JPH07313585A - Wound covering material - Google Patents

Abstract

PURPOSE:To check the occurrence of an infectious disease on a wound surface, and easily discharge an exudate secreting in large quantities in the early stage of forming a wound by layering a hyaluronic acid sponge crosslinked by an epoxy compound on a composite polyurethane film having an opening hole. CONSTITUTION:This wound covering material is formed by layering a polyurethane film formed as a film out a polyurethane resin on a water absorptive cloth-like material, and a composite polyurethane film having an opening hole is used at least as the polyurethane film, and a hyaluronic acid sponge which is crosslinked by an epoxy compound and contains hyaluronic acid, is layered on the polyurethane film. Since the opening hole is arranged in the polyurethane film, an exudate secreting in large quantities in the early stage of application is efficiently exuded, and since the sponge containing hyaluronic acid to fulfill important operation in a wound healing process is arranged so as to contact with a wound surface, healing of a wound is promoted.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a wound dressing applied to the wound surface of a wound such as a burn or an external wound.

2. Description of the Related Art Various types of wound dressings have been developed which are made of synthetic materials, biomaterials, or a combination thereof, and are applied to the treatment of burns, pressure ulcers and the like. In general, the wound surface has a state without infection and a state showing signs of infection, or a state in which there is no necrotic tissue present, and there is an intervening state, so it is important to select a wound dressing that has the optimal function according to the application case. .

A polyurethane resin and a non-porous film useful as such a wound dressing material have been proposed (JP-A-64-9213). This polyurethane resin is
Produced by reacting a random copolymer of tetrahydrofuran and ethylene oxide containing 20 to 80% by weight of ethylene oxide unit and having a number average molecular weight of 800 to 3000 with an alicyclic diisocyanate and extending the chain with an alicyclic diamine. It is what is done. The urethane-based film provided by forming the polyurethane resin produced by this method is breathable and allows the skin to breathe. In addition, it is non-porous and prevents passage of bacteria and the like. have. In addition, since the film itself is elastic, it does not cause peeling, itchiness, rash, etc. even if it is attached to any part of the skin, and it has the characteristic that it does not peel off from the skin by flexion motion. is there.

Composite wound dressings for applying such urethane films to wound surfaces are known. For example, in the pamphlet of PCT International Publication No. WO 92/19194, there is provided a polyurethane film or a cloth-like product, which comprises a film made of a polyurethane resin or a laminate of the polyurethane film and a water-absorbing cloth-like product. Discloses a wound dressing material containing an antibacterial agent and having openings formed in at least a polyurethane film. This wound dressing is composed of a polyurethane film, which is in close contact with the affected area such as a burn and has excellent adhesiveness to the living body and excellent releasability from the wound surface, and has water absorbability on the upper surface of the polyurethane film as necessary. A cloth-like material is provided to improve the controllability of water vaporization. The film is mixed with an antibacterial agent to impart a bactericidal property, and further has a function of easily discharging exudate, which has a bad therapeutic effect when stored.

Further, as an example of indirectly applying the urethane film to the wound surface, for example, a porous sheet containing a chitosan derivative and a collagen derivative is provided on the lower surface (the surface in contact with the wound surface) of the urethane film as described above. A wound dressing material is known (Japanese Patent Laid-Open No. 3-289961). Although these wound dressings are widely applied clinically, they do not have the action of promoting the healing of intractable wounds such as intractable skin ulcers and pressure ulcers, and are not always satisfactory clinically.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a wound dressing useful for treating wounds. One aspect of the object of the present invention is to provide a wound dressing which is effective even when used for treating intractable wounds such as intractable skin ulcers and pressure ulcers. Another aspect of the present invention is to provide a wound dressing having an action of promoting the healing of a refractory wound. Further, the present invention is a wound dressing material that prevents the occurrence of infectious disease on the wound surface and facilitates drainage of exudate that is secreted in a large amount in the initial stage of wound formation, and has a wound surface healing promoting action. Is intended to provide.

[0006]

As a result of diligent efforts to solve the above-mentioned problems, the present inventor has found that a sponge containing hyaluronic acid, which plays an important role in the wound healing process, is arranged so as to contact the wound surface. It has been found that the use of wood promotes wound healing. Further, it has been found that such a wound dressing is effective for treating intractable wounds and has an action of promoting healing.
Furthermore, the present inventor has found that the healing promoting effect is remarkably promoted by incorporating an antithrombotic agent into a sponge containing at least hyaluronic acid among the constituent members of the above wound dressing. The present invention has been completed based on the above findings.

That is, the first embodiment of the present invention comprises (a) a laminate of a polyurethane film formed of a polyurethane resin and a cloth-like material having water absorbability, and at least the polyurethane film has openings. A wound dressing characterized by comprising: a composite polyurethane film being formed; and (b) a hyaluronic acid sponge comprising a hyaluronic acid cross-linked with an epoxy compound and laminated on the polyurethane film.

According to the second aspect of the present invention, (a)
A composite polyurethane film comprising a laminate of a polyurethane film formed by forming a polyurethane resin and a cloth material having water absorbency, wherein at least the polyurethane film has pores formed therein; and (b) crosslinking with an epoxy compound There is provided a wound dressing comprising a hyaluronic acid sponge containing the hyaluronic acid formed thereon and laminated on the polyurethane film, wherein at least the hyaluronic acid sponge contains an antithrombotic agent.

