Medical film

Abstract

Provided is a medical film capable of showing enhanced re-attachability even without forming a layer for controlling solubility. In the medical film of the present invention, the ratio q1 (V1 / V0) of the volume V1 after immersion for 10 seconds in a phosphate buffer (PB) of pH 6.0 and concentration 0.2 M to the volume V0 before the immersion is not more than 1.5.

Description

[Technical Field]

[0001] This invention relates to a medical film. [Background technology]

[0002] Medical films (anti-adhesion materials) are known to be applied to organs after surgery to prevent adhesion between the organ and other organs during wound healing. These anti-adhesion materials utilize bioabsorbable materials such as cross-linked compounds of hyaluronic acid and methylcellulose.

[0003] Medical films that are applied to organs, such as adhesion prevention materials, are required to be able to be repositioned and reapplied after being applied to the organ surface. Patent Document 1 describes an adhesion prevention material that enhances such repositionability, comprising a base layer containing a water-soluble polymer and a support layer formed on its surface containing an aliphatic ester. According to Patent Document 1, this adhesion prevention material has a support layer made of a water-insoluble aliphatic ester on its surface, making it easy to handle with tweezers even when wet and easy to reapply.

[0004] Furthermore, Patent Document 2 describes an anti-adhesion material having a layer containing an aliphatic polyester and a layer containing multiple water-soluble polymers formed on its surface. According to Patent Document 2, this anti-adhesion material can control the solubility of the surface when wet after application using the multiple layers of water-soluble polymers, and it is said to maintain its shape even after being applied to a substrate. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2011 / 081162 [Patent Document 2] International Publication No. 2017 / 164264 [Overview of the project] [Problems that the invention aims to solve]

[0006] As described in Patent Documents 1 and 2, medical films with adjusted solubility immediately after application to organs are known. On the other hand, medical films with a layer on the surface to control solubility, as described in these documents, tend to be thicker, resulting in lower bioavailability or higher cost.

[0007] The present invention has been made in view of the above problems, and aims to provide a medical film that can be repositioned even without providing a layer to control solubility. [Means for solving the problem]

[0008] One embodiment of the present invention for solving the above problems relates to the following medical films [1] to [7]. [1] A medical film comprising a crosslinked polymer material and a biodegradable resin, The aforementioned medical film has a ratio q1 (V1 / V0) of volume V1 after immersion for 10 seconds to volume V0 before immersion in phosphate buffer (PB) with a pH of 6.0 and a concentration of 0.2 M, which is 1.5 or less. Medical film [2] The medical film has a ratio q2(V2 / V0) of volume V2 after immersion for 60 seconds to volume V0 before immersion in phosphate buffer (PB) with a pH of 6.0 and a concentration of 0.2 M, which is 1.9 or less. [1] Medical film as described above. [3] The medical film has a ratio q3 (V3 / V0) of volume V3 after immersion for 900 seconds to volume V0 before immersion in phosphate buffer (PB) with a pH of 6.0 and a concentration of 0.2 M, which is 1.8 or higher. Medical films as described in [1] or [2]. [4] The medical film contains 5 to 95 parts by mass of the biodegradable resin with respect to 100 parts by mass of the crosslinked polymer material. A medical film as described in any of [1] to [3]. [5] The biodegradable resin is a polymer in which the proportion of glycolic acid as a constituent unit to the total mass of the biodegradable resin is 10% by mass or more and 100% by mass or less. A medical film as described in any of [1] to [4]. [6] The thickness is 15 μm or more and 500 μm or less. A medical film as described in any of [1] to [5]. [7] Adhesion prevention material, A medical film as described in any of [1] to [6]. [Effects of the Invention]

[0009] According to the present invention, a medical film is provided that can be repositioned even without providing a layer for controlling solubility. [Modes for carrying out the invention]

[0010] [Medical film] One embodiment of the present invention relates to a medical film (hereinafter also simply referred to as "medical film") comprising a crosslinked polymer material and a biodegradable resin.

[0011] (Crosslinked polymer material) Crosslinked polymer materials are polymer materials that swell when immersed in ultrapure water at 15-25°C. Crosslinked polymer materials are typically gel-like polymer materials, formed by the physical and / or chemical crosslinking of the same or different types of polymer materials. Preferably, crosslinked polymer materials are composed of polymer materials that become soluble after swelling in water.

[0012] The crosslinked polymer material can be, for example, a crosslinked body of an anionic polymer material. The anionic polymer material may be a polymer material having a repeating structure with an anionic group, or may be a polymer material obtained by chemically modifying a polymer compound with an anionic substituent. Further, the anionic polymer material may be a polymer material having a cationic substituent in addition to the anionic substituent. The anionic group can be a carboxyl group, a hydroxy group, a sulfo group, etc. Note that the anionic group may be partially forming a salt with an alkali metal such as sodium and potassium, or an alkaline earth metal such as calcium or magnesium.

[0013] The polymer material may be a polysaccharide, a protein, or a synthetic polymer. Among these, polysaccharides and proteins are preferred.

[0014] Examples of saccharides as anionic polymer materials may be natural saccharides such as pullulan, alginic acid, hyaluronic acid, chondroitin sulfate, dextran sulfate, and pectin, or saccharides having an anionic group introduced by modification such as carboxymethyl amylose, carboxymethyl cellulose, carboxymethyl dextran, carboxymethyl starch, sulfated cellulose, and sulfated dextran. Among these, alginic acid, hyaluronic acid, carboxymethyl amylose, and carboxymethyl cellulose are preferred because they are easy to handle.

[0015] Examples of proteins as anionic polymer materials include gelatin, collagen, albumin, fibrin, and chemical modifications thereof. The protein may be a polymer (polyamino acid) of amino acids having an anionic group such as polyglutamic acid and polyaspartic acid. Among these, acid-treated gelatin having a carboxyl group generated by hydrolysis of the acid amide is preferred.

