Medical film and production method therefor

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

Medical film and its manufacturing method

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

[0002] Medical films (anti-adhesion materials) are known that are applied to organs after surgery to prevent adhesion between the organ and other organs during wound healing. Anti-adhesion materials are made of bioabsorbable materials such as crosslinked hyaluronic acid and carbomethylcellulose.

[0003] A medical film containing a crosslinked polymer material and a disintegration retardant containing a biodegradable polyester such as polyglycolic acid (PGA) can maintain its shape in vivo for a long period of time (Patent Document 1). Patent Document 1 describes that the disintegration retardant releases acid to prevent the medical film from disintegrating. Patent Document 1 also describes that the smaller the molecular weight of the PGA, the higher the acid release capacity.

[0004] International Publication No. 2021 / 201150

[0005] The inventors added particulate PGA to a crosslinked polymer material to prepare a medical film, and found that when the PGA particles were not uniformly dispersed within the medical film, the shape-retaining effect of the medical film was not enhanced.If the shape-retaining effect of the film is not enhanced, for example, when used as an adhesion barrier, the film may tear when the body or organ moves after being attached to the organ, and the barrier function for preventing adhesions may be impaired.

[0006] The present invention aims to provide a medical film having particles containing polyglycolic acid, which is capable of maintaining its shape in a living body for a long period of time, and a method for producing said medical film.

[0007] One embodiment of the present invention for solving the above problems relates to medical films according to the following [1] to [5]. [1] A medical film comprising a crosslinked polymer material and PGA dispersoids, which are particles containing a polymer having structural units derived from glycolic acid or aggregates thereof, wherein the polymer having glycolic acid as structural units is a polymer in which the proportion of structural 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, and the content of the PGA dispersoids per 100 parts by weight of the crosslinked polymer material is 2 parts by mass or more and 40 parts by mass or less, and the coefficient of variation CV of the number of particles contained in each rectangular region is 0.6 or less, as determined from the number of particles measured in each of 16 rectangular regions having dimensions of 5 mm x 4 mm and set so as not to overlap one another on the surface of the medical film. [2] The medical film according to [1], wherein the average number of aggregates having a diameter at least 5 times the average diameter of the PGA dispersoids contained in the rectangular regions is 3 or less in the 16 rectangular regions. [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] The 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] The medical film according to any one of [1] to [4], wherein the medical film is an adhesion barrier.

[0008] Another embodiment of the present invention for solving the above problem relates to a method for producing a medical film as described below in [6]. [6] A method for producing a medical film, comprising the steps of: mixing a solution or dispersion containing a crosslinked polymer material with particles containing a polymer having structural units derived from glycolic acid to composite the crosslinked polymer material and the particles; and forming the composite of the crosslinked polymer and the particles into a film, wherein the polymer has a proportion of structural units derived from glycolic acid of 40% by mass or more and 100% by mass or less relative to the total mass of the polymer, wherein the viscosity of the solution or dispersion containing the crosslinked polymer material in the composite step, measured at 25°C and 10 rpm, is 2,000 mPa s or more, and wherein the number average molecular weight of the polymer in the composite step is 15,000 to 170,000.

[0009] According to the present invention, there are provided a medical film having particles containing polyglycolic acid, which is capable of maintaining its shape in a living body for a long time and is resistant to tearing, and a method for producing said medical film.

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

[0011] [Medical Film] One embodiment of the present invention relates to a medical film (hereinafter simply referred to as "medical film") comprising a crosslinked polymer material and particles (hereinafter simply referred to as "PGA particles") containing a polymer having structural units derived from glycolic acid, or PGA dispersoids which are aggregates thereof.

[0012] (Crosslinked Polymer Material) A crosslinked polymer material is a polymer material that swells when immersed in ultrapure water at 15 to 25°C. A crosslinked polymer material is a polymer material obtained by physically or chemically crosslinking the same or different types of polymer materials, and is typically a gel-like polymer. The crosslinked polymer material is preferably composed of a polymer that swells in water and then becomes soluble.