In a preferred embodiment of the above-mentioned first invention, the polyurethane resin contains 20 to 8 ethylene oxide units.
A wound dressing material, which is a polyurethane resin obtained by reacting a random copolymer of tetrahydrofuran and ethylene oxide having a number average molecular weight of 800 to 3000 with 0% by weight with diisocyanate and chain-extending with a chain extender; Wound dressing with holes as slits; Wound dressing with cloth as a non-woven fabric; Non-woven fabric showing elongation of 30% or more at a load of 250 g / cm in at least one direction. Accordingly, there is provided a wound dressing in which slit-shaped openings are formed in a direction intersecting the direction of easy elongation of the nonwoven fabric; and a wound dressing in which the nonwoven fabric is a mixed fiber of polyester fiber and rayon fiber.

Further, as a preferred embodiment of the above-mentioned second invention, there is provided a wound dressing in which the antithrombotic agent is an antithrombin agent; and a wound dressing in which the antithrombotic agent is argatroban. , A polyurethane resin containing 20 to 80% by weight of ethylene oxide units and a random copolymer of tetrahydrofuran and ethylene oxide having a number average molecular weight of 800 to 3000 is reacted with diisocyanate and chain extended by a chain extender. Wound dressing that is a polyurethane resin obtained; Wound dressing that has slit-shaped openings; Wound dressing that the fabric is a nonwoven fabric; 30% when the nonwoven fabric is loaded in at least one direction at 250 g / cm2 Wound covering that is a non-woven fabric exhibiting the above-mentioned degree of elongation, and in which slit-shaped openings are formed in a direction intersecting with the easy-extending direction of the non-woven fabric, if necessary. ; And nonwoven wound dressing is provided comprising a mixed fiber of polyester fiber and rayon fiber.

As a preferred embodiment of the above first and second inventions, there is provided a wound dressing in which an antibacterial agent is blended in at least a polyurethane film. From still another aspect, the present invention provides a wound healing agent containing an antithrombotic agent. Wound healing agents containing Albatroban as a preferred antithrombotic agent are also provided.

As the polyurethane resin for producing the polyurethane film constituting the wound dressing of the present invention, any polyurethane resin may be used as long as it is excellent in adhesion, flexibility, moisture permeability and peelability from the wound surface. Good. Examples of the polyurethane resin and the polyurethane film which are preferably used to achieve the object of the present invention include, for example, JP-A-64
-9213 Publication or PCT International Publication No. WO 92/19194 pamphlet can be mentioned. This example will be described in detail below.

The polyol component includes tetrahydrofuran (hereinafter abbreviated as THF) and ethylene oxide (hereinafter referred to as EO).
Abbreviated)) is used. This copolymer is prepared by ring-opening a mixture of THF and EO with a short-chain diol such as water or ethylene glycol or 1,4-butanediol as an initiator in the presence of a Lewis acid catalyst such as boron trifluoride ether complex salt. It is synthesized by copolymerization.

Embedded in a random copolymer of THF and EO
The content of EO units is 20% in order to reduce swelling and physical property deterioration during water absorption when a polyurethane resin is manufactured.
The amount may be -80% by weight, more preferably 30-70% by weight, and particularly preferably 40-70% by weight. THF and
The random copolymer with EO has a number average molecular weight of 800-300.
It is preferable to use a material of about 0. Number average molecular weight is
If it is less than 800, the polyurethane film may become hard, and if it is more than 3000, the tackiness may be large and swelling due to water absorption may increase. In consideration of flexibility, it is preferable to use a random copolymer having a number average molecular weight of 1000 to 2500 in order to obtain a polyurethane film having the best coating physical properties.

If necessary, a random copolymer of THF and EO may be added to polytetramethylene ether glycol (hereinafter abbreviated as PTMG), polyethylene glycol, polypropylene glycol, polybutylene adipate, polycaprolactone diol, polycarbonate diol, silicone polyol, etc. You may mix and use a polyol. When using PTMG, the number average molecular weight of PIMG is 80
The number average molecular weight of the polyol mixture can be 800 to 3000, and it is preferably 1000 to 2500 in order to obtain a polyurethane film having well-balanced physical properties. The above-mentioned random copolymer of THF and EO may partially include a partial block copolymer structure generated during polymerization in the polyol chain.

When the above-mentioned random copolymer of THF and EO is used for the polyol component of polyurethane, the water absorption rate is increased by the increase of EO units as compared with the block copolymer of THF and EO and the combined system of PEG. It is preferable because a polyurethane resin exhibiting high moisture permeability can be produced although the amount thereof is small. As the copolymer of THF and EO, in addition to the above, EO is added to PTMG which is a ring-opening polymerized THF, or THF is added to polyethylene glycol (hereinafter abbreviated as PEG) which is a ring-opening polymerized EO. A block copolymer added with can be used. However, the polyurethanes using these block copolymers contain PTMG homopolymer long chains, which have strong hydrophilicity, in their structure.
Swelling due to water absorption may increase remarkably as in the case of mixing PEG with PEG.

In order to obtain a polyurethane resin for producing a polyurethane film for use in the wound dressing of the present invention, an excess equivalent amount of diisocyanate is reacted with the above-mentioned polyol at 70 to 120 ° C. to give an isocyanate group at the end. After making a urethane prepolymer, in an organic solvent
The chain may be extended with a chain extender at a temperature of about 20 to 100 ° C. The equivalent ratio of diisocyanate to polyol in the urethane prepolymer is usually 1.5: 1 to 6: 1, but it is preferably 1.8: 1 to 4.5: 1 in order to combine good physical properties and moisture permeability.

