JP5805522B2 - Powder composite and wound dressing - Google Patents

Description

  The present invention relates to a powdery composite comprising chitosan and β-glucan and a wound dressing using the powdery composite.

  Chitosan is a substance obtained by hydrolyzing chitin with an alkali to remove an acetyl group, that is, deacetylated. In general, not only 100% deacetylated one is called chitosan, but one that has the property of being dissolved in an acidic aqueous solution by the effect of the amino group produced by deacetylation is often called chitosan. Generally, chitin deacetylated by 40% or more is often called chitosan.

  Chitosan is widely used in various foods and beverages represented by diet foods that are dietary fibers, fine powders, and that utilize the cholesterol absorption inhibitory effect. Moreover, chitosan has excellent film-forming properties, so it is also used in cosmetics for uses such as prevention of skin dryness. However, chitosan has a problem that it is extremely inconvenient when used in these applications, such as being poor in water-solubility and becoming dull in water when made into a fine powder.

  Furthermore, chitosan has antithrombogenicity and a hemostatic effect, and thus is useful for medical applications such as pharmaceuticals and medical members. Chitosan is also used in apparel, textile materials, fabrics, textile materials and the like because it has an antibacterial and antifungal action and an infection protection effect against pathogenic bacteria.

  One of the important usage forms of chitosan in medical applications is wound dressing. Wound dressing is a medical member used to promote wound healing by covering the wound site and placing the wound part in a moist environment with moisture and exudate from the wound surface, but chitosan is excellent For this purpose, chitosan sheets obtained by forming chitosan into a sheet shape (see Patent Document 1) are widely used. However, the chitosan sheet described in Patent Document 1 has a problem that mechanical strength such as tension is insufficient, and moisture absorption as a wound dressing is not always satisfactory.

  For this reason, a method of impregnating a chitosan sheet with an ointment (see, for example, Patent Document 2), a method of forming a composite sheet made of chitosan and collagen (see, Patent Document 3), and the like have been proposed. However, with these methods, the chitosan sheet can have a certain degree of flexibility and strength, but when used as a wound dressing, it is used on a complex shaped part of the human body, such as a finger or face. In some cases, there was a problem that it was difficult to adhere.

  On the other hand, chitosan has antithrombogenicity and hemostatic effect as described above, so of course, it is used as a wound dressing material in the form of an ointment or oil agent dispersed in a base material such as oil or cream as a wound dressing. (See Patent Documents 4 and 5). And if it is an ointment, it can be used without the restriction | limiting of said application. However, since chitosan has low water absorption, these ointments have low water absorption as a wound dressing material, and are particularly unpreferable as a wound dressing material for healing under the above-mentioned moist environment. .

  On the other hand, since β-glucan is a water-soluble dietary fiber, it is easier to handle than chitosan and is used in many foods and drinks. In addition, β-glucan has a certain amount of moisture retention, so it is also used in cosmetics for the purpose of improving the moisture retention of the skin. However, since β-glucan is basically water-soluble, its water resistance is low. For example, when it is used in skin care cosmetics, there is a problem in that its effect is reduced by dissolving and running away with sweat or moisture over time. . In addition, β-glucan has low crystal stability, so when used in foods and drinks with a high water content, it causes water separation and turbidity over time, and when used in foods and drinks and cosmetics with low water content, There was a problem of lack of storage stability, such as precipitation or graininess.

  Furthermore, β-glucan has been used in pharmaceuticals because it has an immune enhancing effect. Since β-glucan has higher water absorption than chitosan, an ointment containing the powder has been proposed as a wound healing agent. Examples thereof include ointments containing barley β-glucan powder (see Patent Document 6) and ointments containing extracts from cell walls of yeast and mold (see Patent Document 7). However, β-glucan has a lower antibacterial activity than chitosan, and has low water resistance and dissolves in a moist environment, resulting in low wound healing activity itself. It was not preferable as a wound dressing for healing under the environment.