[0016] Anionic polymer materials can be identified by various instrumental analyses, acid titrations, or combinations thereof. For example, they can be identified by methods using spectroscopic instruments such as FT-IR, by analyzing a solution obtained by heating the polymer material with deuterated dimethyl sulfoxide (deuterated DMSO) to a degree where it dissolves using NMR, or by appropriately using instrumental analyzers such as liquid chromatography to obtain a solution obtained by heating the polymer material with DMSO to a degree where it dissolves.

[0017] The crosslinking of polymer materials may be physical crosslinking, which can be formed by introducing cationic substituents into polyanionic polymer materials, or chemical crosslinking, which can be formed by reacting polymer materials directly or through other molecules. Crosslinking of polymer materials can be carried out by applying crosslinking treatments to the polymer materials, such as ultraviolet treatment, heat treatment, and crosslinking agent treatment. Of these, crosslinking agent treatment is preferred.

[0018] Examples of crosslinking agents used in crosslinking treatment include ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and N,cyclohexyl-N'-(2-morpholinoethyl)carbodiimidemeth-p-toluenesulfonic acid. By treating with these crosslinking agents, cationic groups can be introduced into polyanionic polymer materials. Then, through intermolecular interactions between the anionic group of one molecule and the cationic group of another molecule, the molecules of the polymer material can be physically crosslinked. Of these, EDC is preferred because it is easy to handle.

[0019] Crosslinking with a crosslinking agent can be carried out by dissolving the polymer material in water or an aqueous medium, adding the crosslinking agent, and stirring. The state of the water or aqueous solution 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 0.01 M hydrochloric acid as appropriate to lower the pH during the reaction (for example, pH 4.0 to 5.5) and dissociate the anionic groups of the polyanionic polymer.

[0020] The amount of crosslinking agent is preferably 0.5 eq. to 10 eq. relative to the reactive functional groups of the polymer material (e.g., hyaluronic acid), more preferably 1 eq. to 6 eq., and even more preferably 2 eq. to 5 eq. As will be described later, increasing the amount of crosslinking agent can lower the initial swelling degree of the medical film.

[0021] Furthermore, crosslinking may occur between multiple different types of polymer materials. This crosslinking may be chemical crosslinking, where chemical bonds are formed by chemical reactions between these polymer materials, or it may be physical crosslinking, such as by enhancing intermolecular interactions with a crosslinking agent. For example, from a safety standpoint, a crosslinked combination of hyaluronic acid and carboxymethylcellulose can be used as the crosslinked polymer material.

[0022] (biodegradable resin) Biodegradable resins are resins that decompose in living organisms. Biodegradable resins can be biodegradable polyesters. Examples of biodegradable polyesters include biodegradable aliphatic polyesters, specifically polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, and copolymers thereof. Of these, glycolic acid homopolymers and copolymers containing structures derived from glycolic acid are preferred because they decompose quickly in living organisms.

[0023] The (co)polymer of glycolic acid may be a homopolymer of glycolic acid or a copolymer of glycolic acid with other monomers. The copolymer can be a copolymer of glycolic acid with hydroxycarboxylic acids such as lactic acid, hydroxypropionic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, and hydroxybenzoic acid, lactones such as caprolactone, and water-soluble polymers whose biosafety has been confirmed, such as polyethylene glycol. From the viewpoint of reducing the initial degree of swelling, the proportion of constituent units derived from glycolic acid in the biodegradable resin is preferably 5% by mass or more and 100% by mass or less, more preferably 20% by mass or more and 99% by mass or less, and even more preferably 40% by mass or more and 95% by mass or less.

[0024] The type of biodegradable resin can be identified, for example, using NMR. If the biodegradable resin is a resin that does not dissolve in a solvent at room temperature, such as a glycolic acid polymer, the sample for measurement can be prepared by dissolving it in dehydrated heavy DMSO by heating. Other analytical instruments such as FT-IR and GC-MS may also be used in combination.

[0025] These biodegradable resins release acid through hydrolysis when medical films are applied to organs or come into contact with water. This released acid reduces the degree of swelling of the medical film during the initial application, decreasing its adhesion to organs and thus improving the repositionability of the medical film. Furthermore, the released acid delays the decomposition of the cross-linked polymer material, which is thought to maintain the strength of the medical film and further improve its repositionability.

[0026] The biodegradable resin preferably has a number-average molecular weight of 1,000 to 150,000, more preferably 5,000 to 100,000, and even more preferably 10,000 to 50,000. Furthermore, the biodegradable resin preferably has a weight-average molecular weight of 2,000 to 300,000, more preferably 10,000 to 200,000, and even more preferably 20,000 to 100,000. By reducing both the number-average and weight-average molecular weights, the sustained release ability of the acid can be increased, maintaining the adhesion and strength of the medical film even after time has passed since application. Additionally, when the biodegradable resin is in particulate form, reducing both the number-average and weight-average molecular weights makes the biodegradable resin easier to pulverize, resulting in particles with smaller particle sizes. As will be described later, the smaller the particle size, the greater the effect of reducing the adhesion of the medical film to organs in the initial stages of application.

[0027] The number-average molecular weight and mass-average molecular weight of biodegradable resins refer to values ​​obtained by separating the biodegradable resin from medical films. The number-average molecular weight shall be the value measured in accordance with ISO 16014-1:2012. Specifically, the measurement shall be performed using gel permeation chromatography (GPC) (Resonac Corporation, Shodex GPC-104, detector: RI, column: HFIP-606M x 2), with a solution of CF3COONa dissolved in hexafluoropropanol (HFIP) to a concentration of 5 mM as the solvent, and polymethyl methacrylate (PMMA) as the standard substance.

[0028] The biodegradable resin may be in particulate or fibrous form. When in fibrous form, the biodegradable resin may be monofilament, multifilament, nonwoven fabric, woven fabric, knitted fabric, or braided fabric.

