Medical film and method for manufacturing the same

Abstract

Provided is a medical film having particles containing polyglycolic acid, the particles demonstrating good dispersibility and suppressed aggregation. This medical film comprises: a crosslinked polymer material; and a PGA dispersoid, which is particles, or an aggregate thereof, containing a polymer in which the proportion of a structural unit derived from glycolic acid is 40 mass% or more. The content of the PGA dispersoid is 2 parts by weight to 40 parts by weight with respect to 100 parts by weight of the crosslinked polymer material. The coefficient of variation CV of the number of particles included in a rectangular region is 0.6 or less, as calculated from the number of particles measured in each of rectangular regions which have a size of 5 mm × 4 mm and which are located at 16 positions set on the surface of the medical film so as not to overlap with each other.

Description

Technical Field

[0001] The present invention relates to a medical film and a method for manufacturing the same.

Background Art

[0002] A medical film (anti-adhesion material) for preventing adhesion between an organ and other organs when the wound heals by attaching to the organ after surgery is known. Biodegradable materials such as a cross-linked product of hyaluronic acid and carboxymethyl cellulose are used as the anti-adhesion material.

[0003] A medical film containing a cross-linked polymer material and a disintegration retarder containing a biodegradable polyester such as polyglycolic acid (PGA) can maintain its shape in the living body for a long time (Patent Document 1). Patent Document 1 describes that the disintegration retarder releases an acid to suppress the disintegration of the shape of the medical film. Further, Patent Document 1 describes that the smaller the molecular weight of PGA, the higher the acid release ability.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] When the inventors added particulate PGA to a cross-linked polymer material to produce a medical film, they found that if the dispersion of the PGA particles in the medical film was non-uniform, the shape-maintaining effect of the medical film did not increase. If the maintenance effect of the film does not increase, for example, when used as an anti-adhesion material, the film may break when the body or the organ moves after being attached to the organ, and the barrier function for preventing adhesion may decrease.

[0006] The present invention aims to provide a medical film having particles containing polyglycolic acid, which can maintain its shape in a living body for a long period of time, and a method for producing the medical film. [Means for solving the problem]

[0007] One embodiment of the present invention for solving the above problems relates to the following medical films [1] to [5]. [1] A medical film comprising a crosslinked polymer material and a PGA dispersed phase which is a polymer containing constituent units derived from glycolic acid or an aggregate thereof, The polymer having glycolic acid as a constituent unit is a polymer in which the proportion of constituent units derived from glycolic acid to the total mass of the polymer is 40% by mass or more and 100% by mass or less, The content of the PGA dispersed phase relative to 100 parts by weight of the crosslinked polymer material is 2 parts by weight or more and 40 parts by weight or less. A medical film wherein the coefficient of variation CV of the number of particles contained in a rectangular area, determined from the number of particles measured in each of 16 rectangular areas measuring 5 mm x 4 mm in size, which are set on the surface of the medical film so as not to overlap with each other, is 0.6 or less. [2] In the 16 rectangular areas, The medical film according to [1], wherein the average number of aggregates having a diameter five times or more than the average diameter of the PGA dispersed mass contained in the rectangular region is three or less. [3] The medical film according to [1] or [2], wherein the number average molecular weight of the polymer is 10,000 or more and 150,000 or less. [4] A medical film according to any one of [1] to [3], wherein the tensile strength of the polymer film is 11 MPa or more and 100 MPa or less. [5] A medical film described in any of [1] to [4], which is an adhesion prevention material.

[0008] Furthermore, an embodiment of the present invention for solving the above problems relates to a method for manufacturing the medical film described in [6] below. [6] A step of mixing a solution or dispersion containing a crosslinked polymer material with particles containing a polymer having constituent units derived from glycolic acid to composite the crosslinked polymer material and the particles, The process includes forming a film from the composite of the crosslinked polymer and particles, The polymer is a polymer in which the proportion of constituent units derived from glycolic acid to the total mass of the polymer is 40% by mass or more and 100% by mass or less, In the compounding step, the viscosity of the solution or dispersion containing the crosslinked polymer material, measured at 25°C and 10 rpm, is 2,000 mPa·s or higher. In the compounding step, the number-average molecular weight of the polymer is 15,000 or more and 170,000 or less. A method for manufacturing medical films. [Effects of the Invention]

[0009] The present invention provides a medical film having particles containing polyglycolic acid, which maintains its shape in a living body for a long time and is resistant to tearing, and a method for manufacturing the medical film. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1A is a photograph showing the appearance of film 4 after immersion in pH 8.0 phosphate buffer (PB) for 45 hours, and Figure 1B is a photograph showing the appearance of film 9 after immersion in pH 8.0 phosphate buffer (PB) for 45 hours. [Modes for carrying out the invention]

[0011] [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 particles containing polymers having constituent units derived from glycolic acid (hereinafter also simply referred to as "PGA particles") or a PGA dispersed phase which is an aggregate thereof.

[0012] [Crosslinked polymer material] The crosslinked polymer material is a polymer material that shows swelling when immersed in ultrapure water at 15 - 25°C. The crosslinked polymer material is one in which the same or different types of polymer materials are physically or chemically crosslinked, and is typically a gel-like polymer. The crosslinked polymer material is preferably composed of a polymer having solubility after showing swelling in water.