Examples of the diisocyanate of the polyutane resin used in the present invention include 4,4'-diphenylmethane diisocyanate, 2,4- and 2,6-tolylene diisocyanate, 1,5-naphthalene diisocyanate, m- and p-phenylene diisocyanate. Aromatic diisocyanates such as
Examples thereof include alicyclic diisocyanates such as isophorone diisocyanate, 4,4′-dicyclohexylmethane diisocyanate, 1,4-cyclohexylene diisocyanate, and water additives of tolylene diisocyanate, and aliphatic diisocyanates such as hexamethylene diisocyanate. Of these, alicyclic diisocyanates are preferred as the diisocyanate that gives a polyurethane resin that does not cause yellowing and has good mechanical properties. These isocyanates are usually used alone, but two or more kinds may be used in combination. In addition, among the alicyclic diisocyanates, 4,4′-dicyclohexylmethane diisocyanate is most preferably used from the viewpoint of the balance between mechanical properties and moisture permeability of the polyurethane film.

Examples of the chain extender for the polyurethane resin used in the present invention include low molecular weight diols such as ethylene glycol, propylene glycol, diethylene glycol, 1,4-butanediol and 1,6-hexanediol, ethylenediamine, 1,2- Aliphatic diamines such as propanediamine, tetramethylenediamine, hexamethylenediamine, isophoronediamine, 4,4'-dicyclohexylmethanediamine, 3,3'-dimethyl-4,4'-dicyclohexylmethanediamine, 1,4-cyclohexylene Examples thereof include alicyclic diamines such as diamines, hydrous hydrazine, and water. Of these, the alicyclic diamines may be used alone or in combination of two or more from the viewpoint of the stability of the polyurethane solution and the heat resistance of the resulting polyurethane fill 1. Furthermore, the mechanical properties of the film,
The above-mentioned low molecular weight diols may be used in combination within a range that does not significantly reduce heat resistance and the like. Among the alicyclic diamines, isophorozinamine is particularly preferable from the viewpoint of the balance between solution stability and various physical properties of the film.

The organic solvent used in the synthesis of the polyurethane resin used in the present invention is dimethylformamide,
Solvents having a strong dissolving power such as dimethylacetamide and dimethylsulfoxide are suitable. These may be used alone, toluene, aromatic solvents such as xylene, methyl ethyl ketone, acetone, ketone solvents such as cyclohexanone, ethyl acetate, acetic ester solvents such as butyl acetate, chlorine solvents such as dichloroethane, 1 selected from ether solvents such as tetrahydrofuran and dioxane, alcohol solvents such as methanol and isopropanol 1
You may use it in mixture with 1 type or 2 or more types.

The polyurethane resin thus obtained contains 1% of ethylene oxide units in the total amount of polyurethane.
It is preferably contained in an amount of 5 to 60% by weight (the ethylene oxide unit represents the ratio of ethylene oxide to tetrahydrofuran and ethylene oxide in terms of weight percentage). If the ethylene oxide unit is less than 15% by weight, the moisture permeability of the film may be insufficient, and if it is more than 60% by weight, dimensional change due to swelling during water absorption and deterioration of physical properties may be large, which may be undesirable. .

If necessary, a catalyst which is usually used for accelerating the urethanization reaction, such as a tertiary amine such as triethylenediamine or an organic tin compound such as dibutyltin dilaurate, may be present during the polyurethane synthesis. Further, for the purpose of improving the durability of the polyurethane resin, one or more kinds of hindered phenol antioxidants, benzophenone or benzotriazole ultraviolet absorbers, and hindered amine stabilizers may be contained in advance. In this case, each additive may be added in a proportion of about 0.05 to 3% by weight, preferably about 0.2 to 1% by weight, based on the solid polyurethane content. In order to produce the polyurethane film used for the wound dressing of the present invention, it is particularly effective to use a hindered amine stabilizer, and the deterioration of physical properties is small with respect to acid 1 deterioration and hydrolysis during sterilization treatment. can do.

As the polyurethane film, a polyurethane film having increased moisture permeability by making it porous is suitable. As the film forming method, for example, (1) a polyurethane resin solution is applied on a support and then in a coagulation bath. A wet film-forming method of extracting a solvent or other soluble substance; or (2) a method of applying a water-in-oil emulsion of a polyurethane resin on a support and then drying by heating to obtain a porous film can be employed. For example, by applying this solution to a support or release paper and performing dry film formation by heating and drying, stable moisture permeability can be obtained with good reproducibility, and even a single film has practically sufficient strength, elongation, and durability. A film with The support used in dry film formation is not particularly limited, polyethylene or polypropylene film,
Release paper or cloth coated with a fluorine-based or silicone-based release agent is used.

Since the moisture permeability of the polyurethane resin film used in the present invention is inversely related to the film thickness, it is desirable to use release paper having a uniform thickness. The coating method is not particularly limited, but a knife coater,
A roll coater or the like can be used. The drying temperature can be arbitrarily set depending on the capability of the dryer, but it is necessary to select a temperature range in which insufficient drying or rapid desolvation does not occur. Drying is preferably carried out in the range of 60 to 130 ° C.

The thickness of the polyurea film used in the present invention is usually 10 to 200 μm, preferably 10 to 50 μm. If it is 10 μm or less, pinholes are likely to be formed during coating and the film is likely to be blocked, which may be difficult to handle. If it is 50 μm or more, it tends to be difficult to obtain sufficient moisture permeability. In addition, the polyurethane film produced in this way is characterized in that the film thickness dependence of moisture permeability is smaller than that of other urethane-based films. A foaming film may be prepared by mixing a polyurethane resin with a foaming agent during film formation. The expansion ratio is usually about 1.2 to 5 times.