[0013] The crosslinked polymer material can be, for example, a crosslinked polyanionic polymer. The polyanionic polymer can be a polymer having a repeating structure with anionic groups, or a polymer obtained by chemically modifying a polymer compound with anionic substituents. The anionic groups can be carboxyl groups, hydroxy groups, sulfo groups, etc. The anionic groups can partially form salts with alkali metals such as sodium and potassium, or alkaline earth metals such as calcium and magnesium.

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

[0015] Examples of sugars that are polyanionic polymer materials include natural sugars such as pullulan, alginic acid, hyaluronic acid, chondroitinic acid, dextran acid, and pectin, as well as sugars having anionic groups introduced by modification such as carboxymethyl amylose, carboxymethyl cellulose, carboxymethyl dextran, carboxymethyl starch, sulfated cellulose, and sulfated dextran. Of these, alginic acid, hyaluronic acid, carboxymethyl amylose, and carboxymethyl cellulose are preferred because of their ease of handling.

[0016] Examples of proteins that are polyanionic polymer materials include gelatin, collagen, albumin, fibrin, and chemically modified versions of these. The protein may be a polymer of amino acids (polyamino acids) having anionic groups, such as polyglutamic acid and polyaspartic acid. Of these, acid-treated gelatin, which has carboxyl groups generated by hydrolysis of acid amides, is preferred.

[0017] The crosslinking of the polymeric material may be a physical crosslink formed by introducing a cationic substituent into a polyanionic polymer, or a chemical crosslink formed by reacting polymeric materials with each other directly or via other molecules. The crosslinking of the polymeric material can be obtained by subjecting the polymeric material to a crosslinking treatment such as ultraviolet treatment, heat treatment, or crosslinking agent treatment. Of these, crosslinking agent treatment is preferred.

[0018] Examples of crosslinking agents used in the crosslinking 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. Treatment with these crosslinking agents allows for the introduction of cationic groups into the polyanionic polymer. Furthermore, physical crosslinking can be achieved between the molecules of the polymer material due to intermolecular interactions between the anionic groups of one molecule and the cationic groups of another molecule. Of these, EDC is preferred due to its ease of handling.

[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 medium may be adjusted depending on the type of crosslinking agent. For example, when EDC is used as the crosslinking agent, it is preferable to add an acid such as 0.01 M hydrochloric acid appropriately to maintain a low pH (e.g., pH 4.0 to 5.5) during the reaction to dissociate the anionic groups of the polyanionic polymer.

[0020] The amount of the crosslinking agent is preferably 0.5 eq. or more and 10 eq. or less, more preferably 1 eq. or more and 6 eq. or less, and even more preferably 2 eq. or more and 5 eq. or less, relative to the reactive functional groups of the polymer material (e.g., hyaluronic acid).

[0021] In addition, crosslinking can be generated between different kinds of polymers.Crosslinking at this time can be the chemical crosslinking that occurs by reacting these polymers with each other, or can be the physical crosslinking that is caused by using a crosslinking agent to enhance intermolecular interaction.For example, from the viewpoint of safety, the crosslinked combination of hyaluronic acid and carboxymethyl cellulose can be used as crosslinked polymer material.

[0022] (PGA dispersoid) PGA dispersoid is a particle or aggregate containing a polymer containing PGA (hereinafter also simply referred to as "PGA polymer"). When producing a medical film, a crosslinked polymer material and PGA particles are composited and then formed into a film (film formation). At this time, the PGA particles may aggregate to form aggregates. The medical film may contain only PGA particles, only PGA particle aggregates, or both.

[0023] When the medical film is attached to an organ and comes into contact with water, the PGA dispersoid gradually releases acid through hydrolysis, which inhibits the breakdown of the crosslinked polymer material and extends the period during which the film can maintain its structure in vivo.