[0029] When the biodegradable resin is in particulate form, the average particle size is not particularly limited, but it is preferably 0.1 μm to 30 μm, more preferably 1 μm to 20 μm, and even more preferably 1 μm to 15 μm. The larger the average particle size, the easier it is to handle the biodegradable resin when manufacturing the film. The smaller the average particle size, the larger the surface area of ​​the particles, which increases the contact area with the crosslinked polymer material, and the higher the sustained release ability of the acid, thereby increasing the effect of the biodegradable resin in reducing the adhesion of the medical film to organs in the initial stages of application. The average particle size of the biodegradable resin refers to the value in the medical film, and is observed at 100x magnification using a digital microscope (manufactured by Keyence Corporation) to acquire a digital image. The acquired image of the measurement area is loaded into the image analysis software MIPAR (manufactured by LightStone Corporation), and the circular phase diameter calculated from the area of ​​the biodegradable resin particle image is taken as the diameter. The "Smart Cluster" was defined as "Fill Type: Class", "Classes: 4~10", "Edge Type: Dark to Bright", "Edge Clean: 0~5", and "Speed: 2". The "Basic Threshold" was set to "Value: 80~150". “Reject Features”, “Measurement: Area”, “Target: Objects”, “Edges: Include”, “Units: μm” 2 ”, “Threshold Value: 100”, “Type: Reject Features < / =”

[0030] When it is a nonwoven fabric, the basis weight of the biodegradable resin is 1.2 g / m². 2 More than 100.0g / m 2 Preferably, it is 3.4 g / m 2 More than 65.0g / m 2 It is more preferable that the following is the case: 5.0 g / m 2 More than 31.5g / m 2The following is even more preferable: The larger the basis weight, the easier it is to handle and the lower the initial swelling.

[0031] The biodegradable resin content is preferably 5 to 95 parts by weight, more preferably 15 to 85 parts by weight, and even more preferably 20 to 70 parts by weight, when the cross-linked polymer material content is 100 parts by weight.

[0032] The biodegradable resin content in medical films can be calculated from the amount of biodegradable resin added during the production of the medical film, or by extracting the biodegradable resin from the medical film and measuring its mass. The mass of biodegradable resin extracted from medical films can be measured by the following method, for example: The medical film is treated with an acid-containing solution at room temperature to decompose the cross-linked polymer material and dissolve it in the solution. The resulting acid-containing solution is washed with cold water while suction filtering to remove the cross-linked polymer material, and the solids are further washed with acetone. The resulting solids are dried in a vacuum dryer set to 40°C for 5 minutes, and the weight of the resulting solids is measured.

[0033] (Other ingredients) Medical films may contain lubricants, emulsifiers, colorants, antioxidants, weathering agents, heat stabilizers, nucleating agents, ultraviolet absorbers, 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 medical film.

[0034] (Swelling properties of medical films) Medical films exhibit low initial swelling upon contact with water. Specifically, medical films have a swelling degree of q1(V1 / V0) (ratio of volume V1 after 10 seconds of immersion in pH 6.0, 0.2 M phosphate buffer (PB) to volume V0 before immersion, which is 1.5 or less. Furthermore, it is preferable that the ratio of volume V2 after 60 seconds of immersion in the above phosphate buffer (PB) to volume V0 before immersion, which is q2(V2 / V0) (ratio of volume V2 after 60 seconds of immersion, which is 1.9 or less). The amount of phosphate buffer used in this case must be sufficient to completely immerse the medical film. For example, using a 10 mL vial, 1 cm of medical film... 3 The sample is completely immersed in 5 mL of phosphate buffer, and its swelling properties are evaluated.

[0035] For example, Seprafilm, a commercially available adhesion prevention material (medical film), has a ratio q1 (V1 / V0) of approximately 1.7 between the volume V0 before immersion in the phosphate buffer (PB) and the volume V1 after immersion for 10 seconds. Medical films with high initial water absorption and that swell easily have high adhesion to organs from the initial application, but their strength tends to decrease immediately after application. Therefore, medical films applied to organs are difficult to remove, and attempting to forcibly remove them often results in deformation, making reapplication impossible.

[0036] In contrast, by reducing the initial water absorption of the medical film and making it less prone to swelling, the initial adhesion to the organ can be reduced, making it easier to remove from the organ, and also reducing the likelihood of deformation when removed from the organ. Furthermore, even if the medical film curls up when removed from the organ, the curl can be easily straightened. Therefore, such a medical film can be easily reapplied to organs.

[0037] For example, when using a medical film during abdominal surgery, it is expected that the film will adhere to a location on the organ surface other than the intended location, be peeled off and reapplied after only a few tens of seconds. Therefore, medical films with a low degree of swelling when immersed for 10 or 30 seconds are particularly suitable for use in abdominal surgery. From the above viewpoint, it is preferable that the ratio q1 (V1 / V0) of the volume V1 after immersion for 10 seconds to the volume V0 before immersion in the phosphate buffer (PB) of the medical film is 1.5 or less, more preferably 1.3 or less, and even more preferably 1.2 or less. Furthermore, it is preferable that the ratio q4 (V4 / V0) of the volume V4 after immersion for 30 seconds to the volume V0 before immersion in the phosphate buffer (PB) of the medical film is 1.6 or less, more preferably 1.5 or less, and even more preferably 1.3 or less. The lower limits of the volume ratios q1 and q4 are not particularly limited, but can be 1.0 or higher.

[0038] Furthermore, when using medical films during laparoscopic surgery, the field of view is more limited than in open surgery, and the film is manipulated using forceps, etc., so it is expected that it will take longer to reapply the film than in open surgery. For this reason, medical films with a low degree of swelling after immersion for 60 seconds are particularly suitable for use in laparoscopic surgery. From the above viewpoint, it is preferable that the ratio q2(V2 / V0) of the volume V2 after immersion for 60 seconds to the volume V0 before immersion in the phosphate buffer (PB) of the medical film is 1.9 or less, more preferably 1.7 or less, and even more preferably 1.5 or less. Also, it is preferable that the ratio q5(V5 / V0) of the volume V5 after immersion for 90 seconds to the volume V0 before immersion in the phosphate buffer (PB) of the medical film is 1.6 or less, more preferably 1.5 or less, and even more preferably 1.3 or less. The lower limits of the volume ratios q2 and q5 are not particularly limited, but can be 1.0 or more. Furthermore, when peeling off and reapplying a film that has already been applied, the film may curl up. Even when unfolding the film, it is in contact with water, creating an environment where swelling progresses. However, the film becomes easier to unfold when the volume ratio q2 and q5 are within the preferred range described above.