The polyurethane resin film used for producing the wound dressing of the present invention preferably has a moisture permeability of 1
2,000 g / m ²・ 24hr, preferably 3,000 g / m ²・ 24hr or more at a thickness of 0 to 80 μm (measured by JIS Z0208)
It has a high moisture permeability. If it is less than this, stuffiness occurs when it is applied to the skin, which causes discomfort, which is not preferable. The 100% modulus is 20 kg / cm ² or more, preferably 30 kg / cm ² or more. When the 100% modulus is 20 kg / cm ² or less, the film has high tackiness, and the films are likely to cause blocking. Again 80
If it is more than kg / cm ² , the flexibility tends to be poor and the moisture permeability tends to decrease.

In the production of the wound dressing of the present invention, a composite polyurethane film comprising a laminate of the polyurethane film and an absorbent cloth-like material is used. Such cloth-like material may be any one having a structure that is flexible and capable of absorbing water, such as a woven cloth or a non-woven cloth, but a woven cloth having elasticity from the viewpoint of adhesion to the wound surface, Nonwoven fabric is preferably used. Particularly preferably, a non-woven fabric can be used. Nonwoven fabrics are usually produced by spraying fine fibers on a smooth plate surface and entwining these fibers with each other, or by welding or adhering them. Sometimes you can.

The knitted or woven fabric used in the production of the wound dressing of the present invention preferably has a relatively large elongation. When the elongation is expressed as a percentage of the original length when the load of 1500 g is hung on a nonwoven fabric of 60 cm in length and 6 cm in width, the elongation is 30% to 200% in the case of nonwoven fabric. ,
It is desirable to use 40 to 150%. The thickness of knitted and woven fabrics includes flexibility, durability,
From the viewpoint of workability, water absorption, etc., it is desirable that the thickness is about 0.5 mm to 3 mm, preferably about 0.5 mm to 2 mm.

As the material of the knitted woven fabric or the non-woven fabric, natural fibers such as wood pulp and cotton, regenerated fibers such as rayon and cupra are used from the viewpoints of flexibility, durability, water absorbency and carrying ability of water absorbent resin. , Semi-synthetic fibers such as acetate, and synthetic fibers such as nylon, polyester, and acrylic are suitable. Especially, use a non-woven fabric composed of a mixed fiber of polyester and rayon in a ratio of about 6: 4 to 8: 2 (weight ratio). Thereby, the elasticity is imparted by the heat during the manufacturing process. Polyester fiber is 0.5d as the thickness of the fibers that make up the nonwoven fabric.
(Denier) to 3.0 d are preferred, and rayon fibers are preferably 1.0 d to 3.5 d. The polyester fiber and rayon fiber should have a fineness difference so that the rayon fiber becomes thicker by about 0.5d.

Further, the above cloth-like material carrying a water absorbing resin can also be used. The water-absorbing resin used, hydrophilic groups _{(-OH, -COOH, -SO 3 H} , -NHCO- etc.) resins having a preferably used. For example, a starch-based water-absorbent resin, a cellulose-based water-absorbent resin, or a synthetic polymer-based water-absorbent resin such as a polyacrylic acid-based, poval-based, or polyoxyethylene-based resin is suitable. Specific examples include alginate, carboxyalkyl cellulose, gelatin and the like. These water-absorbent resins can be used by supporting them on a cloth.
As a method of supporting the water-absorbent resin, after moistening the surface of the cloth-like material with water spray or the like, the water-absorbent resin is in a powder form,
A method of forming fine particles and spraying is preferable because it is easy in terms of steps. According to this step, the water-absorbent resin powder absorbs water on the surface of the cloth-like material and is adhered to and carried by the fibers of the cloth-like material.
In addition to the water absorbent resin, an adhesive component may be appropriately adopted depending on the use and purpose. Amount of water absorbent resin used per 100 cm ²
It is about 0.2 to 5 g, preferably about 0.5 to 3 g.

As a method for laminating the polyurethane film and the cloth-like material, when the polyurethane resin solution is applied to a support or release paper and dried by heating to form a dry film, the polyurethane resin solution is in a semi-dried state. At this point, a method of overlapping and pressing the cloth-like materials is convenient. Alternatively, after producing a polyurethane film, a method of blowing a solvent to the surface of the polyurethane film to swell, and then pressing the fabric-like material by stacking it, or after producing the polyurethane film, the fabric-like material using an adhesive A method of bonding may be adopted. When adhering a cloth-like material with an adhesive, if the adhesive is applied to the entire surface of the film, the moisture permeability of the film may be impaired.Therefore, apply the adhesive in spots or on the fiber portion of the cloth-like material. It should be applied and should not impair the breathability. The polyurethane film may be provided on only one side of the cloth-like material, but may be provided on both sides in order to control the evaporation property.

Openings should be formed in the composite polyurethane film obtained above. In order to form the openings, a method of rolling a roller having a large number of cutter blades embedded therein on the film surface of the polyurethane film or the like can be adopted. Openings should be formed in at least the polyurethane film of the composite polyurethane film, but openings may be formed in both the polyurethane film and the cloth-like material. When the polyurethane film is a composite polyurethane film provided on both sides of the cloth-like material, the openings may be provided only in the polyurethane film applied to the wound surface side, or may be provided in the polyurethane films on both sides. Alternatively, the openings may be formed in the entire composite polyurethane film composed of the laminate.

