JP2001340375A - Wound coating material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a wound coating material by which early and efficient treatment can be realized and pain may not be imposed on a patient or the reproduced skin or the like may not be damaged when the wound coating material is replaced, etc., by promoting tissue cell proliferation and neovascularization with the wounded surface being kept in an appropriate moist condition in the whole of treating process, even if the material is applied to an wounded part with much in the amount of an exudate. SOLUTION: The wound coating material is constituted by successively laminating a nonwoven fabric layer, a polyurethane film later with openings and a sponge layer containing crosslinked hyaluronic acid and crosslinked alginic acid both of which are crosslinked by an epoxy compound, and by containing a collagen production promoting substance and an antibacterial agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel wound dressing. More specifically, the wound dressing material of the present invention is applied to a wound part that exudes a large amount of wound fluid when stopping or treating a wound part such as a burn, a pressure sore, a skin ulcer, an abrasion, or a cut, thereby protecting the wound part. At the same time, cells having a tissue repair function are infiltrated into the cells to promote wound healing.

[0002]

2. Description of the Related Art Conventionally, as a method of stopping or treating a wound such as a burn, a pressure sore, a skin ulcer, an abrasion, or a cut, a therapeutic agent is applied to the wound, and then a gauze or cotton wool is applied thereon. There have been proposed many methods for protecting a wound by covering the wound with a wound dressing material.

When gauze is directly applied to a wound, exudate from the wound is directly absorbed by the gauze.
The absorption capacity of the gauze is not very high and exudate accumulation occurs. This storage, on the contrary, promotes the generation of bacteria and makes early healing difficult. In particular, in a wound part where the exudate from the wound is large, the ointment or cream of the therapeutic agent mixes with the exudate to form a muddy state. Therefore, the wound dressing must be replaced frequently and the ointment or cream must be reapplied. Further, if the wound dressing is changed frequently, the amount of medicine to be used increases, and there is a problem that the pain of the patient when changing the wound dressing increases. In addition, these conventional wound dressings have low antibacterial properties and, when protecting the wound for a very short time, even if they can be easily separated from the wound, In the case of peeling after coating for a long time, it is often peeled off integrally with the granulation, and the blood clot is exposed again, causing unpleasant pain and rebleeding, etc. Has disadvantages. Therefore, when the rebleeding wound portion is repeatedly covered with the same wound dressing material again and the final healing is performed, scars easily remain on the wound portion after healing, which is not preferable in cosmetic surgery. There were problems such as.

[0004] As alternatives to these, wound dressing materials made of artificial materials such as silicone gauze and silicone rubber film sheets, and wounds made of biological materials such as freeze-dried pork skin, chitin nonwoven fabric, collagen film, and polyamino acid sponge can be used. Coatings are also known. However, among these, the wound dressing made of an artificial material leaves various problems in terms of adhesion to a wound portion, water vapor permeability, and the like. On the other hand, wound dressings made of biological materials have characteristics such as biocompatibility, but many of them have antigenicity and also have drawbacks such as cell infection and deterioration due to exudate.

Further, from the viewpoint of good affinity with the wound site and promotion of healing, materials derived from living organisms, such as hyaluronic acid and alginic acid, have been taken up in the medical field such as wound dressing. Have been. However, hyaluronic acid is not only highly biocompatible and highly biodegradable, but also can be expected to promote the proliferation and angiogenesis of fibroblasts to promote wound treatment. However, when non-crosslinked hyaluronic acid is applied to a living body, the remaining period is too short, and it is a device to obtain good retentivity in the wound, that is, it exists in the wound only for the period necessary for healing, and healing of defective tissue It has long been desired to provide a substance suitable for the purpose of disappearing from tissue according to the condition. Alginic acid extracted from seaweed is a natural polymer composed of mannuronic acid and guluronic acid as constituent units, and its metal salt has a hemostatic effect, an analgesic effect, and a mucosal protective effect. Although the wound dressing material is practically used, there is a problem that the calcium salt of alginic acid has cytotoxicity.

[0006]

The wound healing process when the living body is damaged with a tissue defect generally includes a stage I (inflammatory stage), a stage II (granulation and reepithelialization stage), and a stage III ( (Matrix formation and reconstitution phase). I
In the anatomical phase, platelets are aggregated and activated at the bleeding site where blood vessels are destroyed due to tissue damage, and various bioactive substances including multiple cell growth factors are released along with the formation of thrombus, which may contribute to healing. It recognized. In stage II, vascular endothelial cells, fibroblasts, epidermal cells, and the like cooperate to cause granulation, and these cells are further responsible for granulation by producing factors that promote the proliferation of surrounding cells. In stage III, fibroblasts and new blood vessels, which were excessively proliferated due to the absorption of granulation tissue, decrease, and are replaced by collagen fibers or elastic fibers to complete healing. Thus, there are various aspects in the process of wound healing. As described above, it is considered that the types of cells and cell growth factors which play a major role in the wound healing process change every moment, and these are controlled in a complicated manner, and eventually head toward the convergence direction.

[0007] However, hyaluronic acid and alginic acid used in the conventional wound dressing materials are used alone, and exhibit different and unique effects in certain aspects of the wound healing process. Was not able to exert an effect in the whole wound healing process.