  Moreover, since yeast and mold contain chitin, a wound dressing containing a complex obtained by extracting β-glucan and chitin simultaneously has also been proposed (see Patent Document 8). However, when extracted in this way, as described in the specification of Patent Document 8, the extract contains β-glucan and chitin, but the chitin fiber is wrapped in β-glucan. Since the composite, that is, each fiber is present in a separated state, each effect has been attenuated, and chitosan, which is the main component of antibacterial activity, does not appear on the surface. As a wound dressing, water absorption and wound healing activity were low, and the wound healing effect was insufficient.

  Here, when a sheet-like composite having a form containing homogeneously is not simply mixed with β-glucan and chitin or β-glucan and chitosan, it is water-insoluble while having sufficient strength and water absorption, and It has been reported that the wound healing effect is also dramatically increased. (For example, see Non-Patent Documents 1 and 2 and Patent Document 9) However, since this sheet-like composite is obtained as a thin and hard sheet, when used as a wound dressing, as in the case of a conventional chitosan sheet, the complex of the human body is required. When it is used for various shaped parts such as a finger or a face, there is a problem that it is difficult to make it adhere.

JP 2004-248949 A JP 2003-265591 A JP 56-133344 A JP-A-62-221357 Japanese Patent Laid-Open No. 10-081628 JP 2001-520982 A Japanese National Patent Publication No. 11-501691 Japanese National Patent Publication No. 11-500159 JP 2010-269137 A

Preparation of wound dressing sheet by β-glucan-chitosan complex Kyoko Koto et al. Drug Deliv Syst Volume: 24 Issue: 3 pages: 303 Pharmacy Volume: 69 Issue: Supplement pages: 151 Preparation of wound dressing sheet with β-glucan-chitosan complex Kyoko Koto et al. Pharmaceutical Science Volume: 69 Issue: Supplement Page: 151 Examination of wound treatment effect by β-glucan-chitosan complex sheet Abstracts of Annual Meeting of Japanese Society of Pharmaceutical Sciences Volume: 130th Issue: 4: 224

  Thus, there is a need for a medical material having a high wound healing effect that has both moderate water absorption and high water resistance when used in a wound dressing material and can be applied to a complex shaped part of the human body. It was.

  As a result of various studies to achieve the above-mentioned object, the present inventor has completely dried the chitosan and β-glucan by a freeze-drying method, not a normal drying method, and further crushed to a strong strength. It was found that the obtained powdery composite could achieve the above object.

  The present invention has been made on the basis of the above findings, and provides a granular composite comprising chitosan and β-glucan.

  Moreover, this invention provides the wound dressing which uses the said granular composite as an active ingredient.

Furthermore, the present invention provides the following method for producing a granular composite comprising chitosan and β-glucan.
Chitosan and β are characterized by suspending chitosan in an aqueous β-glucan solution, then gelling β-glucan, and further granulating a composite gel obtained by dissolving chitosan with an aqueous acidic solution. A method for producing a granular composite comprising glucan.
A method for producing a granular composite comprising chitosan and β-glucan, characterized in that a composite gel obtained by gelling an acidic aqueous solution containing β-glucan and chitosan is granulated.
A method for producing a granular composite comprising chitosan and β-glucan, wherein the composite gel formed on the interface is granulated by overlaying an aqueous solution of β-glucan and an acidic aqueous solution of chitosan.
A method for producing a granular composite comprising chitosan and β-glucan, wherein an acidic aqueous solution containing β-glucan and chitosan is heated under pressure.

  The granular composite of the present invention has moderate water absorption, high water resistance, and storage stability. Further, in addition to the above characteristics, since it is granular, it can be applied to any complex part of a living body, and is therefore particularly useful as a wound dressing.

  Hereinafter, the present invention will be described based on preferred embodiments.

  First, the granular composite of the present invention will be described. The granular composite of the present invention consists of chitosan and β-glucan.

