of a polymer mainly composed of PGA (hereinafter also simply referred to as "PGA polymer"). The adhesion prevention film may contain a PGA dispersed particle, which is a particle or aggregate of a polymer mainly composed of constituent units derived from glycolic acid (hereinafter also simply referred to as "PGA polymer"). When manufacturing the above-mentioned adhesion prevention film containing the bioabsorbable polymer compound and the PGA dispersed particle, the bioabsorbable polymer compound and the PGA polymer particles (PGA particles) are compounded and then formed into a film (film formation). At this time, the PGA particles may aggregate to form aggregates. The adhesion prevention film may contain only PGA particles, or only aggregates of PGA particles, or both.

[0049] When the PGA dispersed phase comes into contact with water, such as when the adhesion prevention film is attached to an organ, it gradually releases acid through hydrolysis. This released acid suppresses the breakdown of bioabsorbable materials, extending the period during which the film can maintain its structure in the body.

[0050] The PGA polymer preferably has a number average molecular weight of 3,000 to 150,000, more preferably 10,000 to 100,000, even more preferably 15,000 to 80,000, and particularly preferably 15,000 to 50,000. By making the number average molecular weight smaller, the sustained release ability of the acid can be increased, allowing the shape of the adhesion prevention film after it has been attached to the organ to be maintained for a longer period of time. Furthermore, by making the number average molecular weight larger, the dispersibility of the PGA particles can be improved.

[0051] The number-average molecular weight of the PGA polymer can be determined by measuring the number-average molecular weight of the PGA polymer in PGA particles separated from the anti-adhesion film in accordance with ISO 16014-1:2012. Specifically, gel permeation chromatography (GPC) (Resonac Corporation, Shodex GPC-104, detector: RI, column: HFIP-606M x 2), with 5 mM CF as the solvent. ３ A solution of COONa dissolved in hexafluoropropanol (HFIP) is used, and polymethyl methacrylate (PMMA) is used as the standard substance.

[0052] 1-2-3. The anti-adhesion film for other materials may also contain lubricants, emulsifiers, colorants, antioxidants, weathering agents, heat stabilizers, nucleating agents, ultraviolet absorbers, colorants, antibacterial agents, etc. The content of these components is preferably 0% to 20% by mass, more preferably 0% to 10% by mass, and even more preferably 0% to 5% by mass, based on the total mass of the anti-adhesion film.

[0053] 2. Method for manufacturing an adhesion-preventing film An adhesion-preventing film can be manufactured by crosslinking a bioabsorbable polymer compound to produce a gel, drying the gel into a film, drying the formed gel while heating it as needed to form a film, pressing it while heating it as needed, and then cooling it as needed.

[0054] As described in Patent Documents 3 and 4, the strength of the film can be increased by heat pressing after film formation and drying. Furthermore, by performing heat pressing, a film with excellent smoothness can be obtained, thus improving the film's adhesion to organs. However, increasing the strength through heat pressing makes the film more prone to cracking. Therefore, in this embodiment, the temperature and time of heat pressing are adjusted to achieve both film adhesion and fold resistance.

[0055] Furthermore, the formed gel film is dried under conditions where the relative humidity is between 25% RH and 95% RH. Compared to drying under conditions close to 15%, such as air drying (Patent Document 3, etc.), drying under higher humidity conditions can improve the bending resistance of the adhesion prevention film.

[0056] Specifically, in this embodiment, the formed gel is dried in an atmosphere with a relative humidity of 25% RH or higher and 95% RH or lower to form a film. By increasing the humidity during drying, the aggregation of molecular chains that occurs during drying is moderately weakened, thereby improving the bending resistance of the adhesion-preventing film.

[0057] Then, the dried film is pressed at a temperature of 25°C to 130°C for a pressurizing time of 1 minute to 1300 minutes. By controlling the thermal energy applied to the film under the above pressing conditions, excessive crosslinking can be suppressed. Excessive crosslinking leads to molecular severance when the film is stretched or bent, reducing its ability to follow deformation. By suppressing excessive crosslinking, the reduction in the film's ability to follow deformation can be suppressed, and the bending resistance of the adhesion prevention film can be improved. Furthermore, by shortening the pressing time, the hardening and thermal decomposition of the film caused by an excessive increase in crosslinking points can be prevented, thereby improving the bending resistance of the adhesion prevention film.

[0058] 2-1. Gel Preparation First, a bioabsorbable polymer compound (such as the anionic polymer compound mentioned above) is crosslinked in solution to prepare a gel containing the crosslinked polymer compound.

[0059] The anionic polymer compound is not particularly limited; any of the anionic polymer compounds described above may be used.

[0060] When HA is used as the anionic polymer compound, the viscosity-average molecular weight of HA is preferably 1,000,000 to 3,000,000, more preferably 1,000,000 to 2,800,000, and even more preferably 1,500,000 to 2,500,000. The lower the viscosity-average molecular weight, the higher the swelling rate of the adhesion prevention film can be. This is thought to be because crosslinking is less likely to occur when the viscosity-average molecular weight is low.

[0061] The viscosity-average molecular weight of HA shall be the value obtained by the following formula. However, η shall be the intrinsic viscosity obtained from the viscosity measurement method shown in Formula 2 below.

[0062]

[0063] Precisely measure the amount of sodium HA dissolved in 100 mL of 0.2 mol / L sodium chloride solution such that the flow time of the solution is 2.0 to 2.4 times that of the 0.2 mol / L sodium chloride solution alone. Dissolve this amount in 100 mL of 0.2 mol / L sodium chloride solution to make 100 mL of sample solution (1). Accurately measure 16 mL, 12 mL, and 8 mL of sample solution (1), and add 0.2 mol / L sodium chloride solution to each to make 20 mL. These are sample solutions (2), (3), and (4). For sample solutions (1) to (4), test them using an Ubbelohde viscometer with a flow time of 200 to 300 seconds for 0.2 mol / L sodium chloride solution at 30 ± 0.1 °C according to the first method of viscosity measurement in the general tests of the Japanese Pharmacopoeia, and determine the intrinsic viscosity when converted to dry weight.

