JPH11319066A - Wound coating material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a wound coating material utilizing a physiologically active substance with which curing of such a wound as a failure of the skin can be conveniently and effectively performed. SOLUTION: A wound coating material consists of a constitution contg. a crosslinked hyaluronic acid sponge material with a crosslinked hyaluronic acid sponge layer obtd. by freeze-vacuum drying of an intermolecular crosslinked substance of hyaluronic acid and/or its deriv. and a physiologically active substance. In addition, this physiologically active substance is pref. incorporated into the crosslinked hyaluronic acid sponge material when it is used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a wound dressing,
Specifically, the present invention relates to a wound dressing utilizing a physiologically active substance, which can easily and effectively treat a wound such as a skin defect wound.

[0002]

2. Description of the Related Art It has been known that the application of a physiologically active substance-containing ointment as a treatment for wounds such as skin defect wounds exhibits excellent clinical effects. However, in general, ointment therapy is problematic in that it requires frequent dressing changes, and thus the pain of the patient and the burden on the medical staff are great. Therefore, it has been desired to develop a novel administration form of a physiologically active substance which can solve these problems in wound treatment with a physiologically active substance and can effectively promote wound healing.

[0003] On the other hand, hyaluronic acid is abundant in the interstitium of animal tissues, and specifically, is one of mucopolysaccharides present in the vitreous body of the eye, umbilical cord, synovial fluid, skin, cartilage, and other connective tissues. Hyaluronic acid and its derivatives, in the form of an aqueous solution or a gel, are widely used in medical applications as an auxiliary for ophthalmic surgery or a composition for preventing tissue adhesion after surgery. In recent years, as a new use form of hyaluronic acid, a crosslinked hyaluronic acid molded article having a sponge structure as described in Japanese Patent Publication No. 7-30124 has been developed. However, no attempt has been made to attempt to treat a wound by combining the above-mentioned physiologically active substance with a hyaluronic acid gel or a molded article.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above point of view, and provides a wound dressing utilizing a physiologically active substance, which can easily and effectively treat wounds such as skin defect wounds. The task is to provide.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems. As a result, the use of a cross-linked hyaluronic acid sponge material in combination with a physiologically active substance makes it possible to prevent skin defect wounds and the like. He discovered that it is possible to treat wounds easily and effectively, and succeeded in producing a new crosslinked hyaluronic acid sponge material that can effectively treat wounds in combination with bioactive substances. Completed the invention.

[0006] In this specification, the term "sponge" is used for a porous body having closed cells or open cells.

That is, the present invention relates to a method for preparing hyaluronic acid and / or
Or a wound dressing comprising a crosslinked hyaluronic acid sponge material having a crosslinked hyaluronic acid sponge layer obtained by freeze-drying an intermolecularly crosslinked product of a derivative thereof and a physiologically active substance.

The cross-linked hyaluronic acid sponge layer of the cross-linked hyaluronic acid sponge material used in the wound dressing of the present invention is specifically a cross-linked hyaluronic acid sponge obtained by a production method including the following steps (A) to (D). It is possible to construct from. (A) a step of mixing a crosslinking agent with an aqueous solution of hyaluronic acid and / or a derivative thereof and concentrating the resulting mixture to obtain an intermolecular crosslinked product of the hyaluronic acid and / or a derivative thereof; )) A step of freeze-drying the intermolecular crosslinked product obtained in the step, (C) a step of washing the intermolecular crosslinked product after the step (B) with alcohol, and further washing with water; (C) A step of obtaining a crosslinked hyaluronic acid sponge by freeze-drying the intermolecularly crosslinked product after the step again.

In the above method for producing a crosslinked hyaluronic acid sponge, a specific example of the crosslinking agent used in step (A) is a water-soluble epoxy compound. further,
Specific examples of the alcohol used in the step (C) in the method for producing a crosslinked hyaluronic acid sponge include methanol.

The crosslinked hyaluronic acid sponge material used in the wound dressing of the present invention is specifically a polymer mesh laminated between two layers of a crosslinked hyaluronic acid sponge layer and the above-mentioned crosslinked hyaluronic acid sponge layer. And a cross-linked hyaluronic acid sponge material having a layer.

Further, the polymer mesh layer of the crosslinked hyaluronic acid sponge material is specifically 100
A polyamide having a mesh width of ~ 300 mesh,
It can be composed of a polymer mesh of a material selected from polyethylene, polypropylene and polyester.