[0024] Incidentally, the phrase "containing PGA" means that the proportion of structural 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 structural 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 a hydroxycarboxylic acid such as lactic acid, hydroxypropionic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, or hydroxybenzoic acid, or a lactone such as caprolactone. Furthermore, the PGA dispersoid can be a mixture of these with a water-soluble polymer such as polyethylene glycol whose biosafety has been confirmed, or a copolymer of glycolic acid and polyethylene glycol.

[0026] The proportion of the PGA polymer contained in the PGA dispersoid is preferably 50% by mass or more and 100% by mass or less, more preferably 60% by mass or more and 100% by mass or less, even more preferably 70% by mass or more and 100% by mass or less, still more preferably 80% by mass or more and 100% by mass or less, and particularly preferably 90% by mass or more and 100% by mass or less, relative to the total mass of the PGA dispersoid.

[0027] The number-average molecular weight of the PGA polymer is preferably 10,000 to 150,000, more preferably 10,000 to 100,000, and even more preferably 15,000 to 50,000. By reducing the number-average molecular weight, the acid sustained-release ability can be increased, allowing the shape of the medical film to be maintained for a longer period after application to an organ. Furthermore, by increasing the number-average molecular weight, the dispersibility of the particles can be improved.

[0028] The number average molecular weight of the PGA polymer can be determined by measuring the number average molecular weight of the PGA polymer in the PGA particles separated from the medical film in accordance with ISO 16014-1: 2012. Specifically, the number average molecular weight of the PGA polymer can be determined by gel permeation chromatography (GPC) (manufactured by Resonac Corporation, Shodex GPC-104, detector: RI, column: HFIP-606M x 2) using 5 mM CF as a solvent. ３ A solution of COONa dissolved in hexafluoropropanol (HFIP) is used, and polymethyl methacrylate (PMMA) is used as a standard substance.

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

[0030] The average particle size of PGA particles can be measured by observing 200 or more unagglomerated PGA particles at 100x magnification using a digital microscope (Keyence Corporation: HVX7000) and acquiring a digital image. The acquired digital image is loaded into image analysis software, and the perimeter of the PGA particles is measured using an image analyzer. The arithmetic mean (average value) and standard deviation of the perimeter of the PGA particles are calculated, and the average perimeter is determined by excluding measurements whose difference from the average value is more than three times the standard deviation. The average perimeter of the particles is then divided by pi (3.1416) to obtain the equivalent diameter of the particles, which is the average particle size of the PGA particles.

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

[0032] Increasing the mixing ratio of PGA dispersoid to the crosslinked polymer material can extend the period during which the medical film maintains its shape in vivo. On the other hand, by maintaining the mixing ratio within an appropriate range, excessive aggregation of the 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 dispersoid to 100 parts by mass of the crosslinked polymer material is 2 to 40 parts by mass, preferably 8 to 30 parts by mass, more preferably 10 to 30 parts by mass, even more preferably 15 to 30 parts by mass, and particularly preferably 20 to 30 parts by mass.

[0033] The mass proportion of PGA dispersoids contained in a medical film can be determined by measuring the mass of the particles remaining after removing the crosslinked polymer material, determining this as the mass of the PGA dispersoids, measuring the mass of the removed crosslinked polymer material, and calculating the mass of the PGA dispersoids relative to the mass of the crosslinked polymer material. When the crosslinked polymer material is a dissolvable and removable material such as hyaluronic acid or its crosslinked form, the material can be dissolved and removed using an appropriate acid compound. The mass of the crosslinked polymer material can then be determined by dividing the mass of the medical film before removal by the mass of water contained in the film and the mass of the PGA dispersoids and other residues remaining after removal.

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

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

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

[0037] The coefficient of variation CV can be calculated by the following method.

[0038] Sixteen rectangular regions selected using the method described below were set on the surface of the medical film, and observed at 100x magnification using a digital microscope (Keyence Corporation: HVX7000) to obtain digital images. The obtained images were loaded into image analysis software, and the number of PGA particles contained in each rectangular region was determined from the perimeter of the PGA dispersoid. Specifically, the average particle number and standard deviation of PGA particles in the 16 rectangular regions were calculated using the method described below, and the calculated standard deviation was divided by the average particle number to obtain the coefficient of variation CV of the number of particles contained in the rectangular region. Note that image analysis can be performed under the same conditions as those used to calculate the average particle size of PGA particles described above.