[0013] The crosslinked polymer material can be, for example, a crosslinked product of a polyanionic polymer. The polyanionic polymer may be a polymer having a repeating structure with an anionic group, or a polymer obtained by chemically modifying a polymer compound with an anionic substituent. The anionic group can be a carboxyl group, a hydroxy group, a sulfo group, etc. Note that the anionic group may partially form a salt with an alkali metal such as sodium and potassium, or an alkaline earth metal such as calcium and magnesium.

[0014] The polymer material may be a polysaccharide, a protein, or a synthetic polymer. Among these, polysaccharides and proteins are preferred.

[0015] Examples of saccharides that are polyanionic 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.

[0016] Examples of the protein which is a polyanionic polymer material include gelatin, collagen, albumin, fibrin, and chemical modifications thereof. The protein may be a polymer (polyamino acid) of amino acids having anionic groups such as polyglutamic acid and polyaspartic acid. Among these, acid-treated gelatin having a carboxyl group generated by hydrolysis of an acid amide is preferable.

[0017] The crosslinking of the polymer material may be a physical crosslinking formed by introducing a cationic substituent into the polyanionic polymer, or may be a chemical crosslinking formed by reacting the polymer materials directly or through other molecules. The crosslinking of the polymer material can be obtained by subjecting the above polymer material to a crosslinking treatment such as ultraviolet treatment, heat treatment, and crosslinking agent treatment. Among these, crosslinking agent treatment is preferable.

[0018] Examples of the crosslinking agent used for the crosslinking agent treatment include ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonic acid. By treating with these crosslinking agents, a cationic group can be introduced into the polyanionic polymer. Then, the molecules of the polymer material can be physically crosslinked by the intermolecular interaction between the anionic group of one molecule and the cationic group of another molecule. Among these, EDC is preferable because it is easy to handle.

[0019] The crosslinking treatment with the 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 medium at this time may be adjusted according to the type of the crosslinking agent. For example, when using EDC as the crosslinking agent, it is preferable to appropriately add an acid such as 0.01M hydrochloric acid to make the pH during the reaction low (for example, pH 4.0 to 5.5) to 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.

[0021] Furthermore, crosslinking may occur between multiple different types of polymers. This crosslinking may be chemical crosslinking resulting from the reaction of these polymers with each other, or it may be physical crosslinking achieved 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] (PGA dispersion) PGA dispersed phase consists of particles or aggregates containing a polymer containing PGA (hereinafter also simply referred to as "PGA polymer"). During the manufacture of medical films, a cross-linked polymer material and PGA particles are compounded, and then a film is formed (film-forming). At this time, the PGA particles may aggregate to form aggregates. Medical films may contain only PGA particles, only aggregates of PGA particles, or both.

[0023] When the PGA dispersed phase comes into contact with water, such as when a medical film is attached to an organ, it gradually releases acid through hydrolysis. This released acid suppresses the breakdown of the cross-linked polymer material, thereby extending the period during which the film can maintain its structure in the body.

[0024] Furthermore, "containing PGA" means that the proportion of constituent units derived from glycolic acid relative to the total mass of the polymer is 40% by mass or more and 100% by mass or less.

[0025] The PGA polymer is not particularly limited in composition as long as the proportion of constituent units derived from glycolic acid is 40% by mass or more. For example, the polymer can be a homopolymer of glycolic acid, or a copolymer of glycolic acid with hydroxycarboxylic acids such as lactic acid, hydroxypropionic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, and hydroxybenzoic acid, or lactones such as caprolactone. The PGA dispersed phase may be a mixture of these with a water-soluble polymer whose biosafety has been confirmed, such as polyethylene glycol, or a copolymer of glycolic acid and polyethylene glycol, etc.

[0026] The proportion of PGA polymer contained in the PGA dispersed phase is preferably 50% to 100% by mass, more preferably 60% to 100% by mass, even more preferably 70% to 100% by mass, even more preferably 80% to 100% by mass, and particularly preferably 90% to 100% by mass, based on the total mass of the PGA dispersed phase.

[0027] The PGA polymer preferably has a number average molecular weight of 10,000 to 150,000, more preferably 10,000 to 100,000, and even more 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 medical film after it has been attached to an organ to be maintained for a longer period of time. Furthermore, by making the number average molecular weight larger, the dispersibility of the particles can be improved.

[0028] The number-average molecular weight of PGA polymers can be determined by measuring the number-average molecular weight of PGA polymers in PGA particles separated from medical films in accordance with ISO 16014-1:2012. Specifically, gel permeation chromatography (GPC) (Resonac Corporation, Shodex GPC-104, detector: RI, column: HFIP-606M x 2) is used, with a solution of CF3COONa dissolved in hexafluoropropanol (HFIP) at 5 mM as the solvent, and polymethyl methacrylate (PMMA) as the standard substance.

[0029] The average particle diameter of PGA particles is not particularly limited, but is preferably between 0.1 μm and 30 μm. The smaller the average particle diameter, the larger the surface area of ​​the particles, which increases the decomposition rate of the PGA particles and the larger the contact area with the cross-linked polymer material, allowing the medical film to maintain its shape for a longer period after being attached to an organ. On the other hand, from the viewpoint of suppressing excessive aggregation of PGA particles and the resulting decrease in dispersion uniformity, it is preferable that the average particle diameter of the PGA particles be somewhat large. Therefore, the average particle diameter of the PGA particles is preferably between 1 μm and 20 μm, more preferably between 1 μm and 15 μm, and even more preferably between 1 μm and 10 μm.