[0012] In the wound dressing of the present invention, the physiologically active substance can be used in a form specifically contained in the crosslinked hyaluronic acid sponge layer.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the wound dressing of the present invention will be specifically described. First, the crosslinked hyaluronic acid sponge material of the wound dressing of the present invention will be described. (1) Crosslinked hyaluronic acid sponge material used in the present invention The crosslinked hyaluronic acid sponge material used in the wound dressing material of the present invention is a crosslinked hyaluronic acid obtained by freeze-drying an intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof. It has a sponge layer. Hereinafter, the crosslinked hyaluronic acid sponge and the crosslinked hyaluronic acid sponge material will be described in this order. (I) Cross-linked hyaluronic acid sponge The cross-linked hyaluronic acid sponge constituting the cross-linked hyaluronic acid sponge layer is, more specifically, a raw material of hyaluronic acid and / or a derivative thereof and a cross-linking agent capable of cross-linking them. It is obtained by reacting in an aqueous solvent to form an intermolecular cross-linked product and freeze-drying under appropriate conditions. The molecular weight of hyaluronic acid and / or a derivative thereof used as a raw material is not particularly limited, but specifically, the average molecular weight is preferably 500,000 to 20
About 100,000, more preferably about 1.5 to 2 million.

Examples of the derivatives of hyaluronic acid include metal salts of hyaluronic acid such as sodium salt of hyaluronic acid and potassium salt of hyaluronic acid, and etherification, esterification, amidation, and acetalization of hydroxyl groups and carboxyl groups of hyaluronic acid. And hyaluronic acid derivatives obtained by ketalization. Among these hyaluronic acid derivatives, sodium hyaluronate is preferably used in the present invention.

[0015] Such hyaluronic acid and / or its derivative can be produced by a conventionally known method. Alternatively, there are many commercial products of hyaluronic acid and its derivatives, and these commercial products can be used in the present invention.

The crosslinking agent is not particularly limited as long as it has a function of crosslinking the molecules of the above-mentioned hyaluronic acid and / or its derivative.
It is possible to use a bifunctional or polyfunctional conventionally known crosslinking agent which produces an ester or amide bond.

A conventionally known method can be applied to a method of reacting hyaluronic acid and / or a derivative thereof with a crosslinking agent in an aqueous solvent to obtain an intermolecular crosslinked product. In addition, as a method for drying the obtained intermolecular crosslinked product, a freeze vacuum drying method is used, and a conventionally known method can be applied without particular limitation.

The crosslinked hyaluronic acid sponge thus obtained can be used in the present invention without any particular limitation. (A) A crosslinker is mixed with an aqueous solution of hyaluronic acid and / or a derivative thereof, and the resulting mixture is concentrated. A step of obtaining an intermolecular cross-linked product of the hyaluronic acid and / or a derivative thereof (hereinafter, referred to as a “cross-linking step”); and (B) a step of freeze-drying the intermolecular cross-linked product obtained in the step (A). (Hereinafter, referred to as "first freeze vacuum drying step"), (C)
After washing the intermolecularly crosslinked product after the step (B) with alcohol, further washing with water (hereinafter, “washing step”)
And (D) a step of freeze-drying the intermolecularly crosslinked product after the step (C) again to obtain a crosslinked hyaluronic acid sponge (hereinafter, referred to as a “second freeze-vacuum drying step”). The crosslinked hyaluronic acid sponge obtained by the method is more preferably used in the present invention. Hereinafter, the steps (A) to (D) will be described in detail. (A) Crosslinking Step In producing the crosslinked hyaluronic acid sponge preferably used in the present invention, first, an aqueous solution of hyaluronic acid and / or a derivative thereof and a crosslinking agent are mixed and concentrated, and the above-mentioned hyaluronic acid and / or its derivative is mixed. An intermolecular crosslinked product of the derivative is obtained.

As the hyaluronic acid and / or its derivative used in this production method, the same as those described above can be used. In this step, an aqueous solution in which such hyaluronic acid and / or its derivative is dissolved in an appropriate amount of water is first prepared. The concentration of hyaluronic acid and / or a derivative thereof in the aqueous solution depends on the type and molecular weight of the hyaluronic acid and / or its derivative to be used, but is generally 0.5 to 1.5% by weight, preferably 1.0 to 1% by weight. It can be about 0.5% by weight. Also,
As the water used as the solvent, ion-exchanged water having a pH of 5 to 6 is preferable.

