JP6154246B2 - Composite film and manufacturing method thereof - Google Patents

Description

  The present invention relates to a composite film in which a film layer made of a water-soluble polymer and a film layer made of an ultrathin biodegradable polymer are laminated by coextrusion.

Conventionally, spin coating methods, electrolytic polymerization methods, vapor deposition methods, vapor deposition polymerization methods and the like have been used as methods for forming thin films of organic molecules. For example, there is a report that aims to develop new molecular devices such as enzyme reactors, biosensors, and light-emitting elements by immobilizing enzymes by electrostatic interaction to the structure obtained by the alternating lamination method. (Patent Documents 1 and 2). This method is suitable for immobilizing molecules such as proteins that may be denatured because a three-dimensional structure can be easily prepared without using any special apparatus. In addition, after forming a self-assembled monolayer on a circular gold substrate, after adsorbing and crosslinking albumin, the circular albumin polymer thin film is simply peeled off from the gold substrate by a surfactant treatment, and albumin nanosheets are formed. Obtaining is proposed in US Pat.
However, although the manufacturing method of these nanosheets as proposed is simple, its productivity is low and it is industrially difficult.

  Incidentally, Patent Document 4 proposes a film obtained by coextruding polylactic acid and PVA as a packaging film. Certainly, co-extrusion is much more productive than spin coating. However, when a film layer made of a very thin biodegradable polymer having a thickness of 100 nm or less is formed, there is a problem that the thickness unevenness is severe and only the quality is unstable.

Japanese Patent No. 3020428 Japanese Patent No. 2996695 International Publication No. 2006/025592 Pamphlet Japanese translation of PCT publication 2010-52562

  An object of the present invention is to provide an ultra-thin film layer of 100 nm or less made of a biopolymer while being laminated with a water-soluble polymer layer, and provide a composite film that can be provided with uniform quality and excellent productivity. Is to provide.

According to this invention, the manufacturing method of the composite film of the following (1)-(9) and the composite film of (10)-(11) is provided.
(1) A composite film in which a plurality of A layers having a thickness of 5 to 100 nm made of a thermoplastic biodegradable polymer and a B layer made of a thermoplastic water-soluble polymer are laminated,
When the cross section along the thickness direction of the composite film is viewed, it is formed by coextrusion molding, wherein the ratio of the B layer is in the range of 25 to 75% and the total thickness of the composite film is 3 μm or more. Composite film.
(2) The biodegradable polymer has a melting point difference (ΔTm = | Tma−Tmb |) of 50 ° C. or less between the melting point (Tma) of the biodegradable polymer and the melting point (Tmb) of the water-soluble polymer. The composite film according to (1) above, wherein both the temperature (Tda) and the decomposition temperature (Tdb) of the water-soluble polymer are higher than Tma and Tmb.
(3) Melting point (Tma) of biodegradable polymer + ratio of melt viscosity of biodegradable polymer and water-soluble polymer at 50 ° C. (biodegradable polymer / water-soluble polymer) is 0.1 to The composite film according to (1), which is in the range of 10.
(4) The above (1), wherein the biodegradable polymer is at least one obtained from the group consisting of polylactic acid (PLA), glycolic acid copolymer (PLGA), polyglycolic acid (PGA) and polycaprolactone (PCL). ) The composite film described.
(5) The composite according to (1) above, wherein the water-soluble polymer is at least one kind obtained from the group consisting of polyacrylic acid, polymethacrylic acid, polyethylene glycol, polyacrylamide, polyvinyl alcohol (PVA), starch, and cellulose acetate. the film.
(6) Any of the above (1) to (5), wherein the composite film is a multilayer film in which A layers and B layers are alternately laminated, and the total number of A layers and B layers is 10 or more. The composite film described in 1.
(7) The composite film according to the above (6), wherein the thickness of at least one surface layer of the composite film is at least twice the average thickness of the A layer and 50% or less of the total thickness.
(8) The composite film according to any one of (1) to (7), wherein the composite film is a stretched composite film stretched in at least one direction within the plane.
(9) The composite film according to any one of (1) to (8), which is used for treatment of a living body.
(10) A method for producing a composite film having a total thickness of 3 μm or more in which a 5 to 100 nm A layer made of a thermoplastic biodegradable polymer and a B layer made of a water-soluble polymer are laminated. ,
A coextrusion step in which a thermoplastic biodegradable polymer and a thermoplastic water-soluble polymer are laminated in a molten state with a layer A made of a biodegradable polymer and a layer B made of a water-soluble polymer, and biodegradation A cooling step of cooling below the glass transition temperature of the conductive polymer, and a winding step of winding up the obtained film,
In the co-extrusion step, the composite film is produced by extruding so that the thickness of the B layer is in the range of 25 to 75% with respect to the total thickness of the composite film when the cross section in the thickness direction of the composite film is viewed.
(11) In the range between the glass transition temperature (Tg1a: ° C.) to (Tg1a + 30 ° C.) of the biodegradable polymer, the film is stretched in at least one direction in the in-plane direction between the cooling step and the winding step ( 10) The manufacturing method of the composite film of description.