[0039] In this case, one side of the medical film is the x-axis, the other side of the film perpendicular to the x-axis is the y-axis, and the intersection of the x-axis and y-axis is the coordinate point x0y0. The medical film is divided into five equal parts along the x-axis, and coordinate points x0y0, x1y0, x2y0, ..., x5y0 are set along the x-axis from x0y0. Similarly, the medical film is divided into five equal parts along the y-axis, and coordinate points x0y0, x0y1, x0y2, ..., x0y5 are set along the y-axis from x0y0. Sixteen rectangular areas, each 5 mm x 4 mm in size and including the 16 points x1y1, x2y1, x3y1, x4y1, x1y2, x2y2, x3y2, x4y2, x1y3, x2y3, x3y3, x4y3, x1y4, x2y4, x3y4, and x4y4 on this coordinate plane, are set so as not to overlap each other, and each is designated rectangular area i (i is an integer from 1 to 16). Furthermore, even when the medical film is not approximately rectangular in plan view, 16 rectangular areas can be determined evenly across the entire planar direction of the medical film in plan view using the same concept.

[0040] The perimeter of PGA particle j observed in rectangular region i is defined as L(j). Assume that the PGA particle and PGA particles are spherical, the particle diameter is proportional to the perimeter of the PGA particle, and the PGA particle diameter is proportional to the perimeter of the PGA particle. Based on this assumption, the number of particles n(j) constituting PGA particle j is calculated from the perimeter L0 of one PGA particle and the perimeter L(j) of PGA particle j using Equation 1. Note that, in the following calculations, the perimeter L0 of the PGA particles can be calculated by temporarily setting the average particle diameter or perimeter of the PGA particles. For example, in the following calculations, the average particle diameter of the PGA particles can be assumed to be 10 μm.

[0041]

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

[0043]

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

[0045]

[0046] Then, the standard deviation S of the number of particles observed in each rectangular region is calculated, and the standard deviation S is divided by the average number of particles X (ave) to calculate the coefficient of variation CV of the number of particles contained in the rectangular region using Equation 4.

[0047]

[0048] The dispersibility of PGA particles can also be evaluated by the average diameter of the PGA dispersoid in the medical film or the average number of aggregates (hereinafter simply referred to as "5A aggregates") having a diameter five times or more the average diameter of the PGA dispersoid in the rectangular region set above. Specifically, the average diameter of the PGA dispersoid in the medical film is preferably 10 μm to 60 μm, more preferably 25 μm to 50 μm, and even more preferably 30 μm to 45 μm. Furthermore, the average number of 5A aggregates in the rectangular region of the medical film is preferably 3 or less, more preferably 2 or less, even more preferably 1 or less, and particularly preferably 0.

[0049] The average diameter of the PGA dispersoid and the average number of 5A aggregates in a rectangular area can be calculated by the following method.

[0050] Each rectangular region is observed at 100x magnification using a digital microscope to obtain a digital image. The obtained digital image is loaded into image analysis software, and the perimeter of the PGA particle contained in each rectangular region is determined in the same manner as when calculating the coefficient of variation CV. Assuming that the PGA particle is a sphere, the diameter D of the j-th particle i among the N particles observed in rectangular region i is （ｊ） is the circumferential length L of the PGA particle obtained by image processing. （ｊ） is divided by pi (3.1416) and calculated using Equation 5.

[0051]

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

[0053]

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

[0055]

[0056] Using a similar method, the average diameter D(i) of the aggregates and the number A(i) of aggregates having a diameter at least five times larger than D(i) are measured in each of the 16 rectangular regions. The average value A(ave) of the number A(i) of aggregates having a diameter at least five times larger than 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]

[0058] (Other Components) The medical film may contain lubricants, emulsifiers, colorants, antioxidants, weathering agents, heat stabilizers, nucleating agents, ultraviolet absorbers, colorants, antibacterial agents, etc. The content of these components is preferably 0% by mass or more and 20% by mass or less, more preferably 0% by mass or more and 10% by mass or less, and even more preferably 0% by mass or more and 5% by mass or less, relative to the total mass of the medical film.