Further, the method can be applied to a wound with a large amount of exudate to absorb a considerable amount of exudate exuding from the wound, and to remove water contained in the exudate at a desired rate. There was a strong need to provide a wound dressing that could be transferred through the dressing to the exterior surface of the wound dressing and evaporate this moisture into the surrounding environment, thereby extending the useful life of the wound dressing. . Therefore,
An object of the present invention is a biomaterial which can be applied to a wound part with a large amount of exudate and promotes proliferation of tissue cells and angiogenesis in the whole process of wound healing while keeping the wound part in an appropriate moist environment. To provide a wound dressing material that can promote early and efficient treatment by applying to a wound site, and that does not cause pain when replacing the wound dressing material or damage the regenerated skin, etc. It is in.

[0009]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, completed the present invention. The present invention is as follows. (1) a nonwoven fabric layer, a polyurethane film layer having openings, and a sponge layer containing a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound are sequentially laminated;
A wound dressing characterized in that at least one layer contains ascorbic acid phosphate. (2) The wound dressing according to the above (1), wherein the basis weight of the nonwoven fabric layer is 30 to 300 g / m ² . (3) The thickness of the polyurethane film layer having openings is 5
The wound dressing according to the above (1) or (2), which has a thickness of from 100 μm to 100 μm. (4) Any of the above (1) to (3), wherein the sponge layer containing the crosslinked hyaluronic acid and the crosslinked alginic acid crosslinked with the epoxy compound contains 1 to 20% by weight of the uncrosslinked hyaluronic acid and / or the uncrosslinked alginic acid. A wound dressing according to any one of the claims. (5) In the sponge layer containing a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound, the content of the crosslinked hyaluronic acid is 10 to 80% by weight, and the content of the crosslinked alginic acid is 20 to 90% by weight. The wound dressing according to any one of (1) to (4). (6) The content ratio of the ascorbic acid phosphate is as follows:
The wound dressing according to any one of (1) to (5), wherein the amount is 0.1 to 10% by weight. (7) The wound dressing according to any one of the above (1) to (6), which contains an antibacterial agent.

[0010]

DETAILED DESCRIPTION OF THE INVENTION The present invention is applied to a wound with a large amount of exudate, absorbs a large amount of wound exudate released from the wound, and evaporates water contained therein into the surrounding environment. Accordingly, it is an object of the present invention to provide a wound dressing that can reduce the frequency of replacing the wound dressing and at the same time realizes early and efficient treatment promotion.

[0011] The wound dressing directly covers and protects the wound, softens the wound, provides an appropriate moist environment, and prevents bacterial contamination. Furthermore, the wound dressing is made of a cell-infiltrating material, and when applied to the wound site, macrophages, neutrophils and other inflammatory cells infiltrate and fibroblasts infiltrate at an early stage. It is preferable that the dermal-like connective tissue is constructed to promote the healing of the wound, and the material is eventually absorbed by the wound surface and disappears with the healing of the wound. As a material that promotes such cell invasion, a sponge layer containing hyaluronic acid and alginic acid, which are biological materials, is suitable.

[0012] Hyaluronic acid and alginic acid are biomaterials and themselves have the effect of promoting wound healing.
Moreover, when these biomaterials are applied to a wound, they are decomposed and absorbed over time. Therefore, a wound dressing using a matrix composed of these biomaterials can not only promote healing, but also does not require peeling or the like at the time of replacement.
There is no risk of adversely affecting the healing wound.

[0013] Hyaluronic acid provides a highly hydrated microenvironment to the wound during the wound healing process. It is known that, in such a microenvironment, adhesion and detachment of a cell membrane and a substrate when various cells move through a wound is controlled, and cell healing is facilitated, so that wound healing is promoted. ing.

[0014] Thus, although hyaluronic acid is not only highly biocompatible and highly biodegradable, it can promote the proliferation and angiogenesis of fibroblasts and help heal wounds. Since hyaluronic acid is derived from living organisms, it has a high affinity for cell tissues, but uncrosslinked hyaluronic acid is easily decomposed and absorbed in vivo by enzymes such as hyalonase. Therefore, when used, it is necessary to introduce cross-links by some means to enhance physical properties. However, the introduction of cross-linking greatly reduces the affinity of hyaluronic acid for cells and tissues before introduction. That is, it is difficult to achieve both enhancement of physical properties and improvement of biological performance such as affinity for cells and tissues.

On the other hand, alginic acid is usually obtained by boiling seaweed with a dilute sodium carbonate solution, but the sodium salt of alginic acid is easily dissolved in the exudate. Alginate fibers, woven fabrics, knitted fabrics, alginate films and the like have been used as calcium alginate salts that are hardly soluble in exudates. However, since the calcium salt of alginic acid is cytotoxic, it is necessary to minimize the amount of calcium salt used.

As a result of extensive studies by the present inventors, a wound dressing material obtained by sequentially laminating a nonwoven fabric layer, a polyurethane film layer having pores, and a sponge layer containing a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound is obtained. Can absorb a significant amount of exudate oozing out of the wound surface and transfer the moisture contained in the exudate through the wound dressing to the outer surface of the wound dressing within a desired rate. The effective life of the wound dressing can be extended by evaporating it into the surrounding environment, and at the same time, the hyaluronic acid sponge layer composed of biomaterials and the ascorbic acid derivative that gradually exudes from the alginate sponge layer (promoting collagen production) ) Was found to promote wound healing and arrived at the present invention.

