JP2019107253A - Wound dressing material sustained-release particle and wound dressing material - Google Patents

Abstract

To provide a wound dressing material that creates a moist environment necessary for fibroblast migration and proliferation as well as that can elute a wound healing component and an antimicrobial component.SOLUTION: The wound dressing material sustained-release particle of the present invention is characterized in comprising a composite particle composed of a biodegradable and/or bioabsorptive polymer, a calcium-based compound and a boron-based compound.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a sustained release particle for a wound dressing that improves the therapeutic effect of a wound dressing that treats wound surfaces such as cuts, tears, bruises, burns and wrinkles, and a wound dressing including the same.

  Conventionally, as treatment for wounds, disinfection is first performed, and then treatment to protect the wound surface with gauze is performed. However, such treatment results in cell death by disinfection. In addition, it has been known in recent years that the cells are less likely to proliferate by drying the wound surface.

  Therefore, plastic surgeon Susumu Natsui et al., Instead of treating with disinfectant solution and gauze, proposed a treatment (moist wound healing) that maintains the wet environment of the wound surface and promotes cell proliferation, and this treatment method is currently used. It is widely spread (Non-Patent Document 1). In such treatment methods, the material used to maintain the moist environment of the wound surface is called a wound dressing.

WO 2011/085092 Publication

Wound treatment from now on by Minoru Natsui Medical School (2003/08)

  In recent years, glass fibers for wound dressings have been developed in which the wound healing effect and the antimicrobial properties are exhibited by the elution of the glass component into the exudate (Patent Document 1). When treating with this type of glass fiber for wound dressing, after attaching the glass fiber to the wound surface, the periphery of the wound surface is covered and fixed with a bandage or a surgical tape so that the glass fiber is not detached from the wound surface. However, since the glass fiber for wound covering has a high absorption rate of exudate, there is a problem that when used for a wound surface with a small amount of exudate, the wound surface is dried. Although it is possible to use glass fibers impregnated with a moisturizing agent such as a cream or an ointment in advance, the workability in treatment is deteriorated. Furthermore, it is difficult to stably obtain an optimum wet environment because the amount of the moisturizing agent changes due to the handling of the worker.

  The present invention has been made in view of the above circumstances, and provides a wound covering material capable of forming a moist environment necessary for migration and proliferation of fibroblasts and capable of eluting a wound healing component and an antibacterial component. To aim.

  As a result of conducting various studies, the present inventors have found that the above-mentioned problems can be solved by using composite particles containing a calcium-based compound and a boron-based compound, and are proposed as the present invention.

  That is, the sustained release particles for wound dressings according to the present invention are characterized by being composed of composite particles composed of biodegradable and / or bioabsorbable polymers, calcium based compounds, and boron based compounds. Do.

  The controlled release particles according to the present invention have calcium (Ca) ions, which have the function of promoting proliferation and migration of fibroblasts when they come in contact with blood or exudate, and boron (B), which has a disinfecting effect on bacteria. Elute the ions. The eluted B ions and Ca ions are supplied to the wound surface, and it is possible to accelerate the wound healing process and to impart the bactericidal property to prevent the critical colonization and infection of bacteria on the wound surface. Thus, the sustained release particles of the present invention, together with the effects of these ions, contribute to the early healing of the wound.

  In the present invention, the biodegradable and / or bioabsorbable polymer preferably contains at least one selected from the group consisting of polylactic acid, polyglycolic acid and copolymers of polylactic acid and polyglycolic acid. .

  In the present invention, the calcium-based compound is preferably at least one selected from the group consisting of calcium carbonate, calcium lactate, calcium hydroxide, calcium oxide, calcium phosphate, calcium chloride and calcium formate.

  In the present invention, the boron-based compound is preferably at least one selected from the group of boric acid, boron oxide, borates such as metaboric acid and zinc borate, and metaborates such as copper metaborate .