[0039] On the other hand, from the viewpoint of suppressing displacement of the medical film due to organ deformation, etc., after it has been applied in the correct position, it is preferable that the medical film swells sufficiently after a predetermined time has elapsed since application. From this viewpoint, it is preferable that the ratio q6(V6 / V0) of the volume V6 after immersion in the phosphate buffer (PB) for 300 seconds to the volume V0 before immersion is 1.6 or higher, and more preferably 1.8 or higher. Furthermore, it is preferable that the ratio q3(V3 / V0) of the volume V3 after immersion in the phosphate buffer (PB) for 900 seconds to the volume V0 before immersion is 1.8 or higher, more preferably 1.9 or higher, and even more preferably 2.0 or higher. The upper limit of the degree of swelling during these periods is not particularly limited, but can be 6.5 or lower.

[0040] Furthermore, even if the pH changes, the degree of swelling of the medical film after 900 seconds of immersion remains the same, so there are no problems with its application to living tissue.

[0041] The volumes V1 to V6 mentioned above can be determined by the following method.

[0042] One side of the film is defined as the x-axis, the other side perpendicular to the x-axis as the y-axis, and the direction perpendicular to the plane formed by the x and y axes as the z-axis. When the thickness of the medical film is thin, it is difficult to measure the thickness after immersion, so the volume of the medical film in this specification is calculated assuming that the rate of increase in the x, y, and z axes is the same. Specifically, the volume V0 before immersion is calculated by placing the medical film and a ruler together on a blue sheet of plastic so that the lengths of the sides of the medical film are visible, and taking a photograph so that the contour of the sample is visible. The lengths of the four sides of the medical film on the same plane, measured from the obtained image, are defined as a1, a2, a3, and a4, and the average value l0 of the four side lengths is calculated, and the volume V0 before immersion is calculated using Equation 1.

[0043]

number

[0044] Similarly, to determine the volumes (V1-V6) after immersion in phosphate buffer, the medical film and a ruler are placed together on a blue sheet of paper so that the lengths of the sides of the medical film are visible, and a photograph is taken so that the outline of the sample is visible. From the obtained image, the four sides of the same plane as the one measured in V0 are designated as b1, b2, b3, and b4, and the average value of the lengths of the four sides, l1, is calculated. The volume after immersion is then calculated using Equation 2. Note that Equation 2 shows how to calculate the volume V1 after immersion for 10 seconds, but volumes V2-V6 can be calculated in the same way.

[0045]

number

[0046] The volume ratios q1 to q6 obtained from these volumes V0 to V6 are the average values ​​of three measurements taken using medical films manufactured with the same formulation. Furthermore, even when the plan view of the medical film is not approximately rectangular, the same approach can be used to determine the volume ratios q1 to q6, assuming that the rate of increase in each direction and the rate of increase in the thickness direction are the same in the plan view.

[0047] (Other properties of medical films) Furthermore, medical films exhibit high initial strength immediately after wetting. Specifically, when a sample cut into strips with a long side of 40 mm and a short side of 10 mm is fixed to a chuck with a distance of 20 mm between the chucks, and the central 10 mm x 10 mm of one side of the sample is brought into contact with ultrapure water for 10 seconds, the maximum tensile strength when pulled on both sides at 0.1 mm / sec can be 1.50 MPa or more, preferably 2.00 MPa or more, and more preferably 6.00 MPa or more. The upper limit of the above maximum tensile strength is not particularly limited, but it can be 300.00 MPa or less.

[0048] Furthermore, medical films exhibit high adhesion strength to organs. Specifically, a sample is cut into strips measuring 50 mm on the long side and 10 mm on the short side, and mending tape (3M Japan, product number 810-1-18, base material: acetate film, adhesive: acrylic) is attached to the opposite side that will come into contact with a simulated organ (AS ONE, silicone rubber sheet (3 mm thick), product number 6-611-05). Using a creep meter (Yamaden, RE2-33005B), the short side of the sample is fixed to one tensile chuck by 5 mm, and the simulated organ is fixed to the other tensile chuck. The sample is then brought into contact with the simulated organ, which has been moistened with ultrapure water, with the long side 40 mm and the short side 10 mm of the sample. After leaving it for 900 seconds, the adhesion strength when pulled at 0.05 mm / sec can be greater than 0.05 N, and even more preferably greater than 1.60 N. This level of adhesive strength prevents the medical film from shifting due to organ deformation or other factors after it has been applied in the correct position.

[0049] The swelling properties of medical films can be adjusted by factors such as the thickness of the medical film, the cross-linking state of the cross-linked polymer material, and the dispersibility of the biodegradable resin (if it is in particulate form).

[0050] For example, the thicker the medical film, the lower the initial swelling. The thickness of the medical film is preferably 15 μm to 500 μm, and more preferably 40 μm to 200 μm. Furthermore, from the viewpoint of combining low initial swelling with a good feel, the thickness of the composite layer is even more preferably 50 μm to 150 μm.

[0051] Furthermore, the cross-linking state of the cross-linked polymer material and the dispersibility of the biodegradable resin can be changed by appropriately adjusting the manufacturing conditions of the medical film.

[0052] (Application) Medical films can be attached to organs and other tissues, and after a predetermined period of time, they begin to decompose and change shape (disintegrate), eventually being absorbed into the body. The time from application until shape change occurs can be adjusted between 3 and 14 days. Furthermore, the time from application until the medical film is absorbed into the body and becomes invisible can be adjusted between 14 and 28 days. These periods can be adjusted depending on the type of cross-linked polymer material and the type of biodegradable resin.

[0053] Due to the properties described above, medical films can be used as wound coverings to prevent adhesion (anti-adhesion material) or to prevent the development of ulcers or perforation. Medical films can also be used as sustained-release substrates for drugs or as substrates for tissue regeneration. Alternatively, medical films can be applied to the walls of tubular structures in the body to maintain voids.