As the hydrophobic fibers used in the present invention, synthetic fibers such as polyester, nylon, acryl, polypropylene and polyethylene are preferable. As the highly absorbent fiber, wood pulp, natural fiber of cotton, rayon, regenerated fiber of cupra, semi-synthetic fiber such as acetate, and the like are used. Particularly, the hydrophobic fiber and the superabsorbent fiber are 6: 4 by weight.
When used in a ratio of 8: 2, the hydrophobic fibers receive water from the highly absorbent fibers that have absorbed the exudate, and serve to evaporate the water in the outer air layer, which is particularly preferable. The thickness of the fiber constituting the nonwoven fabric layer composed of the hydrophobic fiber and the highly absorbent fiber is about 0.3 to 5 denier (d), preferably 0.5 to 3 denier (d).
It is desirably about d.

The non-woven fabric can be prepared by a known method, for example, the following method. A wet process in which a short fiber layer (web) is made with water, impregnated with resin, and dried and hardened, just as paper is made. A dry method in which a web is made mechanically without using water and bonded with resin or adhesive fibers. A needle punch method in which a web of the same type as the dry type is pierced with a pierced needle to mechanically entangle the fibers. Spunlace method in which fibers are entangled with a high-pressure water stream on a web of the same type as the dry type A web with a uniform thickness by arranging a large number of continuous yarns in all directions like a spider web while simultaneously blowing out the melted raw resin from many small holes (nozzles) before forming fibers Spunbonding method, where yarns are naturally and mechanically attached to each other.

The above-mentioned nonwoven fabric layer can also be formed by any of these known methods,
Alternatively, these methods can be used in combination, but depending on the production method, a direction in which the fiber is easily stretched and a direction in which the nonwoven fabric is difficult to stretch can be formed. Since the nonwoven fabric layer used in the present invention needs to have elasticity, a nonwoven fabric layer having a relatively large elongation is used. The elongation is length 60cm width 6cm
Cm when a load of 1500g is hung on a non-woven fabric
The extension is expressed as a percentage of the original length, and the nonwoven fabric used in the present invention is preferably 30 to 200%,
More preferably, the content is 40 to 150%.

The thickness of the nonwoven fabric layer composed of the hydrophobic fiber and the highly absorbent fiber is preferably about 1 to 20 mm, more preferably about 1 to 10 mm in consideration of flexibility, durability, workability, absorbability and the like. Is desirable. The basis weight of the nonwoven fabric layer composed of the hydrophobic fiber and the superabsorbent fiber is preferably from 30 to 300 g / m ² from the viewpoint of the retention of exudate,
More preferably, those having 50 to 200 g / m ² are suitable.

When a nonwoven fabric layer composed of only hydrophobic fibers is further laminated on one or both sides of the nonwoven fabric layer composed of the above-mentioned hydrophobic fibers and superabsorbent fibers, a nonwoven fabric layer composed of the above hydrophobic fibers and superabsorbent fibers is formed. There is an advantage that, at the same time as suppressing fluffing, the adhesiveness of the nonwoven fabric layer composed of the hydrophobic fiber and the highly absorbent fiber can be further improved. Examples of the fiber material of the nonwoven fabric layer composed of only hydrophobic fibers include polyester, polypropylene, polyethylene, nylon, and thermoplastic elastomer. Among these hydrophobic fiber materials, a thermoplastic elastomer is a preferable material as a wound dressing material because it exhibits rubber elasticity at room temperature and is highly elastic. Among the thermoplastic elastomers, polyolefin-based, polyurethane-based, and polyester-based elastomers are particularly preferred because they are soft and rich in elasticity.
As these hydrophobic fiber materials, commercially available products or improved products thereof can be used.

The thickness of the fibers constituting the nonwoven fabric layer composed of only hydrophobic fibers is preferably about 0.3 to 5 d, more preferably about 0.5 to 3 d. The basis weight of the nonwoven fabric layer composed of only hydrophobic fibers is 5 to 100 g.
/ M ² is preferred.

The polyurethane resin suitable for use in the polyurethane film layer of the present invention is produced using three components of a diisocyanate, a polyol and a chain extender as basic materials. In the reaction, first, an excess equivalent of diisocyanate is reacted with the polyol at 50 to 120 ° C. to form a urethane prepolymer having an isocyanate group at a terminal.
The chain may be extended with a chain extender at 0 to 100 ° C. in an organic solvent. Here, the equivalent ratio between the diisocyanate and the polyol in the urethane prepolymer is usually 1.5.
The ratio is preferably from 1.8 to 4.5: 1 in order to combine good physical properties and moisture permeability.

The diisocyanate used in the present invention includes 4,4'-diphenylmethane diisocyanate,
m- and p-phenylene diisocyanate, 2,4-
And aromatic diisocyanates such as 2,6-tolylene diisocyanate, isophorone diisocyanate,
4′-dicyclohexylmethane diisocyanate, 1,
Alicyclic diisocyanates, such as 4-cyclohexylene diisocyanate, and aliphatic diisocyanates, such as hexamethylene diisocyanate. Usually, these compounds are used alone, but two or more kinds may be used in combination.

The polyol used in the present invention includes:
Polyether polyol, polyester polyol, or polycarbonate polyol is used. And
Examples of the polyether polyol include polypropylene ether glycol and polytetramethylene glycol. Examples of the polyester polyol include polybutylene adipate and polycaprolactone glycol. Moreover, as polycarbonate polyol, 1,
6-hexane polycarbonate diol.
Usually, these compounds are used alone, but two or more kinds may be used in combination.