  In the present invention, it is preferable that the composition contains 10 to 60% by mass of a calcium-based compound, 1 to 40% of a boron-based compound, and at least 30% or more of a biodegradable and / or bioabsorbable polymer.

  With the above configuration, it is possible to supply an optimal amount of Ca ions and B ions to the wound surface in order to accelerate the wound healing process.

  In the present invention, the particle diameter (D50) when the cumulative abundance ratio of particles by laser diffraction type particle size distribution measurement is 50% is preferably 0.1 to 800 μm, particularly 10 to 800 μm.

  The wound dressing of the present invention comprises the above-mentioned sustained release particles, hydrophilic polymer particles, and an adhesive substrate, and the sustained release particles and the hydrophilic polymer particles are dispersed in the adhesive substrate. It is characterized by

  If the above configuration is adopted, the hydrophilic polymer in the adhesive substrate absorbs blood and exudate flowing out from the wound surface, and a wet environment is constructed on the wound surface. For this reason, proliferation, migration, and differentiation of fibroblasts are promoted. When blood or exudate absorbed by the adhesive substrate comes in contact with the sustained release particles, calcium (Ca) ions and boron (B) ions are eluted. The eluted B ions and Ca ions are supplied to the wound surface, which makes it possible to accelerate the wound healing process and to impart bactericidal properties to prevent critical colonization and infection of bacteria on the wound surface. The wound dressing of the present invention can cure the wound early by combining the effects of these ions.

  In the present invention, the hydrophilic polymer particles are preferably hydrophilic colloid particles.

  In the present invention, the hydrophilic colloid particles are preferably at least one selected from the group consisting of gelatin, pectin and sodium carboxymethylcellulose.

  If the above configuration is adopted, it is possible to sufficiently absorb blood and exudate flowing out from the wound surface.

  In the present invention, the adhesive substrate preferably contains at least one selected from the group consisting of polyisobutylene, styrene isoprene styrene block copolymer, liquid paraffin and rosin ester.

  With the above configuration, it becomes easy to form a moist environment necessary for fibroblast migration and proliferation.

  In the present invention, the shape of the adhesive substrate is preferably a sheet.

  Adopting the above configuration makes it easy to maintain the adhesion to the application site of the human body.

  The wound dressing of the present invention is a simulated bodily fluid in a dissolution test in which five wound dressings cut into 2 cm square are immersed in 100 ml of simulated bodily fluid for 2 days at 37 ° C. and stirred once / day. It is preferable that the B ion concentration in the medium be 0.1 to 70 mM and the Ca ion concentration be 3.1 to 21 mM.

  If the above configuration is adopted, it is possible to supply a necessary and sufficient amount of B ions and Ca ions to the wound surface.

  In the present invention, it is preferable that a waterproof layer is formed on one side of the adhesive substrate.

  In the present invention, the waterproof layer preferably contains at least one selected from the group consisting of polyurethane, polyethylene, polypropylene, polyvinyl chloride and polyvinylidene chloride.

  If the above configuration is adopted, the shape retention property of the wound covering material is improved, the handling becomes easy, and the wound surface can be easily protected from bacterial infection and contamination.

It is an explanatory view showing one embodiment of a wound dressing of the present invention.

  Hereinafter, the present invention will be described in detail.

(1) Sustained-release particles for wound dressings The sustained-release particles for wound dressings (hereinafter simply referred to as sustained-release particles) of the present invention are biodegradable and / or bioabsorbable polymers, and calcium based It is a complex composed of a compound and a boron-based compound. More specifically, calcium-based compound particles and boron-based compound particles are supported in a matrix phase made of a biodegradable and / or bioabsorbable polymer. Each component will be described below.