  The chitosan used in the present invention is not particularly limited as long as it is dissolved in an acidic aqueous solution by deacetylation of chitin, and is preferably 40% or more, more preferably 70% or more. Acetylated one is preferable, and 80% or more deacetylated chitosan is more preferable. Commercially available chitosan can also be used.

  The molecular weight of the chitosan is not particularly limited as long as it has a molecular weight capable of forming a sheet, and the weight average molecular weight is preferably 10,000 to 4,000,000, more preferably 50,000. 000 to 3,000,000.

  The β-glucan used in the present invention is not particularly limited as long as it is a water-soluble β-glucan, but two or more different bonds among β1,3 bond, β1,4 bond, and β1,6 bond are used. Β-glucan having a β1,3 bond and β1,4 bond, β-1,3-1,4-glucan having a β1,3 bond, and β-1,3-bond having a β1,3 bond and a β1,6 bond are preferable. Examples include 1,6-glucan. Among these, β-1,3-1,6-glucan is preferable because a complex having high antibacterial properties can be obtained.

  Examples of the β-1,3-1,4-glucan include cereal-derived β-glucan. As the cereals, gramineous plants are preferable. Examples of gramineous plants include cereals such as rice, wheat, corn, sorghum, millet, millet, millet, barley, oats (crown) and rye In particular, those derived from barley are preferred because a highly purified β-glucan can be obtained. In addition, a β-glucan obtained by extraction from these gramineous plants is particularly preferable because a complex of uniform quality with moderate water absorption can be easily obtained.

  In addition, examples of the β-1,3-1,6-glucan include basidiomycete-derived or microorganism-derived β-glucan, and the microorganism-derived β-glucan provides a β-glucan having a higher degree of purification and In addition to high production efficiency of β-glucan, it is preferable in that a complex having higher antibacterial properties can be obtained, and in particular, a wound dressing having a high wound healing effect can be obtained.

  As the basidiomycetes, cultivars are most preferable, but basidiomycetes that are not subjected to commercial production may be used. Examples include Agaricus blazei, Agaricus mushrooms, Agaricus mushrooms, Ezoharitake, Enokitake, Kanzotake, Mushroom, Kinugasatake, Agaricus, Salmonella mushroom, Sakerihi Toyotake, Sangohatake, Shitaketake, Shirotaketa, Shirotaketa Winter summer grass, sea cucumbers, aratake, naruto bamboo shoots, dandelion medusae, nikawaurokotake, nikawaharitake, numeri suritake, numeri suritake, mushrooms, oyster mushrooms, scallops, kurotake mushrooms, mushrooms, mushrooms, mushrooms , Mukitake, Murasakishiji, Yamadoritake, Yamabushitake, Willow Matsutake, Hanabiratake, Meshimako Etc. The.

  As the microorganisms, microorganisms that have been conventionally used for food are suitable because of their high safety. That is, examples include yeasts, lactic acid bacteria, natto bacteria, acetic acid bacteria, koji molds, algae such as chlorella and spirulina, microorganisms belonging to the genus Aureobasidium, and the like. Among these microorganisms, by culturing microorganisms, β-glucan is secreted outside the cell body, and it is easy to separate and purify, and it is easy to obtain β-glucan with high solubility and low contaminants. In some respects, microorganisms belonging to the genus Aureobasidium are particularly preferred.

  As the microorganism belonging to the genus Aureobasidium, Aureobasidium pullulans is preferable, and Aureobasidium pullulans ADK-34 (FERM P -18932) or Aureobasidium pulullans ADK-34 (FERM BP-8391) is particularly preferred.

  The molecular weight of β-glucan is not particularly limited, as is the molecular weight of chitosan, but the weight average molecular weight is preferably 1,000 to 3,000,000, more preferably 5,000 to 1,000,000. is there.

In the present invention, the granular composite refers to a composite of the chitosan and the β-glucan, the form of which is granular.
In addition, since it takes various shapes by the state of crystallization like a general dietary fiber, the concrete shape of the said composite body is not limited to powder form-granular form, but shall also include a fibrous form.