[0054] [Method of manufacturing medical films] Medical films can be manufactured by crosslinking polymer materials, compounding them with biodegradable resins, and forming them into films.

[0055] The crosslinking of polymer materials can be carried out by methods appropriate to the polymer material, 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 material is dissolved in water or an aqueous medium while stirring. At this time, it is preferable to add an acid such as HCl 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.

[0056] The compounding with biodegradable resins can be carried out using a method appropriate to the shape and type of the biodegradable resin. For example, if the biodegradable resin is in particulate, monofilamental, or multifilamental form, it can be added to a solution or dispersion containing the crosslinked polymer material and stirred. If the biodegradable resin is in the form of a nonwoven fabric, woven fabric, knitted fabric, or braided fabric, the biodegradable resin and the crosslinked polymer material can be compounded within a frame used to cast the solution or dispersion during film formation.

[0057] Film formation can be carried out by drying the composite of the crosslinked polymer material and the biodegradable resin within a frame. Drying may be performed by air drying at room temperature, freeze-drying, or by removing the solvent by heating. Alternatively, hot pressing (heating and pressurizing) may be used. These drying methods may be combined.

[0058] At this time, by adjusting the manufacturing conditions, the cross-linking state of the cross-linked polymer material and the dispersibility of the biodegradable resin can be controlled, thereby adjusting the initial degree of swelling of the medical film.

[0059] For example, increasing the stirring speed when crosslinking polymer materials increases the frequency of contact between reacting molecules, thereby advancing the reaction and increasing the degree of crosslinking, thus lowering the initial swelling of the medical film. On the other hand, stirring applies strong shear force to the crosslinked polymer gel, which can lead to a faster rate of molecular cleavage than the rate of crosslink formation due to the reaction, or the generation of bubbles which reduces reaction efficiency and lowers the degree of crosslinking. From the viewpoint of preventing an increase in the initial swelling of the composite layer due to this decrease in the degree of crosslinking, it is preferable to use a moderate stirring speed. From the viewpoint of balancing these factors, the stirring speed is preferably 50 rpm or more and less than 750 rpm, and more preferably 150 rpm or more and less than 700 rpm.

[0060] Furthermore, the lower the temperature of the solution used for the polymer crosslinking reaction, the lower the initial swelling of the medical film can be. By carrying out the reaction at a low temperature, a moderate number of crosslinking sites can be generated. As a result, it is thought that a medical film can be obtained in which the degree of crosslinking is moderately high, resulting in a low initial swelling, while the degree of crosslinking is not too high, so the swelling increases over time. On the other hand, if the solution temperature is too low, it will take a long time for the reaction to proceed, or the reaction may not proceed at all. Therefore, from the viewpoint of allowing the reaction to proceed sufficiently in a short time and generating a moderate number of crosslinking sites, it is preferable to carry out the polymer crosslinking reaction at a temperature of 0°C to less than 60°C, and more preferably at 0°C to less than 50°C.

[0061] By appropriately changing these manufacturing conditions, the initial degree of swelling of the composite layer can be adjusted to the range described above.

[0062] [Other embodiments] It should be noted that the embodiments described above are exemplary embodiments of the present invention, and it goes without saying that the present invention may include embodiments other than those described above within the scope of its core technical concept. [Examples]

[0063] The present invention will be described in detail based on examples, but the present invention is not limited to these examples.

[0064] The weight-average molecular weights listed below are the manufacturer's published values ​​for those with a manufacturer's name, and for those without a specific mention, they were measured by gel permeation chromatography (GPC) using 5 mM CF3COONa hexafluoropropanol (HFIP) solvent, with polymethyl methacrylate (PMMA) used as the standard substance. Similar results can be obtained using any instrument, but in this example, a Shodex GPC-104 (detector: RI, column: HFIP-606M x 2) manufactured by Resonaq was used.

[0065] [Experiment 1] In Experiment 1, we investigated the relationship between the initial swelling degree of the medical film, its ease of repositioning, ease of unfolding after peeling, tensile strength, and adhesive strength.

[0066] 1. Preparation of medical films 1-1. Preparation of Crosslinked Polymer Materials 1-1-1. Preparation of HA / CMC condensate-1 1,650 mg of hyaluronic acid (HA) (manufactured by Kewpie Corporation, molecular weight 2.2 to 2.5 million) and 750 mg of carboxymethylcellulose (CMC) (manufactured by Tokyo Chemical Industry Co., Ltd., molecular weight 250,000, degree of etherification 0.5 to 0.8) were weighed. HA was added to a beaker containing 300 mL of ultrapure water and dissolved, then CMC was added and dissolved to obtain a mixed solution. Subsequently, 0.1 N HCl was added to adjust the pH of the contents to 4.50 to 5.20 to obtain the HA / CMC solution. 3,180 mg of ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (manufactured by Dojin Chemical Laboratories Co., Ltd.) was weighed and dissolved in 7.5 mL of ultrapure water to obtain the EDC solution. The HA / CMC solution was stirred at 25°C at a stirring speed of 600 rpm, and an appropriate amount of 0.1N HCl was added to adjust the pH to 4.70-5.10, while the entire volume of the EDC solution was added. After adding the solution, the mixture was stirred for approximately 120 minutes until the pH stopped fluctuating 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 stirred in ultrapure water. The dialysate (ultrapure water) was completely replaced three times during the 36 hours from the start of dialysis to obtain HA / CMC condensate-1 (crosslinked polymer material) (condensate 1).

[0067] 1-1-2. Preparation of HA / CMC condensate-2 4,400 mg of hyaluronic acid (HA) (manufactured by Kewpie Corporation, molecular weight 2.2 million) and 2,000 mg of carboxymethylcellulose (CMC) (manufactured by Tokyo Chemical Industry Co., Ltd., molecular weight 1,500,000, degree of etherification 0.5-0.8) were weighed. HA was added to a beaker containing 800 mL of ultrapure water and dissolved, then CMC was added and dissolved to obtain an HA / CMC solution. 8,500 mg of ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (manufactured by Dojin Chemical Laboratories Co., Ltd.) was weighed and dissolved in 20.0 mL of ultrapure water to obtain an EDC solution. While stirring the HA / CMC solution at 80°C at a stirring speed of 800 rpm, 0.1 N HCl was added to adjust the pH to 4.50-5.20, and the entire volume of the EDC solution was added. After adding, the mixture was stirred for approximately 120 minutes until the pH stopped fluctuating to obtain the reaction solution. Finally, the agitated reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 12,000 to 14,000 and stirred in ultrapure water. The dialysate (ultrapure water) was changed three times during the 36 hours from the start of dialysis to obtain HA / CMC condensate-2 (condensate 2).