  The biodegradable and / or bioabsorbable polymer functions as a matrix component that carries a calcium-based compound and a boron-based compound. Biodegradable and / or bioresorbable polymers are highly biocompatible and biodegradable and / or bioresorbable polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid and polyglycolic acid It is preferable that it is a copolymer etc. Although PLA or PGA can be used alone, it is difficult to control the decomposition rate. On the other hand, a copolymer obtained by copolymerizing PLA and PGA at an arbitrary ratio is preferable because the decomposition rate can be controlled by the ratio. The preferred ratio of PLA to PGA is 43:57 to 58:42. In addition to these components, aliphatic polyesters such as polycaprolactone, polyglycerol sebacic acid, polyhydroxyalkanoic acid, polybutylene succinate, aliphatic polycarbonates such as polytrimethylene carbonate, cellulose diacetate, cellulose triacetate, methyl cellulose, It is also possible to introduce biodegradable and / or bioabsorbable polymers such as polysaccharide derivatives such as propyl cellulose and benzyl cellulose, proteins such as silk fibroin, gelatin, collagen, and derivatives thereof.

It is important that the calcium-based compound contains calcium and contains as much as possible no harmful component to the living body. Preferred examples of such calcium-based compounds include calcium carbonate, calcium lactate, calcium hydroxide, calcium oxide, calcium phosphate, calcium chloride, calcium formate and the like. Boron-based compounds contain boron and are harmful to the living body. It is important not to contain the components as much as possible. Preferred examples of such boron compounds include boric acid, boron oxide, borates such as metaboric acid and zinc borate, and metaborates such as copper metaborate.

  The controlled release particle of the present invention contains 10 to 60% by mass of a calcium-based compound, 1 to 40% of a boron-based compound, and at least 30% or more of a biodegradable and / or bioabsorbable polymer. Is preferred. In particular, 17 to 45% of a calcium-based compound, 13 to 32% of a boron-based compound, and 30 to 55% of a biodegradable and / or bioabsorbable polymer are desirable.

  If the blending ratio of the calcium-based compound is too low, the Ca ion concentration on the wound surface will be low, and it will be difficult to obtain the effect of promoting cell growth. On the other hand, if the compounding ratio of the calcium-based compound is too large, the Ca ion concentration will be excessive and cytotoxicity will be exerted.

  If the blending ratio of the boron-based compound is too small, the B ion concentration on the wound surface will be low, and it will be difficult to obtain criticality of bacteria to the wound surface and sterilization properties for preventing infection. On the other hand, if the compounding ratio of the boron compound is too high, the B ion concentration becomes excessive, and an excessive bactericidal effect works to reduce the wound healing rate.

  If the blending ratio of the biodegradable and / or bioabsorbable polymer is too small, the concentration of Ca ion and B ion will be excessive, and the wound healing rate will be reduced due to the above-mentioned reason. On the other hand, if the blending ratio of the biodegradable and / or bioabsorbable polymer is too high, the concentration of Ca and B decreases, and the wound healing rate decreases for the above-mentioned reason.

  The controlled release particles of the present invention preferably have a particle diameter (D50) of 0.1 to 800 μm when the cumulative abundance ratio of particles by laser diffraction particle size distribution measurement is 50%. The particle size (D50) is particularly preferably 0.8 to 500 μm, 2 to 200 μm, and particularly 5 to 80 μm. If the particle size (D50) is too small, particle aggregation tends to occur, and when mixed in a wound dressing, the dispersibility decreases and the dispersion of elution behavior increases. In addition, Ca and B may be dissolved early, and frequent replacement of the wound dressing may be necessary. On the other hand, if the particle size (D50) is too large, it will be easily detached from the wound dressing during handling. In addition, the sustained release particles become noticeable, and the appearance of the wound covering material is deteriorated, and the discomfort at the time of attachment is also likely to be increased.

  The controlled release particles of the present invention are not limited in shape, and may take various forms such as flakes and dendrites other than spherical ones.

  The controlled release particles of the present invention can be produced as follows. However, this is merely an example, and the present invention is not limited to this. First, the biodegradable and / or bioabsorbable polymer is melted at a temperature above the melting point. Next, a mixed powder of a calcium-based compound and a boron-based compound is added to the melt, and the mixture is thoroughly kneaded in that state, and then solidified by cooling to prepare a composite. Subsequently, the composite is crushed and classified to produce sustained release particles having a desired particle size.