[0064] Furthermore, when CMC is used as the anionic polymer compound, the degree of etherification (DS) of CMC is preferably 0.3 to 1.5, more preferably 0.5 to 1.0, even more preferably 0.6 to 1.0, and particularly preferably 0.6 to 0.8. Here, the degree of etherification is the proportion of hydroxyl groups in CMC that are replaced by carboxyl groups linked by ether bonds, and a higher degree of etherification indicates a larger proportion of carboxyl groups linked by ether bonds.

[0065] The higher the degree of etherification, the higher the swelling rate of the adhesion prevention film, suggesting a lower degree of crosslinking. The crosslinking reactions here are the reaction between the carboxyl groups of HA and the hydroxyl groups of CMC by the crosslinking agent EDC, and the reaction between the hydroxyl groups of HA and the carboxyl groups of CMC by EDC. Based on the inventors' findings, it is presumed that the reaction between the carboxyl groups of HA and the hydroxyl groups of CMC proceeds predominantly among the above reactions. Therefore, the higher the degree of etherification of CMC (the smaller the proportion of hydroxyl groups that serve as crosslinking sites for CMC and the larger the proportion of carboxyl groups), the higher the swelling rate of the adhesion prevention film tends to be, and the lower the degree of crosslinking tends to be.

[0066] Furthermore, the lower the degree of etherification (the larger the proportion of hydroxyl groups that act as crosslinking points in CMC and the smaller the proportion of carboxyl groups), the higher the stiffness (loop stiffness) of the adhesion prevention film can be. It is thought that increasing the proportion of hydroxyl groups in CMC that act as crosslinking points with the carboxyl groups of HA increases the degree of crosslinking and thus the stiffness. The degree of etherification of CMC shall be the value measured by the pickling flotation method, electrostatic titration method, ash content measurement method, colorimetric method, or colloidal titration method.

[0067] The solvent used to dissolve the anionic polymer compound is not particularly limited, and water or liquids miscible with water can be used. Examples of liquids miscible with water include alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; ketones such as acetone and methyl ethyl ketone; tetrahydrofuran; acetonitrile; dimethyl sulfoxide; and dimethylformamide. One or more of these solvents may be used.

[0068] The crosslinking of anionic polymer compounds can be carried out by methods appropriate to the polymer compound, such as ultraviolet treatment, heat treatment, and crosslinking agent treatment. For example, crosslinking with EDC can be performed by adding EDC to a solution in which the polymer compound is dissolved in water or an aqueous medium while stirring. At this time, it is preferable to add an acid such as hydrochloric acid to make the solution acidic (for example, pH 4.0 to 5.5). After the crosslinking treatment with the crosslinking agent, it is preferable to remove unwanted substances by dialysis or the like.

[0069] When performing the crosslinking agent treatment, the addition rate of EDC (amount of EDC added / (amount of HA sodium added + amount of CMC sodium added) × 100) relative to the amount of polymer compound (in this case, HA sodium and CMC sodium) is preferably 20% to 350% by mass, more preferably 50% to 250% by mass, and even more preferably 100% to 200% by mass. The higher the addition rate of the crosslinking agent, the more the crosslinking progresses, and the longer the barrier properties of the adhesion prevention film can be maintained in vivo. By not making the addition rate of the crosslinking agent excessively high, the progress of side reactions can be suppressed, the uniformity of crosslinking can be improved, and the stiffness (loop stiffness) of the adhesion prevention film can be increased. The improvement in stiffness is thought to be due to the fact that by using an appropriate amount of crosslinking agent, the occurrence of relatively weak physical crosslinks due to side reactions that occur during the crosslinking reaction is suppressed, and the amount of relatively strong chemical crosslinks due to the main reaction is increased. Note that when performing the crosslinking agent treatment, EDC is usually added in the form of a salt such as hydrochloride. In such cases, the addition rate of EDC is calculated based on the mass of salt in the EDC.

[0070] During crosslinking, it is preferable to stir the solution. The stirring blades used for stirring the solution are not particularly limited as long as they can mix liquids together, such as turbine blades, disperser blades, anchor blades, ribbon blades, full-zone blades, paddle blades, and propeller blades. As the crosslinking reaction progresses, the viscosity of the solution increases, so disperser blades capable of stirring high-viscosity solutions are preferred, and full-zone blades are preferred from the viewpoint of uniformly stirring the liquid in the reaction apparatus. An appropriate stirring blade can be selected considering the shape of the reaction vessel, the viscosity of the solution, etc.

[0071] The solution temperature (reaction temperature) during crosslinking is not particularly limited, but is preferably between 4°C and 80°C, more preferably between 10°C and 50°C, and even more preferably between 15°C and 35°C. The higher the reaction temperature, the more crosslinking points can be formed, thereby increasing the tensile strength of the adhesion prevention film. By keeping the reaction temperature relatively low, a decrease in the film's ability to follow deformation due to excessive crosslinking formation can be suppressed, and molecular severance when the film is stretched or bent can be suppressed, thereby increasing the adhesion strength and fold resistance of the adhesion prevention film.

[0072] When preparing an anti-adhesion film containing a PGA dispersed phase, PGA particles can be added to a gel containing a cross-linked polymer compound.

[0073] 2-2. Film deposition can be carried out by known methods such as coating and spreading the gel on a substrate, or injecting the gel into a frame and spreading it. Preferably, the coated or injected gel is made uniform in thickness by spreading it with a blade or by shaking the frame.