As the chain extender used in the present invention, a low molecular weight diol or diamine is used. Representative examples of the low molecular weight diol include ethylene glycol, propylene glycol, diethylene glycol, 1,4-butanediol, 1,6-hexamethylene glycol, and the like. Representative examples of low molecular weight diamines include aliphatic diamines such as ethylenediamine, 1,2-propanediamine, tetramethylenediamine, and hexamethylenediamine, isophoronediamine, 4,4′-dicyclohexylmethanediamine, and 1,4-cyclohexylene. Alicyclic diamines such as diamines; Of these, isophoronediamine is preferable from the balance of various physical properties of the polyurethane layer, and can be used alone or in combination of two or more.

As the organic solvent used for synthesizing the polyurethane of the present invention, solvents having a strong dissolving power such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like are suitable. These solvents are used alone or aromatic solvents such as toluene and xylene, methyl ethyl ketone, and the like. One or more selected from ketone solvents such as acetone and cyclohexanone, ether solvents such as tetrahydrofuran and dioxane, acetate solvents such as ethyl acetate and butyl acetate, and alcohol solvents such as methanol, ethanol and isopropanol. It can be used as a mixture with two or more kinds.

The concentration of the polyurethane solution is 2 to 30% by weight, preferably 3 to 25% by weight. In the present invention, for laminating the polyurethane film layer on the nonwoven fabric layer, for example, a solvent coating method, a hot melt coating method, a lamination method, or the like is used. In the case of the solvent coating method, a polyurethane film layer is obtained by uniformly dissolving a polyurethane resin in a solvent, applying the solution on a nonwoven fabric layer, and drying the solvent. In the case of the hot melt coating method, the polyurethane resin is heated and stirred at a temperature of 100 to 220 ° C. under nitrogen replacement to dissolve, and then, using a hot melt coater, applied on the nonwoven fabric layer and dried. A polyurethane film layer is obtained.

In the laminating method, first, polyurethane is first applied on a support by a solvent coating method or a hot melt coating method and then dried or semi-dried by a dry method, or a polyurethane resin solution is applied on the support and solidified. After extracting the solvent and other soluble substances in the bath, the polyurethane film layer is formed by a wet method of drying or semi-drying. Next, the polyurethane film layer prepared by the above method is bonded to the nonwoven fabric layer. As a method of pasting,
After laminating the semi-dried polyurethane film layer with the non-woven fabric layer, and then drying, or an organic solvent that moderately swells the surface of the dried polyurethane film layer, such as alcohols such as methanol, and other solvents, and swelling. After that, there is a method of laminating with a nonwoven fabric layer and drying. Further, a method of laminating both with an adhesive is adopted. When the nonwoven fabric layer and the polyurethane film layer are laminated via an adhesive, if the adhesive is applied to the entire surface, the function of the moisture-permeable polyurethane film layer is impaired. It is preferable that the adhesive be used.

The support used when the polyurethane film layer is formed by the above-mentioned dry method or wet method is not particularly limited, but is preferably a release paper coated with a release agent of polyethylene, polypropylene, fluorine or silicone. Cloth or the like is used.

The thickness of the polyurethane film layer can be adjusted by, for example, the concentration of the polyurethane solution or the amount of the solution to be applied. The thickness of the polyurethane film layer is not particularly limited, but is usually 5 to 100 μm, preferably 8 to 5 μm.
0 μm. When the thickness is 5 μm or less, pinholes are easily formed during coating, and the polyurethane layer is easily blocked and is difficult to handle. If it is 50 μm or more, it tends to be difficult to obtain sufficient moisture permeability. Further, the polyurethane film layer becomes hard, and the adhesion to the skin tends to be impaired.

The polyurethane film obtained by the above method has practically sufficient strength, elongation and durability. The wound dressing material of the present invention is intended to be applied to a wound surface that exudes a large amount of wound fluid during the healing process, and is used for promoting the healing of the wound. Therefore, even if a polyurethane film having moisture permeability and air permeability is used, a large amount of exudate from the wound surface cannot be transmitted.Therefore, an opening is formed in the polyurethane film, and the exudate from the wound surface is removed. It must be absorbed by the absorbent fibers of the wound dressing.

The shape of the opening may be a needle hole, a punch hole, a cross, or a single slit. The slits are not limited to those formed at a predetermined interval in the length direction, and may be formed in any shape, such as randomly formed or ring-shaped, and their length is not particularly limited. As a method of forming these openings, for example, a method of rolling a roller or the like in which a number of cutter blades are embedded on the surface of the polyurethane film can be adopted.

In the wound dressing of the present invention, openings may be formed not only in the polyurethane film layer but also in both the polyurethane film layer and the nonwoven fabric layer. Another object of the present invention is to provide a wound dressing capable of maintaining the effect of promoting wound healing for a long period of time. By using a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound for the sponge layer of the wound dressing according to the present invention, it is possible to achieve both the enhancement of the physical properties of the above hyaluronic acid and the improvement of biological performance. At the same time, the cytotoxicity caused by the calcium salt of alginic acid is reduced, and the effect of promoting wound healing can be maintained for a long time. That is, when the carboxyl groups of hyaluronic acid are cross-linked with an epoxy compound, a cross-linked hyaluronic acid that is strong and has high enzyme decomposability can be obtained without affecting the basic structure of hyaluronic acid. When the cross-linked hyaluronic acid is decomposed by the enzyme again, the hyaluronic acid is regenerated and effectively acts on the wound healing, so that a highly safe wound dressing material having a long-term healing promoting effect can be obtained. Further, by cross-linking alginic acid with an epoxy compound, the healing effect can be maintained for a long time without being easily dissolved by the exudate even if the calcium salt is minimized. Further, since the sponge layer containing the crosslinked hyaluronic acid and crosslinked alginic acid of the biomaterial comes into contact with the wound site, it not only promotes the healing of the wound site, but also damages the wound site when removing the wound dressing of the present invention. Nothing.