[0030] The average particle diameter of PGA particles can be measured by observing 200 or more unaggregated PGA particles at 100x magnification using a digital microscope (Keyence HVX7000) and acquiring digital images. The acquired digital images are loaded into image analysis software, and the circumference length of the PGA particles is measured using an image analysis device. The arithmetic mean (average) and standard deviation of the circumference lengths of the PGA particles are calculated, and measurements whose difference from the average is more than three times the standard deviation are excluded to obtain the average circumference length. The equivalent diameter of the particles obtained by dividing the average circumference length of the particles by pi (3.1416) is taken as the average particle diameter of the PGA particles.

[0031] Image processing can be performed by loading the images into MIPAR (manufactured by LightStone) and setting the conditions of the image analysis software as follows. Set “Smart Cluster” to “Fill Type: Class”, “Classes: 4~10”, “Edge Type: Dark to Bright”, “Edge Clean: 0~5”, and “Speed: 2”. Set “Basic Threshold” to “Value: 80~150”. “Reject Features”, “Measurement: Area”, “Target: Objects”, “Edges: Include”, “Units: μm 2 ”, “Threshold Value: 100”, “Type: Reject Features < / =”とする。

[0032] By increasing the mixing ratio of PGA dispersed phase to the crosslinked polymer material, the period during which the medical film maintains its shape in vivo can be extended. On the other hand, by keeping the mixing ratio within an appropriate range, excessive aggregation of PGA particles can be suppressed, improving dispersion uniformity and preventing a shortening of the period during which the medical film maintains its shape. The mass ratio of PGA dispersed phase to 100 parts by mass of crosslinked polymer material is 2 parts by mass or more and 40 parts by mass or less, preferably 8 parts by mass or more and 30 parts by mass or less, more preferably 10 parts by mass or more and 30 parts by mass or less, even more preferably 15 parts by mass or more and 30 parts by mass or less, and particularly preferably 20 parts by mass or more and 30 parts by mass or less.

[0033] The mass ratio of PGA dispersed phase contained in a medical film can be determined by removing the cross-linked polymer material, measuring the mass of the remaining particles to determine the mass of the PGA dispersed phase, and then measuring the mass of the removed cross-linked polymer material to calculate the mass of the PGA dispersed phase relative to the mass of the cross-linked polymer material. If the cross-linked polymer material is something that can be dissolved and removed, such as hyaluronic acid and its cross-linked forms, the material can be dissolved and removed using an appropriate acid compound. The mass of the cross-linked polymer material can then be determined by dividing the mass of the medical film before removal by the mass of the water contained in the film and the mass of the remaining residue, such as the PGA dispersed phase, after removal.

[0034] In the medical film according to this embodiment, excessive aggregation of PGA particles is suppressed, resulting in a uniform dispersion of PGA particles. This increases the decomposition rate of PGA particles and increases the contact area with the crosslinked polymer material, thereby extending the period during which the medical film can maintain its shape.

[0035] In this embodiment, the coefficient of variation is used as an index to represent the dispersibility of PGA particles in a medical film. Since the coefficient of variation is not affected by the average particle size of the PGA particles, it is possible to evaluate the dispersibility of particles with different average particle sizes.

[0036] Specifically, the medical film has a coefficient of variation (CV) of 0.6 or less, which is determined from the number of PGA particles measured in each of 16 non-overlapping rectangular areas measuring 5 mm x 4 mm on its surface. The coefficient of variation (CV) is an index indicating the degree to which PGA particles are uniformly dispersed in the medical film. A smaller coefficient of variation (CV) indicates that the PGA particles are uniformly dispersed within the medical film. A coefficient of variation (CV) of 0.5 or less is preferred, 0.4 or less is more preferred, 0.3 or less is even more preferred, and 0.2 or less is particularly preferred.

[0037] The coefficient of variation (CV) can be calculated using the following method.

[0038] Sixteen rectangular regions are set on the surface of a medical film using the method described below. These regions are observed at 100x magnification using a digital microscope (Keyence HVX7000) and digital images are acquired. The acquired images are loaded into image analysis software, and the number of PGA particles contained in each rectangular region is determined from the outer length of the PGA dispersed mass. Specifically, the average number of PGA particles and the standard deviation value are calculated in the 16 rectangular regions using the method described below. The coefficient of variation (CV) of the number of particles contained in each rectangular region is obtained by dividing the calculated standard deviation value by the average number of particles. The image analysis can be performed under the same conditions as the calculation of the average particle diameter of PGA particles described above.