[0074] 2-3. Drying After drying, the formed gel is dried to remove the solvent. Drying may be carried out at room temperature or by removing the solvent by heating. Of these, drying at room temperature is preferred in order to suppress deformation of the film due to heating.

[0075] The drying temperature is preferably 10°C to 70°C, more preferably 20°C to 60°C, and even more preferably 20°C to 45°C. The drying humidity (relative humidity RH) is preferably 25% RH to 95% RH, more preferably 40% RH to 95% RH, even more preferably 60% RH to 95% RH, and particularly preferably 80% RH to 95% RH. Increasing the drying humidity improves the bending resistance, suppresses the aggregation of molecular chains during drying, increases the swelling rate of the adhesion prevention film, weakens the aggregation of molecular chains during drying, and increases the loop stiffness of the adhesion prevention film by forming appropriate crosslinks. In addition, increasing the drying humidity slows down the drying rate, resulting in a uniform film without thickness variations, thus increasing the tensile strength of the adhesion prevention film.

[0076] 2-4. The pressing method is not particularly limited as long as it can apply pressure while controlling the temperature, such as with a flat plate press or a roll press. For example, the film peeled from the base material or frame can be sandwiched between pressing members from both sides and then pressed. Pressing makes it easier to maintain the shape of the adhesion prevention film attached to the affected area.

[0077] The pressing temperature is 25°C to 130°C, preferably 30°C to 130°C, more preferably 50°C to 130°C, even more preferably 80°C to 130°C, and particularly preferably 100°C to 130°C. By not setting the pressing temperature too high, the tensile strength of the adhesion prevention film can be increased. The improvement in tensile strength is thought to be because as the temperature increases, the amount of crosslink formation increases, and the force on each crosslink decreases when the film is stretched. On the other hand, if the temperature is too high, an excessive crosslink structure is formed, the flexibility of the molecular chains is lost, and elongation is limited, making it prone to breakage. In addition, the swelling rate when it absorbs moisture is small, and it is difficult for it to conform (deform) to the surface shape of an organ when it is applied to it. By controlling the upper limit temperature during pressing, the decrease in the swelling rate, adhesion strength, bending resistance, and tensile strength of the adhesion prevention film can be suppressed. The improvement in the swelling rate is thought to be due to the suppression of excessive crosslink formation by setting the pressing temperature to an appropriate temperature. The improvements in adhesion strength, flex resistance, and tensile strength are thought to be due to suppressing the reduction in the film's ability to follow deformation caused by excessive crosslinking formation by controlling the pressing temperature to an optimal level, and suppressing molecular severance when the film is stretched or bent.

[0078] The pressing time is between 1 minute and 1300 minutes, preferably between 1 minute and 400 minutes, more preferably between 1 minute and 200 minutes, even more preferably between 1 minute and 120 minutes, particularly preferably between 3 minutes and 120 minutes, very preferably between 5 minutes and 120 minutes, and most preferably between 8 minutes and 120 minutes. The longer the pressing time, the faster the water absorption rate by the film when attached to the organ can be increased, thereby improving the adhesion of the anti-adhesion film. On the other hand, by shortening the pressing time appropriately, the amount of crosslinking can be appropriately adjusted, thereby suppressing a decrease in the stiffness (loop stiffness), bending resistance, and tensile strength of the anti-adhesion film.

[0079] The gauge pressure for the press is preferably 0.001 MPaG to 15.000 MPaG, more preferably 0.001 MPaG to 10.000 MPaG, even more preferably 0.005 MPaG to 8.000 MPaG, particularly preferably 0.010 MPaG to 6.000 MPaG, very preferably 0.05 MPaG to 5.000 MPaG, and most preferably 0.100 MPaG to 4.000 MPaG. Pressing with a pressure of 0.001 MPaG or higher results in a film with uniform thickness and high flatness. Furthermore, pressing with a pressure of 15.000 MPaG or lower prevents alteration (changes in the physical and chemical crosslinking structure) of bioabsorbable polymer compounds. In addition, the cost of mass production of the press equipment can be kept low.

[0080] The press member can be a known sheet member made of polytetrafluoroethylene (PTFE), but by using a breathable material such as a kitchen sheet, the amount of moisture remaining in the film can be further reduced, and the tensile strength of the adhesion prevention film can be increased by strengthening the intermolecular forces between molecular chains.

[0081] 2-5. Cooling Afterwards, the pressed film can be cooled as needed to obtain an adhesion-preventing film. The cooling conditions are not particularly limited, but from the viewpoint of suppressing a decrease in swelling rate, fold resistance, and tensile strength due to excessive crosslinking caused by an extremely long cooling time, and from the viewpoint of suppressing shrinkage of the film (wrinkling) caused by an extremely short cooling time, it is preferable to avoid extremely slow cooling and rapid cooling, for example, 1.2°C / min to 50.0°C / min is preferred.

[0082] The film produced in this manner may be used as a single-layer anti-adhesion film, or it may be laminated with other layers to form a multi-layer anti-adhesion film.

[0083] [Other Embodiments] It goes without saying that the embodiments described above are exemplary embodiments of the present invention, and the present invention may include embodiments other than those described above within the scope of its core technical concept.

[0084] The present invention will be described in detail based on examples, but the present invention is not limited to these examples.