Next, a crosslinking agent is added to and mixed with the aqueous solution of hyaluronic acid and / or a derivative thereof. The cross-linking agent used in this production method has an action of intermolecularly cross-linking hyaluronic acid and / or a derivative thereof, and can be sufficiently removed by washing with an alcohol, preferably methanol, in the subsequent (C) washing step. Is not particularly limited as long as it is appropriate. As such a crosslinking agent,
Specific examples include a water-soluble epoxy compound and glutaraldehyde. In the present invention, a water-soluble epoxy compound is preferably used.

Specific examples of the water-soluble epoxy compound include ethylene glycol diglycidyl ether, glycerol diglycidyl ether, and glycerol triglycidyl ether. When a water-soluble epoxy compound is used as a cross-linking agent, the amount of the water-soluble epoxy compound added to the aqueous solution of hyaluronic acid and / or a derivative thereof is generally about 1 to 1 mol of the repeating unit of hyaluronic acid and / or its derivative. / 2 to 1/10 mol, preferably 1/5 to 1 mol.
/ 10 mol, particularly preferably about 1/5 mol.

The addition and mixing of the crosslinking agent to the aqueous solution of hyaluronic acid and / or its derivative causes the intermolecular crosslinking of hyaluronic acid and / or its derivative, but a mixed solution is required to promote the intermolecular crosslinking reaction. It is preferable to heat while stirring according to the conditions. The heating temperature is about 30 when a water-soluble epoxy compound is used as a crosslinking agent.
~ 60 ° C is preferred, and more preferred temperatures are about 40-6 ° C.
0 ° C., a particularly preferred temperature is about 50 ° C. 60
When the mixture is heated at a high temperature exceeding ℃, bubbles may be generated in the mixed solution, and the sponge structure of the resulting crosslinked hyaluronic acid sponge may not be uniform enough. At a temperature lower than 30 ° C., the rate of the intermolecular cross-linking reaction decreases, and it may take a long time to obtain a desired concentration of the intermolecular cross-linked product.

As described above, by heating the mixed solution, the intermolecular crosslinking of the hyaluronic acid and / or a derivative thereof, preferably a water-soluble epoxy compound, proceeds in the mixed solution, and the mixed solution is concentrated. As a result, an intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof is obtained. In order to obtain an intermolecularly crosslinked product of hyaluronic acid and / or a derivative thereof in the present production method, although it depends on the solute concentration in the aqueous solution of hyaluronic acid and / or its derivative to be used, the type and amount of the crosslinking agent, When a water-soluble epoxy compound is used as a cross-linking agent, it is preferable to concentrate the mixed solution until the volume becomes approximately 1/2 to 1/10 of the initial volume. Further, in consideration of the mechanical strength of the obtained crosslinked hyaluronic acid sponge, it is more preferable that the mixed solution is concentrated to about 1/5 of the initial volume.

The crosslinked product of hyaluronic acid and / or a derivative thereof obtained by concentration as described above is used in the following step (B) (first freeze-drying step).

The final crosslinked hyaluronic acid sponge can be obtained in the form of the intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof obtained here. In this step, the intermolecular crosslinked product is formed into a desired shape. Is preferred.
Specifically, a shape such as a sheet shape or a rod shape is given. (B) First Freezing and Vacuum Drying Step In the present production method, the intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof obtained in the above step (A) is:
Then, freeze-drying is performed. The conditions for freeze-vacuum drying are about -30 to -85 in order not to form large ice crystals.
° C, preferably about -50 to -85 ° C, more preferably about -85 ° C. The vacuum condition is preferably about 50 to 5 mmHg, and more preferably about 10 to 5 mmHg.

The time for the freeze-vacuum drying treatment depends on the size of the freeze-vacuum drying apparatus and the amount and shape of the intermolecular cross-linked product of hyaluronic acid and / or a derivative thereof, and may be appropriately selected according to them. (C) Washing Step The dried product of the intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof obtained in the above step (B) is then washed with an alcohol to remove an unreacted crosslinking agent. The alcohol used is not particularly limited, but specific examples include methanol, ethanol, propanol, and butanol. In the present invention, preferably, methanol is used.

The washing method is not limited as long as the unreacted cross-linking agent can be removed. As a specific washing method, a sufficient amount, for example, by volume, of the dried intermolecular cross-linked product is used. A method of immersing the dried product of the above-mentioned intermolecular cross-linked product in 10 to 50 times the amount of alcohol, and leaving it for an appropriate time, for example, 12 to 24 hours while adding stirring or shaking as necessary, may be mentioned. Further, such washing with alcohol may be performed twice or more as necessary.