[0059] (Strength) By dispersing PGA particles well, the strength of the medical film when wet can be increased, thereby making it less likely to tear when applied and reapplied. The tensile strength of the medical film when wet is preferably 11 MPa or more, more preferably 13 MPa or more, and even more preferably 15 MPa or more. The upper limit of the tensile strength is not particularly limited, but can be 100 MPa or less.

[0060] [Method for Producing Medical Film] The medical film can be produced by crosslinking a polymer material, compounding it with PGA particles, and forming it into a film (film formation).

[0061] Crosslinking of polymeric materials may be carried out by a method appropriate for the polymer, such as ultraviolet treatment, heat treatment, or crosslinking agent treatment. For example, crosslinking with EDC can be carried out by adding EDC to a solution of the polymer dissolved in water or an aqueous medium while stirring. In this case, it is preferable to add an acid such as HCl to make the solution acidic (e.g., pH 4.0 to 5.5). After crosslinking with a crosslinking agent, it is preferable to remove unnecessary substances by dialysis or the like.

[0062] The composite with PGA particles can be achieved by adding PGA particles to a solution or dispersion containing the crosslinked polymer material and mixing the mixture by stirring.

[0063] The film can be formed by drying the composite of the crosslinked polymer material and the PGA particles in a frame. Drying can be performed by air drying at room temperature, freeze-drying, or by removing the solvent by heating. Alternatively, heat pressing (heating and pressurization) can be performed. These drying methods can also be combined.

[0064] According to the findings of the present inventors, reducing the molecular weight of the PGA polymer or reducing the particle size of the PGA particles to enhance the shape-retaining effect tends to cause aggregation of the PGA particles, leading to uneven dispersion of the PGA particles. Excessive aggregation of the PGA particles and uneven dispersion reduces the shape-retaining effect of the PGA particles. Furthermore, excessive aggregation and uneven dispersion of the PGA particles reduces the tensile strength of the medical film when wetted with water, making it more susceptible to tearing. This makes it difficult to apply the medical film as an adhesion barrier to organs or to remove it from an organ and reapply it to another organ. Furthermore, a medical film applied to an organ as an adhesion barrier may end up adhering to an unintended organ when the attached organ or the human body moves. Therefore, to extend the time that the medical film can maintain its shape in vivo and to resist tearing when wetted with water, it is important to uniformly disperse the PGA particles and prevent excessive aggregation.

[0065] In the above-mentioned composite forming step, the dispersibility of the PGA particles can be adjusted and excessive aggregation can be suppressed by adjusting the viscosity of the solution or dispersion containing the crosslinked polymer material, the average particle size of the PGA particles, or the amount of PGA particles added. From the above viewpoints, 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 the uniformity of the thickness 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 more, more preferably 8,000 mPa·s or more and 300,000 mPa·s or less, and even more preferably 15,000 mPa·s or more and 150,000 mPa·s or less.

[0066] The particle size of the PGA particles to be composited can be adjusted by the number-average molecular weight of the PGA polymer that constitutes the PGA particles. The larger the number-average molecular weight, the harder the particles become, and the larger the particles tend to become when crushed. The number-average molecular weight of the PGA polymer is preferably 15,000 or more and 170,000 or less, more preferably 20,000 or more and 170,000 or less, and even more preferably 30,000 or more and 170,000 or less. Note that the number-average molecular weight of the PGA polymer may decrease during film production.