[0085] 1. Preparation of anti-adhesion film 1-1. Preparation of crosslinked polymer 1-1-1. Preparation of HA / CMC condensate-1 5,280 mg of sodium hyaluronate (HA) (manufactured by Kewpie Corporation, viscosity-average molecular weight 2,450,000) and 2,400 mg of sodium carboxymethylcellulose (CMC) (manufactured by Sigma-Aldrich, degree of etherification 0.7) were weighed out. 960 mL of ultrapure water, measured with a graduated cylinder, was added to a 1 L beaker. While stirring the ultrapure water with a full-zone blade, HA and CMC were added to the beaker little by little and stirred for 1 hour until completely dissolved. Then, 0.1 N HCl was added to adjust the pH of the contents to 4.8 to obtain the HA / CMC solution. 10,176 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride (manufactured by Dojin Chemical Laboratories, Inc.) (addition rate: 133% by mass) was weighed and dissolved in 24.0 mL of ultrapure water to prepare the EDC solution. Using a full-zone blade stirrer, the HA / CMC solution was stirred at a stirring speed of 600 rpm, and 2 mL of the EDC solution was added to the HA / CMC solution, which was kept warm at 25°C, at a time. During this time, an appropriate amount of 0.1 N HCl was added to adjust the pH to 4.70-5.10. After adding the entire volume of the EDC solution, the mixture was stirred for approximately 120 minutes while keeping it warm at 25°C until the pH stabilized to obtain the reaction solution. Finally, the stirred reaction solution was placed into a dialysis membrane with a molecular weight cutoff of 12,000-14,000, placed in a 3 L plastic bucket filled with ultrapure water, and slowly stirred. The entire volume (3 L) of dialysate (ultrapure water) was replaced 2 hours, 16 hours, and 24 hours after the start of dialysis. The reaction solution after dialysis was poured into a sieve with a mesh size of approximately 1000 μm, and the entire volume was filtered to obtain HA / CMC condensate-1 (crosslinked polymer compound).

[0086] 1-1-2. Preparation of HA / CMC Condensate-2 1,650 mg of sodium hyaluronic acid (HA) (manufactured by Kewpie Corporation, viscosity-average molecular weight 2,450,000) and 750 mg of sodium carboxymethylcellulose (CMC) (manufactured by Sigma-Aldrich, degree of etherification 0.7) were weighed. 300 mL of ultrapure water, measured using a graduated cylinder, was added to a 1 L beaker. While stirring the ultrapure water with a disperser blade, HA and CMC were gradually added to the beaker and stirred for about 1 hour until completely dissolved. Then, 0.1 N HCl was added to adjust the pH of the contents to 4.8 to obtain the HA / CMC solution. 3,180 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (manufactured by Dojin Chemical Laboratories) (addition rate: 133 mass%) was weighed and dissolved in 7.5 mL of ultrapure water to obtain the EDC solution. Using a disperser blade agitator, the HA / CMC solution was stirred at a stirring speed of 600 rpm while 2 mL of EDC solution was added to the HA / CMC solution, which was kept warm at 25°C. During this time, an appropriate amount of 0.1 N HCl was added to adjust the pH to 4.70-5.10. After adding the entire volume of EDC solution, the mixture was stirred for approximately 120 minutes while maintaining the temperature at 25°C until the pH stabilized, to obtain the reaction solution. Finally, the stirred reaction solution was placed into a dialysis membrane with a molecular weight cutoff of 12,000-14,000, and then slowly stirred in a 3 L plastic bucket filled with ultrapure water. The entire volume (3 L) of dialysate (ultrapure water) was replaced at 2 hours, 16 hours, and 24 hours after the start of dialysis. The reaction solution after dialysis was poured into a sieve with a mesh opening of approximately 1000 μm, and the entire volume was filtered to obtain HA / CMC condensate-2 (crosslinked polymer compound).

[0087] 1-1-3. Preparation of HA / CMC condensate-3 HA / CMC condensate-3 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-2, except that sodium HA with a number average molecular weight of 1,560,000 was used as the hyaluronic acid (HA).

[0088] 1-1-4. Preparation of HA / CMC condensate-4 HA / CMC condensate-4 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-3, except that sodium CMC with a degree of etherification of 0.9 was used as the carboxymethylcellulose (CMC).

[0089] 1-1-5. Preparation of HA / CMC condensate-5 HA / CMC condensate-5 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-3, except that sodium CMC with a degree of etherification of 1.2 was used as the carboxymethylcellulose (CMC).

[0090] 1-1-6. HA / CMC condensate-6 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-2, except that the temperature of the HA / CMC solution used to obtain the reaction solution for HA / CMC condensate-6 was set to 4°C.

[0091] 1-1-7. HA / CMC condensate-7 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-2, except that the temperature of the HA / CMC solution used to obtain the reaction solution for HA / CMC condensate-7 was set to 40°C.

[0092] 1-1-8. Preparation of HA / CMC condensate-8 HA / CMC condensate-8 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-2, except that the addition rate of EDC hydrochloride was set to 199% by mass.

[0093] 1-1-9. Preparation of HA / CMC condensate-9 HA / CMC condensate-9 (bioabsorbable polymer compound) was obtained by the same procedure as for the preparation of HA / CMC condensate-2, except that the amount of EDC hydrochloride added was 265% by mass.

[0094] The preparation conditions for HA / CMC condensate-1 to HA / CMC condensate-9 are shown in Table 1.

[0095]

[0096] 1-2. Preparation of Adhesion Prevention Film 1-2-1. Preparation of Film 1 A 110 x 110 mm frame (frame thickness 10 mm) was prepared on a glass plate using silicone rubber, and 100 g of HA / CMC condensate-1 was poured into the frame. A constant temperature and humidity chamber was set to a temperature of 30°C and a relative humidity of 80% RH, and the glass plate was placed on a rotating sample table and dried for about 3 days while rotating with an airflow of 0.1 m / s. After drying, the film was peeled off the glass plate and left to stand in a desiccator for more than 2 days. Then, the film was sandwiched between two PTFE sheets and heat-pressed using a hot press machine at a temperature of 120°C and a gauge pressure of 4.0 MPaG for 10 minutes to obtain Film 1.