  The controlled release particles of the present invention having the above characteristics are chemically stable when not in contact with water, and release calcium ions and B ions when in contact with water. Ca ions promote proliferation and migration of fibroblasts, and B ions have a bactericidal effect against bacteria such as Staphylococcus aureus, E. coli, MRSA. The controlled release particles can also function as a filler that improves the shape retention and mechanical strength of the wound dressing. Therefore, it can be complexed with other materials to suitably form a wound dressing. In particular, as described later, it is preferable to use by dispersing in a tacky substrate containing hydrophilic polymer particles.

(2) Wound dressing The wound dressing of the present invention comprises sustained release particles, hydrophilic polymer particles, and an adhesive substrate. The controlled release particles and the hydrophilic polymer particles are dispersed in the adhesive substrate. Each component will be described below. The controlled release particles are as described above and will not be described here.

  The hydrophilic polymer is a component that absorbs exudate and blood flowing out from the wound surface to construct a moist environment. It also functions to bring the absorbed exudate or blood into contact with the sustained release particles. As such a hydrophilic polymer, hydrophilic colloid particles are preferable. Examples of hydrophilic colloid particles include gelatin, pectin, sodium carboxymethylcellulose and the like.

  The adhesive substrate imparts adhesiveness to the skin and has a role of a matrix phase supporting sustained release particles and hydrophilic polymer particles. The adhesive substrate preferably contains a rubber elastomer (rubber adhesive) as a main component in order to secure the permeability of Ca ions and B ions. Examples of the rubber elastomer include hydrophobic polymers such as polyisobutylene, styrene isoprene styrene block copolymer, liquid paraffin, rosin ester and the like. These rubber elastomers can easily transmit ions since they have a network structure in which polymer chains are crosslinked.

  The adhesive substrate (or wound dressing) is preferably in the form of a sheet. More specifically, it is preferable to be in the form of a sheet having a thickness of 0.1 to 2.0 mm, particularly 0.3 to 1.5 mm. If the thickness of the adhesive substrate is too large, the appearance may deteriorate, and if it is too thin, the absorption of blood or exudate flowing out from the wound may be extremely reduced to cause liquid leakage or the skin may become dull due to excessive wetting. Do.

  The wound covering material of the present invention is 5% to 45% of sustained release particles, 15 to 50% of hydrophilic polymer particles, 25 to 60% of an adhesive base, particularly 13 to 31% of sustained release particles, in mass% 26 to 42% of the hydrophobic polymer particles and 37 to 52% of the tacky substrate. If the proportion of the sustained release particles is too high, entanglement of polymer chains of the adhesive substrate will be insufficient, and the mechanical strength will be significantly reduced. Conversely, if the percentage of sustained release particles is too low, the rate of wound healing is reduced. If the proportion of the hydrophilic polymer particles is too high, the wound surface will be excessively moist and the liquid leakage and normal skin are likely to be macerated. On the other hand, if the proportion of the hydrophilic polymer particles is too low, the wound surface becomes dry, making it difficult to form a wet environment. When the proportion of the tacky substrate is too high, the flexibility of the wound dressing is significantly reduced and it becomes difficult to stick to the bending site. Conversely, if the proportion of the tacky substrate is too low, entanglement of the polymer chains of the tacky substrate is insufficient, and the mechanical strength is significantly reduced.

  The wound dressing of the present invention is a simulated bodily fluid in a dissolution test in which five wound dressings cut into 2 cm square are immersed in 100 ml of simulated bodily fluid for 2 days at 37 ° C. and stirred once / day. It is preferable that the B ion concentration therein is 0.1 to 70 mM (especially 1.3 to 25 mM) and the Ca ion concentration is 3.1 to 21 mM (especially 3.8 to 7.2 mM). When the B ion concentration or the Ca ion concentration in the simulated body fluid after the test is too low, it becomes difficult to obtain the bactericidal effect necessary as a wound covering material. Furthermore, the effect of promoting cell proliferation is also difficult to obtain. On the other hand, when the B ion concentration or the Ca ion concentration is too high, the wound healing may be delayed due to an excessive bactericidal effect exerted on the wound surface or cytotoxicity being exerted.