In the sponge layer of the wound dressing according to the present invention, the cross-linked hyaluronic acid and the cross-linked alginic acid may be composed in an arbitrary ratio, but the content of the cross-linked hyaluronic acid is 10 to 80% by weight, It is preferable to use a sponge layer having a content of alginic acid of 20 to 90% by weight. Furthermore, when 1 to 20% by weight of uncrosslinked hyaluronic acid and / or uncrosslinked alginic acid is added to a sponge layer composed of crosslinked hyaluronic acid and crosslinked alginic acid, the hyaluronic acid is applied immediately after the wound dressing material is applied to a wound. as well as/
Or, it is particularly preferable because the effect of alginic acid is exerted.

As the hyaluronic acid to be crosslinked, for example, those having a molecular weight of preferably 500,000 to 3,000,000, more preferably 1.8 to 2.2 million are used. As the crosslinking agent, a water-soluble polyfunctional epoxy compound can be used. As the polyfunctional epoxy compound, for example,
Ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, dipropylene glycol diglycidyl ether, tripropylene glycol diglycidyl ether, glycerol diglycidyl ether, glycerol triglycidyl ether, trimethylol Examples thereof include propane triglycidyl ether, sorbitol polyglycidyl ether, diglycidyl succinate, and diglycidyl adipate.

The crosslinking reaction is generally carried out at 0.2 to 2.0% by weight of hyaluronic acid, preferably at 0.5 to 1% by weight.
An aqueous solution is prepared and the pH of the solution is 4-7, preferably about 5
After adjusting to ~ 6, a reaction in which the epoxy compound is added so as to be about 1 / 5,000 to 1 mol, preferably about 5 / 5,000 to 1/5 mol with respect to the repeating unit of hyaluronic acid. It can be performed using a liquid. As the solvent, in addition to the above-mentioned water, an alcohol-water system can be used.

The reaction temperature may be, for example, about 20 to 80 ° C., preferably about 40 to 60 ° C., and the reaction time is preferably 2 to 10 hours, more preferably 4 to 6 hours. The degree of crosslinking of hyaluronic acid is determined by the type, proportion, and reaction conditions of the epoxy compound used for the crosslinking reaction.
Since the biodegradability, moisture content, and hydrolysis rate of the formed hyaluronic acid vary depending on the degree of cross-linking, the degree of cross-linking should be appropriately selected according to the application site of the wound dressing and the purpose of use.

On the other hand, as the alginic acid to be cross-linked, alkali salts of alginic acid, for example, sodium, potassium, ammonium salts of alginic acid are used. Further, as the crosslinking agent, the same polyfunctional epoxy compound as used for crosslinking of hyaluronic acid can be used.

The crosslinking reaction is generally carried out at 0.2 to 5.0% by weight of alginic acid, preferably at 0.5 to 3% by weight.
An aqueous solution is prepared and the pH of the solution is 4-7, preferably about 5
After adjusting to ~ 6, the reaction can be carried out using a reaction solution in which the epoxy compound is added in an amount of 1/20 to 2 mol, preferably about 1/10 to 1 mol, based on the repeating unit of alginic acid. it can. As the solvent, in addition to the above-mentioned water, an alcohol-water system can be used.

The reaction temperature may be, for example, about 20 to 80 ° C., preferably about 40 to 60 ° C., and the reaction time is preferably 2 to 10 hours, more preferably 4 to 6 hours. The degree of cross-linking of alginic acid is determined by the type, ratio, and reaction conditions of the epoxy compound used in the cross-linking reaction.However, the degree of cross-linking changes the biodegradability, water content, and hydrolysis rate of alginic acid after molding. The degree of crosslinking should be appropriately selected according to the application site of the coating material and the purpose of use.

In general, the degree of cross-linking of hyaluronic acid and alginic acid is such that about 5 to 30% by weight of hyaluronic acid and / or alginic acid remains after being implanted in a living body (for example, subcutaneously of Wistar rats) and allowed to stand for one week. Is preferred. The biomaterial used in the present invention needs to have good contact with the wound, and for that reason, a sponge-like material is particularly preferable. The sponge-like biomaterial may be a mixed sponge layer formed by mixing an aqueous solution containing cross-linked hyaluronic acid and a solution containing cross-linked alginic acid, and then freeze-drying, or a sponge layer containing cross-linked hyaluronic acid. And a sponge layer containing cross-linked alginic acid may be laminated.