[0039] In this case, one side of the medical film is defined as the x-axis, and the other side of the film perpendicular to the x-axis is defined as the y-axis, with the intersection of the x-axis and y-axis being defined as coordinate point x0y0. The medical film is divided into 5 equal parts along the x-axis, and coordinate points x0y0, x1y0, x2y0, ..., x5y0 are set along the x-axis starting from x0y0. Similarly, the medical film is divided into 5 equal parts along the y-axis, and coordinate points x0y0, x0y1, x0y2, ..., x0y5 are set along the y-axis starting from x0y0. In this coordinate plane, 16 rectangular regions, each measuring 5mm x 4mm, are defined, each containing one of the 16 points x1y1, x2y1, x3y1, x4y1, x1y2, x2y2, x3y2, x4y2, x1y3, x2y3, x3y3, x4y3, x1y4, x2y4, x3y4, and x4y4, and these regions do not overlap. Each of these regions is designated as rectangular region i (where i is an integer from 1 to 16). Similarly, when the planar view of the medical film is not approximately rectangular, 16 rectangular regions can be determined evenly from the entire planar direction of the medical film in the planar view using the same approach.

[0040] Let L(j) be the length of the perimeter of the PGA dispersed mass j observed in the rectangular region i. We assume that the PGA dispersed mass and PGA particles are spherical, that the diameter of the dispersed mass is proportional to the length of the perimeter of the PGA dispersed mass, and that the diameter of the PGA particles is proportional to the length of the perimeter of the PGA particles. Based on this assumption, the number of particles n(j) constituting the PGA dispersed mass j is calculated from the perimeter length L0 of one PGA particle and the perimeter length L(j) of the PGA dispersed mass j using Equation 1. When performing the following calculations, it is sufficient to use the perimeter length L0 of the PGA particles, which is obtained by setting a hypothetical average particle diameter or perimeter length of the PGA particles. For example, when performing the following calculations, we can assume that the average particle diameter of the PGA particles is 10 μm.

[0041]

number

[0042] From the number of PGA particles n(j) contained in each of the N PGA dispersed particles observed in rectangular region i, the total number of PGA particles X(i) in rectangular region i is calculated using Equation 2.

[0043]

number

[0044] The average number of particles X(ave), which is the average number of particles contained in the 16 rectangular regions, is calculated using Equation 3.

[0045]

number

[0046] Then, the standard deviation S of the number of particles observed in each rectangular region is determined, and the coefficient of variation CV of the number of particles contained in the rectangular region is obtained by dividing the standard deviation S by the average number of particles X(ave) using equation 4.

[0047]

number

[0048] The dispersibility of PGA particles can also be evaluated by the average diameter of the PGA dispersed in the medical film, or by the average number of aggregates (hereinafter also simply referred to as "5A aggregates") having a diameter five times or more than the average diameter of the PGA dispersed in the defined rectangular area. Specifically, the medical film preferably has an average diameter of 10 μm to 60 μm of PGA dispersed, more preferably 25 μm to 50 μm, and even more preferably 30 μm to 45 μm. Furthermore, the medical film preferably has an average number of 5A aggregates in the rectangular area of ​​three or less, more preferably two or less, even more preferably one or less, and particularly preferably zero.

[0049] The average diameter of the PGA dispersed mass and the average number of 5A aggregates in a rectangular region can be calculated using the following method.

[0050] A digital microscope is used to observe each rectangular region at 100x magnification and acquire a digital image. The acquired digital images are loaded into image analysis software, and the perimeter length of the PGA dispersed particles contained in each rectangular region is determined using the same method as when calculating the coefficient of variation CV. Assuming the PGA dispersed particles are spheres, the diameter D of the j-th dispersed particle i among the N dispersed particles observed in rectangular region i is calculated. (j) The outer length L of the PGA dispersed mass, which is determined by image processing. (j) We divide this by pi (π(3.1416)) and obtain it using formula 5.

[0051]

number

[0052] Then, the average diameter D(i) of the dispersed mass contained in the rectangular region i is calculated using equation 6.

[0053]

number

[0054] Furthermore, the average value D(ave) of the average diameter D(i) of the dispersed mass in 16 rectangular regions is calculated using Equation 7. In this embodiment, this D(ave) is taken as the average diameter of the PGA dispersed mass.

[0055]

number

[0056] Similarly, in each of the 16 rectangular regions, the average diameter D(i) of the aggregates and the number A(i) of aggregates with a diameter at least five times that of D(i) are measured. The average value A(ave) of the number of aggregates with a diameter at least five times that of D(i) in the 16 rectangular regions is calculated using Equation 8. In this embodiment, this A(ave) is taken as the average value of the number of 5A aggregates in the rectangular region.

[0057]

number

[0058] (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.

[0059] (strength) By effectively dispersing the PGA particles, the strength of the medical film when wet can be increased, thereby reducing the likelihood of tearing during application and reapplication. The tensile strength of the medical film when wet is preferably 11 MPa or higher, more preferably 13 MPa or higher, and even more preferably 15 MPa or higher. The upper limit of the tensile strength is not particularly limited, but it can be 100 MPa or lower.

[0060] [Method of manufacturing medical films] Medical films can be manufactured by crosslinking polymer materials, compounding them with PGA particles, and forming them into a film (film deposition).

[0061] The crosslinking of polymer materials can be carried out by methods appropriate to the polymer, such as ultraviolet treatment, heat treatment, and crosslinking agent treatment. For example, crosslinking with an EDC (electrolytic crosslinking agent) can be performed by adding EDC to a solution in which the polymer 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.

[0062] The compounding with PGA particles can be carried out by adding PGA particles to a solution or dispersion containing a crosslinked polymer material and stirring to mix them.