[0067] Typically, the viscosity of the sol is reduced to improve the dispersibility of particulate matter added to the sol. However, if a solvent is added to reduce the concentration to reduce the sol viscosity, the dispersed PGA particles move in the low-viscosity sol during drying after casting, which can easily cause aggregation and uneven distribution of the PGA particles. Furthermore, when the concentration is reduced, a larger casting amount is required to produce a film having a certain thickness or greater. If the casting amount is increased, the sol tends to move unevenly during drying after casting, resulting in uneven thickness. Furthermore, if the casting amount is increased, aggregation and uneven distribution due to particle movement during drying are even more likely to occur. In contrast, in this embodiment, the viscosity of the sol is increased to prevent excessive aggregation of the particles and to reduce uneven thickness of the film.

[0068] Furthermore, increasing the viscosity of the solution or dispersion containing the crosslinked polymer material can make it less likely for the solution or dispersion to spill from the casting frame when placed in a dryer after casting, facilitating the production of medical films. Meanwhile, lowering the viscosity to a certain extent can facilitate the dispersion of PGA particles and the delivery of the solution during production. Therefore, by combining a sol with PGA particles having the above-mentioned viscosity, a medical film with high PGA particle dispersibility can be produced.

[0069] By adjusting these conditions, it is possible to improve the dispersibility of the PGA particles and reduce the amount of coarse aggregates of PGA particles in the medical film, thereby suppressing the shortening of the period during which the structure can be maintained in vivo and the decrease in strength in vivo, which are caused by aggregation of PGA particles.

[0070] The film thus produced can be used as a medical film.

[0071] (Uses) The medical film can be attached to organs, etc., and after a certain period of time, it begins to change shape (disintegrate) through decomposition and is ultimately absorbed into the body. The period from application until the change in shape occurs can be adjusted between 3 and 14 days. Furthermore, the period 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 crosslinked polymer material and the type of biodegradable resin.

[0072] Due to the above-mentioned properties, medical films can be used as a dressing material for the affected area to cover surgical wounds to prevent adhesions (anti-adhesion material) or to prevent the development of ulcers or perforations. Medical films can also be used as a sustained-release base material for drugs or a base material for tissue regeneration. Alternatively, medical films can be applied to the wall surface of a lumen in a living body and used as a gap-maintaining material to maintain gaps.

[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 goes without saying that the above-described embodiments are exemplary embodiments of the present invention, and the present invention may include embodiments other than the above-described embodiments within the scope of its core technical concept.

[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) (Kewpie Corporation, molecular weight 2.2-2.5 million) and 750 mg of carboxymethyl cellulose (CMC) (Tokyo Chemical Industry Co., Ltd., molecular weight 250,000, degree of etherification 0.5-0.8) 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 an HA / CMC solution. 3,180 mg of ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (Dojindo Laboratories) was weighed and dissolved in 7.5 mL of ultrapure water to prepare an 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 EDC solution was then added. Stirring was continued for approximately 120 minutes until the pH no longer fluctuated, yielding a reaction solution. Finally, the stirred reaction solution was placed in 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 over the course of 36 hours from the start of dialysis, yielding HA / CMC condensate-1 (a 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 %, and 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 (a solution of a 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 for dilution used as materials)) was 0.67 wt %, and the solution viscosity measured at 25°C and 1 rpm was approximately 11,000 mPa s, and 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 (a solution of a crosslinked 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 for dilution used as materials)) was 0.41 wt%, and 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 film Biodegradable polyester particles were prepared as shown in Table 1. All of these particles were passed through a sieve with 38 μm openings before use.

[0081]

[0082] 1-2-1. Preparation of Film 1 29.8 g of HA / CMC condensate-1 and 62.7 mg of biodegradable polyester particles (particles 3) were weighed and added to a beaker. The contents of the beaker containing particles 3 were subjected to ultrasonic waves for 1 minute while stirring with a spatula. A 6 x 6 cm frame (frame thickness 2 cm) was prepared on a glass plate, and the HA / CMC condensate-1 containing particles 3 was poured into the frame. The glass plate was placed on a rotating sample table at a temperature of 30°C and dried for approximately 3 days while rotating. After drying, the film was peeled from the glass plate and heat-treated using a heat press at 90°C for 15 minutes, then at 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 in the preparation of Film 1, except that the biodegradable polyester particles were changed to Particle 4 and the amount of Particle 4 added was changed to 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 changed to Particle 4 and the amount of Particle 4 added was changed 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 changed to Particles 4 and the amount of Particles 4 added was changed to 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 particles 4 added was 62.7 mg.