As a method of forming the sponge layer of the present invention,
Generally, a solution composed of a biomaterial is stored at -20 ° C to -10C.
0 ° C., preferably −40 ° C. to −80 ° C. in a freezer, freeze-freeze and vacuum dry, or freeze-dry in a freeze dryer.
It is obtained by gradually freezing at 0 to -50 ° C and drying under vacuum. For example, when preparing a mixed sponge layer containing cross-linked hyaluronic acid and cross-linked alginic acid, after mixing a solution containing cross-linked hyaluronic acid and a solution containing cross-linked alginic acid, −20 ° C. to −100 ° C., preferably −40 ° C. to −100 ° C. 8
It may be manufactured by quenching and freeze-drying in a freezer at 0 ° C. and freeze-drying, or may be manufactured by gradually freezing to −30 to −50 ° C. in a freeze dryer and vacuum drying. . Also, when laminating a sponge layer containing crosslinked hyaluronic acid and a sponge layer containing crosslinked alginic acid, first inject a solution containing crosslinked hyaluronic acid into a molding container, and then inject a solution containing crosslinked alginic acid thereover, -20 ° C ~-
100 ° C., preferably may be produced by quenching and freeze-drying in a freezer at −40 to −80 ° C., or after gradually freezing to −30 to −50 ° C. in a freeze dryer,
It may be manufactured by vacuum drying.

When the sponge layer containing cross-linked hyaluronic acid and cross-linked alginic acid contains uncross-linked hyaluronic acid and / or uncross-linked alginic acid, each non-cross-linked solution is mixed with the cross-linked solution and freeze-dried. Can be Examples of the method for forming the sponge layer include the freeze-drying method as described above, but are not limited thereto, and those skilled in the art can employ an appropriate method.

The thickness of the sponge layer made of a biomaterial may be arbitrarily set according to the purpose of use of the wound dressing material and the site to be applied, but preferably the thickness of the sponge layer is 1 to 20 m.
m, more preferably about 2 to 10 mm. When a sponge layer containing cross-linked hyaluronic acid and a sponge layer containing cross-linked alginic acid are laminated, the sum of the thicknesses is 1 to 20 m.
m, more preferably about 2 to 10 mm.

The thickness of the sponge layer containing the crosslinked hyaluronic acid and the thickness of the sponge layer containing the crosslinked alginic acid are arbitrarily set by changing the concentrations and ratios of the solution containing the crosslinked hyaluronic acid and the solution containing the crosslinked alginic acid to be poured into the molding container. You can do it.

As a method of laminating the sponge layer made of the above-mentioned biomaterial and the polyurethane film layer, any known method may be used. However, when the sponge layer containing cross-linked hyaluronic acid and cross-linked alginic acid is prepared, the polyurethane film layer and the non-woven fabric are used. It is preferable to laminate on a laminate composed of layers. For example, first, a laminate comprising a nonwoven fabric layer and a polyurethane film layer is prepared, a mold having the same shape is placed on the polyurethane film layer, and a solution containing crosslinked hyaluronic acid and crosslinked alginic acid is put therein. It is obtained by freeze-drying.

The substance for promoting collagen production used in the present invention includes ascorbic acid, ascorbic acid phosphate, and sugar ester of ascorbic acid. It is said that ascorbic acid acts on fibroblasts and has an effect of promoting collagen synthesis and cell growth.However, in practical use, ascorbic acid can be easily oxidized especially in neutral aqueous solution and lose its biological activity. As is known, its derivative, ascorbic acid phosphate, is stable under physiological conditions.

The wound dressing material has a problem that the antibacterial effect is not exerted at the wound site. Therefore, the wound dressing material may be any of the constituent members of the nonwoven fabric layer, the polyurethane film layer and the sponge layer made of a biomaterial. Alternatively, it is preferable to mix an antibacterial agent in all the constituent members. As the antibacterial agent, any antibacterial agent such as a sulfa drug, penicillin, nalidixin, silver sulfadiazine, polymyxin sulfate, and gentamicin sulfate can be used. Is to use. The content of the antibacterial agent may be determined according to the type of the drug, the purpose of use of the wound dressing, and the application site. When silver sulfadiazine is used, the content or the amount of the wound dressing is 20 to 500 μg / cm ² , preferably 30
４００400 μg / cm ² . With such a content, the growth of bacteria on the wound surface can be suppressed, and at the same time, the growth of cells inside the wound dressing that has absorbed the exudate can be effectively suppressed.

The wound dressing can be formed into an arbitrary shape such as a bandage or a pad having a size of several cm square to several tens cm square, and is appropriately selected according to the degree and depth of the wound, the area of the wound surface, and the like. Can be used.

[0051]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the effects of the present invention will be specifically described. However, the present invention is not limited to the following Examples.

Example 1 Production of a Wound Dressing Material Production of a Nonwoven Fabric Layer A nonwoven fabric layer composed of a hydrophobic fiber and a high-absorbency fiber was prepared by mixing a polyester fiber having an average fineness of 1.5d and a rayon fiber having a average size of 2.0d in a weight ratio of 70 to 70%. After mixing at a ratio of 30, an extremely thin fiber layer (web) is made, and the webs are superimposed so that the basis weight is 100 g / m ^2, and the web layer is pierced with a pierced needle. The fibers were mechanically entangled with each other (needle punch method). Next, a hydrophobic polyester-based thermoplastic elastomer (trade name: Perprene, manufactured by Toyobo Co., Ltd.) was bonded to both surfaces of the nonwoven fabric layer by a spun bond method so that the total weight of the nonwoven fabric layer was 140 g / m ² . .

