JPH09262278A - Adhesive plaster - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an adhesive plaster capable of absorbing adequately exudate from the wound and aiding effectively the heal up of new skin by forming the plaster with a film or sheet like polymer substrate layer and an adhesive layer containing poly-alpha-amino acid particle of which average diameter is writhin specified extent. SOLUTION: This adhesive plaster suitable to apply on and heal the wound such like cut, scratch, burn and bedsore is composed of a film or sheet like polymer substrate layer and an adhesive layer containing poly-alpha-amino acid particle of which average diameter is within 0.1-100μm, concurrently forming the polymer substrate layer with porous material. Applied for the polymer substrate should be a polymer composed of, for example, polyurethane, polytetrafluoroethylene or polydimethylsiloxane with the thickness basically 5-1000μm. Vapor permeability of the applied substrate layer should fall within 3,000-10,000g/m<2> .24h. Applied suitably for the adhesive agent in the layer is a rubber-based adhesive polymer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a wound dressing material, and more particularly to a wound dressing material suitable for the treatment of external wounds such as cuts, abrasions, burns, and wounds.

[0002]

2. Description of the Related Art Conventionally, as wound dressing materials used for treatment of skin deficiency damage such as burns, trauma or wounds, lyophilized porcine dermis, collagen non-woven fabric, bio-derived materials such as chitin non-woven fabric, synthetic materials such as polyurethane film, Bio / synthetic composite materials such as silicone membrane / nylon fabric / collagen composite membrane (called bioprene) are known. However, in the above-mentioned biological material, the hydrophilicity is good on the wound surface, excellent exudate dischargeability, and adheres well to the wound surface, on the other hand, the coating material is inferior in durability. However, there is a problem in that it may be decomposed and melted due to, and the function of the covering material may be lost. In addition, the above-mentioned synthetic materials such as polyurethane film are used for the durability of the covering material,
Although it is excellent in transparency, it has poor adhesion to the wound surface, tends to cause the accumulation of exudate between the wound surface and the covering material, and has a drawback of delaying wound healing. Furthermore, in the case of silicone membrane / nylon fabric / collagen composite membrane, the adhesion between the nylon fabric and the wound surface is too strong and inhibits the epithelialization of the wound surface. Since the silicone membrane is essentially hydrophobic, the wound surface is rich in exudate. However, there is a problem in that the adhesiveness is lowered due to storage between the wound surface and the covering material.

[0003]

DISCLOSURE OF THE INVENTION The present invention has been made based on the above circumstances, and its object is to provide:
Absorbs exudate from the body well, does not accumulate exudate between the wound surface and wound dressing, has good biocompatibility with the wound surface, and causes excessive inflammatory reaction and dry necrosis of the wound surface. It is an object of the present invention to provide a wound dressing which is free of defects and has good generation of new epidermis from the wound edge.

[0004]

That is, the present invention comprises a sheet-like or film-like polymer base layer and a pressure-sensitive adhesive layer containing poly-α-amino acid particles having an average particle size of 0.1 to 100 μm. A wound dressing comprising the above is the first invention, and a wound dressing in which the polymer substrate layer is porous is the second invention.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The material of the film-shaped or sheet-shaped polymer substrate of the present invention is not particularly limited, for example, polyurethane, polytetrafluoroethylene, a polymer mainly composed of polydimethylsiloxane, a polyamide-based polymer,
Polyester polymer, polyethylene, polypropylene, ethylene / α-olefin copolymer, ethylene-vinyl acetate copolymer, polyolefin polymer such as polymethylpentene, styrene-isoprene-styrene block copolymer, styrene-butadiene- Examples thereof include aromatic vinyl compound-diene-based polymers such as styrene block copolymers and hydrogenated diene-based polymers such as hydrogenated styrene-butadiene-styrene block copolymers. The thickness of the polymer substrate layer is usually 5 to 1000 μm, preferably 50 to 1000 μm. Further, as the polymer substrate layer, a porous film or sheet-like structure having an average pore size of 0.01 to 100 μm is preferable from the viewpoint of water vapor permeability and air permeability. In the present invention, when a porous film or sheet-like polymer base layer is used, the water vapor permeability of the base layer is 3000 to 10
Those having a range of 000 g / m ² · 24 h are preferably used.