The particle size of the composite is not particularly limited, but in the case of powdery to granular, the average particle size may be in the range of 1 μm to 5 mm, but the average particle size is preferably 10 μm to 1 mm.
When the powder of the composite is fibrous, the preferred diameter is the same as the above particle diameter, but the length is preferably 5 mm or less, more preferably 2 mm or less.

In the present invention, the ratio of chitosan and β-glucan is preferably 1 to 3000 parts by mass, more preferably 10 to 2000 parts by mass, and still more preferably 25 to 1000 parts by mass with respect to 100 parts by mass of chitosan.
Even if there is too much chitosan exceeding the above ratio or too much β-glucan, it is difficult to obtain the effect of the present invention.

In the present invention, the “complex” is not simply obtained by mixing chitin or chitosan and β-glucan powder, and a chitin fiber such as a microbial cell containing both chitin and β-glucan is β-glucan. It is necessary that the chitosan and β-glucan be present in a homogeneous manner, not in a form wrapped by the.
A “complex” and a simple mixture can be distinguished by solubility in an acidic aqueous solution and an alkaline aqueous solution.
That is, the “complex” is insoluble in both acidic aqueous solutions and alkaline aqueous solutions, but the mixture is partially or completely dissolved in both solutions.
This is because chitosan is soluble in acidic aqueous solution, insoluble in alkaline aqueous solution, and β-glucan is soluble in acidic aqueous solution and alkaline aqueous solution.
Such a “complex” is obtained by making an aqueous solution in which both chitosan and β-glucan are dissolved, or by contacting or mixing an aqueous solution in which each is dissolved.
Specifically, the granular composite of the present invention can be obtained by, for example, the following production methods (1) to (4).
(1) Chitosan is suspended in β-glucan aqueous solution, then β-glucan is gelled, and then the complex gel obtained by dissolving chitosan with acidic aqueous solution and infiltrating into β-glucan gel is granulated. A process for producing a granular composite comprising chitosan and β-glucan, characterized in that
(2) A method for producing a granular composite comprising chitosan and β-glucan, characterized in that a composite gel obtained by gelling an acidic aqueous solution containing β-glucan and chitosan is granulated.
(3) A method for producing a granular composite comprising chitosan and β-glucan, wherein the composite gel formed on the interface is granulated by overlaying an aqueous solution of β-glucan and an acidic aqueous solution of chitosan .
(4) A method for producing a granular composite comprising chitosan and β-glucan, wherein an acidic aqueous solution containing β-glucan and chitosan is heated under pressure.

First, a preferred embodiment of the production method (1) will be described in detail.
First, a β-glucan aqueous solution is prepared. The β-glucan aqueous solution may be obtained by dissolving the isolated water-soluble β-glucan in water, or may be produced as a β-glucan aqueous solution in the β-glucan production process.
The concentration of the β-glucan aqueous solution used is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass.

Next, chitosan is suspended in this β-glucan aqueous solution to prepare a chitosan suspension containing β-glucan. The chitosan used may be powdered chitosan or a chitosan suspension suspended in water. In this case, the ratio of chitosan and β-glucan aqueous solution is such that the ratio of chitosan and β-glucan is preferably in the range of 1 to 3000 parts by mass, more preferably 10 to 2000 parts by mass with respect to 100 parts by mass of chitosan. 25-1000 mass parts is still more preferable.
The chitosan suspension containing β-glucan as described above is prepared by previously mixing powdered β-glucan and powdered chitosan, and then suspending this mixed powder in water (the β-glucan component is dissolved in water and the chitosan component is It is also preferable to obtain it by suspending.

  Next, this chitosan suspension containing β-glucan is put into a container such as a petri dish. Depending on the concentration of the suspension, for example, when the ratio of chitosan and β-glucan is in the above range, the suspension is 0.1 g to 30 g, preferably 0.5 g to a petri dish having an inner diameter of 28 mm. 10 g, more preferably 1 g to 5 g may be added.