[0063] Film formation can be achieved by drying the composite of the crosslinked polymer material and PGA particles within a frame. Drying may be carried out by air drying at room temperature, freeze-drying, or by removing the solvent by heating. Alternatively, hot pressing (heating and pressurizing) may be performed. These drying methods may be combined.

[0064] Incidentally, according to the inventors' findings, reducing the molecular weight of the PGA polymer or the particle size of the PGA particles to enhance the shape retention effect makes aggregation of the PGA particles more likely, and the dispersion of the PGA particles tends to become uneven. When the PGA particles aggregate excessively and the dispersion becomes uneven, the shape retention effect of the film by the PGA particles becomes less effective. Furthermore, when the PGA particles aggregate excessively and the dispersion becomes uneven, the tensile strength of the medical film decreases when wet, making it more prone to tearing. This makes it difficult to attach the medical film as an adhesion prevention material to organs, or to peel it off an organ once it has been attached and reattach it to another organ. In addition, a medical film attached to an organ as an adhesion prevention material may stick to other organs unintended when the organ to which it is attached or the human body moves. Therefore, in order to extend the time that the medical film can maintain its shape in vivo and to make it less prone to tearing when wet, it is important to uniformly disperse the PGA particles and suppress excessive aggregation.

[0065] Furthermore, in the compounding process described above, the dispersibility of the PGA particles can be adjusted and excessive aggregation suppressed by adjusting the viscosity of the solution or dispersion containing the crosslinked polymer material, the average particle size of the PGA particles, and the amount of PGA particles added. From this viewpoint, the viscosity of the solution or dispersion containing the crosslinked polymer material, measured at 25°C and 10 rpm, is preferably 2,000 mPa·s or more and 60,000 mPa·s or less, more preferably 3,000 mPa·s or more and 60,000 mPa·s or less, and even more preferably 5,000 mPa·s or more and 50,000 mPa·s or less. Furthermore, from the viewpoint of improving thickness uniformity when forming a film, the viscosity of the solution or dispersion containing the crosslinked polymer material, measured at 25°C and 1 rpm, is preferably 5,000 mPa·s or higher, more preferably 8,000 mPa·s to 300,000 mPa·s, and even more preferably 15,000 mPa·s to 150,000 mPa·s.

[0066] The particle size of the composite PGA particles can be adjusted by the number-average molecular weight of the PGA polymer constituting the PGA particles. The larger the number-average molecular weight, the harder the particles tend to be, and the larger the particles tend to be when pulverized. The number-average molecular weight of the PGA polymer is preferably 15,000 to 170,000, more preferably 20,000 to 170,000, and even more preferably 30,000 to 170,000. Note that the number-average molecular weight of the PGA polymer may decrease during film manufacturing.

[0067] Normally, to improve the dispersibility of particulate matter added to a sol, the viscosity of the sol is reduced. However, when a solvent is added to lower the sol viscosity and thus the concentration, the dispersed PGA particles tend to move in the low-viscosity sol during drying after casting, leading to aggregation and uneven distribution of the PGA particles. Furthermore, when the concentration is reduced, a larger casting volume is required to produce a film with a certain thickness or higher. A larger casting volume tends to cause uneven distribution of the sol during drying after casting, resulting in thickness inconsistencies. Moreover, a larger casting volume further increases the likelihood of aggregation and uneven distribution due to particle movement during drying. In contrast, in this embodiment, the viscosity of the sol is increased to prevent excessive aggregation of the particles and to reduce film thickness inconsistencies.

[0068] Furthermore, increasing the viscosity of the solution or dispersion containing the cross-linked polymer material makes it less likely for the solution or dispersion to spill from the casting frame when placed in the dryer after casting, thus facilitating the manufacture of medical films. On the other hand, lowering the viscosity to a certain extent facilitates the dispersion of PGA particles and the transfer of the liquid during manufacturing. Therefore, by combining a sol with PGA particles of the aforementioned viscosity, it is possible to manufacture medical films with high dispersibility of PGA particles.

[0069] By adjusting these conditions, the dispersibility of PGA particles can be improved, reducing the amount of coarse aggregates formed by the aggregation of PGA particles in medical films. This also helps to suppress the shortening of the period during which PGA particles can maintain their structure in vivo and the decrease in their strength in vivo, which can result from the aggregation of PGA particles.

[0070] The film produced in this way can be used as a medical film.

[0071] (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.

[0072] Due to the characteristics 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.

[0073] When used for these various applications, the medical film may be used alone or as a laminate with other layers.

[0074] [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]

[0075] The present invention will be described in detail based on examples, but the present invention is not limited to these examples.

[0076] 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 and CMC were added to a beaker containing 300 mL of ultrapure water and stirred until completely dissolved. Then, 0.1 N HCl was added to adjust the pH of the contents to 4.80 to prepare 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 prepare the EDC solution. While stirring the HA / CMC solution at a stirring speed of 600 rpm, an appropriate amount of 0.1 N HCl was added to adjust the pH to 4.70 to 5.10, and the entire volume of the EDC solution was added. The reaction solution was stirred for approximately 120 minutes until the pH stabilized, and the reaction mixture was obtained. Finally, the stirred reaction solution was placed into a dialysis membrane with a molecular weight cutoff of 12,000 to 14,000 and stirred with 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 (solution of crosslinked polymer material).