[0068] 1-1-3. Preparation of HA / CMC condensate-3 HA / CMC condensate-3 (condensate 3) was obtained in the same manner as the preparation of HA / CMC condensate-1, except that the HA / CMC solution was stirred at a stirring speed of 200 rpm and the EDC solution was added.

[0069] 1-1-4. Preparation of HA / CMC condensate-4 HA / CMC condensate-4 (condensate 4) was obtained in the same manner as the preparation of HA / CMC condensate-1, except that the EDC solution was added while stirring the HA / CMC solution at a stirring speed of 800 rpm.

[0070] 1-1-5. Preparation of HA / CMC condensate-5 HA / CMC condensate-5 (condensate 5) was obtained in the same manner as the preparation of HA / CMC condensate-1, except that the HA / CMC solution was stirred at 60°C and the EDC solution was added.

[0071] 1-1-6. Preparation of HA / CMC condensate-6 While stirring the HA / CMC solution at 40 °C, HA / CMC condensate-6 (condensate 6) was obtained in the same manner as the preparation of HA / CMC condensate-1, except that the EDC solution was added.

[0072] The concentrations of condensates 1 to 6 ((mass of HA used as material + mass of CMC) / (mass of HA, CMC, and water used during reaction)) were all 0.77 wt%.

[0073] 1-2. Preparation of Medical Films The biodegradable resins shown in Table 1 were prepared. For the powdery ones, those that passed through a sieve with a mesh size of 38 μm were used, and for the non-woven ones, those with a basis weight of 10.5 g / m 2 were used.

[0074]

Table 1

[0075] 1-2-1. Preparation of Film 1 100 g of HA / CMC condensate-1 was weighed and added to a beaker. 210.5 mg of Resin 3 was weighed and added to the HA / CMC condensate-1 in the beaker, and then stirred. A 11×11 cm frame was made on a glass plate, and the condensate 1 added with PGA powder was poured into the frame. It was dried at 30 °C for about 3 days. After drying, heat treatment was performed using a hot press machine at 90 °C for 15 minutes and then at 120 °C for 10 minutes to obtain Film 1.

[0076] 1-2-2. Preparation of Film 2 Film 2 was obtained in the same manner as the preparation of Film 1, except that Resin 3 was replaced with Resin 2.

[0077] 1-2-3. Preparation of Film 3 100g of condensate 1 was weighed and added to a beaker. The contents of the beaker were stirred. An 11 x 11 cm frame was prepared on a glass plate, and 50g of condensate 1 was poured into the frame. Three pieces of resin 4, which is a nonwoven fabric cut to 11 x 11 cm (approximately 210.0 mg), were stacked on top of the resin, filling the frame without any gaps, and covering the condensate 1. After confirming that the PGA nonwoven fabric had adhered to the HA / CMC condensate-1, the remaining 50g of HA / CMC condensate-1 was poured into the frame. It was dried at a temperature of 30°C for approximately 3 days. After drying, heat treatment was performed using a hot press at 90°C for 15 minutes, followed by 120°C for 10 minutes, to obtain film 3.

[0078] 1-2-4. Preparation of Film 4 Film 4 was obtained in the same manner as film 1, except that resin 3 was replaced with resin 5.

[0079] 1-2-5. Preparation of Film 5 Film 5 was obtained in the same manner as film 1, except that resin 3 was replaced with resin 6.

[0080] 1-2-6. Preparation of Film 6 Film 6 was obtained in the same manner as film 1, except that resin 3 was replaced with resin 1.

[0081] 1-2-7. Preparation of Film 7 Film 7 was obtained in the same manner as film 1, except that condensate 1 was replaced with condensate 3.

[0082] 1-2-8. Preparation of Film 8 Film 8 was obtained in the same manner as film 1, except that condensate 1 was replaced with condensate 6.

[0083] 1-2-9. Preparation of Film 9 Film 9 was obtained in the same manner as film 1, except that the amount of resin 3 added was 701.7 mg.

[0084] 1-2-10. Preparation of film 10 Film 10 was obtained in the same manner as in the preparation of film 1, except that the amount of resin 3 added was 70.2 mg.

[0085] 1-2-11. Preparation of Film 11 Film 11 was obtained in the same manner as film 1, except that the amount of resin 3 added was 140.3 mg.

[0086] 1-2-12. Preparation of Film 12 A commercially available medical film (Seprafilm, manufactured by Baxter Corporation; "Seprafilm" is a registered trademark of Baxter International Corporation) was used as film 12.

[0087] 1-2-13. Preparation of Film 13 Film 13 was obtained in the same manner as film 1, except that biodegradable resin was not added.

[0088] 1-2-14. Preparation of Film 14 Film 14 was obtained in the same manner as film 1, except that resin 3 was replaced with resin 7.

[0089] 1-2-15. Preparation of Film 15 90 g of condensate 2 was weighed and added to a beaker. 252.0 mg of resin 8 was weighed and added to the beaker, and the contents of the beaker were stirred. An 11 × 11 cm frame was made on a glass plate using silicone rubber, and condensate 2 with PGA powder added was poured into the frame. After drying by air drying at room temperature, heat treatment was performed using a hot press at 90°C for 15 minutes, followed by 120°C for 10 minutes to obtain film 15.

[0090] 1-2-16. Preparation of Film 16 Film 16 was obtained in the same manner as film 15, except that biodegradable resin was not added.

[0091] 1-2-17. Preparation of Film 17 Film 17 was obtained in the same manner as film 1, except that condensate 4 was used.