  Next, the suspension placed in this container is gelled. This gelation method is not particularly limited, and may be a method by evaporation of water or a method of adding a liquid that can be gelled, but it takes a short time to manufacture and is highly productive. A method of adding a liquid that can be gelled is preferable, and a method of injecting a liquid that can be gelled on the surface is more preferable because a homogeneous composite can be stably produced. As such a liquid, it is preferable to use ethanol because it is easy to remove after gelation, is easy to handle and has high safety. The amount of ethanol to be injected may be appropriately selected depending on the amount of β-glucan, but when the ratio of chitosan and β-glucan is in the above range, it is preferably 0.1 to 20 mL, more preferably 0. 5 to 10 mL, more preferably 1 to 5 mL may be injected. Ethanol may be held while β-glucan is gelled, and preferably 30 minutes to 6 hours, more preferably about 1 hour to 3 hours. In this way, β-glucan gels and chitosan particles are retained in the gel network of β-glucan.

Next, preferably, after removing the excess ethanol used previously, an acidic aqueous solution capable of dissolving chitosan particles is injected into the gelled suspension. The pH of the acidic aqueous solution is not particularly limited as long as it is 2 or more and less than 7, but is preferably 3 to 5 and more preferably 3 because it is preferably an acidic region that does not affect the gel of β-glucan. 5-5. Also, the type of acid used is not particularly limited. However, for example, formic acid, malic acid, acetic acid, adipic acid, hydrochloric acid, or other acids or acid buffer solutions can be used to produce a complex with high solubility of chitosan. For example, a 0.1 M aqueous acetic acid solution having a pH of 4.5 can be preferably used.
The acidic aqueous solution is preferably 0.1 to 20 mL, more preferably 0.5 to 10 mL, still more preferably 1 to 5 mL, with respect to a solution obtained by gelling 2 g of suspension with 2 mL of ethanol. That's fine. What is necessary is just to hold | maintain acidic aqueous solution, while chitosan is melt | dissolved, Preferably it should just hold | maintain 6 hours-2 day and night, More preferably, 12 hours-24 hours. In this way, an acidic aqueous solution of chitosan infiltrate into the gel network of β-glucan, and a water-containing sheet (complex gel) in which β-glucan and chitosan are combined is formed.

The composite gel obtained by the above method is granulated after removing excess liquid and acid used for gelation such as acidic aqueous solution and ethanol as necessary.
In addition, you may dry as needed before and after granulation.
As the drying method, freeze drying, hot air drying, cold air drying, air drying, spray drying, vacuum drying, etc. can be used without particular limitation, but since the composite gel is a strong gel, before the granulation When a hot air drying method, a cold air drying method, or an air drying method is used as the drying method, the dried body also becomes a plate having a high hardness, which makes it difficult to granulate. Therefore, when drying before granulation, it is preferable to use freeze-drying as a drying method. Since the dried product by freeze-drying is a spongy sponge having a high disintegration property, a finer one can be easily obtained during subsequent granulation.
The granulation method is not particularly limited, and a general crushing method such as a mixer, a mortar, or a roller can be used.

Next, a preferred embodiment of the production method (2) will be described in detail.
The difference between the production method of (2) and the production method of (1) described above is that the production method of (1) once produces a β-glucan gel in which chitosan particles are held in a gel network of β-glucan. In contrast, in the production method of (2), only the chitosan is dissolved to produce the composite gel directly from the state in which both are dissolved. Compared with the manufacturing method of 1), it is preferable at the point which can manufacture a granular gel more easily in a short time.

In the production method (2), first, an acidic aqueous solution containing β-glucan and chitosan is prepared.
Since this acidic aqueous solution only needs to obtain an acidic aqueous solution in which β-glucan and chitosan are finally dissolved, the addition method and the order of dissolution are not particularly limited. For example, β-glucan and chitosan powder are mixed with acidic aqueous solution. Directly dissolved in a solution, acidified by adding an acid to a suspension of chitosan suspended in an aqueous solution of β-glucan, a method of adding and dissolving β-glucan in an acidic aqueous solution of chitosan, an aqueous solution of β-glucan and chitosan The method etc. which mix acidic aqueous solution can be mentioned.