By washing the dried product of the intermolecular cross-linked product with the alcohol in this manner, it is possible to completely remove the unreacted cross-linking agent, and to obtain the cross-linked product after the second freeze-vacuum drying step. The resulting cross-linked hyaluronic acid sponge can have good final morphology and a strong sponge structure. In addition, the intermolecular crosslinked product itself after the alcohol washing is excellent in strength, and the subsequent washing with water does not destroy the shape of the intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof. .

The intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof after the above-mentioned alcohol washing is then washed with water after removing the alcohol in the intermolecular crosslinked product by an appropriate method, if necessary. As the water to be used, neutral ion-exchanged water is preferable. The washing with water is performed for the purpose of extracting and removing water-soluble unreacted substances and completely removing alcohol in order to smoothly carry out a second freeze-vacuum drying step to be performed thereafter. The washing method with water can be performed in the same manner as in the above-described alcohol washing. For example, a sufficient amount of the intermolecular cross-linked product after the above-mentioned alcohol washing is immersed in water, specifically, 10 to 30 times the volume of water, and stirring or shaking is performed as necessary for an appropriate time,
For example, there is a method of leaving it for 12 to 24 hours.
Further, such washing with water may be performed twice or more as necessary.

The intermolecular cross-linked product of hyaluronic acid and / or its derivative after washing with water is in a state of being swollen with water. (D) Second Freeze-Vacuum Drying Step In the present production method, the water-swelled product of the intermolecularly crosslinked product of hyaluronic acid and / or a derivative thereof obtained in the above step (C) is then freeze-vacuum-dried. The conditions for freeze-vacuum drying can be the same as the conditions for the first freeze-vacuum drying in step (B). The time for the freeze-vacuum drying treatment depends on the size of the freeze-vacuum drying apparatus and the amount and shape of the intermolecular cross-linked product of hyaluronic acid and / or its derivative, and may be appropriately selected according to them.

The water-swelled product of the intermolecular cross-linked product of hyaluronic acid and / or its derivative obtained in the step (C) is freeze-dried and vacuum-dried, whereby the cross-linked hyaluronic acid sponge according to the present production method is obtained. can get.

The crosslinked hyaluronic acid sponge obtained by such a production method is one in which water has been sufficiently removed while maintaining the shape of the water-containing state at the time of the intermolecular cross-linking in the step (A). Is sufficiently high, and the unreacted raw material components, specifically the cross-linking agent such as a water-soluble epoxy compound, are removed by washing with alcohol and water, so that it is excellent in safety as a medical device. It is. (Ii) Crosslinked hyaluronic acid sponge material The crosslinked hyaluronic acid sponge material used for the wound dressing of the present invention has a layer composed of the crosslinked hyaluronic acid sponge described in (i) above.

The structure of the crosslinked hyaluronic acid sponge material used in the present invention is not particularly limited as long as it has a crosslinked hyaluronic acid sponge layer as described above. It may be composed of only a hyaluronic acid sponge layer, or a layer composed of a crosslinked hyaluronic acid sponge layer and one or more other materials, for example, a polymer mesh layer, a polymer nonwoven fabric layer, a polymer knitted sheet layer, a polymer And the like. Further, the crosslinked hyaluronic acid sponge material used in the present invention may have two or more crosslinked hyaluronic acid sponge layers. But,
As the crosslinked hyaluronic acid sponge material used in the wound dressing of the present invention, preferably, two layers composed of crosslinked hyaluronic acid sponge, and a crosslinked hyaluronic acid having a polymer mesh layer laminated between the layers of the crosslinked hyaluronic acid sponge layer Sponge materials can be mentioned.

In the crosslinked hyaluronic acid sponge material used in the present invention,
When used as a wound dressing, it contains a physiologically active substance. Accordingly, it is desired that the crosslinked hyaluronic acid sponge layer has an ability to contain a sufficient amount of a physiologically active substance to be used as a wound dressing. Specifically, the porosity and shape of the cross-linked hyaluronic acid sponge used,
Although it depends on the degree of the wound to which the wound dressing is applied and the like, when formed into a sheet, the thickness of the crosslinked hyaluronic acid sponge layer is approximately 2 to 20 mm, preferably,
By setting the thickness to about 3 to 5 mm, a sufficient amount of a physiologically active substance can be contained.