  In the wound dressing of the present invention having the above-mentioned constitution, when water (exudate or blood) comes in contact with the adhesive substrate, part of the water remains on the wound surface and excess water is hydrophilic in the adhesive substrate Is absorbed by the sex polymer. This function makes it easier to create a moist environment on the wound surface. In addition, the moisture held by the adhesive substrate comes in contact with the sustained release particles. As a result, the controlled release particles dissolve in exudate and blood and release Ca ions and B ions. These ions diffuse through the adhesive layer to the wound side due to the concentration gradient formed between the wound surface and the inside of the adhesive substrate.

  In addition to the above-mentioned components, a small amount of pharmacologically active ingredients can be contained in the adhesive substrate to promote wound healing. For example, antibiotics (eg, chlorhexidine gluconate, benzalkonium chloride, benzenium chloride, sulfa drug), disinfectants (eg, popidone, iodine), anti-inflammatory agents (eg, hydricorulizone, triamcinolone acetonide), skin protection agents (eg, zinc oxide), etc. Can be blended.

  In the wound dressing of the present invention, as shown in FIG. 1, it is preferable to provide a waterproof layer 3 on one side of the adhesive substrate 1 as needed. Providing a waterproof layer facilitates the handling of the wound dressing. Moreover, it becomes possible to protect the surface of the adhesive substrate from dirt, moisture and the like. Furthermore, the waterproof layer also has a function as a support of the adhesive substrate. That is, the adhesive base material may lose its shape-retaining property if it absorbs moisture and swells, but if a waterproof layer is provided, it becomes easy to maintain its shape. In the figure, 2 is a controlled release particle and 4 is a hydrophilic polymer particle.

  The waterproof layer preferably prevents the infiltration of water but has the property of transmitting moisture (moisture permeability). Further, in consideration of the fact that the wound covering material is also attached to a bending site such as a fold, it is desirable that the waterproof layer has flexibility capable of following the shape change of the wound covering material. As such materials, polyurethane, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride and the like can be used.

  The wound dressing of the present invention can be produced as follows. However, the present invention is not limited to this.

  First, the polymer constituting the adhesive substrate is kneaded. Furthermore, sustained release particles and a hydrophilic polymer are added to the kneaded product, and the mixture is thoroughly kneaded again. The kneaded product is filled in a mold and formed into a desired shape. For example, it is formed into a sheet by press molding. Thus, the wound dressing of the present invention can be obtained.

Hereinafter, the present invention will be described in detail based on examples.
<Adjustment of controlled release particles>

  Table 1 shows the compounding ratio of the controlled release particles of the present invention and the particle size D50.

The controlled release particles in Table 1 are prepared as follows. First, PGA or PLA-PGA copolymer (polymerization ratio: 53: 47) of the compounding ratio described in Table 1 is prepared. The resultant is charged into a kneader and melted at 180 to 250 ° C. Subsequently, reagent grade products of each calcium compound and boron compound in the compounding ratio described in Table 1 are prepared. Each compound is charged into a kneader and thoroughly kneaded. The mixed melt is allowed to cool in air to prepare a composite. The composite is charged into a rotary ball mill, ground for about 2 hours, and adjusted to the particle size shown in Table 1 using an air classifier. In addition, the sample was extract | collected in the middle of air classification, and the particle size distribution of each powder was measured with the laser diffraction type particle size distribution measuring apparatus (SIMADZU SALD-2200). From the particle size distribution obtained, the particle diameter D50 at which the cumulative abundance ratio becomes 50% is determined, and if the desired value is not obtained, the classification condition is changed and the same operation is performed again.