The preferable β-glucan concentration of the acidic aqueous solution is 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, and the preferable chitosan concentration is 0.01 to 10% by mass, more preferably 0.1. ˜5 mass%.
The pH of the acidic aqueous solution is not particularly limited as long as it is 2 or more and less than 7, but is preferably 3 to 5, more preferably 3.5 to 5 for the same reason as in the production method (1) above. is there. Further, the type of acid to be used is not particularly limited, but for the same reason as the production method of (1) above, an acid or an acid buffer such as formic acid, malic acid, acetic acid, adipic acid, hydrochloric acid is preferable. A 0.1 M aqueous acetic acid solution having a pH of 4.5 can be preferably used.

  Next, the acidic aqueous solution in which β-glucan and chitosan are dissolved is put in a container such as a petri dish. Depending on the concentration of the acidic aqueous solution, for example, when the concentration of β-glucan and chitosan is in the above range, the acidic aqueous solution is 0.1 g to 30 g, preferably 0.5 g to 10 g, if the petri dish has an inner diameter of 28 mm. Preferably, 1 g to 5 g may be added.

Next, the acidic aqueous solution put in this container is gelled. This gelation method is not particularly limited, and may be a method by evaporation of water or a method of adding a liquid that can be gelled. For the same reason as in the production method of (1) above, β-glucan A method of adding a liquid capable of gelling is preferable, and a method of injecting a liquid capable of gelling β-glucan on the surface is preferable. As such a liquid, it is preferable to use ethanol for the same reason as the manufacturing method of said (1). The amount of ethanol to be injected may be appropriately selected depending on the amount of β-glucan, but when the concentration of β-glucan and chitosan is in the above range, the amount is preferably 0.1 to 20 mL, more preferably 0. 5 to 10 mL, more preferably 1 to 5 mL may be injected. Ethanol may be held while β-glucan is gelled, and preferably 30 minutes to 6 hours, more preferably about 1 hour to 3 hours. In this way, β-glucan is first gelled and chitosan is retained in the gel network of β-glucan, and a water-containing sheet (complex gel) in which β-glucan and chitosan are complexed is formed.
The composite gel obtained by the above method is granulated after removing excess liquid and acid used for gelation such as acidic aqueous solution and ethanol as necessary.
In addition, you may dry as needed before and after granulation.
As the granulation method and the drying method, the same method as the production method (1) can be used.

Next, a preferred embodiment of the production method (3) will be described in detail.
First, a β-glucan aqueous solution is prepared. As the β-glucan aqueous solution, the same production method as in the above (1) can be used.
Next, an acidic aqueous solution of chitosan is prepared. Although the density | concentration of chitosan becomes like this. Preferably it is 0.01-10 mass%, More preferably, it is 0.1-5 mass%, pH will not be specifically limited if it is 2-7, However, The manufacturing method of said (1) For the same reason, it is preferably 3-5, more preferably 3.5-5. Further, the type of acid to be used is not particularly limited, but for the same reason as the production method of (1) above, an acid or an acid buffer such as formic acid, malic acid, acetic acid, adipic acid, hydrochloric acid is preferable. A 0.1 M aqueous acetic acid solution having a pH of 4.5 can be preferably used.

Next, the β glucan aqueous solution and an acidic aqueous solution of chitosan are layered. Any aqueous solution may be used as the lower layer, but a β-glucan aqueous solution is preferably used as the lower layer. When the β-glucan aqueous solution is used as the upper layer, the two aqueous solutions are likely to be mixed with time, and the formation of the interface tends to be difficult.
By layering, a water-containing sheet (sheet-like complex gel) in which β-glucan and chitosan are complexed at the interface is formed.
The layering time is preferably 20 minutes to 12 hours, more preferably 2 hours to 8 hours. When the β-glucan aqueous solution is used as the lower layer, the sheet settles after 1 to 3 hours from the formation of a sheet having good physical properties, and can be used as a sufficiently complex judgment criterion.
The composite gel obtained by the above method is granulated after removing excess liquid and acid used for gelation such as acidic aqueous solution and ethanol as necessary.
In addition, you may dry as needed before and after atomization.
As the granulation method and the drying method, the same method as the production method (1) can be used.