Preparation of Polyurethane Film Layer 700 parts by weight of polytetramethylene glycol having a number average molecular weight of 2,000 and 180.6 parts by weight of 4,4'-dicyclohexylmethane diisocyanate were placed in a flask under dry nitrogen at 75 ° C. for 5 hours. After the reaction, a urethane prepolymer having an isocyanate group at the terminal was obtained, and a chain extension reaction was carried out in dimethylacetamide solvent using isophoronediamine as a chain extender for 2 hours while maintaining the temperature at 20 ° C., and the polyurethane solid concentration was 25 wt% by weight. A colorless, transparent and viscous polyurethane solution was obtained. Methyl ethyl ketone was added to this solution to prepare a 15 wt% polyurethane solution, which was applied to a release paper having a silicon-based film formed on its surface so that the polyurethane film layer had a thickness of 10 μm when dried. Then put in a hot air dryer and put 100
The solvent was removed by drying at ℃ for 3 minutes.

Production of crosslinked hyaluronic acid solution containing ascorbic acid One of hyaluronic acid having a molecular weight of 2,000,000 produced by the fermentation method
Ethylene glycol diglycidyl ether as a crosslinking agent was added to a 1% by weight aqueous solution (pH = 6) so as to be 1/10 mol of the molecular weight of the repeating unit of hyaluronic acid. Next, the mixture was allowed to stand in a dryer set at 50 ° C. for 5 hours to perform an intermolecular crosslinking reaction. Next, magnesium L-ascorbic acid phosphate was added to the obtained reaction solution so as to have a final concentration of 1 mM, and the mixture was sufficiently stirred to prepare a crosslinked hyaluronic acid solution containing ascorbic acid.

Production of crosslinked alginic acid solution containing ascorbic acid Commercially available sodium alginate (Wako Pure Chemical Industries, Ltd.)
Of ethylene glycol diglycidyl ether as a cross-linking agent was added to a 2% by weight aqueous solution (pH = 6) of the formula (1) in an amount of 1 mol based on the molecular weight of the repeating unit of alginic acid.
Next, the mixture was allowed to stand in a dryer set at 50 ° C. for 5 hours to perform an intermolecular crosslinking reaction. Next, L-
Magnesium ascorbic acid phosphate was added to a final concentration of 1 mM, and the mixture was sufficiently stirred to prepare a crosslinked alginic acid solution containing ascorbic acid.

A 10 μm-thick polyurethane film layer produced by an adhesive was partially adhered to one side of the nonwoven fabric layer produced in the preparation of the wound dressing material. Next, a slit-shaped opening having a length of 3 mm is provided linearly at intervals of 10 mm, and the pitch of the lines (parallel spacing between lines) is 10 mm, thereby preparing a composite polyurethane film layer having openings. did. 8 cc of an ascorbic acid-containing crosslinked alginic acid aqueous solution produced by ascorbic acid-containing crosslinked alginic acid aqueous solution produced by 4 cc of a 1% by weight aqueous solution of uncrosslinked hyaluronic acid into a circular polystyrene container having an inner diameter of 50 mm and a height of 20 mm;
1 mg of silver sulfadiazine was mixed well. A laminate comprising the nonwoven fabric layer and the polyurethane layer having openings was cut into a circular shape having a diameter of 50 mm, and release paper was peeled from the polyurethane film layer. Then, the polyurethane film layer was placed so as to be in contact with the aqueous solution layer. . This polystyrene container was frozen at −40 ° C., and then dried under vacuum to produce a wound covering material containing a spongy biomaterial.

Example 2 Production of Wound Dressing Material Production of Crosslinked Hyaluronic Acid Solution Containing Ascorbic Acid One of hyaluronic acid having a molecular weight of 2,000,000 produced by a fermentation method.
Ethylene glycol diglycidyl ether as a cross-linking agent was added to a 1% by weight aqueous solution (pH = 6) so as to be 1/100 mol based on the molecular weight of the repeating unit of hyaluronic acid. Next, the mixture was allowed to stand in a dryer set at 50 ° C. for 5 hours to perform an intermolecular crosslinking reaction. Production of crosslinked alginic acid solution containing ascorbic acid Commercially available sodium alginate (Wako Pure Chemical Industries, Ltd.)
Of ethylene glycol diglycidyl ether as a cross-linking agent was added to a 2% by weight aqueous solution (pH = 6) of the formula (1) in an amount of 1 mol based on the molecular weight of the repeating unit of alginic acid.
Next, the mixture was allowed to stand in a dryer set at 50 ° C. for 5 hours to perform an intermolecular crosslinking reaction. Next, L-
Magnesium ascorbic acid phosphate was added to a final concentration of 1 mM, and the mixture was sufficiently stirred to prepare a crosslinked alginic acid solution containing ascorbic acid. Manufacture of wound dressing Crosslinked hyaluronic acid aqueous solution 12c manufactured in a circular polystyrene container having an inner diameter of 50 mm and a height of 20 mm
c, 1 mg of silver sulfadiazine was added, followed by 8 cc of the cross-linked alginate aqueous solution prepared above. After laminating the laminate comprising the nonwoven fabric layer and the polyurethane layer having openings formed in Example 1 into a circular shape with a diameter of 50 mm and peeling off the release paper from the polyurethane film layer, the polyurethane film layer comes into contact with the aqueous solution layer. I put it. This polystyrene container was frozen at −40 ° C., and then dried under vacuum to produce a wound covering material containing a spongy biomaterial.