Examples of the shape of the opening include a needle hole shape, a punch hole shape, a cross shape, or a single-character slit-shaped opening, but the single-character slit shape is preferable from the viewpoint of water absorption retention. preferable. In this case, it is desirable to form the slit so that the longitudinal direction of the slit intersects with the easily stretchable direction of the cloth-like material. Such an arrangement is preferable because the opening degree of the slit changes depending on the extension degree of the cloth-like material. The length of the slits is preferably about 2 mm to 5 mm, and the slits can be formed in an arbitrary array such as a parallel shape or a staggered shape.
By providing the polyurethane film with the above-mentioned openings, it is possible to efficiently drain (drainage) the exudate that is secreted in a large amount at the initial application of the wound dressing, and prevent the exudate from being retained on the wound surface. . Since the exudate is less secreted after a while after the use of the wound dressing, the exudate is solidified and the openings are closed, so that the hydration environment of the wound surface can be maintained.

The wound dressing of the present invention is characterized in that a sheet-shaped hyaluronic acid sponge which contacts the wound surface is laminated on the polyurethane film surface of the above-mentioned composite polyurethane film. The hyaluronic acid sponge preferably used for the wound dressing of the present invention can be produced by crosslinking hyaluronic acid with an epoxy compound and then forming a sponge-like sheet. The cross-linking reaction of hyaluronic acid is described in, for example, the method of Tomihata et al. (Abstract No. 1-P-09: Proceedings) proposed at the 15th Annual Meeting of the Japan Society for Biomaterials (October 25-26, 1993: Kobe). Page 91).

The hyaluronic acid to be crosslinked has, for example, a molecular weight of 500,000 to 3,000,000, preferably 1.8 to 2
About 200,000 can be used. As the epoxy compound which is a cross-linking agent, for example, a water-soluble diepoxide compound can be used. The crosslinking reaction is generally carried out by preparing an aqueous solution of about 0.2 to 2.0% by weight, preferably 1% by weight, of hyaluronic acid and adjusting the pH of the solution to 4 to 7, preferably about 5 to 6, and then the epoxy compound. Can be carried out using a reaction solution added to the repeating unit of hyaluronic acid in an amount of 1/20 to 1/5 mol, preferably about 1/10 mol. The reaction temperature is, for example, 20 to 60.
C., preferably about 50.degree. C., and the reaction time is usually about 2 to 5 hours. As the reaction solvent, an alcohol-water system can be used in addition to the above water.

After the above crosslinking reaction, the reaction solution was poured into a molding container and allowed to stand in a dryer set at 20 to 60 ° C., preferably about 50 ° C. for 3 to 8 hours, preferably about 5 hours.
Further, the hyaluronic acid sponge can be produced by quenching and freezing in a freezer at -20 to -80 ° C, preferably -60 ° C and freeze-drying. Examples of the method for forming the sponge-like sheet include a freeze-drying method and the like, but the method is not limited thereto, and those skilled in the art can employ an appropriate method. The thickness of hyaluronic acid sponge is
It may be about 1 to 5 mm, preferably about 2 mm.

The degree of crosslinking of hyaluronic acid is determined by the ratio of the epoxy compound used in the above crosslinking reaction and the reaction conditions. The biodegradability, water content and hydrolysis rate of the hyaluronic acid sponge after molding are determined by the degree of crosslinking. Therefore, the degree of crosslinking should be appropriately selected depending on the application site of the wound dressing and the purpose of use. Generally, after being implanted in a living body (for example, Wistar rat subcutaneously) and left for 1 week,
It is preferable to use a hyaluronic acid sponge in which about 30% by weight remains. Also, phosphate buffered saline at 37 ° C
A hyaluronic acid sponge having a hydrolysis degree of 5 to 30% by weight when immersed in (PBS) overnight is preferably used.
In addition, in order to laminate the polyurethane film and the hyaluronic acid sponge, a method similar to the above-mentioned method for laminating the polyurethane film and the cloth-like material can be adopted.

It is preferable that an antibacterial agent is incorporated into any or all of the constituent members of the polyurethane film, the cloth-like material, and the hyaluronic acid sponge, which are the constituent members of the wound dressing of the present invention. It is particularly preferable that at least the polyurethane film contains an antibacterial agent. As the antibacterial agent, Pseudomonas spp, Enterobacter spp, Klebsiella spp, Staphylococcus spp, preferably an antibacterial agent effective against Escherichia coli, for example, sulfa drug system, cephalosporin system, penicillin system, Quinolonecarboxylic acid type, macrolide type, polypeptide type,
Any antibacterial agent such as aminoglycoside can be used. As a method of incorporating these antibacterial agents, the raw material polyurethane, the cloth-like raw material, and / or the raw material hyaluronic acid may be blended or impregnated into the cloth-like material or the polyurethane film, or the cloth-like material or the polyurethane film may have the antibacterial agent. It is possible to employ a method of spraying a polymer solution containing the above and supporting it in the form of micro beads. The content of the antibacterial agent may be appropriately determined depending on the kind of the drug, the purpose of use of the wound dressing and the site of application.

According to another aspect of the present invention, there is provided the above-mentioned wound dressing containing an antithrombotic agent. The antithrombotic agent is preferably blended in the hyaluronic acid sponge, which is a constituent member of the above-mentioned wound dressing material, but may be blended in the polyurethane film and / or the cloth-like material in addition to the hyaluronic acid sponge, if necessary. . The mixing ratio of the antithrombotic agent to the hyaluronic acid sponge is appropriately selected according to the type of wound to be treated and the state of the wound surface. For example, when argatroban is used as an antithrombotic agent, the effective dissolution rate of argatroban from the article (artificial organ) is about
1.0 × 10 ^-4 to 1.0 × 10 ^-1 μg / cm ² min, preferably 2.5
× 10 ⁻⁴ to 7.0 × 10 ⁻³ μg / cm ² · min (artificial organ, 14 (2), pp.679-682, 1985), so that the Albatroban from the wound dressing of the present invention It is advisable to select the addition amount so that the elution amount falls within the above range. The amount of the antithrombotic agent to be blended with the polyurethane film and / or the cloth-like material may be determined according to the above.