Next, a preferred embodiment of the production method (4) will be described in detail.
About the acidic aqueous solution containing β-glucan and chitosan, the same production method as in the above (2) can be used.

Then, pressure heating is performed. As an example of an apparatus for this purpose, a general apparatus such as an autoclave or a retort can be used.
A preferable heating temperature is 100 to 130 ° C, more preferably 105 to 125 ° C.
Moreover, a preferable pressure is 0.05-5 MPa, More preferably, it is 0.1-0.5 MPa.
The heating and pressing time is preferably 1 minute to 2 hours, more preferably 5 to 30 minutes.
By such heating and pressurization, chitosan and β-glucan in the mixed solution are formed into a complex gel and directly formed as a precipitate of fine particle to fine fiber powder composite.
The formed precipitate is filtered, washed, and dried if necessary.

  In the present invention, among the above methods (1) to (4), a complex with a certain quality can be obtained even if there is some variation in the concentration of β-glucan or chitosan. It is preferable to use the production method of 4). Above all, it is possible to obtain a powdery composite directly by filtration, and is easy to produce, and to a certain extent if the pressure and heating conditions are constant. It is more preferable to use the production method of the above (4) in that a complex with a uniform quality can be obtained even if the concentration of β-glucan or chitosan varies.

Further, the powdery composite may be swollen. The water content during swelling is preferably 90% by mass or less, more preferably 80% or less, and still more preferably 50% by mass or less of the fine powder.
As the production method, when the production method (4) is performed, the generated precipitate itself is in a slightly swollen state. Therefore, the precipitate is separated by filtration and dried to the moisture content. It can also be in a state.

  Thus, the obtained granular composite body can be used for various food-drinks, a pharmaceutical, and cosmetics. Among them, the powdery composite of the present invention is preferably used for a wound dressing material because it has moderate water absorption, high water resistance, storage stability, and wound healing activity.

  Next, the wound dressing of the present invention will be described. In addition, about the point which is not demonstrated especially, the description in the granular composite material of this invention is applied suitably.

  The wound dressing of the present invention comprises the powdery composite of the present invention as an active ingredient. In the wound dressing of the present invention, the powder composite of the present invention may be used alone as it is, or mixed with various additives and base materials, and powders, granules, tablets, You may formulate and use it in shapes, such as ointment, a liquid agent, hydrogel, and jelly.

  Additives for formulating powders, granules, tablets, etc. include thickening polysaccharides such as alginic acids, pectin, seaweed polysaccharides, carboxymethylcellulose, and lactose, starch, silicon dioxide, etc. Agents, glucose, fructose, sucrose, maltose, sorbitol, stevia and other sweeteners, fine silicon dioxide, magnesium carbonate, disodium phosphate, magnesium oxide, calcium carbonate, calcium phosphate and other anti-caking agents, vitamins, flavors, An antioxidant, a brightener, etc. are mentioned, These 1 type (s) or 2 or more types are selected suitably, and are used. Although content of the said additive in the wound dressing of this invention changes with kinds of additive, Preferably it is 99 mass% or less, More preferably, it is 90 mass% or less.

  Known bases such as fat, wax, petrolatum, lanolin, macrogol (polyethylene glycol) can be used as a base for formulating into an ointment form. The content of the substrate in the wound dressing of the present invention varies depending on the type of the substrate, but is preferably 99% by mass or less, more preferably 90% by mass or less.

  In addition, as a base material for formulation into a hydrogel or jelly shape, a known base material such as polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, pectin, carboxymethylcellulose, agar, dextran, sodium alginate, etc. is used. be able to. Although content of the said base material in the wound dressing of this invention changes with kinds of base material, Preferably it is 1-30 mass%, More preferably, it is 3-20 mass%.