  According to the present invention, an ultra-thin film layer of 100 nm or less made of a biopolymer can be provided by coextrusion with a uniform quality and excellent productivity while being laminated with a water-soluble polymer layer. As a result, wounds such as lacerations and burns on the human body are covered with a very thin layer A film made from the composite film of the present invention, so that the surface affected areas of complex shapes can be protected from bacterial infection while healing. Can be planned.

The composite film of the present invention comprises a plurality of A layers having a thickness of 5 to 100 nm made of a biodegradable polymer A that is hardly soluble or insoluble in water and is thermoplastic, and a water-soluble polymer B that is thermoplastic. B layer is a composite film laminated by coextrusion.
The present invention is described in detail below.

<Biodegradable polymer>
The biodegradable polymer in the present invention is a thermoplastic resin. The term “thermoplastic” means that the melting point (Tm: ° C.) can be confirmed in the DSC measurement described later. The melting point (Tma: ° C.) of the preferred biodegradable polymer is in the range of 50 to 300 ° C., more preferably in the range of 100 to 250 ° C. When the melting point of the biodegradable polymer is in this range, the polymer is suitable for the melt extrusion process.

  Examples of the biodegradable polymer in the present invention include at least one obtained from the group consisting of polylactic acid (PLA), glycolic acid copolymer (PLGA), polyglycolic acid (PGA), and polycaprolactone (PCL). Among these, polylactic acid (PLA) and glycolic acid copolymer (PLGA) are preferable, and polylactic acid is particularly preferable. Of the polylactic acids, poly L-lactic acid is preferred. Among biodegradable polymers, biodegradable polymers for living bodies that do not contain Sn for prevention of poisoning and have a residual monomer content of 5 mol% or less from the viewpoint of preventing inflammation of the affected area are preferable. Examples of such biodegradable polymers for biological use include LACTEL (registered trademark) manufactured by Duct and RESOMER (registered trademark) manufactured by Sigma-Aldrich.

In addition, the biodegradable polymer in the present invention is a hydrolytic agent known per se, such as carbodiimide in the case of polylactic acid, from the viewpoint of controlling the rate of biodegradation and the like within a range not impairing the effects of the present invention. It may be copolymerized.
The weight-average molecular weight of the biodegradable polymer in the present invention is preferably 50,000 or more from the viewpoint of facilitating the stretching step in melt extrusion molding, and more preferably 100,000 or more is stably stretched. It is preferable because it can be performed. The upper limit of the weight average molecular weight is not particularly limited, but is preferably 300,000 or less, more preferably 250,000 or less, from the viewpoint of facilitating extrusion during melt extrusion molding. If the molecular weight is too high, the polymer viscosity at the time of melting is too high, so that stable extrusion cannot be performed.

The decomposition temperature of the biodegradable polymer in the present invention is preferably Tma + 10 ° C. or more, and more preferably Tma + 20 ° C. or more from the viewpoint of suppressing generation of decomposition products during melt extrusion and thermal degradation of the biodegradable polymer. It is preferable. The upper limit of the decomposition temperature is not particularly limited.
The biodegradable polymer in the present invention is hardly soluble or insoluble in water and is thermoplastic. In the present invention, “insoluble or insoluble in water” means that a biodegradable polymer (weight after drying is 5 g) is immersed in 1 L of pure water at 23 ° C. and stirred for 1 hour. It means that the weight of the biodegradable polymer after taking out and drying is 4.5 g or more, and preferably 4.75 g or more. Since the biodegradable polymer is hardly soluble or insoluble in water, it can be easily separated from the B layer later.

<Water-soluble polymer>
The water-soluble polymer in the present invention can be dissolved in water and is thermoplastic. The term “water-soluble” as used in the present invention means that a water-soluble polymer (weight after drying is 5 g) is immersed in 1 L of pure water at 23 ° C. and stirred for 1 hour, and then the water-soluble polymer is taken out and water-soluble after drying. This means that the weight of the conductive polymer is 2.5 g or less, and preferably 2 g or less. By being water-soluble, separation from the aforementioned A layer can be performed more easily.
Moreover, the thermoplasticity in this invention means that melting | fusing point (Tm: degreeC) can be confirmed in the below-mentioned DSC measurement. The melting point (Tmb: ° C) of the preferred water-soluble polymer is in the range of 50 to 300 ° C, more preferably in the range of 100 to 250 ° C. When the melting point of the water-soluble polymer is in this range, the layer structure in the coextrusion molding with the biodegradable polymer becomes stable.