[0092] 1-2-18. Preparation of Film 18 Film 18 was obtained in the same manner as film 1, except that condensate 5 was used.

[0093] Table 2 shows the type, concentration, and amount of HA / CMC condensate used to prepare each sample, the type and amount of biodegradable resin used, and the parts by weight of the biodegradable resin per 100 parts by mass of HA / CMC.

[0094] [Table 2]

[0095] 2. Evaluation 2-1. Swelling degree Films 1 through 18 were each cut into 1cm x 1cm pieces using a rotary cutter to create samples.

[0096] 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 PB solution.

[0097] Each sample was placed on a blue plastic sheet along with a ruler, and photographed to show the outline of each sample.

[0098] 5 mL of the prepared PB solution was added to a 10 mL vial, and each sample was immersed in the PB solution for 10 seconds. After that, the samples were removed and placed on a blue sheet with a ruler, and the outline of the sample was photographed. After the photograph, the samples were returned to the PB solution and immersed for 30 seconds, then the samples were removed and placed on a blue sheet with a ruler, and the outline of the sample was photographed. After immersion for 60 seconds, the samples were removed and placed on a blue sheet with a ruler, and the outline of the sample was photographed. After immersion for 300 seconds, the samples were removed and placed on a blue sheet with a ruler, and the outline of the sample was photographed. After immersion for 900 seconds, the samples were removed and placed on a blue sheet with a ruler, and the outline of the sample was photographed.

[0099] From the captured images, the lengths of the four sides of each sample were determined. The average of the four side lengths of the sample before immersion in PB solution was defined as l0, and the average of the four side lengths after each immersion time was defined as l1. Then, the ratio of these (l1) was calculated. 3 / l0 3 The degree of swelling after each immersion time was calculated and defined as the degree of swelling.

[0100] The degree of swelling for each sample is shown in Table 1.

[0101] [Table 3]

[0102] [Consideration] Table 3 shows that films 1 to 11 all exhibit high swelling after a predetermined time has elapsed, while suppressing initial swelling.

[0103] 2-2-1. Ease of repositioning Films 1 through 18 were placed on a simulated organ (manufactured by Kotobuki Medical, VTT-STANDARD-TYPE, VTT-STD) that had been thoroughly moistened with ultrapure water. After wiping off the surface moisture with a Kimwipe, the 1x2cm films 1 through 18 were placed on the simulated organ and left undisturbed for 30 seconds. Then, they were peeled off the simulated organ and reattached to an adjacent area of ​​the same simulated organ. Five monitors evaluated the ease of reattachment on a 9-point scale, with 1 being difficult and 9 being easy. The average of the monitors' evaluations was used as the ease of reattachment for each film.

[0104] 2-2-2. Ease of spreading after peeling Simulated organs (manufactured by Kotobuki Medical, VTT-STANDARD-TYPE, VTT-STD) were thoroughly moistened with ultrapure water, and the surface moisture was wiped off with Kimwipes. Then, 200 μL of ultrapure water was poured over the entire surface of the simulated organ. Films 1 to 18, each measuring 1 x 3 cm, were placed on the simulated organ and left for 30 seconds. After that, they were peeled off the organ and reattached to an adjacent area of ​​the same simulated organ. Five monitors evaluated the condition of the film when it was reattached. The average of the monitors' evaluations was used as the ease of unfolding each film after peeling. The evaluation criteria were as follows, with a score of 4 or higher indicating ease of reattachment. 1: Cannot be spread open, torn 2: It takes more than 90 seconds to spread It can be spread out within 3:30 to 90 seconds. 4. The entire thing can be rolled up and then unrolled within 30 seconds. 5: Part of it is rolled up and unrolled.

[0105] Table 4 shows the evaluation results for ease of repositioning and ease of spreading after peeling.

[0106] [Table 4]

[0107] [Consideration] Table 4 shows that films 1 to 11 have a low initial swelling degree, indicating that they are easy to reposition and can be easily spread out after being applied and removed. Furthermore, according to the inventors' findings, the swelling degree of a film after being left standing for 30 seconds with water on one side is considered to be equivalent to the swelling degree of a film after being immersed entirely in PB solution for 10 seconds. Therefore, Tables 3 and 4 show that medical films with a low swelling degree after 10 seconds of immersion in PB solution have high repositionability.

[0108] 2-3. Tensile Strength Films 1, 5-6, and 9-13 (film 12 is Seprafilm (Baxter)) were cut into strips measuring 40 mm on the long side and 10 mm on the short side to prepare the samples. The tensile strength of the samples, which had been wetted with ultrapure water, was measured using a creep meter (Yamaden Co., Ltd., RE2-33005B). The sample was fixed to the chuck so that the distance between the chucks was 20 mm, and a Berglin (AION Co., Ltd., part number E-2) soaked in ultrapure water was applied to the center 10 mm x 10 mm of one side of the sample and left for 10 seconds. After 10 seconds, the sample was pulled at 0.1 mm / sec and the tensile strength (MPa) was measured.

[0109] Table 5 shows the tensile strength measurement results for each sample.

[0110] [Table 5]

[0111] [Consideration] Table 5 shows that medical films with a low initial degree of swelling do not lose strength easily when applied to organs, and are easier to peel off and reapply from organs. The cross-linked polymer material, which is a component of medical films, swells and gels when it absorbs water. Although the strength decreases as the film turns into a gel, it is thought that the decrease in strength of the medical film was slower due to the low initial degree of swelling. Furthermore, it is thought that films 5 and 6 showed high tensile strength because they used resins 6 and 1, which have small molecular weights, resulting in a larger amount of sustained acid release, which further slowed the decrease in strength of the medical film.