Any antithrombotic agent may be used as long as it has an antithrombotic effect, and, for example, a drug having an antithrombin activity can be used. Examples of preferable antithrombotic agents include synthetic antithrombin agents. For example, the antithrombin agent described in JP-B-61-48829 is an antithrombotic agent that can be preferably used in the present invention. As a particularly preferable antithrombotic agent, a general name “argatroban” [(2R, 4R) -4-methyl-1- [N ² -((R
S) -3-Methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid hydrate: see Table 1 of JP-B-61-48829. Described as compound 6]. However, the antithrombotic agent blended in the wound dressing of the present invention is not limited to those exemplified above, and any one or more antithrombotic agents can be used. From another viewpoint of the present invention, the present invention provides a wound healing agent containing an antithrombotic agent such as argatroban as an active ingredient. The wound dressing described above can be used as an example of the dosage form.

Without wishing to be bound by any particular theory, the action of the hyaluronic acid sponge and antithrombotic agent in the wound dressing of the present invention can be explained as follows. Hyaluronic acid, the main component of hyaluronic acid sponge, provides a highly hydrated microenvironment on the wound surface during the wound healing process. In such a microenvironment, adhesion / desorption of a cell membrane and a substrate during the movement of various cells across the wound surface is controlled and the migration of the cells is facilitated, so that the healing of the wound is promoted. In addition, the antithrombotic agent has the action of immediately leaching from the hyaluronic acid sponge and moving into the above-mentioned microhydration environment, thereby preventing the formation of blood clots and the like formed on the wound surface. When the formation of blood clots on the wound surface is prevented, the formation of granulation tissue and cell neogenesis on the wound surface are activated, so that the healing promoting effect of hyaluronic acid on the wound surface is remarkably promoted. That is, hyaluronic acid and the antithrombotic agent synergistically exert a wound healing promoting action.

Although the wound dressing of the present invention is used so that the hyaluronic acid sponge side is in contact with the wound site, it can be used in any shape such as a bandage shape or a pad shape of several cm square to several tens cm square. It can be appropriately selected and used according to the degree and depth of the wound, the area of the wound surface, and the like. Examples of wounds that are applications of the wound dressing of the present invention include, for example, abrasions, skin exfoliation, cutaneous wounds, skin trauma such as split-thickness skin wounds, fever, skin ulcers such as leg ulcers, and pressure ulcers. Intractable wounds such as Further, the application site of the wound dressing of the present invention is not limited to the skin outside the living body, and for example, it is applied to the surface of internal tissues / organs during surgery to prevent tissue adhesion after laparotomy. In some cases, such as in the case of complex fracture, the case where the tissue (for example, bone) inside the living body is applied to the site exposed outside the body is also included in the scope of the present invention. Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples.

[0043]

【Example】

A. Production of wound dressing of the present invention 1. Production of THF / EO random copolymer Production Example 1 Ethylene glycol: 17.2 parts by weight, THF: 241.4 parts by weight, EO: 241.4 parts by weight, BF ₃ · ethyl ether complex salt: 1
A formulation of 9.7 parts by weight was used. Using ethylene glycol as an initiator and BF ₃ · ethyl ether complex salt as an acid catalyst, THF and EO were randomly copolymerized at 30 ° C. under atmospheric pressure in an autoclave. After the polymerization, the acid catalyst in the product was neutralized with an alkali, the precipitate was filtered, and further dried by blowing dry nitrogen at 100 ° C. The obtained THF / EO random copolymer (hereinafter referred to as a polyol) was a colorless transparent liquid having a number average molecular weight of 1800 and an EO content of 50% by weight (polyol A).

Production Example 2 Ethylene glycol: 28.2 parts by weight, THF: 236 parts by weight,
A polyol was produced in the same manner as above except that the formulation of EO: 236 parts by weight and BF ₃ · ethyl ether complex salt: 32.3 parts by weight was used. The obtained polyol was a colorless transparent liquid, and had a number average molecular weight of 1,100 and an EO content of 50% by weight (polyol B). Production Example 3 Ethylene glycol: 13.4 parts by weight, THF: 194.6 parts by weight, EO: 291.9 parts by weight, BF ₃ · ethyl ether complex salt: 1
A polyol was prepared as described above, except that the formulation was 5.3 parts by weight. The obtained polyol was a colorless transparent liquid, and had a number average molecular weight of 2,300 and an EO content of 60% by weight (polyol C). The number average molecular weight was calculated by OH value measurement, and the EO content was calculated from the charged amount.

2. Production of Polyurethane Resin (a) Production of Polyurethane Solution Production Example 4: 359.6 parts by weight of the polyol A obtained in Production example 1 and 104.7 parts by weight of 4,4′-dicyclohexylmethane diisocyanate (diisocyanate component A). Parts and 35.7 parts by weight of isophoronediamine were reacted in a flask at 100 ° C. for 6 hours under dry nitrogen to produce a urethane prepolymer having an isocyanate group at the end. Using isophoronediamine as the chain extender, this prepolymer was prepared in 2% while maintaining the temperature at 30 ° C in a dimethylformamide solvent.
A time-chain extension reaction was performed to obtain a colorless transparent viscous polyurethane solution having a polyurethane solid content concentration of 25% by weight. The viscosity of this polyurethane solution at a temperature of 25 ° C is 20,000 cps, E
The O 2 content was 36% by weight.