When the crosslinked hyaluronic acid sponge material has a polymer mesh layer as a constituent element, the polymer mesh layer is not particularly limited as long as it is a polymer mesh layer formed by forming a polymer material into a mesh shape. The polymer material constituting the polymer mesh is not particularly limited as long as the material can be formed into a mesh shape, and specific examples thereof include polyamide, polyethylene, polypropylene, and polyester. Of these, polyamides are preferably used in the present invention. The mesh width of the polymer mesh used in the present invention is, specifically, about 100 to 300 mesh, preferably 200 to 300 mesh.
About 300 mesh is mentioned. 100 mesh width
If the mesh size is less than the mesh, the mesh may be embedded in the new tissue when applied to the wound surface. If the mesh size exceeds 300, the mesh may be minute and the adhesiveness between the sponge layer and the mesh may decrease.

The thickness of the polymer mesh layer constituting the crosslinked hyaluronic acid sponge material used in the present invention depends on the shape of the crosslinked hyaluronic acid sponge material and the thickness of the crosslinked hyaluronic acid sponge layer. When used, it is approximately 0.2-1.0 mm, preferably 0.1 mm.
It can be about 3 to 0.5 mm.

In the crosslinked hyaluronic acid sponge material preferably used for the wound dressing of the present invention, the above-mentioned crosslinked hyaluronic acid sponge layer is laminated on both sides of such a polymer mesh layer. In this case, the thickness of the crosslinked hyaluronic acid sponge layer can be the same as the thickness of the crosslinked hyaluronic acid sponge layer described above. Further, it may be different or the same on both sides of the polymer mesh layer.

In the crosslinked hyaluronic acid sponge material preferably used in the wound dressing of the present invention, a method of laminating a crosslinked hyaluronic acid sponge layer and a polymer mesh layer is not particularly limited. It is also possible to form a laminate by laminating three layers in the order of / polymer mesh layer / cross-linked hyaluronic acid sponge layer, and to gently or firmly connect each layer by, for example, applying pressure or using an adhesive. It is also possible to combine them into a laminate.

It should be noted that these laminating methods can be similarly used in laminating a crosslinked hyaluronic acid sponge layer and a layer made of a material other than the polymer mesh layer.

Further, in the method for producing a crosslinked hyaluronic acid sponge including the above-mentioned steps (A) to (D), the crosslinked hyaluronic acid sponge material is obtained by the step (A).
Before concentrating the mixture, a process exactly the same as the method for producing a crosslinked hyaluronic acid sponge is used, except that a step of introducing the mixture into a molding container together with the polymer mesh in a manner of sandwiching the polymer mesh in the middle is provided. It is possible to manufacture.

The above-mentioned molding container is appropriately selected according to the shape of the crosslinked hyaluronic acid sponge material finally obtained. For example, the shape of the molding container can be a shape such that the obtained crosslinked hyaluronic acid sponge material has a sheet shape, a rod shape, and the like.

The method of introducing the polymer mesh and the mixed solution into the molding container is as follows. When a sheet-like crosslinked hyaluronic acid sponge material is produced, for example, first, one side of the polymer mesh sandwiched between the molding containers. A suitable amount of the mixed solution is poured in consideration of the thickness of the crosslinked hyaluronic acid sponge layer of above, a polymer mesh is placed thereon, and the thickness of the crosslinked hyaluronic acid sponge layer on the other side sandwiching the polymer mesh is further placed thereon. A method of injecting an appropriate amount of a mixed liquid in consideration of the above is mentioned.

By using such a manufacturing method, not only the formation of the crosslinked hyaluronic acid sponge layer and the lamination of the crosslinked hyaluronic acid sponge layer and the polymer mesh layer are carried out simultaneously, but also the crosslinked hyaluronic acid sponge obtained thereby. The material is excellent in porosity and mechanical strength.

Next, the wound dressing material of the present invention containing such a crosslinked hyaluronic acid sponge material and a physiologically active substance will be described. (2) Wound dressing material of the present invention The wound dressing material of the present invention contains a crosslinked hyaluronic acid sponge material and a physiologically active substance.

The crosslinked hyaluronic acid sponge material used in the present invention is as described in the above (1). Further, as a physiologically active substance used in the wound dressing of the present invention,
Specific examples include dibutyl cyclic AMP and epidermal growth factor. These physiologically active substances can be produced by a known method, or are commercially available, and such commercially available products can be used in the present invention.