[0087] 1-2-6. Preparation of Film 6 Film 6 was obtained in the same manner as in the preparation of Film 1, except that the biodegradable polyester particles were changed to Particles 6 and the amount of Particles 6 added was changed to 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-2 was used instead of HA / CMC condensate-1, the amount of HA / CMC condensate-2 added was 33.8 g, and the amount of particles 4 added was 10.5 mg.

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

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

[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 59.6 g, the biodegradable polyester particles were Particles 1, and the amount of Particles 1 added was 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 Particles 2 were used instead of biodegradable polyester particles.

[0093] 1-2-12. Preparation of Film 12 Film 12 was obtained in the same manner as in the preparation of Film 1, except that Particles 5 were used instead of the biodegradable polyester particles.

[0094] 1-2-13. Preparation of Film 13 Film 13 was obtained in the same manner as in the preparation of Film 1, except that Particles 9 were used instead of the biodegradable polyester particles.

[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 changed to Particles 10.

[0096] 1-2-15. Preparation of Film 15 Film 15 was obtained in the same manner as in the preparation of Film 1, except that the biodegradable polyester particles were changed to Particle 4 and the amount of Particle 4 added was changed to 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-3 was used instead of HA / CMC condensate-1, the amount of HA / CMC condensate-3 added was 55.8 g, the biodegradable polyester particles were used as particles 4, and the amount of particles 4 added was 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 changed to Particles 7 and the amount of Particles 7 added was changed to 62.7 mg.

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

[0100]

[0101] 2. Evaluation 2-1. Calculation of the Coefficient of Variation of Particle Count Sixteen rectangular regions selected by the method described below were set on the surface of each of Films 1 to 17, and observed at 100x magnification using a digital microscope (Keyence Corporation: HVX7000), and digital images were obtained. The obtained images were loaded into image analysis software (LightStone Corporation: MIPAR), and the number of biodegradable polyester particles contained in each rectangular region was determined from the perimeter of the particles or their aggregates (dispersoids). The average particle number and standard deviation value in the 16 rectangular regions were calculated using the method described below, and the standard deviation value was divided by the average particle number to determine the coefficient of variation CV of the number of particles contained in the rectangular region.

[0102] When identifying the dispersoids and measuring their perimeter, the image analysis software conditions were set as follows: "Smart Cluster" was set to "Fill Type: Class", "Classes: 4-10", "Edge Type: Dark to Bright", "Edge Clean: 0-5", and "Speed: 2". "Basic Threshold" was set to "Value: 80-150".

[0103] One side of the film was defined as the x-axis, and the other side of the film perpendicular to the x-axis was defined as the y-axis, with the intersection of the x-axis and y-axis represented as 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 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 from x0y0. On 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 5 mm × 4 mm rectangular regions, each of which was set so as not to overlap with another. These rectangular regions were designated rectangular region i (i is an integer from 1 to 16). The perimeter of particle j observed in rectangular region i was designated L(j). The particle and particle were assumed to be spherical, and the diameter of the particle was assumed to be proportional to the perimeter of the particle, and the diameter of the particle was assumed to be proportional to the perimeter of the particle. Based on this assumption, the number of particles constituting particle j, n(j), was calculated from the perimeter of one particle, L0, and the perimeter of particle j, L(j), using Equation 1. The circumferential length L0 of the particles was determined assuming that the average particle diameter of the particles was 10 μm.