Production Example 5 305.7 parts by weight of polyol B and diisocyanate component A
Was 145.6 parts by weight and 48.7 parts by weight of isophoronediamine to prepare a polyurethane solution in the same manner as in Production Example 5. The viscosity of this polyurethane solution at a temperature of 25 ° C is 35,000.
The cps :, EO content was 31% by weight. Production Example 6 383.0 parts by weight of polyol C, diisocyanate component A
Was 87.3 parts by weight, and isophorone diamine was 29.7 parts by weight to prepare a polyurethane solution in the same manner as in Production Example 5. The viscosity of this polyurethane solution at a temperature of 25 ° C is 15,000.
The cps and EO content was 46%.

(B) Preparation of Polyurethane Films A to F The above-mentioned polyurethane solution was diluted with methanol to a concentration of 1% by weight, and 0.1% by weight of silver sulfadiazine was added to the polyurethane solution of Production Example 4 and that of Production Example 5. 0.01% by weight of gentamicin in the polyurethane solution, 0.01% by weight of polymyxin B in the polyurethane solution of Production Example 6.
Was compounded. Each of the mixed solutions is poured onto a glass plate provided with a spacer, spread with a glass rod to apply a uniform thickness, and then dried at 80 ° C for a whole day and night. Three types of colorless and transparent polyurethane dry films (Films A, B, C) )
Got At this time, the thickness of the film was adjusted by a spacer so as to be about 25μ. Similarly, polyurethane dry films D, E, and F containing no antibacterial agent were produced from the respective polyurethane solutions.

The water vapor permeability of the polyurethane film is
According to the method of JIS Z-0208, it was determined by weight measurement using a moisture permeable cup under the conditions of 40 ° C. and 90% RH. The results were as follows. Film A: Water vapor transmission rate 4400g / m ² / 24hr Film B: Water vapor transmission rate 3500g / m ² / 24hr Film C: Water vapor transmission rate 4800g / m ² / 24hr

3. Production of Composite Polyurethane Film Production Examples 7 to 9: As a cloth-like material, a basis weight of rayon fibers having an average fineness of 3d and polyester fibers of 2.5d (22:78) (weight ratio) was 100 g / m ^2. A non-woven fabric having a thickness of 0.8 mm was used.
The elongation of this non-woven fabric is 47% in the longitudinal direction and 1 in the lateral direction.
It was 28%. 50/50 methanol and water on this non-woven fabric
After absorbing a small amount of the solution, sodium alginate powder was sprayed as a water absorbent resin at a rate of 0.7 g / 100 cm ² .
The above-mentioned non-woven fabric supporting the absorbent resin or non-woven fabric not supporting the absorbent resin is bonded to each of the six 25 μm-thick polyurethane films A to F obtained in the above 2 (b) and then dried. To produce a composite polyurethane film. In each polyurethane film of each composite polyurethane film, slit-like openings with a length of 3 mm are provided on the straight line at intervals of 2 mm in the transverse direction and at the right angle direction, and the pitch of the lines (the parallel interval between the lines) is 5 mm. As the slits are arranged in a staggered manner, composite polyurethane films G to L on which a nonwoven fabric carrying an absorbent resin is laminated,
And the composite polyurethane film MR laminated | stacked with the nonwoven fabric which does not carry | support an absorbent resin was manufactured.

Production Example 8: Production of Composite Polyurethane Film Segmented polyurethane (PC-200-1: manufactured by Mitsubishi Kasei Co., Ltd.) was suspended in isopropanol, and silver sulfadiazine (AgSD) was added to the final polyurethane film at 50 μg / cm ^2.
To prepare a suspension. The suspension was coated on a release paper using a film forming machine (M200 manufactured by Hirano Techseed Co., Ltd.), and dried by warm air treatment. Non-woven fabric (material: polyester; thickness: about 2 mm; made by Cotec Co., Ltd.) is attached to the semi-dry sheet during the drying process.
A composite polyurethane film was produced by further drying. A 5-mm long slit was formed in the above-mentioned composite polyurethane film at 5-mm intervals to manufacture a composite polyurethane film T.

4. Production of Hyaluronic Acid Sponge Production Example 9 Water-soluble epoxide compound Denacol EX810 (Nagase Kasei) was added to a 1% aqueous solution (pH 5.9) of hyaluronic acid (Kibun Food Chemifa) having a molecular weight of 1.8 to 2.2 million. The acid was added in an amount of 1/10 mol based on the molecular weight of the repeating unit. Add 90 ml of this mixture to a polystyrene container (10
cm x 18 cm) and place it in a dryer set at 50 ° C.
After left standing for 5 hours, it was rapidly frozen and frozen in a -60 ° C freezer, and then vacuum dried to produce hyaluronic acid sponge HA.
Hyaluronic acid sponge HAa containing a synthetic antithrombin agent Argatonban (manufactured by Mitsubishi Kasei Co., Ltd.) was added to a concentration of 500 μg / cm ² after adding a water-soluble epoxy compound according to the above manufacturing process. Manufactured. The thickness of hyaluronic acid sponge HA and HAa above is about 2 mm
Met.

5. Production of Wound Dressing Material of the Present Invention By using the composite polyurethane films G to L, the composite polyurethane films M to R, and the composite polyurethane film T, hyaluronic acid sponge HA or HA was formed on the polyurethane film surface of each laminate. HAa was pressure-bonded to produce the wound dressing of the present invention. In addition, ethylene oxide gas was used for sterilization of each of the polyurethane films, the composite polyurethane film, and the hyaluronic acid sponge.

B. Evaluation of Wound Dressing of the Invention Hyaluronic acid sponge H on composite polyurethane film T
The wound dressing was evaluated using a wound dressing laminated with A or HAa. 1. Creation of granulation tissue wound surface A chronic granulation tissue wound model was created in order to evaluate a wound dressing material for a chronic granulation tissue wound with delayed healing.