In the wound dressing of the present invention, the above-mentioned physiologically active substance can be used, specifically, in a form contained in a cross-linked hyaluronic acid sponge layer.
The physiologically active substance is preferably contained in the crosslinked hyaluronic acid sponge layer at the time of use. In this case, the crosslinked hyaluronic acid sponge material and the physiologically active substance are in a separate state until the time of use and are integrated for the first time during use, but the wound dressing material of the present invention includes such a form. Should be understood as

The reason that the physiologically active substance is preferably contained at the time of use is that the physiologically active substance is generally unstable, so that it is difficult to perform a sterilization operation or long-term storage in a dry state. However, when the physiologically active substance has stability, the present invention is not limited thereto, and the physiologically active substance can be added in advance to the crosslinked hyaluronic acid sponge layer of the crosslinked hyaluronic acid sponge material. The addition of the physiologically active substance to the crosslinked hyaluronic acid sponge layer is usually performed in the form of an aqueous solution. The concentration of the aqueous solution is appropriately selected depending on the type of the physiologically active substance and the like. In addition, the aqueous solution of the physiologically active substance may contain a substance other than the physiologically active substance, if necessary. As such a substance, specifically, a pharmaceutically acceptable substance generally contained in an injection solution or the like. And the like.

For example, a crosslinked hyaluronic acid sponge material having two layers composed of a crosslinked hyaluronic acid sponge and a polymer mesh layer laminated between layers of the crosslinked hyaluronic acid sponge layer, which is preferably used in the present invention; When a wound dressing composed of AMP is applied to the wound surface, dibutyl cyclic AM
An approximately 0.1-2.0% aqueous solution of P is applied to the cross-linked hyaluronic acid sponge layer using a syringe or the like immediately before or immediately after the cross-linked hyaluronic acid sponge material is applied in a manner covering the wound surface to be treated. The wound dressing of the present invention is used, for example, by injection.

Although the crosslinked hyaluronic acid sponge itself is water-insoluble, it has a water absorbing ability due to its sponge structure, which makes it possible to hold an aqueous solution of a physiologically active substance, and provides excellent wound healing. The effect can be exhibited. Further, in the crosslinked hyaluronic acid sponge layer composed of the crosslinked hyaluronic acid sponge obtained by the above preferred production method, the porosity is high, and the mechanical strength is excellent, so that the absorbability and retention ability of the physiologically active substance aqueous solution is excellent. It is.

Further, in the crosslinked hyaluronic acid sponge material in which a polymer mesh is incorporated in the intermediate layer preferably used in the present invention, the polymer mesh greatly contributes to the improvement of the mechanical strength of the crosslinked hyaluronic acid sponge material. Not only enables the use of a stapler for use, etc., but also functions as a semi-closed wound covering material, and prevents the outflow of bodily fluids and the like from the wound surface. It contributes to the wound covering effect.

The wound to which the wound dressing of the present invention is applied is not particularly limited, and can be widely applied to wounds such as burns, pressure ulcers, and intractable skin ulcers. The method of applying the wound dressing of the present invention to a wound can be the same as the method of applying a conventional wound dressing to a wound. In addition, by using the wound dressing of the present invention in combination with another wound dressing having waterproof and moisture-permeable properties, for example, a polyurethane film wound dressing or the like, an aqueous solution of a physiologically active substance can be appropriately stored on the wound surface. It becomes possible.

When a wound is treated using the wound dressing of the present invention, the pain of the patient is reduced and the treatment is simpler than in the conventional method in which a physiologically active substance is added to an ointment and administered. It can be said that the effect is equal or higher.

[0053]

Embodiments of the present invention will be described below. First, a production example of a crosslinked hyaluronic acid sponge material used for the wound dressing of the present invention will be described.

[0054]

[Production Example 1] Production of crosslinked hyaluronic acid sponge material 30 g of hyaluronic acid (molecular weight: 2,000,000, manufactured by Kibun Food Chemifa) was dissolved in 2 L of deionized water having a pH of 6.
A 5% aqueous solution of hyaluronic acid was prepared. A water-soluble epoxy compound (EX810: ethylene glycol diglycidyl ether) was added to this hyaluronic acid aqueous solution at a ratio of 1/5 mol per 1 mol of the repeating unit of hyaluronic acid, followed by stirring. 42.7 mL of the resulting mixture was weighed to 9c in diameter.
m into a plastic petri dish with a diameter of 9c
m 300 mesh nylon mesh (thickness: 0.2
mm), and 42.7 mL of the mixture is poured onto the nylon mesh, and then left at 50 ° C. for 8 hours so that the volume of the mixture above and below the nylon mesh is about the initial volume. Concentrated to 1/5. Thus, a laminate in which a nylon mesh was laminated on the intermediate layer of the intermolecular cross-linked product of hyaluronic acid was obtained.