[0077] The concentration of HA / CMC condensate-1 ((mass of HA and CMC used as materials) / (mass of HA, CMC, and ultrapure water used as materials)) was 0.77 wt%, the solution viscosity measured at 25°C and 1 rpm was approximately 30,000 mPa·s, and the viscosity measured at 10 rpm was approximately 8,000 mPa·s.

[0078] HA / CMC condensate-1 was diluted with ultrapure water to obtain HA / CMC condensate-2 (solution of crosslinked polymer material). The concentration of HA / CMC condensate-2 ((mass of HA and CMC used as materials) / (mass of HA, CMC, ultrapure water, and ultrapure water used for dilution)) was 0.67 wt%, and the viscosity of the solution measured at 25°C and 1 rpm was approximately 11,000 mPa·s, while the viscosity measured at 10 rpm was approximately 4,000 mPa·s.

[0079] HA / CMC condensate-1 was diluted with ultrapure water to obtain HA / CMC condensate-3 (solution of cross-linked polymer). The concentration of HA / CMC condensate-3 ((mass of HA and CMC used as materials) / (mass of HA, CMC, ultrapure water, and ultrapure water used for dilution)) was 0.41 wt%, the solution viscosity measured at 25°C and 1 rpm was approximately 1,500 mPa·s, and the viscosity measured at 10 rpm was approximately 9.50 mPa·s.

[0080] 1-2. Preparation of medical films The biodegradable polyester particles shown in Table 1 were prepared. All of these particles were passed through a sieve with a mesh size of 38 μm.

[0081] [Table 1]

[0082] 1-2-1. Preparation of Film 1 29.8 g of HA / CMC condensate-1 and 62.7 mg of biodegradable polyester particles (particle 3) were weighed and added to a beaker. The contents of the beaker with particle 3 were stirred with a spatula and subjected to ultrasonic waves for 1 minute. A 6 x 6 cm frame (frame thickness 2 cm) was prepared on a glass plate, and the HA / CMC condensate-1 with particle 3 added was poured into the frame. The glass plate was placed on a rotating sample table at a temperature of 30°C and dried while rotating for approximately 3 days. After drying, the film was peeled off the glass plate and heat-treated using a hot press at 90°C for 15 minutes, followed by 120°C for 10 minutes to obtain film 1.

[0083] 1-2-2. Preparation of Film 2 Film 2 was obtained in the same manner as film 1, except that the biodegradable polyester particles were set to particle 4 and the amount of particle 4 added was 10.5 mg.

[0084] 1-2-3. Preparation of Film 3 Film 3 was obtained in the same manner as in the preparation of Film 1, except that the biodegradable polyester particles were set to particle 4 and the amount of particle 4 added was set to 20.9 mg.

[0085] 1-2-4. Preparation of Film 4 Film 4 was obtained in the same manner as in the preparation of Film 1, except that the biodegradable polyester particles were made into particle 4 and the amount of particle 4 added was 62.7 mg.

[0086] 1-2-5. Preparation of Film 5 Film 5 was obtained in the same manner as in the preparation of Film 1, except that the amount of HA / CMC condensate-1 added was 59.6 mg and the amount of particle 4 added was 62.7 mg.

[0087] 1-2-6. Preparation of Film 6 Film 6 was obtained in the same manner as film 1, except that the biodegradable polyester particles were set to particle 6 and the amount of particle 6 added was 62.7 mg.

[0088] 1-2-7. Preparation of Film 7 Film 7 was obtained in the same manner as in the preparation of Film 1, except that HA / CMC condensate-1 was replaced with HA / CMC condensate-2, the amount of HA / CMC condensate-2 added was set to 33.8 g, and the amount of particle 4 added was set to 10.5 mg.

[0089] 1-2-8. Preparation of Film 8 Film 8 was obtained in the same manner as film 1, except that the biodegradable polyester particles were used as particle 8.

[0090] 1-2-9. Preparation of Film 9 Film 9 was obtained in the same manner as film 1, except that biodegradable polyester particles were used as particle 1.

[0091] 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 HA / CMC condensate-1 added was set to 59.6 g, the biodegradable polyester particles were set to particle 1, and the amount of particle 1 added was set to 67.7 mg.

[0092] 1-2-11. Preparation of Film 11 Film 11 was obtained in the same manner as in the preparation of film 1, except that the biodegradable polyester particles were used as particle 2.

[0093] 1-2-12. Preparation of Film 12 Film 12 was obtained in the same manner as film 1, except that the biodegradable polyester particles were set to particle 5.

[0094] 1-2-13. Preparation of Film 13 Film 13 was obtained in the same manner as film 1, except that the biodegradable polyester particles were set to particle 9.

[0095] 1-2-14. Preparation of Film 14 Film 14 was obtained in the same manner as in the preparation of film 1, except that the biodegradable polyester particles were set to particle 10.

[0096] 1-2-15. Preparation of Film 15 Film 15 was obtained in the same manner as film 1, except that the biodegradable polyester particles were set to particle 4 and the amount of particle 4 added was 2.1 mg.