The water-soluble polymer in the present invention is preferably at least one obtained from the group consisting of polyacrylic acid, polymethacrylic acid, polyethylene glycol, polyacrylamide, polyvinyl alcohol (PVA), starch, and cellulose acetate. Among these, polyacrylic acid, polymethacrylic acid, polyethylene glycol, polyacrylamide, and polyvinyl alcohol (PVA) are preferable, and PVA is particularly preferable.
Further, the decomposition temperature of the water-soluble polymer in the present invention is preferably Tmb + 10 ° C. or higher from the viewpoint of suppressing generation of decomposition products during melt extrusion and thermal degradation of the biodegradable polymer, and more preferably Tmb + 30 ° C. or higher. Preferably there is. The upper limit of the decomposition temperature is not particularly limited.

<Relationship between biodegradable polymer and water-soluble polymer>
In the present invention, the biodegradable polymer and the water-soluble polymer preferably have the following relationship.
First, the melting point (Tma) of the biodegradable polymer and the melting point (Tmb) of the water-soluble polymer are such that the difference in melting point (ΔTm) is 50 ° C. or less. Is preferable from the viewpoint of facilitating heat treatment, and is preferably 30 ° C. or lower. The lower limit of the melting point difference (ΔTm) is not particularly limited, and may be 0 ° C.

Next, it is preferable that the decomposition temperature (Tda) of the biodegradable polymer and the decomposition temperature (Tdb) of the water-soluble polymer are both higher than Tma and Tmb. When Tda and Tdb are higher than Tma and Tmb, generation of cracked gas during melt extrusion and thermal degradation of the polymer can be suppressed.
Finally, the ratio (biodegradable polymer / water-soluble polymer) of the biodegradable polymer and the water-soluble polymer having a melt viscosity at a melting point (Tma) + 50 ° C. of the biodegradable polymer is 0.1 to It is preferable from the point which suppresses the thickness variation of A layer that it exists in the range of 10. A preferred melt viscosity ratio is in the range of 0.1 to 8, more preferably 0.2 to 5.

<Composite film>
In the composite film of the present invention, the aforementioned A layer and the aforementioned B layer are laminated, and the thickness of the A layer is 5 to 100 nm. The thickness of A layer here means the thickness of each A layer, when a some A layer exists in a composite film. When the thickness of the A layer is less than the lower limit, it becomes difficult to handle when the B layer is dissolved and removed with water or the like, and when it exceeds the upper limit, the adhesion to the affected area is lowered. A preferable thickness of the layer A is in the range of 5 to 80 nm, and further 5 to 50 nm.

  By the way, one of the characteristics of the composite film of the present invention is that when a cross section along the thickness direction of the composite film is viewed, a plurality of A layers are present, and the ratio of the B layer is in the range of 25 to 75%. And the thickness of the whole composite film is 3 micrometers or more. The ratio of B layer here means the ratio of the total thickness of all the B layers which occupies the thickness of the whole composite film, when the cross section along the thickness direction of the composite film is seen. Even though the total thickness of the composite film is 3 μm or more, which is extremely thick compared to the thickness of the A layer, a plurality of A layers are present and the ratio of the B layer is within the above range, thereby making the thickness of the A layer uniform. Further, the composite film itself can be provided with processability such as winding property after being co-extruded.

The reason for this is not clear, but by providing a plurality of A layers, the discharge during film formation can be made more stable, and when the two types of polymers merge in the molten state, the balance of the fluidity of both resins is balanced. It is presumed that the fact that it can be taken has an influence.
A preferable ratio of the B layer is in the range of 30 to 70%, and further 35 to 65%. Moreover, the minimum of the preferable thickness of the whole composite film is 5 micrometers or more, Furthermore, 10 micrometers or more. On the other hand, the upper limit of the preferable thickness of the entire composite film is 75 μm or less, and further 50 μm or less from the viewpoint of winding workability.

  The layer structure of the composite film of the present invention is 3 layers of A layer / B layer / A layer, 4 layers of A layer / B layer / A layer / B layer, A layer / B layer / A layer / B layer / A It is possible to raise five layers, a multilayer stack in which A layers / B layers are alternately stacked, and the like. In addition, since the several A layer can be manufactured simultaneously and it becomes easy to make thickness of A layer more uniform, it is preferable that the total number of layers of A layer and B layer is 10 layers or more, and also 30 layers or more. In particular, by making the total number of layers of the A layer and the B layer 40 or more, peeling between the A layer and the B layer can be further suppressed, and the handleability can be further improved. The upper limit of the number of layers is not particularly limited, but is preferably 1000 layers or less, and more preferably 850 layers or less from the viewpoint of dissolving the B layer and facilitating separation of the A layer.

  Further, the composite film of the present invention may have either the A layer or the B layer on the surface. In addition, when the composite film of the present invention is a multilayer laminate in which A layers / B layers are alternately laminated, a thick thickness adjusting layer is provided on the surface layer from the viewpoint of making the thickness of the A layer more uniform and improving the handleability. It is preferable to provide it. As the thickness adjusting layer, the same resin as the A layer or the same resin as the B layer may be used. However, when the A layer that is used after separating the A layer and the B layer is used, the B layer is more preferably the B layer. When dissolved and removed, an A layer having a uniform thickness can be obtained, which is preferable.