[0104]

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

[0106]

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

[0108]

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

[0110]

[0111] 2-2. Average Diameter of Aggregates Each rectangular region was observed at 100x magnification using a digital microscope (Keyence Corporation: HVX7000) to obtain a digital image. The obtained digital image was loaded into image analysis software, and the perimeter of the dispersoids contained in each rectangular region was determined in the same manner as when calculating the coefficient of variation CV. Assuming that the dispersoids are spherical, the diameter D of the jth dispersoid i among the N dispersoids observed in rectangular region i was calculated as （ｊ） is the circumferential length L of the particle obtained by image processing. （ｊ） was calculated using Equation 5 by dividing by the constant π (3.1416).

[0112]

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

[0114]

[0115]

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

[0117]

[0118] 2-4. Degradability 1 cm of each material of Films 1 to 14 was dissolved in 8 mL of phosphate buffer solution (pH 8.0). ２ Samples (dimensions: 1 cm x 1 cm) were immersed in the solution and stored at 37°C. After 24 hours, 40 hours, and 45 hours of immersion, the shape of each sample was visually observed and evaluated. A rating of 2 or higher on the following scale was considered to have maintained the film-like shape.

[0119] The results of the appearance observation were expressed as the average of the following scores determined from the images of the appearance of each sample by multiple skilled technicians (5 people) while referring to the images: 4 points: The appearance is almost identical to the planar shape of the sample before immersion 3 points: The appearance is bulging overall from the planar shape of the sample before immersion, but the presence of the sample can be seen 2 points: The appearance is bulging overall from the planar shape of the sample and includes some slightly collapsed areas, but the presence of the sample can be seen 1 point: The appearance is collapsed overall, or is found to be irregular due to droplets 0 point: It has dissolved, and the appearance cannot be confirmed

[0120] 2-5. Strength Films 1 to 14, 17, and 18 were cut into strips with long sides of 40 mm and short sides of 10 mm to prepare samples. Using a creep meter (Yamaden Co., Ltd., RE2-33005B), the tensile strength of the samples wetted with ultrapure water was measured. The samples were fixed to the chucks so that the distance between the chucks was 20 mm, and a Bellclean (Ion Co., Ltd., product number E-2) soaked in ultrapure water was placed in close contact with a 10 mm x 10 mm central area on 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] The results of evaluations 2-1 to 2-5 for films 1 to 17 are shown in Table 3.

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

[0123]

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

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

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

[0127] This application claims priority from Japanese Patent Application No. 2023-077268, filed May 9, 2023. The entire disclosures of the specification, claims, and drawings of that application as originally filed are incorporated herein by reference.

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

Claims

1. A medical film comprising a crosslinked polymer material and a PGA dispersoid which is a particle or an aggregate thereof containing a polymer having a structural unit derived from glycolic acid, The polymer having glycolic acid as a constituent unit is a polymer in which a ratio of the constituent unit 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 dispersoid is 2 parts by weight or more and 40 parts by weight or less relative to 100 parts by weight of the crosslinked polymer material, A medical film, wherein the coefficient of variation CV of the number of particles contained in a rectangular area is 0.6 or less, as calculated from the number of particles measured in each of 16 rectangular areas each having a size of 5 mm x 4 mm and set so as not to overlap each other on the surface of the medical film.

2. In the 16 rectangular regions, The medical film according to claim 1 , wherein the average number of aggregates having a diameter at least five times the average diameter of the PGA dispersoid contained in the rectangular regions is three or less.

3. 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.

4. The medical film according to claim 1 , wherein the tensile strength of the medical film is 11 MPa or more and 100 MPa or less.

5. The medical film according to any one of claims 1 to 4, which is an adhesion preventing material.

6. A step of mixing a solution or dispersion containing a crosslinked polymer material with particles containing a polymer derived from polyglycolic acid to composite the crosslinked polymer material with the particles; and forming the composite of the crosslinked polymer material and the particles into a film. The polymer having glycolic acid as a constituent unit is a polymer in which a ratio of the constituent unit 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 step of forming the crosslinked polymer material, 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 more; In the step of compounding, the number average molecular weight of the polymer is 15,000 or more and 170,000 or less. A method for manufacturing medical films.