[0097] 1-2-2. Preparation of Film 2 Film 2 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-2 was used instead of HA / CMC condensate-1.

[0098] 1-2-3. Preparation of Film 3 Film 3 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-3 was used instead of HA / CMC condensate-1.

[0099] 1-2-4. Preparation of Film 4 Film 4 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-4 was used instead of HA / CMC condensate-1.

[0100] 1-2-5. Preparation of Film 5 Film 5 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-5 was used instead of HA / CMC condensate-1.

[0101] 1-2-6. Preparation of Film 6 Film 6 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-6 was used instead of HA / CMC condensate-1.

[0102] 1-2-7. Preparation of Film 7 Film 7 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-7 was used instead of HA / CMC condensate-1.

[0103] 1-2-8. Preparation of Film 8 Film 8 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-8 was used instead of HA / CMC condensate-1.

[0104] 1-2-9. Preparation of Film 9 Film 9 was obtained using the same procedure as for the preparation of Film 1, except that HA / CMC condensate-9 was used instead of HA / CMC condensate-1.

[0105] 1-2-10. Preparation of Film 10 Film 10 was obtained using the same procedure as for the preparation of Film 2, except that the constant temperature and humidity chamber was set to a temperature of 30°C and a relative humidity of 20%RH.

[0106] 1-2-11. Preparation of Film 11 Film 11 was obtained using the same procedure as for the preparation of Film 2, except that the constant temperature and humidity chamber was set to a temperature of 30°C and a relative humidity of 40% RH.

[0107] 1-2-12. Preparation of Film 12 Film 12 was obtained using the same procedure as for the preparation of Film 2, except that the constant temperature and humidity chamber was set to a temperature of 30°C and a relative humidity of 60% RH.

[0108] 1-2-13. Film 13 was prepared using a hot press machine, and film 13 was prepared using the same procedure as for film 2, except that it was pressed at a temperature of 30°C and a gauge pressure of 4.0 MPaG for 10 minutes.

[0109] 1-2-14. Film 14 was prepared using a hot press machine, and film 14 was obtained using the same procedure as for film 2, except that it was subjected to a hot press treatment at a temperature of 140°C and a gauge pressure of 4.0 MPaG for 10 minutes.

[0110] 1-2-15. Film 15 was prepared using a hot press machine, and film 15 was prepared using the same procedure as for film 2, except that it was hot-pressed at a temperature of 160°C and a gauge pressure of 4.0 MPaG for 10 minutes.

[0111] 1-2-16. Film 16 was prepared using a hot press machine, and film 16 was obtained using the same procedure as for film 2, except that it was heat-treated at a temperature of 105°C and a gauge pressure of 0.01 MPaG for 120 minutes.

[0112] 1-2-17. Film 17 was prepared using a hot press machine, and film 17 was obtained using the same procedure as for film 2, except that it was heat-treated at a temperature of 105°C and a gauge pressure of 0.01 MPaG for 300 minutes.

[0113] 1-2-18. Preparation of Film 18 Film 18 was obtained using the same procedure as for the preparation of Film 2, except that it was heat-treated using a hot press at a temperature of 105°C and a gauge pressure of 0.01 MPaG for 1200 minutes.

[0114] 1-2-19. Preparation of Film 19 A film was prepared according to the conditions described in Patent Document 3. Specifically, a 110 x 110 mm frame (frame thickness 10 mm) was made on a glass plate using silicone rubber, 100 g of HA / CMC condensate-2 was poured into the frame, and it was air-dried for about 3 days. The room temperature during air-drying was 20°C and the relative humidity was 15% RH. After air-drying, the film was peeled off the glass plate and left to stand in a desiccator for more than 2 days. Then, the film was sandwiched between two PTFE sheets and heat-treated using a hot press at a temperature of 105°C and a gauge pressure of 0.01 MPaG for 1440 minutes to obtain film 19.

[0115] 1-2-20. Preparation of Film 20 100 g of HA / CMC condensate-2 was weighed and added to a beaker. The HA / CMC condensate-2 in the beaker was vacuum-degassed for approximately 5 minutes, and 210.5 mg of polyglycolic acid (PGA) powder (number average molecular weight 80,000) was weighed and added to the beaker. The contents of the beaker with the added PGA powder were degassed using ultrasound for 15 minutes while stirring with a spatula. A 110 x 110 mm frame was made on a glass plate using silicone rubber, and the HA / CMC condensate-2 with the added PGA powder was poured into the frame. The constant temperature and humidity chamber was set to a temperature of 30°C and a relative humidity of 80% RH, and the glass plate was placed on a rotating sample table and dried while rotating for approximately 3 days. After drying, the film was peeled off the glass plate and left to stand in a desiccator for at least 2 days. Subsequently, a heat treatment was performed using a hot press machine at a temperature of 120°C and a gauge pressure of 4.0 MPaG for 10 minutes to obtain film 20.

[0116] 1-2-21. Preparation of Film 21 Film 21 was obtained using the same procedure as for the preparation of Film 1, except that the constant temperature and humidity chamber was set to a temperature of 50°C.

[0117] 1-2-22. Preparation of Film 22 Film 22 was obtained using the same procedure as for the preparation of Film 1, except that the constant temperature and humidity chamber was set to a temperature of 70°C.

[0118] 1-2-23. Preparation of Film 23 Film 23 was obtained using the same procedure as for the preparation of film 20, except that the constant temperature and humidity chamber was set to a temperature of 30°C and a relative humidity of 15%RH.

[0119] The manufacturing conditions for films 1 to 23 are shown in Table 2.

[0120]

[0121] 2. The following evaluations were performed on evaluation films 1 to 23.