The pressure-sensitive adhesive component used in the pressure-sensitive adhesive layer constituting the wound dressing of the present invention is not particularly limited, and known ones can be used. In the present invention, as the adhesive polymer contained in the adhesive component, natural rubber, isoprene rubber, styrene-butadiene rubber, polybutene, rubber-based adhesive polymer such as polyisobutylene, acrylic acid or alkyl acrylate Acrylic adhesive polymers such as homopolymers or copolymers, vinyl ether adhesive polymers mainly composed of polymers such as vinyl ethyl ether, vinyl butyl ether, vinyl isobutyl ether, and silicone based polydimethylsiloxane. Adhesive polymers, and other urethane-based, polyvinylacetamide-based adhesive polymers are preferably used.
Of these adhesive polymers, polybutene and polyisobutylene are particularly preferable for rubber-based adhesive polymers, and methyl acrylate and acrylic acid 2 for acrylic-based adhesive polymers.
A copolymer with -ethylhexyl and the like are preferable. In the present invention, the tacky polymer, if necessary, a tackifying resin,
You may mix | blend a softener etc.

The average particle size of the poly-α-amino acid particles contained in the pressure-sensitive adhesive layer constituting the wound dressing of the present invention is usually 0.01 to 100 μm, preferably 0.1.
The average particle size variation coefficient is usually 1 to 30%, preferably 1 to 20%. If the average particle size is less than 0.01 μm, the composite particles described below may not be stably produced. Further, if it is made larger than 100 μm, the particles may not be formed into particles.
The poly-α-amino acid particle may have a single or a plurality of pores inside the particle. The existence ratio of the pores is usually 0.0001 to 1000 in terms of volume ratio (volume of pores per particle / volume of poly-α-amino acid per particle) with respect to poly-α-amino acid particles. , Preferably in the range of 0.001 to 100.

In order to produce the above poly-α-amino acid particles, a method of emulsion-polymerizing α-amino acid-N-carbonic anhydride (hereinafter abbreviated as amino acid-NCA), amino acid-
Examples thereof include a method in which NCA is solution-polymerized and then re-emulsified, a method in which a polyamino acid bulk is pulverized, and the like.
Among these methods, the method of (1) prepares a polymer solution, (2) emulsifies the polymer solution in an aqueous medium, and (3) removes an organic solvent, which is a purpose unless the steps are totaled three steps. It is inefficient because it is not possible to obtain poly-α-amino acid particles of the method described above, and in the other method, the coefficient of variation of the average particle diameter may be 30% or more, which is preferable. Amino acid-NC used in the present invention
A may be derived from any α-amino acid as long as it is solid at room temperature. However, when an amino acid-NCA is produced from an α-amino acid having a functional group such as a carboxyl group, a hydroxyl group, a thiol group, an amino group, or a guanidyl group in its side chain as a raw material, these functional groups should be protected with an appropriate protecting group. Amino acid-NC after protection with
It may be necessary to lead to A.

Specific examples of α-amino acids include (a) neutral amino acids such as glycine, alanine, valine, norvaline, leucine, isoleucine, norleucine, phenylalanine, methionine and proline; (ro) glutamic acid-γ-ester; Acidic amino acid-ω-esters such as aspartic acid-β-ester (here, ester means methyl ester, ethyl ester, propyl ester, butyl ester, octyl ester, 2-ethylhexyl ester, cyclohexyl ester, phenyl ester, benzyl ester. Etc.), (C) N-
N-acyl basic amino acids such as carbobenzoxylysine, N-carbobenzoxyornithine and N-acetyllysine, and esters of hydroxyl group-containing α-amino acids such as (d) serine, threonine, cystine and tyrosine (here ester And are methyl ester, ethyl ester, propyl ester, butyl ester, octyl ester,
2-ethylhexyl ester, cyclohexyl ester, phenyl ester, benzyl ester and the like are shown. ).

The amino acid-NCA obtained from these α-amino acids may be in an optically active form, a racemic form or a mixture thereof, and if necessary, two or more kinds may be used in combination. The amino acid-NCA can also be crushed before being added to water. In the method for producing poly-α-amino acid particles by emulsion polymerization of the above amino acid-NCA, water and / or an organic solvent can be used as a reaction medium. The water and the organic solvent are used in a weight ratio of water: organic solvent of 100: 0.
It is preferably 50:50. When an organic solvent is used, the solubility of water under the conditions of 1 atm and 25 ° C. is 10 g / 100 ml or less, preferably 5 g.
/ 100 ml or less is preferable. When an organic solvent having a water solubility of more than 10 g / 100 ml is used, a particulate polymer may not be obtained.