Thus, the controlled release particles (A, B) described in Table 1 are produced.
<Production of wound dressings>

  Table 2 shows the amounts of controlled release particles, hydrophilic polymer particles and adhesive substrate in the wound dressing of the present invention.

First, with respect to polyisobutylene, the compounding amounts described in Table 1 are placed in a small kneader and thoroughly kneaded. The gelatin, pectin, carboxymethylcellulose Na and sustained release particles A and B in the amounts described in Table 1 are added to the kneaded product, and the mixture is thoroughly kneaded until uniform.

  The kneaded product is filled in a 50 cm × 50 cm mold and formed into a sheet about 1 mm thick by press molding. Thus, sheet-like wound dressings (No. 1 and 2) are produced.

  Next, a commercially available polyurethane film (35 μm in thickness) is prepared. Subsequently, the wound dressings (Nos. 1 and 2) are laminated on the side to which the adhesive is applied, and pressed to obtain a wound dressing having a waterproof layer formed on one side of the adhesive substrate. .

1 adhesive substrate 2 sustained release particle 3 waterproof layer 4 hydrophilic particle

Claims (14)

  A controlled release particle for a wound dressing comprising a composite particle composed of a biodegradable and / or bioabsorbable polymer, a calcium compound and a boron compound.   The biodegradable and / or bioresorbable polymer comprises at least one selected from the group consisting of polylactic acid, polyglycolic acid and copolymers of polylactic acid and polyglycolic acid. The sustained release particles for wound dressings according to 1.   The wound covering according to claim 1 or 2, wherein the calcium compound is at least one selected from the group consisting of calcium carbonate, calcium lactate, calcium hydroxide, calcium oxide, calcium phosphate, calcium chloride and calcium formate. Controlled release particles.   The wound dressing according to any one of claims 1 to 3, wherein the boron-based compound is at least one selected from the group of boric acid, boron oxide, metaboric acid, borate, and metaborate. Controlled release particles.   5. The method according to claim 1, wherein the calcium-based compound is contained by 10 to 60% by mass, 1 to 40% of the boron-based compound, and at least 30% or more of a biodegradable and / or bioabsorbable polymer. Sustained-release particles for wound dressings according to any of the foregoing.   6. The wound according to any one of claims 1 to 5, wherein the particle diameter (D50) when the cumulative percentage of particles by laser diffraction particle size distribution measurement is 50% is 0.1 to 800 μm. Sustained release particles for coating material.   A controlled release particle according to any one of claims 1 to 6, a hydrophilic polymer particle, and an adhesive substrate, wherein the controlled release particle and the hydrophilic polymer particle are contained in the adhesive substrate. Wound dressing characterized in that it is dispersed.   The wound dressing according to claim 7, wherein the hydrophilic polymer particles are hydrophilic colloid particles.   The wound dressing according to claim 8, wherein the hydrophilic colloid particles are at least one selected from the group consisting of gelatin, pectin and sodium carboxymethylcellulose.   The adhesive substrate according to any one of claims 7 to 9, characterized in that the adhesive substrate contains at least one selected from the group consisting of polyisobutylene, styrene isoprene styrene block copolymer, liquid paraffin and rosin ester. Wound dressings.   The wound dressing according to any one of claims 7 to 10, wherein the adhesive substrate has a sheet-like shape.   In a dissolution test in which 5 wound dressings cut into 2 cm square were immersed in 100 ml of simulated body fluid at 37 ° C. for 2 days and stirred once / day, the B ion concentration in the simulated body fluid was 0. The wound dressing according to any one of claims 7 to 11, wherein 1 to 70 mM and the Ca ion concentration is 3.1 to 21 mM.   The wound covering material according to any one of claims 7 to 12, wherein a waterproof layer is formed on one side of the adhesive substrate.   The wound dressing according to claim 13, wherein the waterproof layer contains at least one selected from the group consisting of polyurethane, polyethylene, polypropylene, polyvinyl chloride and polyvinylidene chloride.