[0122] 2-1. Folding resistance (cracking resistance) measured by MIT testing machine The folding resistance measured by the MIT testing machine was determined by a method based on JIS P 8115:2001. Specifically, the film was cut to 10 mm x 110 mm so as to include the intersection of the diagonals of the film, and an MIT folding resistance tester (MIT-D, manufactured by Toyo Seiki Seisakusho Co., Ltd.) was used to fix both ends of the sample with a spring load clamp and a bending clamp, and the number of back-and-forth folds until breakage was measured. The measurement conditions were: temperature 25°C, relative humidity 50% RH, bending speed 175 times per minute, bending angle 90°, load 2.5 N, and the bending surface of the bending clamp had a radius of curvature of 0.38 mm and an opening width of 0.5 mm. Measurements were taken with n=3, and the average value obtained was taken as the folding resistance of the adhesion prevention film.

[0123] 2-2. Thickness The thickness of the film was measured by the following method. The rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A 50 mm x 50 mm rectangle was cut so that the center of each section was included, and a sample was prepared. After drying the sample at 80°C for 1 hour, it was cooled in a desiccator and its mass was measured. The mass was divided by the area of ​​the sample, and then by the density of the film to obtain the value obtained, which was taken as the thickness of the anti-adhesion film. The measurement was performed with n=3, and the average value obtained was taken as the thickness.

[0124] The density of the film was measured in a measurement room maintained at 25°C using the following method. The rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A sample was prepared by cutting the film into a 50 mm x 50 mm rectangle that included the center of each section. The sample was shredded so that it would fit into a 5 mL volumetric flask, dried in air at atmospheric pressure and 80°C for 1 hour, then cooled in a desiccator, and the shredded sample was maintained at 25°C. Corn oil (Fujifilm Wako Pure Chemical Industries, Ltd., for biochemical use, density 0.912-0.920 g / mL) with a density in the range of 0.91-0.92 g / mL at 25°C and a 5 mL volumetric flask were also stored in a room maintained at 25°C beforehand, and the temperatures of the corn oil and the volumetric flask were maintained at 25°C for use in density measurement. The mass of the volumetric flask was measured and defined as Wa. Next, the corn oil was added to the mark in the volumetric flask, and after degassing at 10 kPa for 5 minutes, if the bubbles had dissipated and the liquid level had fallen below the mark, more corn oil kept at 25°C was added up to the mark, and the mass of the volumetric flask containing the corn oil was measured and determined as Wd. After the corn oil was drained from the volumetric flask, it was washed and dried, and the volumetric flask was kept at 25°C. The shredded sample was added to the volumetric flask, and the mass of the volumetric flask containing the adhesion prevention film was measured and determined as Wb. The corn oil kept at 25°C was added to the mark in the volumetric flask containing the shredded sample film, and after degassing at 10 kPa for 10 minutes, if the bubbles had dissipated and the liquid level had fallen below the mark, more corn oil kept at 25°C was added up to the mark, and the mass of the volumetric flask containing the corn oil and the shredded sample was measured and determined as Wc. The density of the corn oil was determined in accordance with the method for measuring density and specific gravity using a specific gravity bottle as specified in JIS Z 8804:2012. The density of the corn oil was 0.915 g / mL. The density of the anti-adhesion film was determined using Equation 1. Measurements were taken with n=3, and the average value obtained was taken as the density of the anti-adhesion film.

[0125]

[0126] 2-3. Swelling Rate The swelling rate was measured by the following method. A rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A 10 mm x 10 mm rectangle was cut so that the center of each section was included, and a sample piece was prepared. The rectangular anti-adhesion film (sample piece) used for measuring the swelling rate was photographed, and the lengths of the four sides were measured from the captured image. The arithmetic mean of the lengths of the four sides was taken as the side length L of the anti-adhesion film before swelling. ０ That's what I decided.

[0127] 6.24 g of sodium dihydrogen phosphate dihydrate and 14.33 g of disodium hydrogen phosphate dodecahydrate were dissolved in 0.2 L of ultrapure water to prepare 0.2 M solutions. These solutions were then mixed to prepare a pH 6.0 phosphate buffer solution. 5 mL of the obtained phosphate buffer solution was placed in a 10 mL vial. A rectangular anti-adhesion film for swelling rate measurement was immersed in the phosphate buffer solution for 900 seconds. After removing the film from the vial and allowing it to stand for 5 seconds, it was photographed. The lengths of the four sides were measured from the captured image, and the arithmetic mean of the lengths of the four sides was used to determine the side length L of the anti-adhesion film after swelling. Ｓ This was done. If the outline of the removed film could not be confirmed, the phosphate buffer was removed with Technowipe to make the film outline visible, and then the image was taken again.

[0128] The ratio of the cube of the side lengths of the adhesion prevention film before and after swelling (L Ｓ ３ / L ０ ３ The swelling rate of the adhesion prevention film was defined as the volume-based percentage (volume %). Measurements were performed with n=3, and the average of the measured values ​​obtained was used as the swelling rate.

[0129] 2-4. Tensile Strength The tensile strength was measured by the following method. A rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. Each section was cut into strips measuring 40 mm on the long side and 10 mm on the short side, so as to include the center of each section, and samples were prepared. The thickness of the sample at the center was measured with a micrometer and was used as the thickness of the sample to be measured.

[0130] The temperature of the measurement room was set to 25°C and the relative humidity to approximately 60% RH. Using a creep meter (Yamaden Co., Ltd., RHEONERII RE2-33005B), the sample was fixed so that the distance between the grips was 20 mm, and the sample was pulled at a tensile speed of 0.1 mm / second. The tensile strength (MPa) of the adhesion prevention film was defined as the value obtained by dividing the load value at which the adhesion prevention film broke by the cross-sectional area of ​​the sample. The measurement was performed with n=4, and the average of the measured values ​​obtained for each sample was defined as the tensile strength.