Specific examples of such an organic solvent include chloromethane, dichloromethane, chloroform and 1,1-
Dichloroethane, 1,2-dichloromethane, 1,1,2
-Aliphatic halogenated hydrocarbons such as trichloroethane; chlorobenzene, o-dichlorobenzene, 1,2,
Aromatic halogenated hydrocarbons such as 4-trichlorobenzene; Esters such as ethyl acetate, butyl acetate and ethyl butyrate; Ethers such as ethyl ether, butyl ether, hexyl ether, octyl ether, anisole, ethoxybenzene, tetrahydrofuran and dioxane Hydrocarbon compounds such as pentane, hexane, heptane, octane, cyclohexane, benzene, toluene and xylene, and the like. These organic solvents can be used alone, of course, but by combining two or more kinds, the solubility of water and amino acid-N
It is possible to obtain an organic solvent in which important properties such as solubility of CA are preferably adjusted. The ratio of amino acid-NCA to water, which is a polymerization reaction medium, is the same as that of amino acid-NC.
The weight ratio of A: water is 1: 0.5 to 1: 100, preferably 1: 1 to 1:50.

In the present invention, the polymerization initiator is not particularly limited as long as it is a compound capable of causing the amino acid-NCA polymerization reaction. Specific examples thereof include (a) primary amines such as methylamine, ethylamine, isopropylamine, butylamine, hexylamine, heptylamine, octylamine, (b) dimethylamine, diethylamine, dibutylamine, dihexylamine, diheptyl. Secondary amines such as amines and dioctylamines, (c) tertiary amines such as trimethylamine, triethylamine, tributylamine, trihexylamine, triheptylamine, trioctylamine, (d) ethanolamine, diethanolamine, triethanolamine , Alcohol amines such as N, N-dimethylethanolamine, (e) ethylenediamine, hexamethylenediamine, N, N-dimethyl-1,
Examples include polyamines such as 3-propanediamine and triethylenediamine, and the like. These polymerization initiators can be used alone or in combination of two or more kinds.

The proportion of the polymerization initiator used is 1/2 to 1/500 with respect to 1 mol of amino acid-NCA as a monomer.
It is 0 mol, preferably 1/5 to 1/1000 mol.
By adjusting the amount of the polymerization initiator used within this range, polymer particles having a desired molecular weight can be obtained. In the present invention, the emulsifier is not particularly limited as long as it does not inhibit the polymerization reaction of the amino acid-NCA used, but a nonionic emulsifier is particularly preferable. Specific examples of the nonionic emulsifier include polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene fatty acid ester, polyethylene glycol alkyl ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid. Examples thereof include esters and glycerin fatty acid esters. These emulsifiers can be used alone or in combination of two or more kinds. The use ratio of the emulsifier is 0.1 to 100 parts by weight, preferably 1 to 50 parts by weight, relative to 1 part by weight of the amino acid-NCA used. If the proportion of the emulsifier used is less than 0.1 part by weight, the polymer particles produced may not have a sufficiently large molecular weight.

In the present invention, the order of adding the polymerization initiator, the emulsifier and the amino acid-NCA is not limited as long as the amino acid-NCA can be stably dispersed by the emulsifier. That is, in the present invention,
Amino Acid-NCA Before Amino Acid-NCA Hydrolyzes
It is necessary to make the emulsified state. Specifically, it is preferable to add the above-mentioned amino acid-NCA to water containing a polymerization initiator and an emulsifier to perform polymerization. At this time, it is preferable to stir the water in the reactor, and therefore, a mechanical stirring means or a means by ultrasonic irradiation can be used, and they may be used in combination. According to such a method, the monomer amino acid-NCA
In the polymerization reaction medium consisting of water to which is added, since the conditions necessary for the immediate polymerization of the amino acid-NCA as it is are satisfied, the amino acid-NCA is
At the same time that A is added, a polymerization reaction is generated from the surface thereof, but since this polymerization reaction is preferentially performed over the hydrolysis reaction, the polymerization reaction is not hindered by the hydrolysis reaction. Polymer particles of useful poly-α-amino acid are produced, and as a result, the polymerization reaction system becomes an emulsion of the polymer particles of poly-α-amino acid as it is.

The amino acid-NCA polymerization reaction occurs spontaneously when the amino acid-NCA contacts a polymerization initiator in water. The polymerization temperature depends on the type of amino acid-NCA,
Although it varies depending on the type of the polymerization initiator, it is usually 0 to 10
It is 0 ° C, preferably 5 to 90 ° C. By controlling the polymerization temperature, it is possible to produce poly-α-amino acid polymer particles having a desired molecular weight. The polymerization pressure is not particularly limited. During the polymerization reaction, it is necessary to stir the system to maintain the emulsified state. This stirring is preferably carried out, for example, by means of mechanical stirring in a reactor, and the number of rotations thereof is usually 20 to 3000 rpm. p. m. It is.