The thickness adjusting layer is located on at least one surface layer of the composite film of the present invention, and the thickness thereof is at least twice the average thickness of the A layer and 50% or less of the total thickness of the composite film. It is preferable because the thickness of the A layer of the layer is easily made uniform. Furthermore, the minimum of the thickness of a preferable thickness adjustment layer is 3 times or more with respect to the average thickness of A layer, Most preferably, it is 4 times or more, and an upper limit is 40%, Most preferably, it is 30%.
By the way, although the unstretched film may be sufficient as the composite film of this invention, since it is easy to make thickness of A layer more uniform, it is preferable that it is the stretched composite film extended | stretched at least to one direction in the surface.

  The composite film of the present invention can be produced by dissolving the B layer with water or the like to remove the B layer, thereby producing a uniform A layer with a small thickness composed of the biopolymer A. It can be suitably used as a composite film for the treatment. In addition, a therapeutic compound in which a drug is gradually introduced according to the degradation rate of the A layer by encapsulating the drug between the A layer and the A layer after the removal of the B layer and introducing it into the human body. It can also be suitably used as a film.

  The composite film of the present invention may contain inert particles known per se from the viewpoint of improving the winding property after film formation. When the inert particles are contained, from the viewpoint of making the thickness of the A layer uniform, the A layer contains no or even inert particles, but is contained in a smaller amount than the B layer, and the inert particles are contained in the B layer. It is preferable to contain.

<Impact resistance improver>
The biodegradable polymer in the present invention preferably contains an impact resistance improver in the range of 0.1 to 10% by mass based on the mass of the biodegradable polymer. The impact resistance improver in the present invention is not particularly limited as long as it can be used for improving the impact resistance of a biodegradable polymer, and is a rubber-like substance that exhibits rubber elasticity at room temperature, for example, And the following various impact resistance improvers.

  Specific impact resistance improvers include ethylene-propylene copolymers, ethylene-propylene-nonconjugated diene copolymers, ethylene-butene-1 copolymers, various acrylic rubbers, ethylene-acrylic acid copolymers, and Its alkali metal salt (so-called ionomer), ethylene-glycidyl (meth) acrylate copolymer, ethylene- (meth) acrylic acid alkyl ester copolymer (for example, ethylene-methyl acrylate copolymer, ethylene-ethyl acrylate copolymer) Polymer, ethylene-butyl acrylate copolymer, ethylene-methyl methacrylate copolymer), ethylene-vinyl acetate copolymer, acid-modified ethylene-propylene copolymer, diene rubber (eg, polybutadiene, polyisoprene, polychloroprene) ), Copolymers of diene and vinyl monomers and The hydrogenated product (for example, styrene-butadiene random copolymer, styrene-butadiene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene random copolymer, styrene-isoprene block copolymer, styrene) -Isoprene-styrene block copolymer, styrene-ethylene-butylene-styrene block copolymer, styrene-ethylene-propylene-styrene block copolymer, polybutadiene grafted with styrene, butadiene-acrylonitrile copolymer ), Polyisobutylene, copolymers of isobutylene and butadiene or isoprene, natural rubber, thiocol rubber, polysulfide rubber, acrylic rubber, silicone rubber, polyurethane rubber, polyether rubber, epichrome Hydrin may be like that mentioned polyester elastomer or polyamide elastomer. Further, those having various cross-linking degrees, those having various microstructures such as cis structure and trans structure, and multilayer polymers composed of a core layer and one or more shell layers covering it are also used. be able to. In the present invention, as the impact resistance improver, the various (co) polymers mentioned in the above specific examples may be any of random copolymers, block copolymers or graft copolymers. it can. Furthermore, when producing these (co) polymers, it is also possible to copolymerize monomers such as other olefins, dienes, aromatic vinyl compounds, acrylic acid, acrylic ester or methacrylic ester. is there.

  Among these impact modifiers, a polymer containing an acrylic unit and a polymer containing a unit having an acid anhydride group and / or a glycidyl group are preferable. Preferable examples of the acrylic unit here include methyl methacrylate unit, methyl acrylate unit, ethyl acrylate unit or butyl acrylate unit, and preferable examples of the unit having an acid anhydride group or glycidyl group. May include maleic anhydride units or glycidyl methacrylate units.