6 5-week-old SD rats had a diameter of 30
mm full-thickness skin defect wound is created, outer diameter 30 mm, inner diameter 25 mm
The polystyrene ring was fixed by suture along the circumference of the wound. 35 mm diameter by applying epoxy adhesive on the ring
Nylon net or Gore-tex membrane (manufactured by Japan GORE-TEX Co., Ltd.) was adhered and fixed, and gauze was applied onto this to protect it with a stainless net and fixed with elastic tape. Since this nylon mesh or GORE-TEX membrane is fixed without adhering to the wound surface, the air permeability is maintained and the environment close to a semi-open wound can be provided. Rats were sacrificed one by one after 3, 6 and 10 days under this condition, and the condition of the wound surface was observed histologically, and the preparation conditions of the chronic granulation tissue wound model used for evaluation of the wound dressing were examined. .

When the wound was completely covered with nylon mesh in a non-contact manner, the exudate was not temporarily stored on the wound surface but was absorbed by the outer gauze. Further, the central part of the nylon net came into contact with the wound surface, resulting in mechanical irritation to the wound surface due to friction accompanying the movement of the animal. Histological observation by HE staining showed a tissue structure similar to that of a fresh wound when coated for 3 days, and formation of a granulation tissue having a dense matrix structure when coated for 6 days or more. Had been started.

On the other hand, when the GORE-TEX film was non-contactly coated on the skin defect of the whole wound, there was no evidence that the exudate was absorbed by the outer gauze. Since the GORE-TEX membrane has the property of allowing air to permeate but not exudate, it was possible to provide an environment in which the exudate was temporarily stored on the wound surface. When coated for 3 days, it showed a tissue structure similar to that of a fresh wound, but when coated for 6 days, formation of granulation tissue having a loose matrix structure was observed. But 9
When it was coated for more than one day, it changed into a tissue structure having a dense matrix structure. From the above experimental results, it was determined that applying the Gore-Tex membrane in a non-contact manner for 6 days was suitable as the preparation condition for the chronic granulation tissue wound model.

2. Evaluation of Wound Dressing Material The above hyaluronic acid sponge HA (3 animals) or hyaluronic acid sponge HAa was applied to the wound surface of granulation tissue prepared by coating nine 5-week-old rats with a Gore-tex membrane for 6 days.
(3 animals) were attached, and the above composite polyurethane film T was further laminated thereon and fixed with an elastic tape. As a target, only the composite polyurethane film T (3 animals) was attached and fixed with an elastic tape. After this, on the 5th day, the coating on the wound surface was removed from all the rats, and the rats were visually observed. At this point, one animal was sacrificed in each group and the state of the wound surface was observed histologically (5th day of application). For the remaining rats, the wound surface was newly coated in each group in the same manner, and the wound surface was observed histologically on the 5th day (10th day of application). Furthermore, the same coating was applied again to the remaining rats, and the state of the wound surface was observed histologically on the 5th day (15th day of application).

When hyaluronic acid sponge HA or hyaluronic acid sponge HAa was applied and covered with the composite polyurethane film T, the wound surface was compared with the target group (the one in which the wound surface was directly covered with the composite polyurethane film T). The condition was remarkably improved and the wound area was remarkably contracted. This result clearly shows that the wound dressing of the present invention using the hyaluronic acid sponge is useful for treating a difficult-to-heal wound surface such as intractable skin ulcer and pressure ulcer. Further, according to the result of histological observation by HE staining, promotion of vascular hyperplasia was observed.

From the above results, it is clear that when hyaluronic acid sponge HAa containing argatroban is applied, vascular hyperplasia in the reconstructed tissue is promoted, and the present invention containing hyaluronic acid sponge sheet HAa is shown. It is shown that the wound dressing of (1) is more useful for treating intractable wounds than the wound dressing using hyaluronic acid sponge sheet HA containing no argatroban.

[0060]

INDUSTRIAL APPLICABILITY The present invention provides a wound dressing useful for treating intractable wounds such as intractable skin ulcers and pressure ulcers. The wound dressing of the present invention is excellent in adhesion, flexibility, durability, ease of handling, bacteria blocking property, affinity with living body, water evaporation controllability, exudate hydration property, and the like, It is useful because it promotes healing of the wound surface. It is also useful as a covering material that can provide an optimal environment for engrafting artificially cultured skin.

Claims (6)

[Claims] 1. A composite polyurethane film comprising: (a) a laminate of a polyurethane film formed by forming a polyurethane resin and a cloth-like material having water absorbability, wherein at least the polyurethane film has openings formed therein; and
(b) A wound dressing characterized by comprising a hyaluronic acid sponge which comprises hyaluronic acid crosslinked with an epoxy compound and is laminated on the polyurethane film. 2. A composite polyurethane film comprising: (a) a laminate of a polyurethane film formed by forming a polyurethane resin and a cloth-like material having water absorbability, wherein at least the polyurethane film has openings formed therein; and
(b) A wound dressing material, comprising a hyaluronic acid sponge containing hyaluronic acid crosslinked with an epoxy compound and laminated on the polyurethane film, wherein at least the hyaluronic acid sponge contains an antithrombotic agent. . 3. The wound dressing according to claim 2, wherein the antithrombotic agent is argatroban. 4. The wound dressing according to claim 1, wherein at least the polyurethane film contains an antibacterial agent. 5. A wound healing agent containing an antithrombotic agent. 6. The wound healing agent according to claim 5, wherein the antithrombotic agent is argatroban.