According to the method of the present invention, an emulsion of polymer particles consisting of poly-α-amino acid can be obtained. The polymer particles can be used in the state of emulsion or separated from water. It can also be used. As means for separating the polymer particles in the emulsion from water, means for evaporating water all at once using a spray dryer or the like, sedimentation and separation of the polymer particles by centrifuging the emulsion to separate the solid matter obtained Means for drying, means for drying the solid after concentrating the emulsion using a water separation membrane, and the like can be mentioned. If necessary, the emulsifier can be removed by washing the polymer particles with water or the like.

The poly-α-amino acid particles obtained above can be modified by the following method. For example, as a monomeric amino acid-NCA,
Obtained when N-carbonic anhydride of an acidic amino acid ester such as glutamic acid ester or aspartic acid ester or N-carbonic acid anhydride of a basic amino acid such as N-carbobenzoxylysine or N-carbobenzoxyornithine is used. Particles or polymer particles are
In the case of particles made of a copolymer obtained by copolymerizing a carbonic anhydride and an N-carbonic acid anhydride of a neutral amino acid, the surface of these particles is hydrolyzed to generate an amino group or a carboxyl group. By doing so, the surface of the particles can be made hydrophilic. Further, the surface of the particles can be hydrophilized by reacting the poly-α-amino acid particles with alcohol amines such as ethanolamine, propanolamine and butanolamine. Further, poly-α-amino acid particles are prepared by adding diamines such as ethylenediamine, propylenediamine, hexamethylenediamine, octamethylenediamine, ethylene glycol,
The polymer particles can be crosslinked by reacting with glycols such as propylene glycol or dicarboxylic acids such as malonic acid, succinic acid and adipic acid.

The poly-α-amino acid particles obtained by the above method may contain a liquid and / or solid substance such as a biological substance, an organic compound and an inorganic compound. Specific examples of the substance to be contained in the poly-α-amino acid particles include physiologically active substances such as immunoglobulin that promote wound healing, drugs such as analgesics or antibiotics, silver sulfadiazine, sulfadiazine zinc, sulfadiazine cerium, and silver nitrate. , Gentamicin, neomycin, cephalosporin, antibacterial agents such as zeolite containing antibacterial metal ions, and the like. In order to contain a liquid and / or solid substance in the poly-α-amino acid particles, (i) the liquid and / or solid substance is dissolved in an organic solvent as necessary, and if necessary, After mixing with water to make an emulsion,
Mixing with poly-α-amino acid particle aqueous dispersion, poly-α-
A method of absorbing and immobilizing a liquid and / or solid substance in amino acid particles, (ii) emulsion-polymerizing amino acid-NCA by adding a solution obtained by dissolving or dispersing the liquid and / or solid substance in an organic solvent, Examples thereof include a method of immobilizing a liquid and / or solid substance in the poly-α-amino acid particles. The content of the poly-α-amino acid particles in the pressure-sensitive adhesive layer of the present invention is 100% in the pressure-sensitive adhesive polymer in the pressure-sensitive adhesive layer.
It is usually 0.1 to 50 parts by weight, preferably 0.1 to 20 parts by weight, based on parts by weight. When the content of the poly-α-amino acid particles exceeds 50 parts by weight, the adhesive force of the pressure-sensitive adhesive layer decreases, and when it is less than 0.1 parts by weight, the biocompatibility with the wound surface and the absorbability of exudate are reduced. Inferior.

In the present invention, the method for adding poly-α-amino acid particles to the pressure-sensitive adhesive layer is usually used,
A mixed dispersion process can be used. For example, a method may be mentioned in which the pressure-sensitive adhesive composition is dissolved in a solvent such as toluene, the polyamino acid particles are dispersed and mixed, and then the solvent is applied to the polymer substrate and dried.

EXAMPLES Examples of the present invention will now be described in detail, but the present invention is not limited to these examples. The average particle size of the polymer particles in the following examples is measured by observing with a transmission electron microscope, and the CV value of the polymer particles shows a value calculated from the formula represented by the following mathematical formula 1.