[0131] 2-5. Loop Stiffness Loop stiffness was measured by the following method. A rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A 10 mm x 40 mm rectangle was cut so that the center of each section was included, and a sample piece was prepared. The ends of the rectangular film (sample piece) in the longitudinal direction were joined together with double-sided tape, and a width of 5 mm from the ends was used to create a loop shape (teardrop shape) with a loop length of 30 mm, and a measurement sample was prepared. The measurement was performed at a temperature of 25°C and a relative humidity of approximately 60% RH, and the portion (5 mm) joined with double-sided tape was clamped in the chuck and fixed to a creep meter (Yamaden Co., Ltd. RHEONERII RE2-33005B). To compress the loop of the sample being measured, the upper indenter (φ30 mm) attached to the creep meter was moved at a speed of 0.5 mm / second in the direction of the loop. The load (N) when the sample was compressed 5 mm from the contact point was recorded and defined as the loop stiffness value (N / 10 mm). Measurements were performed with n=4, and the average of the measured values ​​obtained for each measurement was defined as the loop stiffness value.

[0132] 2-6. Adhesion Strength The adhesion strength was measured by the following method. A rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. Each section was cut into strips measuring 50 mm on the long side and 10 mm on the short side, so as to include the center of each section, to prepare the measurement sample. Mending tape (3M Japan, part number 810-1-18) was applied to the side of the measurement sample opposite to the adhesion strength measurement surface to reinforce the measurement sample. Next, 0.1 mL of pure water was uniformly sprayed onto a 40 mm x 20 mm area of ​​the adhesion strength measurement surface of a simulated organ (AS ONE Corporation, silicone rubber sheet (3 mm thick), product number 6-611-05). Then, the adhesion prevention film for adhesion strength measurement and the simulated organ were brought into contact at 25°C for 15 minutes, with a 40 mm long side and a 10 mm short side area, so that a 10 mm area of ​​non-adhesion remained on one side of the long side of the sample to be measured. After that, the adhesion strength was measured using a creep meter (Yamaden Co., Ltd., RHEONERII RE2-33005B). In a sample in which the adhesion prevention film and the simulated organ are in close contact, the areas not in contact with the other sample are fixed to a creep meter, and the adhesion prevention film is pulled along its longitudinal direction at 0.05 mm / second. The maximum load value (N) measured during the time until the adhesion prevention film peels off is recorded as the area in which the adhesion prevention film and the simulated organ were in close contact (40 mm × 10 mm = 4.0 cm²). ２ Divide by ) to obtain the adhesion strength (N / cm ２ The adhesion strength was determined by measuring n=4, with the average of the measured values ​​obtained from each measurement being used as the adhesion strength.

[0133] 2-7. Thermogravimetric Analysis (TGA) The thermogravimetric analysis of the film was performed using a simultaneous thermal analyzer (Mettler Toledo TGA / DSC2). The rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side to the opposite side. A 10 mg sample was taken from the center of each section and placed in an alumina pan. The film was heated from 30°C to 400°C at a heating rate of 10°C / min under a nitrogen stream, and the thermogravimetric analysis of the film was performed. A thermogravimetric (TG) curve was obtained by plotting the mass of the film against the heating temperature at 0.5°C intervals, and the temperature T ｎThe mass in W ｎ In that case, T ｎ+１ Mass change with respect to °C (W) ｎ＋１ -W ｎ The differential curve of the thermogravimetric curve was obtained by plotting the curve. In the obtained differential curve, the peak observed between 215°C and 230°C was designated as Peak 1, and the peak observed between 270°C and 310°C was designated as Peak 2, and the temperature of each peak top (TGA differential peak temperature 1 and TGA differential peak temperature 2) was determined. Measurements were performed with n=3, and the average value of the TGA differential peak temperature 1 and TGA differential peak temperature 2 obtained for each measurement was taken as the measured value.

[0134] 2-8. １ For the H-NMR measurement, a rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side towards the opposite side. A sample piece was prepared by cutting the film into a 10 mm x 10 mm rectangle that included the center of each section. The sample was placed in a 5 mL vial, and 1 mL of heavy TFA (manufactured by Kanto Chemical Co., Ltd.) was added and allowed to stand for 1 hour. 12 mg of pyrazine was placed in a different 5 mL vial, and 1.0 mL of heavy TFA was added to the vial containing the pyrazine. The mixture was then mixed for several seconds using a vortex mixer to prepare a pyrazine solution. 0.1 mL of the obtained pyrazine solution was added to the vial containing the sample piece and mixed for several seconds using a vortex mixer to prepare the measurement solution. Next, the obtained measurement solution was... １ The 1H-NMR spectrum was measured using a nuclear magnetic resonance spectrometer (JEOL JNM-ECZ600R / S1 (JEOL, 600MHz) manufactured by JEOL Ltd). The spectrum was normalized so that the pyrazine resonance peak was 9.45 ppm. The integral value of the maximum resonance peak measured in the range of 9.4 to 9.5 ppm was taken as A, and the integral value of the maximum resonance peak measured in the range of 5.0 to 5.2 ppm was taken as B, and B / A was calculated. In addition, the peak intensity of the maximum resonance peak measured in the range of 2.5 to 4.0 ppm was taken as I. ａ The peak intensity of the maximum resonance peak measured in the range of 5.0 to 5.2 ppm is defined as I ｂ To, I ｂ / I ａThe following was calculated. The measurement was performed with n=3, and the B / A and I were calculated for each. ｂ / I ａ The average value was used as the measured value.