  In the present invention, as the impact resistance improver, a multilayer structure polymer composed of a core layer and one or more shell layers covering the core layer is more preferable from the viewpoint of the effect of the present invention. In the present invention, the multilayer structure polymer is composed of a core layer and one or more shell layers covering the core layer, and a so-called core-shell type structure in which adjacent layers are composed of different polymers. It is a polymer having. In addition, the number of layers constituting the multilayer structure polymer is not particularly limited, and may be two or more, and may be three or more or four or more. Specific examples of the multilayer polymer include “Metablene” manufactured by Mitsubishi Rayon, “Kane Ace” manufactured by Kaneka, “Paraloid” manufactured by Rohm and Haas, “Staffroid” manufactured by Ganz Kasei, “Nanostrength” manufactured by Arkema Japan, or manufactured by Kuraray. "Paraface" can be mentioned.

  In the present invention, the blending amount of the impact resistance improver is preferably in the range of 0.1 to 10% by mass based on the mass of the biodegradable polymer in terms of the effects of the present invention. If it is less than the lower limit, the layer with the water-soluble polymer tends to peel excessively. From such a viewpoint, the lower limit of the blending amount of the preferred impact modifier is 0.5% by mass and further 1% by mass, and the upper limit is 9% by mass and further 8% by mass. It should be noted that the reason why it is possible to suppress peeling from the water-soluble polymer without degrading the degradability of the film by incorporating such an impact resistance improver is not clear, but the obtained biodegradability This is considered to be because flexibility can be imparted to the polymer layer, and as a result, the interface with the water-soluble polymer layer can be stabilized.

<Remaining monomer of layer A>
When used for treatment, the A layer in the present invention preferably has a residual monomer content of 0.5 wt% or less, and more preferably 0.3 wt% or less from the viewpoint of suppressing irritation to the site to be treated. . For such residual monomers, select biopolymers with few residual monomers as biopolymers to be used, depolymerize biopolymers, lower the temperature during melt extrusion, or shorten the time This can be reduced. The lower limit of the residual monomer content is preferably as small as possible, but is usually about 0.001 wt% from the viewpoint of not impairing productivity excessively.
In addition, the residual monomer in this invention means the 1-3mer of a repeating unit.

<Production method of composite film>
Although the manufacturing method of the composite film of this invention is explained in full detail below, the same thing as having demonstrated with the above-mentioned composite film can be said unless there is particular notice.
In the method for producing a composite film of the present invention, a plurality of A layers having a thickness of 5 to 100 nm made of a biodegradable polymer A that is thermoplastic and a B layer made of a water-soluble polymer B that is thermoplastic are laminated. A method for producing a composite film, wherein a biodegradable polymer and a water-soluble polymer are laminated in a molten state with a layer A made of a biodegradable polymer and a layer B made of a water-soluble polymer, respectively. A co-extrusion step, a cooling step for cooling below the glass transition temperature of the biopolymer, and a winding step for winding up the obtained film. In the co-extrusion step, a cross section in the thickness direction of the composite film is observed. The layer B is extruded so that the thickness of the layer B is in the range of 25 to 75% with respect to the thickness of the entire composite film.

  The temperature at the time of melt extrusion is preferably in the range of Tma to Tma + 80 ° C. for the biopolymer A, and more preferably in the range of Tma to Tma + 50 ° C. from the viewpoint of suppressing the amount of residual monomer generated in the A layer. B is preferably in the range of Tmb to Tmb + 80 ° C., and more preferably in the range of Tmb to Tmb + 50 ° C. from the viewpoint of suppressing the deterioration of the resin.

  The biopolymer A and the water-soluble polymer B are laminated in a molten state, and the lamination is preferably carried out in a die at a temperature of Tma to Tma + 30 ° C. and then extruded into a film. Any of the methods of extruding from a die in a molten state and then laminating and rapidly solidifying to form a laminated unstretched film may be used. In addition, when laminating | stacking with the above-mentioned multilayer structure of 10 layers or more, the method of laminating in a molten state in the feed block before the die and extruding from the die is preferable because the number of layers can be easily increased. For example, as a more preferable method for obtaining a multilayer film having 200 layers or more, a melt in an alternately laminated state is obtained in a range of 200 layers or less, and a ratio of 1: 1 in the direction perpendicular to the lamination direction is maintained while maintaining such a layer configuration. It is possible to increase the number of stacked layers by a method in which the number of stacked layers is doubled and the number of stacked layers (doubling number) is increased to 2 to 4 times. When performing such doubling processing, it can be performed by a known method.

The composite unstretched film thus obtained undergoes a cooling step of cooling below the glass transition temperature of the biopolymer A. A method of cooling the composite unstretched film extruded from the die with a rotating cooling drum is preferred. Under the present circumstances, it is preferable from a viewpoint of making thickness of A layer more uniform to apply an electric charge from the surface of the side which is not in contact with the cooling drum of a composite unstretched film, and to improve adhesion with a composite unstretched film and a cooling drum.
The composite unstretched film thus obtained may be wound as it is, or may be stretched at least in one in-plane direction to form a composite stretched film. Preferably, the thickness of the layer A is made uniform by stretching. Since it is easy, it is preferable that it is a composite stretched film.