The obtained laminate was heated at -85 ° C. and 10 mmHg.
For 48 hours under reduced pressure to form a sponge-like layer of the crosslinked product of hyaluronic acid molecules of the laminate. Next, the laminate was removed from the Petri dish and washed with stirring in a large amount of methanol for about 24 hours to remove unreacted water-soluble epoxy compounds. After washing with methanol, the laminate was taken out of methanol, the methanol contained in the sponge was removed with a paper towel, and then in a large amount of ion-exchanged water,
The mixture was washed with stirring for about 24 hours. Here, the amount of methanol and water used for the methanol washing and the water washing is appropriately about 1 L for 10 sheets of the laminate.

After washing with water, the laminate containing a suitable amount of ion-exchanged water in the hyaluronic acid intermolecular crosslinked layer was returned to a plastic petri dish, and again freeze-dried at −85 ° C. and 10 mmHg for 48 hours to remove the crosslinked hyaluronic acid sponge. A crosslinked hyaluronic acid sponge material in which a nylon mesh was laminated between the two layers was prepared.

The obtained cross-linked hyaluronic acid sponge material was dried while maintaining the cross-linked hyaluronic acid sponge portion in a water-containing state, and had a high porosity.
Since it contained a nylon mesh, it had sufficient mechanical strength.

[0058]

Example 1 Wound Dressing A wound dressing containing the crosslinked hyaluronic acid sponge material obtained in the above production example and dibutyl cyclic AMP was prepared at the time of use in the following animal experiments, and the evaluation of the wound treatment effect was evaluated. went. <Animal Experiment 1> A full-thickness skin defect wound having a diameter of 3 cm was prepared on the back of an SD rat. The crosslinked hyaluronic acid sponge material obtained in the above production example was cut into a diameter of 3 cm, and applied to the full-thickness skin defect wound, and sutured and fixed around the wound by a general suturing method. In addition, the crosslinked hyaluronic acid sponge material of the production example had a mechanical strength capable of sufficiently suturing around the wound because the nylon mesh was incorporated. 2 ml of a solution prepared by dissolving 300 mg of dibutyl cyclic AMP powder in 10 ml of injection solution in the crosslinked hyaluronic acid sponge layer of the crosslinked hyaluronic acid sponge material.
Was injected and impregnated using a syringe. This means that the wound dressing of the present invention has been applied to the wound surface. Further, a bioclusive (polyurethane film wound dressing (trade name: manufactured by J & J)) was applied thereon, and sterile gauze was placed thereon and fixed with an elastic bandage. Two weeks after application of the wound dressing of the present invention, it was removed and the wound surface was observed.

As a control experiment, the wound dressing material of the present invention was replaced with only the crosslinked hyaluronic acid sponge material of the production example or Sorbusan (calcium alginate salt wound dressing material). In the same manner, an experiment was conducted to apply various wound dressings to skin-deficient wounds of animals.

The results show that the rats to which the wound dressing of the present invention was applied showed marked granulation tissue formation and a consequent decrease in the wound area (the wound area was reduced to about 1.2 cm in diameter) at 2 weeks after application. ) Was observed. Rats to which only the cross-linked hyaluronic acid sponge material was applied showed marked granulation tissue formation and a corresponding decrease in wound area (the wound area was reduced to about 2 cm in diameter) at 2 weeks after application. The degree of wound healing was clearly lower than that of the rat to which the wound dressing of the present invention was applied. Further, in the rats to which Sorbusan was applied, granulation tissue was formed to almost the same height as the wound periphery but the wound area was not significantly changed 2 weeks after application (the diameter of the wound area was about 2.8 cm). ).
Furthermore, it was observed that alginate fibers partially remained on the wound surface and were slightly white. <Animal Experiment 2> A full-thickness skin defect wound was prepared on the abdomen of an SD rat, preserving the skin having a diameter of 3 cm and a diameter of 5 mm at the center. In the same manner as described above, the crosslinked hyaluronic acid sponge material obtained in the above Production Example was cut into a diameter of 3 cm, applied to the full-thickness skin defect wound, and sutured and fixed around the wound by a general suturing method. In addition, the crosslinked hyaluronic acid sponge material of the above-mentioned production example had sufficient mechanical strength to be sutured around the wound because the nylon mesh was incorporated. 2 ml of a solution prepared by dissolving 300 mg of dibutyl cyclic AMP powder in 10 ml of injection solution in the crosslinked hyaluronic acid sponge layer of the crosslinked hyaluronic acid sponge material.
Was injected and impregnated using a syringe. This means that the wound dressing of the present invention has been applied to the wound surface.