[0135] 2-9. Barrier Time The barrier time was measured by the following method. A rectangular anti-adhesion film was divided into four sections by drawing perpendicular lines from the center of each side towards the opposite side. A 13 mm x 13 mm rectangle was cut to include the center of each section to prepare a sample piece. The film on the bottom of a 6-well plate cell culture insert (CCI) was peeled off. A nylon mesh with a mesh size of 108 μm (manufactured by AS ONE, part number 3-3069-15) was attached with adhesive to the opening on the bottom created by peeling off the bottom film, and then the sample piece was placed on the nylon mesh so as to be at the center of the opening. Next, a silicone rubber sheet (manufactured by AS ONE, part number 6-611-04, thickness 2 mm) was cut into a disc shape with a diameter of 25 mm, a hole with a diameter of 10 mm was made in the center of the disc, and the silicone rubber sheet was placed on the sample piece while being firmly pressed with tweezers to prevent any gaps.

[0136] 6.24 g of sodium dihydrogen phosphate dihydrate and 14.33 g of disodium hydrogen phosphate dodecahydrate were each dissolved in 0.2 L of ultrapure water to prepare 0.2 M solutions. Then, the respective solutions were mixed to a pH of 8.0 to prepare a 0.2 M phosphate buffer solution. 1 g of blue dextran (Sigma-Aldrich, weight-average molecular weight 500,000) was dissolved in 100 mL of the 0.2 M phosphate buffer solution to prepare the test solution.

[0137] The CCI containing the sample piece was placed in a 20 mL mini-cup (manufactured by Maruemu Co., Ltd.) containing 15 mL of 0.2 M phosphate buffer solution. After 20 seconds, 200 μL of the test solution was added to the CCI. To prevent evaporation of the test solution, the opening of the CCI was covered with a plastic plate, and the CCI was maintained at 37°C and approximately 95% RH relative humidity. After a predetermined time, the 0.2 M phosphate buffer solution in the mini-cup was stirred, and approximately 2 mL of the solution was collected. The absorbance of the collected solution at a wavelength of 620 nm was measured using a UV-Vis spectrophotometer (Shimadzu Corporation, UV-2450).ｔ The absorbance at 620 nm was measured. The absorbance at 620 nm can be used as an indicator of the concentration of blue dextran. In addition, the absorbance of the 0.2 M phosphate buffer solution was measured in the same manner, and absorbance I ０ The barrier properties of the adhesion prevention film decrease as much as I ｔ The tendency is for I to increase ｔ -I ０ The time at which the value became 0.03 was defined as the barrier time of the adhesion prevention film. Measurements were taken with n=3, and the average of the times obtained for each measurement was defined as the barrier time.

[0138] The evaluation results for films 1 to 23 are shown in Tables 3 and 4.

[0139]

[0140]

[0141] As is clear from Tables 1 to 4, the adhesion prevention film obtained by drying the formed gel in an atmosphere of 10°C to 70°C and a relative humidity of 25% RH to 95% RH, and then pressing the dried film at a temperature of 25°C to 130°C for a pressurized time of 1 minute to 1300 minutes, was resistant to cracking.

[0142] These applications claim priority to Japanese Patent Applications No. 2024-198095, No. 2024-198098, and No. 2024-198102, all filed on 13 November 2024. The matters described in the original specifications, claims, and drawings of these applications are incorporated herein by reference.

[0143] The anti-adhesion film according to the present invention is less likely to crack when bent or rolled up.

Claims

1. An anti-adhesion film containing a bioabsorbable polymer compound, having a thickness of 10 μm or more and 500 μm or less, and a fold resistance of 10 to 2000 times as measured by an MIT tester under measurement conditions of 25°C and 50% relative humidity.

2. The adhesion prevention film according to claim 1, wherein the tensile strength measured at a temperature of 25°C and a relative humidity of 60% is 20.0 MPa or more and 150.0 MPa or less.

3. The anti-adhesion film according to claim 1, wherein the loop stiffness is 0.030 N / 10 mm or more and 0.600 N / 10 mm or less.

4. After being in close contact with a water-moistened simulated organ at 25°C for 15 minutes, the adhesion strength to the simulated organ was 0.650 N / cm. ２ 1.500N / cm or more ２ The adhesion prevention film according to claim 1 is as follows:

5. The temperature is raised from 30°C to 400°C in a nitrogen atmosphere at a heating rate of 10°C / min, and thermogravimetric analysis (TGA) is performed. The mass of the film against the heating temperature is plotted at 0.5°C intervals to obtain a thermogravimetric (TG) curve, and the temperature T ｎ The mass in W ｎ Toshi, T ｎ＋１ Mass change with respect to °C (W) ｎ＋１ -W ｎ The adhesion prevention film according to claim 1, wherein the differential curve of the thermogravimetric curve obtained by plotting the curve has peaks with peak tops at least 215°C to 230°C and 270°C to 310°C, respectively.

6. Using a sample solution prepared by adding the film and 1.2 mg of pyrazine to 1.1 mL of deuterated trifluoroacetic acid, the resonance peak of the standard substance pyrazine was normalized to 9.45 ppm. １ The adhesion prevention film according to claim 1, wherein when the film is measured by H-NMR, and the integral value of the maximum resonance peak measured in the range of 9.4 to 9.5 ppm is taken as A, and the integral value of the maximum resonance peak measured in the range of 5.0 to 5.2 ppm is taken as B, B / A is 0.10 or less.

7. A method for producing an adhesion-preventing film according to claim 1, comprising the steps of: forming a gel containing a bioabsorbable polymer compound; drying the formed gel in an atmosphere of 10°C to 70°C and a relative humidity of 25% RH to 95% RH to form a film; and pressing the dried film at a temperature of 25°C to 130°C for a pressurizing time of 1 minute to 1300 minutes.

8. The method for producing an adhesion-preventing film according to claim 7, wherein the bioabsorbable polymer compound comprises HA and carboxymethylcellulose.

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