  In the present invention, when a composite stretched film is used, at least one direction in the in-plane direction (for example, the film forming direction and the width direction (the film forming direction and the thickness direction are orthogonal to each other) between the cooling step and the winding step described above. Direction), or an oblique direction between them. The stretching temperature is preferably in the range of the glass transition temperature (Tga) to Tga + 30 ° C. of the biodegradable polymer of the A layer. The draw ratio at this time is preferably 2 to 10 times, more preferably 2.5 to 7 times, still more preferably 3 to 6 times, and particularly preferably 4.5 to 5.5 times. The larger the draw ratio, the more preferable the variation of the A layer because it becomes smaller when thinned by stretching. As the stretching method at this time, known stretching methods such as heat stretching with a rod heater, roll heating stretching, and tenter stretching can be used. From the viewpoints of reducing scratches due to contact with the roll and stretching speed, tenter stretching is performed. preferable. In addition, a biaxial stretching may be performed by performing a stretching process in a direction (Y direction) orthogonal to the stretching direction.

  The invention is further described by way of examples. In addition, the physical property and characteristic in an Example were measured or evaluated by the following method.

(1) Melting point (Tm) and glass transition point (Tg) of biodegradable polymer and water-soluble polymer
10 mg of the polymer was sampled, and the melting point and glass transition point were measured using DSC (TA Instruments, trade name: DSCQ100) at a heating rate of 20 ° C./min.

(2) Decomposition temperature of biodegradable polymer and water-soluble polymer 10 mg of the polymer was sampled, and the weight loss rate at a temperature increase rate of 20 ° C./min using TGA (TA Instruments, product name: TGA Q50). Was measured. The decomposition temperature was calculated from the slope of the tangent of the decrease start part of the obtained temperature-weight loss rate curve.

(3) Melt viscosity of biodegradable polymer and water-soluble polymer Using a flow tester CFT-500D manufactured by Shimadzu Corporation as a measuring device, measurement temperature: Tma + 50 ° C., preheating time: 5 minutes, nozzle diameter: 1 mm, nozzle length: Measurement was performed at 10 mm, and the melt viscosity at a shear rate of 100 (1 / second) was determined from the regression equation.

(4) Average thickness (nm) and average thickness unevenness (%) of layer A
A film sample having a length of 1 m each in the film forming direction (longitudinal direction) and the width direction is prepared, and then at the center of the film sample, then at four points on both sides at intervals of 10 cm in the width direction, and from the center of the film Cut out from a total of 17 points, 4 points on each side at 10 cm intervals in the film-forming direction, 2 mm in the film longitudinal direction and 2 cm in the width direction, fixed to the embedded capsule, and then epoxy resin (Refotech Epomount) Embedded in. The embedded sample was cut with a microtome (LETRAC ULCT UCT manufactured by LEICA) in the direction perpendicular to the width direction and along the thickness direction to obtain a thin film slice having a thickness of 5 nm. Using a field emission scanning electron microscope (S-4700, manufactured by Hitachi, Ltd.), the film was observed and photographed at an acceleration voltage of 100 kV, and the thickness of each layer A was measured from the photograph.
And about the thickness of each A layer of a composite film, the value which divided the difference of the thickness of the thinnest A layer from the average value and the thickness of the thickest A layer in 17 points by the average value is calculated as thickness spots (%) did. And when several A layers exist in a composite film, the average value of each A layer and the thickness variation of each A layer are averaged, the average thickness of A layer in a composite film, and the average thickness variation of A layer Calculated as

(5) Film forming property Each polymer polymer is melted and joined to obtain an unstretched sheet that is rapidly cooled by extrusion and casting. The unstretched sheet is sequentially biaxially stretched in the longitudinal direction and then in the lateral direction, and subjected to heat setting treatment. First, the appearance of the unstretched sheet at the time of casting is observed and judged according to the following criteria. Furthermore, it is also judged whether the film can be stably formed without breaking in the stretching step.
◎: Appearance is very good and film formation is stable ○: Appearance is good and film formation is stable △: Appearance is not good, but film formation is stable ×: Appearance Is bad or can't be filmed at all

(6) Solubility in water 5 g of a water-soluble polymer and 1 L of pure water at 23 ° C. were placed in a flask and stirred for 60 minutes at a stirring speed of 200 rpm with a magnetic stirrer.
The aqueous solution after dissolution was filtered through a 150 μm wire mesh and washed with 1000 ml of pure water. Thereafter, the wire mesh was dried at 120 ° C. for 3 hours, and the solubility in water was determined from the remaining amount of the unmelted material.
Water-soluble: remaining amount after drying is 2.5 g or less Water-insoluble (slightly soluble or insoluble in water): remaining amount after drying is 4.5 g or more