Further, a bio-crucible material (a wound dressing made of polyurethane film (trade name: manufactured by J & J)) was applied on the crosslinked hyaluronic acid sponge material, and then fixed with an elastic bandage. One week after application of the crosslinked hyaluronic acid sponge material, it was removed and the wound surface was observed. After the observation, the crosslinked hyaluronic acid sponge material was applied again in the same manner as described above, and one week later (the second week from the start of the experiment), the wound surface was observed again.

As a control experiment, instead of using the wound dressing of the present invention in combination with the bioclusive in the above experiment, the crosslinked hyaluronic acid sponge material of the production example was applied, and then the bioclusive was used. Alternatively, an experiment for applying various wound dressings to a skin defect wound of an animal was performed in exactly the same manner as described above except that only the bioclusive was used without applying the crosslinked hyaluronic acid sponge material.

As a result, the rats to which the wound dressing of the present invention was applied were observed one week after the application, and the formation of granulation tissue, the reduction of the wound area, and the enlargement of the central insular skin (about 10 m in diameter) were observed.
m), and after 2 weeks, the wound was almost closed and the central island skin was enlarged. Also,
One week after the application of the cross-linked hyaluronic acid sponge material, the observation of one week after application showed formation of granulation tissue, a decrease in the wound area, and enlargement of the central island-like skin (expansion to about 7 mm in diameter). Later observation showed that the wound was almost closed and the central island-like skin was enlarged, but the degree of wound healing was clearly lower than that of the rat to which the wound dressing of the present invention was applied.

Further, in the rats having only the bioclusive and the elastic bandage, granulation tissue formation was not observed at one week after observation, and granulation tissue formation was slightly observed at two weeks after observation. No enlargement of the insular skin was observed.

From these results, it is clear that the wound dressing of the present invention has excellent wound healing ability due to the high water absorption and water retention of the crosslinked hyaluronic acid sponge layer. Furthermore, if a crosslinked hyaluronic acid sponge material incorporating a polymer mesh in the intermediate layer is used, it is possible to suture around the wound and further improve the ability of the wound dressing to retain a physiologically active substance. It was found that the contribution to the effect was large.

[0066]

According to the wound dressing material of the present invention, it is possible to easily and effectively treat a wound such as a skin defect wound using a physiologically active substance.

Claims (7)

[Claims] 1. A wound dressing comprising a crosslinked hyaluronic acid sponge material having a crosslinked hyaluronic acid sponge layer obtained by freeze-drying an intermolecular crosslinked product of hyaluronic acid and / or a derivative thereof, and a physiologically active substance. 2. The wound dressing according to claim 1, wherein the crosslinked hyaluronic acid sponge layer comprises a crosslinked hyaluronic acid sponge obtained by a production method including the following steps (A) to (D): (A) hyaluronic acid and / or Or a step of mixing a cross-linking agent with an aqueous solution of a derivative thereof and concentrating the resulting mixture to obtain an intermolecular cross-linked product of the hyaluronic acid and / or a derivative thereof; (B) a molecule obtained in the step (A). A step of freeze-drying the intercrosslinked product, (C) a step of washing the intermolecular crosslinked product after the step (B) with an alcohol, and further washing with water, and (D) a molecule after the step (C). A step of freeze-drying the intercrosslinked product again to obtain a crosslinked hyaluronic acid sponge. 3. The wound dressing according to claim 2, wherein the crosslinking agent used in the step (A) is a water-soluble epoxy compound. 4. The wound dressing according to claim 2, wherein the alcohol used in the step (C) is methanol. 5. The cross-linked hyaluronic acid sponge material,
The wound dressing according to claim 1, comprising two layers of a crosslinked hyaluronic acid sponge and a polymer mesh layer laminated between the crosslinked hyaluronic acid sponge layers. 6. The method according to claim 1, wherein the polymer mesh layer has a thickness of 100 to 300.
The wound dressing according to claim 5, comprising a polymer mesh of a material selected from polyamide, polyethylene, polypropylene, and polyester, having a mesh width of the mesh. 7. The wound dressing according to claim 1, wherein the crosslinked hyaluronic acid sponge layer contains a physiologically active substance.