[0018]

[Equation 1]

[00194]

Example 1 A round bottom separable flask was charged with 2 liters of purified water and 14.4 mmol of triethylamine as an initiator, and an emulsifier (polyoxyethylene sorbitan monolaurate "Tween 20" (manufactured by Kao Corporation) 1
g was added and thoroughly mixed to disperse and emulsify. After emulsification, 14.4 mmol of triethylamine was added and stirred, and 100 g (380 mmol) of powder of γ-benzyl-L-glutamate-N-carbonic anhydride (hereinafter referred to as “BLG-NCA”) was added to this emulsion. Then, BLG-NCA was polymerized at room temperature for 5 hours with continuous stirring to obtain an emulsion of poly-γ-benzyl-L-glutamate (hereinafter referred to as “PBLG”) particles. After the reaction, the organic solvent was removed by steam stripping, and the produced particles and the dispersion medium were separated by filtration. The obtained particles were washed with water and filtered twice. The particles thus obtained are dried to obtain the poly-
α-Amino acid particles were obtained. Poly-obtained in the above
The average particle size of the α-amino acid particles is 10 μm, and the CV value is 1.
It was 9%. Polyurethane emulsion solution 30 (w
/ V%) (Heimlen X-3040, Dainichi Seika Co., Ltd.)
Was applied onto a silicone release paper using an applicator to form a layer having a uniform thickness, and then dried at 60 to 100 ° C. using a dryer, and cured there for 2 to 3 hours. A polyurethane film having a thickness of 30 μm was obtained. Then, a one-pack heat-crosslinking acrylic adhesive 60 (w
/ V%) (Cybinol AT-H4, manufactured by Saiden Chemical Co., Ltd.) 50 g and poly-α-amino acid particles 0.5.
An adhesive having g mixed therein was applied to the polyurethane film using an applicator so as to have a thickness of 20 μm to obtain a dressing (1). The water vapor transmission rate of the dressing (1) was 2000 g / m ² .

[0020]

Comparative Example 1 A dressing (2) was obtained in the same manner as in Example 1 except that poly-α-amino acid particles were not added to the adhesive component, and the water vapor permeability of the dressing (2) was 1000 g / m 2. ^{Was 2} .

Example 2 A dressing (3) was obtained in the same manner as in Example 1 except that a polyurethane porous filter (thickness: 25 μm, average pore size: 0.1 μm) was used instead of the polyurethane film of Example 1. The water vapor transmission rate of the dressing (3) was 4000 g / m ² .

[0021]

Example 3 A dressing (4) was obtained in the same manner as in Example 1 except that the poly (α-amino acid) particle of Example 1 contained gentamicin as an antibacterial agent component. The transmittance was 1200 g / m ² . Using a rabbit of about 3 kg in weight, under general anesthesia with sodium pentoparbital, after shaving and disinfecting the back, 1 ml of physiological saline was injected into the skin to swell the skin and freehand dermatol on the surface. By cutting, a split-layer skin defect portion having a depth of about 0.70 mm and a diameter of about 15 mm was created at four locations. The wound surface of each of the dressings (1) to (4) shown in Examples 1 to 3 and Comparative Example 1 was coated on the wound surface, the periphery of each coating was fixed with an adhesive tape, and sterile gauze was placed thereon. Then, a sterilized absorbent cotton was put on and fixed under pressure. On the 7th day after the operation, the wound site was visually observed, and then the wound site was observed histologically by hematoxylin-eosin staining. The results are shown in Table 1.

[0022]

The present invention provides a wound dressing comprising a film layer and an adhesive layer containing poly-α-amino acid particles, wherein the poly-α-amino acid particles contained in the adhesive layer are biocompatible and absorb water. Absorbs exudate from the living body due to its water-repellent property and oil absorbency, does not cause accumulation of exudate between the wound surface and the wound dressing material, has good biocompatibility with the wound surface, excessive inflammatory reaction, and wound surface. It is possible to obtain a wound dressing which does not cause dry necrosis of the above, and also has good generation of new epidermis from the wound edge. Further, this effect becomes remarkable by containing an antibacterial agent inside the polypoly-α-amino acid particles and by making the film layer porous.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshitaka Yamakawa 2-11-24 Tsukiji, Chuo-ku, Tokyo Within Nippon Synthetic Rubber Co., Ltd. (72) Inventor Kyoko Kuroda 2-11-24 Tsukiji, Chuo-ku, Tokyo Within Nippon Synthetic Rubber Co., Ltd.

Claims (1)

[Claims] 1. A wound dressing comprising a polymer base layer in the form of a film or sheet and an adhesive layer containing poly-α-amino acid particles having an average particle size of 0.1 to 100 μm.