(7) Measurement of weight average molecular weight and residual monomer content of layer A A resin sample was dissolved in chloroform containing 1% hexafluoroisopropanol to give a concentration of 1 mg / ml as a measurement solution. This was measured by gel permeation chromatography (GPC) and converted to standard polystyrene to obtain the weight average molecular weight and the residual monomer content (weight%) of the A layer. The measurement apparatus and measurement conditions in the measurement were as follows.
Detector: Differential refractometer "RID-6A" Shimadzu Corporation column; Tosoh "TSKgel G3000HXL""TSKgelG4000HXL""TSKgelG5000HXL""TSKguardcocumnHXL-L" or Tosoh "TSKgel GTSH" ”,“ TSKguardcocumumHXL-L ”connected in series.
Mobile phase; chloroform column temperature; temperature 40 ° C
Flow rate: 1.0 ml / min
Injection volume: 10 μl
Calibration curve sample: polystyrene

(8) Appropriateness for treatment The anti-adhesion effect in the postoperative adhesion model was confirmed in rats. Specifically, a circular tissue defect having a direct diameter of 1 cm is created on the abdominal wall of the rat. Then, as an adhesion organ, the cecum is scraped to such an extent that blood slightly bleeds. A layer A sheet (2.5 × 2.5 cm) obtained in each example is covered with the defect portion. One week later, the frequency and strength of adhesion between organs was evaluated according to the following criteria.
A: There is no adhesion frequency and there is no inflammation. O: There is almost no adhesion frequency and there is almost no inflammation. Δ: A little adhesion frequency is observed, but the strength is not so strong. X: The adhesion frequency is high. Firmly adhere

(9) Resin PLA1: Bio-poly L-lactic acid (manufactured by Duct, trade name: LACTEL “B6002-2”, melt viscosity at 220 ° C .: 700 a · S, Tma: 170 ° C., Tga: 60 ° C., Tda: 230 ° C, not water soluble)
PLA2: Poly L-lactic acid (manufactured by NatureWorks, trade name: PLA Polymer “4032D”, melt viscosity at 220 ° C .: 900 Pa · S, weight average molecular weight 190,000, Tma: 170 ° C., Tga: 55 ° C., Tda: 230 ℃, no water solubility)
PVA1: Polyvinyl alcohol (Kuraray Co., Ltd., trade name: Kuraray Poval “CP-1000”, melt viscosity at 220 ° C .: 800 Pa · S, Tmb: 175 ° C., Tgb: 57 ° C., Tdb: 200 ° C., water-soluble)
PVA2: polyvinyl alcohol (manufactured by Nippon Synthetic Chemical Co., Ltd., trade name: Nichigo G-Polymer “OKS-8074P”, melt viscosity at 220 ° C .: 1000 Pa · S, Tmb: 185 ° C., Tgb: 75 ° C., Tdb: 230 ° C., Water soluble)
PVA3: polyvinyl alcohol (manufactured by Nippon Synthetic Chemical Co., Ltd., trade name: Nichigo G-Polymer “OKS-8089P”, melt viscosity at 220 ° C .: 1100 Pa · S, Tmb: 148 ° C., Tgb: 65 ° C., Tdb: 230 ° C. Water soluble)
PVA4: Polyvinyl alcohol (manufactured by Nippon Synthetic Chemical Co., Ltd., trade name: Nichigo G-Polymer “OKS-8049P”, melt viscosity at 220 ° C .: 1400 Pa · S, Tmb: 185 ° C., Tgb: 75 ° C., Tdb: 230 ° C. Water soluble)
PVA5: Polyvinyl alcohol (Kuraray Co., Ltd., trade name: Kuraray Poval “CP-1220T10”, melt viscosity at 220 ° C .: 300 Pa · S, Tmb: 176 ° C., Tgb: 42 ° C., Tdb: 200 ° C., water-soluble)

[Example 1]
PLA1 of (9) above was prepared as biodegradable polymer A, and PVA1 of (9) was prepared as water-soluble polymer B.
The prepared poly L-lactic acid is dried at 110 ° C. for 5 hours and then supplied to the extruder, heated to 190 ° C. to be in a molten state, and the prepared polyvinyl alcohol is dried at 60 ° C. for 16 hours and then supplied to the extruder. The total number of layers 201 in which the A layer and the B layer are alternately laminated using a multilayer feedblock device after branching the A layer to 100 layers and the B layer to 101 layers by heating to 190 ° C. The layer was laminated and extruded from a die onto a cooling drum at 20 ° C., and the average layer thickness ratio of the A layer and the B layer was adjusted to 1: 1, and a multilayer unstretched film having a thickness of 144 μm was prepared.
This multilayer unstretched film was stretched 3 times in the film forming direction (longitudinal direction) and 3 times in the width direction (transverse direction) at a temperature of 75 ° C., and heat-fixed at 110 ° C. for 3 seconds, and then at 95 ° C. After cooling once, it was further cooled to room temperature and wound up. The total thickness of the obtained composite film was 16 μm.
The properties of the obtained composite film are shown in Table 1.