Comparative Example 1 A wound dressing material for a control experiment A circular polystyrene container having an inner diameter of 50 mm and a height of 20 mm was filled with 20 cc of a 1% by weight aqueous solution of hyaluronic acid having a molecular weight of 2,000,000 prepared by fermentation. Above the polyurethane film produced in Example 1 with a diameter of 50 mm
And put it in a circle. Next, the polystyrene container was placed in a freeze dryer, frozen at -40 ° C, and vacuum-dried to prepare a sponge-like wound dressing.

COMPARATIVE EXAMPLE 2 Wound dressing material for control experiment A circular 2 wt% aqueous solution of sodium alginate 10c was placed in a circular polystyrene container having an inner diameter of 50 mm and a height of 20 mm.
c was poured, and the polyurethane film produced in Example 1 was cut into a circular shape having a diameter of 50 mm and mounted thereon. Next, the polystyrene container was placed in a freeze dryer, frozen at -40 ° C, and vacuum-dried to prepare a sponge-like wound dressing.

Example 3 Animal Experiment The wound dressings obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were sterilized with ethylene oxide gas, and then subjected to the following experiment. That is, Wistar rats (8
After shaving the two backs of the rabbits and disinfecting them with isodine, a full-thickness skin defect wound was created on both backs of the rabbit so that one side would be 3 cm square (9 cm ² ), and an example was formed on the right back. 1 or 2
The wound dressing according to the present invention manufactured by the above method is applied, and the wound dressing for the control experiment manufactured in Comparative Example 1 or 2 is applied as a control experiment to the left back, and a stretchable adhesive tape is applied by applying gauze thereon. Fixed.

One week later, the dressing was removed under anesthesia, the condition of the wound surface was observed, and the area around the wound was disinfected with isodine.
The wound dressing according to the present invention and a wound dressing for control experiments were applied. Thereafter, a new wound dressing material was replaced every week, and the state of the wound was observed over time. When the wound dressing according to the present invention was applied, almost all of hyaluronic acid and / or alginic acid was decomposed and absorbed when removed in one week.

On the right back to which the wound dressing according to the present invention is applied, the wound surface is maintained in an appropriate moist environment, the formation of granulation tissue and the shrinkage from around the wound are promoted, and the wound dressing is applied.
At the time of the week, the area of the skin defect wound is 0 to 0.5 cm ²
Became. On the other hand, on the left back to which the wound dressing for control experiment consisting only of the hyaluronic acid or alginate sponge layer was applied, the area of the skin defect wound was 1 to 4 cm ² at 3 weeks after the application of the wound dressing. In addition, there were cases in which infection occurred in cases using alginic acid. As described above, the wound dressing according to the present invention was found to have a healing promoting effect as compared with the wound dressing for control experiments using only hyaluronic acid or alginic acid.

[0063]

As described above, the wound dressing according to the present invention has the following effects. Since the wound dressing material is laminated with a nonwoven fabric layer composed of a hydrophobic fiber and a highly absorbent fiber, even when a large amount of exudate is released from the wound, the exudate is absorbed and contained therein. The wound can be constantly kept in a moderately moist environment because the moisture that has been evaporated can be evaporated into the surrounding environment. Hyaluronic acid and alginic acid used in the present wound dressing are biomaterials each having an effect of promoting the healing of skin defects, but by combining these biomaterials, furthermore, in the whole process of wound healing, The effect is that the healing can be promoted very quickly and efficiently. By crosslinking hyaluronic acid and alginic acid with an epoxy compound, the effect of promoting wound healing can be maintained for a long time. Hyaluronic acid and alginic acid are biomaterials that are degraded and absorbed over time when applied to a wound surface. Therefore,
Wound dressings using matrices of these biomaterials not only provide enhanced healing, but also do not require long-term replacement. Even if it is replaced, there is an effect that there is no damage to the new tissue and no pain. By blending L-ascorbic acid phosphate, the healing effect of the therapeutic component consisting of hyaluronic acid and alginic acid could be further enhanced. By adding an antibacterial agent, the proliferation of bacteria is suppressed, and a further excellent healing promoting effect can be obtained.

Claims (7)

[Claims] 1. A nonwoven fabric layer, a polyurethane film layer having openings, and a sponge layer containing a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound are sequentially laminated, and at least one of the layers is an ascorbic acid phosphate. A wound dressing comprising: 2. The nonwoven fabric layer has a basis weight of 30 to 300 g / m.
^2. The wound dressing according to claim 1, which is ² . 3. The wound dressing according to claim 1, wherein the thickness of the polyurethane film layer having openings is 5 to 100 μm. 4. The sponge layer containing a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound, wherein the sponge layer contains 1 to 20% by weight of uncrosslinked hyaluronic acid and / or uncrosslinked alginic acid. A wound dressing according to claim 1. 5. A sponge layer comprising a crosslinked hyaluronic acid and a crosslinked alginic acid crosslinked with an epoxy compound,
The content of cross-linked hyaluronic acid is 10 to 80% by weight,
The wound dressing according to any one of claims 1 to 4, wherein the content of the crosslinked alginic acid is 20 to 90% by weight. 6. The wound dressing according to claim 1, wherein the content ratio of the ascorbic acid phosphate is 0.1 to 10% by weight. 7. The wound dressing according to claim 1, further comprising an antibacterial agent.