[0097] 1-2-16. Preparation of Film 16 Film 16 was obtained in the same manner as in the preparation of Film 1, except that HA / CMC condensate-1 was changed to HA / CMC condensate-3, the amount of HA / CMC condensate-3 added was set to 55.8 g, the biodegradable polyester particles were changed to particle 4, and the amount of particle 4 added was set to 10.5 mg.

[0098] 1-2-17. Preparation of Film 17 Film 17 was obtained in the same manner as in the preparation of Film 1, except that the biodegradable polyester particles were set to particle 7 and the amount of particle 7 added was set to 62.7 mg.

[0099] Table 2 shows the composition, solution viscosity, and amount of HA / CMC condensate used to prepare each sample, as well as the composition, particle size, and amount of PGA particles added, and the weight of the particles added per 100 parts by weight of HA / CMC.

[0100] [Table 2]

[0101] 2. Evaluation 2-1. Calculation of the coefficient of variation of particle number Sixteen rectangular regions were set on the surface of each of the films 1 to 17 using the method described below. These regions were observed at 100x magnification using a digital microscope (Keyence HVX7000), and digital images were acquired. The acquired images were loaded into image analysis software (LightStone MIPAR), and the number of biodegradable polyester particles contained in each rectangular region was determined from the length of the outer circumference of the particles or aggregates (dispersed phases). The average number of particles and the standard deviation value for each of the 16 rectangular regions were calculated using the method described below, and the coefficient of variation (CV) of the number of particles contained in each rectangular region was obtained by dividing the standard deviation value by the average number of particles.

[0102] When identifying the dispersed particles and measuring their perimeter length, the following conditions were set in the image analysis software. 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".

[0103] One side of the film was defined as the x-axis, and the other side perpendicular to the x-axis was defined as the y-axis. The intersection of the x-axis and y-axis was represented as the coordinate point x0y0. The film was divided into five equal parts along the x-axis, and coordinate points x0y0, x1y0, x2y0, ..., x5y0 were set along the x-axis starting from x0y0. Similarly, the film was divided into five equal parts along the y-axis, and coordinate points x0y0, x0y1, x0y2, ..., x0y5 were set along the y-axis starting from x0y0. In this coordinate plane, 16 points x1y1, x2y1, x3y1, x4y1, x1y2, x2y2, x3y2, x4y2, x1y3, x2y3, x3y3, x4y3, x1y4, x2y4, x3y4, and x4y4 were each included in a 5mm x 4mm rectangular region, and these regions were set up so that they did not overlap, and each was designated as rectangular region i (where i is an integer from 1 to 16). The length of the perimeter of the dispersed mass j observed in rectangular region i was denoted as L(j). It was assumed that the dispersed mass and particles were spherical, and that the diameter of the dispersed mass was proportional to the length of its perimeter, and the diameter of the particles was proportional to the length of the particle's perimeter. Based on this assumption, the number of particles n(j) constituting the dispersed mass j was calculated from the perimeter length L0 of one particle and the perimeter length L(j) of the dispersed mass j using Equation 1. The outer circumference length L0 of the particles was calculated assuming an average particle diameter of 10 μm.

[0104]

number

[0105] The number of particles X(i) contained in rectangular region i was calculated using Equation 2 from the number of particles n(j) contained in each of the N dispersed particles observed in rectangular region i.

[0106]

number

[0107] The average number of particles X(ave), which is the average number of particles contained in the 16 rectangular regions, was calculated using Equation 3.

[0108]

number

[0109] The standard deviation S of the number of particles observed in each rectangular region was determined, and the coefficient of variation CV of the number of particles contained in the rectangular region was obtained by dividing the standard deviation S by the average number of particles X(ave) using Equation 4.

[0110]

number

[0111] 2-2. Average diameter of aggregates Digital images were acquired by observing each rectangular region at 100x magnification using a digital microscope (Keyence HVX7000). The acquired digital images were loaded into image analysis software, and the perimeter length of the dispersed particles contained in each rectangular region was determined using the same method as when calculating the coefficient of variation CV. Assuming the dispersed particles are spheres, the diameter D of the j-th dispersed particle i out of the N dispersed particles observed in rectangular region i was calculated. (j) The outer length L of the dispersed mass is determined by image processing. (j) This was obtained by dividing it by pi (π(3.1416)) and using equation 5.

[0112]

number

[0113] Then, the average diameter D(i) of the dispersed particles contained in the rectangular region i was calculated using Equation 6. Furthermore, the average value D(ave) of the average diameter D(i) of the dispersed particles in the 16 rectangular regions was calculated using Equation 7.

[0114]

number

[0115]

number

[0116] 2-3. Average number of 5A particles within the rectangular region In each of the 16 rectangular regions, the average diameter D(i) of the aggregates and the number A(i) of aggregates with a diameter at least five times that of D(i) were measured. The average value A(ave) of the number of aggregates with a diameter at least five times that of D(i) in the 16 rectangular regions was calculated using Equation 8.

[0117]

number

[0118] 2-4. Degradability Add 1 cm of each material from Film 1 to Film 14 to 8 mL of phosphate buffer (pH 8.0). 2 A sample measuring 1 cm x 1 cm was immersed and stored at 37°C. After 24, 40, and 45 hours of immersion, the shape of each sample was visually observed and evaluated. A score of 2 or higher on the following scale indicated that the film-like structure was maintained.