[Examples 2-15, Comparative Examples 1-3]
As shown in Table 1, the same operations as in Example 1 except that the melt extrusion temperature, the number of layers, the ratio of the B layer, the types of biodegradable polymer and water-soluble polymer, the draw ratio, and the thickness of each layer were changed. Was repeated. In addition, when adjusting a draw ratio and the thickness of each layer, the discharge amount at the time of extrusion was adjusted so that it might become the thickness shown in Table 1.
The properties of the obtained composite film are shown in Table 1.

[Examples 16 and 17]
As the thickness adjusting layer, the thickness of the B layer located on the surface layer of the composite film is 450 nm (Example 16) and 4000 nm (Example 17), and the thicknesses of the A layer and B layer located on the inner layer are as shown in Table 1. Except for the change, the same operation as in Example 1 was repeated.
The properties of the obtained composite film are shown in Table 1.

  PLA 1-2 and PVA 1-5 in Table 1 are the resins described in (9) Resin. Further, the average thickness of the A layer and the average thickness of the B layer in Table 1 are average values of the thicknesses of the A layer and the B layer located in the inner layer, and the surface layer B and the surface layer B ′ are combined with the surface layer B. B layer forming one surface layer of the film, surface layer B 'is the B layer forming the other surface layer of the composite film, the ratio of the B layer is the total thickness of the B layer of the inner layer and the B layer located on the surface layer Is divided by the thickness of the entire composite film.

  The composite film of the present invention can be used, for example, as a liquid for preventing infection of wounds by dispersing it in water and dropping it as a PLA nanosheet suspension onto an affected area such as a wound and covering the affected area with the nanosheet. In addition, the use of this coextrusion laminating technique makes it possible to obtain nanosheets very easily and in large quantities, so it is considered that the social contribution is great.

Claims (11)

A composite film in which a plurality of A layers having a thickness of 5 to 100 nm made of a thermoplastic biodegradable polymer and a B layer made of a thermoplastic water-soluble polymer are laminated,
When the cross section along the thickness direction of the composite film is viewed, it is formed by coextrusion molding, wherein the ratio of the B layer is in the range of 25 to 75% and the total thickness of the composite film is 3 μm or more. Composite film.   The melting point difference (ΔTm = | Tma−Tmb |) between the melting point (Tma) of the biodegradable polymer and the melting point (Tmb) of the water-soluble polymer is 50 ° C. or less, and the decomposition temperature (Tda) of the biodegradable polymer And the decomposition temperature (Tdb) of the water-soluble polymer are both higher than Tma and Tmb.   The melting point ratio (Tma) of the biodegradable polymer + the ratio of the melt viscosity of the biodegradable polymer and the water-soluble polymer at 50 ° C. (biodegradable polymer / water-soluble polymer) is in the range of 0.1-10. The composite film according to claim 1.   The composite according to claim 1, wherein the biodegradable polymer is at least one obtained from the group consisting of polylactic acid (PLA), glycolic acid copolymer (PLGA), polyglycolic acid (PGA), and polycaprolactone (PCL). the film.   The composite film according to claim 1, wherein the water-soluble polymer is at least one kind obtained from the group consisting of polyacrylic acid, polymethacrylic acid, polyethylene glycol, polyacrylamide, polyvinyl alcohol (PVA), starch, and cellulose acetate.   The composite film according to claim 1, wherein the composite film is a multilayer film in which A layers and B layers are alternately laminated, and the total number of A layers and B layers is 10 or more.   The composite film according to claim 6, wherein the thickness of at least one surface layer of the composite film is at least twice the average thickness of the A layer and 50% or less of the total thickness of the composite film.   The composite film according to any one of claims 1 to 7, wherein the composite film is a stretched composite film stretched in at least one in-plane direction.   The composite film according to any one of claims 1 to 8, which is used for treatment of a living body. This is a method for producing a composite film having a total thickness of 3 μm or more in which a plurality of layers A having a thickness of 5 to 100 nm made of a thermoplastic biodegradable polymer and a layer B made of a water-soluble polymer are laminated. And
A coextrusion step in which a thermoplastic biodegradable polymer and a thermoplastic water-soluble polymer are laminated in a molten state with a layer A made of a biodegradable polymer and a layer B made of a water-soluble polymer, and biodegradation A cooling step of cooling below the glass transition temperature of the conductive polymer, and a winding step of winding up the obtained film,
In the co-extrusion step, the composite is extruded such that the thickness of the B layer is in the range of 25 to 75% with respect to the total thickness of the composite film when the cross section in the thickness direction of the composite film is viewed. A method for producing a film.   11. The film according to claim 10, wherein the film is stretched in at least one direction in the in-plane direction of the biodegradable polymer within the range of the glass transition temperature (Tga: ° C.) to (Tga + 30 ° C.) between the cooling step and the winding step. A method for producing a composite film.