[0112] 2-4. Adhesion strength Films 1, 5-6, 12 (Seprafilm (Baxter)), and 13 were cut into strips measuring 50 mm on the long side and 10 mm on the short side to prepare the samples. Using a creep meter (Yamaden Co., Ltd., RE2-33005B), the surface adhesion strength to a simulated organ (AS ONE Corporation, silicone rubber sheet (3 mm thick), part number 6-611-05) moistened with ultrapure water was measured. At this time, mending tape (3M Japan, part number 810-1-18, base material: acetate film, adhesive: acrylic) was applied to the opposite side of each sample from the side in contact with the simulated organ. The short side of the measurement sample was fixed to one tension chuck by 5 mm, and the simulated organ was fixed to the other tension chuck. The long side of the sample (40 mm) and the short side (10 mm) were brought into close contact with the moistened simulated organ and left for 900 seconds. The adhesion strength (N) was measured after 900 seconds by pulling at 0.05 mm / sec. For comparative examples, measurements were also taken for commercially available synthetic adhesion prevention materials, Interseed (manufactured by Johnson & Johnson) and Tenalef (manufactured by Gunze).

[0113] Table 6 shows the results of the adhesion strength measurements for each sample.

[0114] [Table 6]

[0115] [Consideration] Table 6 shows that films 1, 5, and 6 exhibit high adhesion strength, although there were differences in adhesion strength among the films. This is thought to be due to the release of acid by the glycolic acid component in the glycolic acid (co)polymer upon contact with water, and the suppression of decomposition of the crosslinked polymer material by this acid. Film 6 has a smaller molecular weight of glycolic acid (co)polymer than film 1 and a larger amount of glycolic acid in the glycolic acid (co)polymer than film 5. As a result, a larger amount of acid is released, and consequently, the decomposition of the crosslinked polymer material is suppressed. Therefore, it is thought that film 6 has higher adhesion strength than film 1, which shows a similar degree of swelling after 900 seconds, and also higher adhesion strength than film 5 even with a lower degree of swelling.

[0116] [Experiment 2] In Experiment 2, the relationship between the thickness and swelling degree of medical films was investigated using films 1 and 6, as well as films with varying thicknesses.

[0117] 1. Preparation of medical films 1-1. Film 1-2 53 g of condensate 1 was weighed and added to a beaker. 111.6 mg of resin 3 was weighed and added to the beaker, and the mixture was stirred. An 11 × 11 cm frame was prepared on a glass plate, and condensate 1 with resin 3 added was poured into the frame. The mixture was dried at 30°C for approximately 3 days. After drying, the film 1-2 was obtained by heat treatment using a hot press at 90°C for 15 minutes, followed by 120°C for 10 minutes.

[0118] 1-2. Film 1-3 90 g of condensate 1 was weighed and added to a beaker. 189.5 mg of resin 3 was weighed and added to the beaker, and film 1-3 was obtained by preparing it in the same manner as film 1-2.

[0119] 1-3. Film 1-4 200 g of condensate 1 was weighed and added to a beaker. 421 mg of resin 3 was weighed and added to the beaker, and film 1-3 was obtained by preparing it in the same manner as film 1-2.

[0120] 1-4. Film 6-2 50g of condensate 1 was weighed and added to a beaker. Film 6-2 was then obtained in the same manner as in the preparation of film 1-2, except that resin 3 was not added.

[0121] 1-5. Film 6-3 75g of condensate 1 was weighed and added to a beaker. Film 6-3 was then obtained in the same manner as in the preparation of film 1-2, except that resin 3 was not added.

[0122] 2. Measurement The degree of swelling of film 1, films 1-2 to 1-4, film 13, film 13-2, and film 13-3 was measured using the same procedure as in Experiment 1.

[0123] Table 7 shows the results of the swelling degree measurements for each sample.

[0124] [Table 7]

[0125] As shown in Table 7, the greater the thickness, the lower the initial swelling degree of the medical film.

[0126] This application claims priority to Japanese Patent Application No. 2023-077267, filed on 9 May 2023. The matters set forth in the original specification and claims of said application are incorporated herein by reference. [Industrial applicability]

[0127] The medical film according to the present invention has good repositioning properties for application to the affected area.

Claims

1. A crosslinked polymer material comprising at least one polysaccharide selected from the group consisting of alginic acid, hyaluronic acid, carboxymethylamylose, and carboxymethylcellulose, wherein the polysaccharide is crosslinked with a crosslinking agent, A medical film that is an anti-adhesion material comprising a glycolic acid homopolymer or a copolymer containing a structure derived from glycolic acid, The medical film has a ratio q1 (V1 / V0) of volume V1 after immersion for 10 seconds to volume V0 before immersion in phosphate buffer (PB) with a pH of 6.0 and a concentration of 0.2 M, and The ratio q3 (V3 / V0) of the volume V3 after immersion for 900 seconds to the volume V0 before immersion in phosphate buffer (PB) at pH 6.0 and concentration 0.2 M is 1.8 or higher. Medical film.

2. The medical film according to claim 1, wherein the crosslinking agent is ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

3. The aforementioned medical film has a ratio q2 (V2 / V0) of volume V2 after immersion for 60 seconds to volume V0 before immersion in phosphate buffer (PB) with a pH of 6.0 and a concentration of 0.2 M, which is 1.9 or less. The medical film according to claim 1.

4. The medical film contains, with respect to 100 parts by mass of the crosslinked polymer material, 5 to 95 parts by mass of a copolymer containing a glycolic acid homopolymer or a structure derived from glycolic acid. The medical film according to claim 1.

5. The aforementioned glycolic acid homopolymer is included, The medical film according to claim 1.

6. The thickness is between 15 μm and 500 μm. The medical film according to claim 1.

7. A step of preparing a reaction solution by stirring at least one polysaccharide selected from the group consisting of alginic acid, hyaluronic acid, carboxymethylamylose, and carboxymethylcellulose, and a crosslinking agent capable of introducing cationic groups into the polysaccharide, at a temperature of 0°C or higher and less than 60°C, and at a stirring speed of 50 rpm or higher and less than 750 rpm. A step of mixing the reaction solution with particles containing a glycolic acid homopolymer or a copolymer containing a structure derived from glycolic acid, The process includes a step of forming a film from the reaction solution containing the aforementioned particles. A method for manufacturing medical films, which are used as adhesion prevention materials.

8. The method for producing a medical film according to claim 7, wherein the crosslinking agent is ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

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