[0119] The results of the visual observation were expressed as the average of the scores determined by multiple skilled technicians (5 people) who referred to the images of the appearance of each sample, assigning the following scores to each sample. 4 points: The appearance closely matches the planar shape of the sample before immersion. 3 points: The appearance is generally bulging compared to the planar shape of the sample before immersion, but the presence of the sample is still visible. Points 2: The appearance is generally bulging from the planar shape of the sample, and includes some slightly collapsed parts, but the presence of the sample is visible. 1 point: The overall appearance is distorted or appears irregular due to droplet formation. 0 points: Dissolved and its appearance cannot be confirmed.

[0120] 2-5.Strength Films 1-14, 17, and 18 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.

[0121] Table 3 shows the results of evaluations 2-1 to 2-5 for films 1 to 17.

[0122] Figure 1A is a photograph showing the appearance of film 4 after 45 hours of immersion, and Figure 1B is a photograph showing the appearance of film 9 after 45 hours of immersion.

[0123] [Table 3]

[0124] The results in Table 3 show that when the PGA particles have good dispersibility, the film is less likely to dissolve, and the film is more likely to maintain its shape in vivo.

[0125] In film 15 (Comparative Example 7), where the amount of PGA particles was 0.9 parts by weight per 100 parts by weight of crosslinked polymer material, the film was prone to collapse despite having good dispersibility. On the other hand, in films 1 to 8 (Examples 1 to 8), where the amount of particles was 2 parts by weight or more but the coefficient of variation CV of the number of particles contained in the rectangular region was small, the film collapse was slower and suppressed. Furthermore, films 12 to 14 and 17 (Comparative Examples 4 to 6 and 9), which contained biodegradable polyester particles that did not have constituent units derived from polyglycolic acid or contained less than 40% by mass of constituent units derived from polyglycolic acid, had poor particle dispersibility and were prone to collapse. In addition, films 9 to 11 (Comparative Examples 1 to 3), which contained PGA particles but had a large coefficient of variation CV of the number of particles contained in the rectangular region, were also prone to collapse.

[0126] The results in Table 3 show that good dispersibility of PGA particles results in high tensile strength of the film even when wet. Medical films with high tensile strength even when wet are less likely to tear in vivo and are easier to use in vivo.

[0127] This application claims priority to Japanese Patent Application No. 2023-077268, filed on 9 May 2023. The matters described in the original specification, claims and drawings of said application are incorporated herein by reference. [Industrial applicability]

[0128] The medical film according to the present invention can maintain its shape in the body for a long period of time.

Claims

1. A medical film that is an anti-adhesion material comprising a crosslinked polymer material containing a polyanionic polymer material, and a PGA dispersed phase which is a polymer containing a polymer having constituent units derived from glycolic acid or an aggregate thereof, The polymer having glycolic acid as a constituent unit is a polymer in which the proportion of constituent units derived from glycolic acid to the total mass of the polymer is 40% by mass or more and 100% by mass or less, The content of the PGA dispersed phase relative to 100 parts by weight of the crosslinked polymer material is 2 parts by weight or more and 40 parts by weight or less. The coefficient of variation CV of the number of particles contained in each of the 16 rectangular areas, each measuring 5 mm x 4 mm and set on the surface of the medical film so as not to overlap, is 0.6 or less. In the aforementioned 16 rectangular regions, The average number of aggregates having a diameter five times or more than the average diameter of the PGA dispersed mass contained in the rectangular region is three or less. Medical film.

2. The medical film according to claim 1, wherein the number-average molecular weight of the polymer is 10,000 or more and 150,000 or less.

3. The medical film according to claim 1, wherein the sample is fixed to the chucks of a creep meter so that the distance between the chucks is 20 mm, and a bellclin soaked in ultrapure water is brought into close contact with the center 10 mm x 10 mm of one side of the sample, and the tensile strength of the medical film measured after 10 seconds is 11 MPa or more and 100 MPa or less.

4. The medical film according to claim 1, wherein the polyanionic polymer material comprises at least one material selected from the group consisting of alginic acid, hyaluronic acid, carboxymethylamylose, and carboxymethylcellulose.

5. A step of compounding the crosslinked polymer material and the particles by mixing a solution or dispersion containing a crosslinked polymer material containing a polyanionic polymer material with particles containing a polymer having constituent units derived from glycolic acid, The process includes a step of forming a film from the composite of the crosslinked polymer material and particles, The polymer having the constituent units derived from glycolic acid is a polymer in which the proportion of the constituent units derived from glycolic acid to the total mass of the polymer is 40% by mass or more and 100% by mass or less, In the compounding step, the viscosity of the solution or dispersion containing the crosslinked polymer material, measured at 25°C and 10 rpm, is 2,000 mPa·s or higher. In the compounding step, the number-average molecular weight of the polymer is 15,000 or more and 170,000 or less. A method for manufacturing medical films used as adhesion prevention materials.

6. The particle size of the polymer containing the constituent units derived from glycolic acid is 6.86 μm or more and 30 μm or less. A method for manufacturing a medical film according to claim 5.

7. The method for producing a medical film according to claim 5, wherein the polyanionic polymer material comprises at least one material selected from the group consisting of alginic acid, hyaluronic acid, carboxymethylamylose, and carboxymethylcellulose.

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