  In the case of formulating into a liquid form, it is obtained by dissolving and dispersing in a liquid. Examples of such a liquid include water, ethanol, propylene glycol and the like. The content of the liquid in the wound dressing of the present invention is preferably 99% by mass or less, more preferably 90% by mass or less.

  The above-mentioned various preparations include emulsifiers, antioxidants, fragrances, coloring agents, pH adjusters, fillers, extenders, masking agents, solubilizers, suspensions, etc. that are usually used to prepare drugs according to the dosage form. Turbidizing agents, buffering agents, stabilizers, preservatives and the like may be added.

  In addition, when used as a wound healing material, the powdery composite may be filled between two sheets, and a wound dressing material in the form of an ointment is impregnated into a sheet-like dressing material. It can also be used.

  EXAMPLES The present invention will be further described below with reference to examples and the like, but the present invention is not limited to these.

[Example 1] <Production of granular composite (1)>
A powder of β-1,3-1,6-glucan (β-glucan derived from Aureobasidium pulullans ADK-34 (FERM BP-8391): manufactured by ADEKA Corporation: weight average molecular weight 300,000) Dissolved in water to obtain a 1% by mass β-glucan aqueous solution. On the other hand, chitosan powder (manufactured by Yaizu Suisan Kagaku Kogyo Co., Ltd., trade name: LL-40: deacetylation rate of 80% or more) is dissolved in 0.1 M acetic acid aqueous solution at pH 4.5 so as to be 1% by mass, An acidic aqueous solution of chitosan having a pH of 4.8 was obtained. 10 ml of the above β-glucan aqueous solution is put in a petri dish (inner diameter 50 mm), and then 10 ml of an acidic aqueous solution of chitosan is poured on top of it and left for 6 hours to form a sheet-like β-glucan / chitosan complex gel at the interface. It was. The obtained composite gel was immersed in water for 6 hours to remove the acid, freeze-dried, crushed with a vertical mixer, and powdered composite (0.1 g) consisting of chitosan and β-glucan (average particle size) 100 μm in diameter) was obtained. The obtained powdery composite was insoluble in acidic aqueous solution and alkaline aqueous solution and had sufficient water resistance and water absorption.
The ratio of chitosan and β-glucan in the obtained granular composite of the present invention was determined from the β-glucan content and chitosan content of the β-glucan aqueous solution and the acidic aqueous solution of chitosan before and after the formation of the complex gel. It was 500 parts by mass of β-glucan with respect to 100 parts by mass.

[Example 2] <Production of granular composite (2)>
A powder of β-1,3-1,6-glucan (β-glucan derived from Aureobasidium pulullans ADK-34 (FERM BP-8391): manufactured by ADEKA Corporation: weight average molecular weight 300,000) This was dissolved in water to obtain a 0.5% by mass β-glucan aqueous solution. Meanwhile, chitosan powder (manufactured by Yaizu Suisan Kagaku Kogyo Co., Ltd., trade name: LL-40: deacetylation rate of 80% or more) is dissolved in a 0.1 M aqueous acetic acid solution having a pH of 4.5 so as to be 0.5% by mass. And an acidic solution of chitosan having a pH of 4.8 was obtained.
100 g of an aqueous β-glucan solution was added to 100 g of the acidic aqueous solution of chitosan to obtain an acidic aqueous solution (pH = 4.8) containing β-glucan and chitosan. This acidic aqueous solution was used in an autoclave and heated at 121 ° C. and 0.2 MPa for 15 minutes. Thereafter, the solution was filtered, washed, and air-dried to obtain a fibrous composite (0.39 g) (average diameter 100 μm, length 2 mm or less) composed of chitosan and β-glucan. The obtained fibrous composite was insoluble in acidic aqueous solution and alkaline aqueous solution and had sufficient water resistance and water absorption.
In addition, the ratio of chitosan and β-glucan in the obtained granular composite of the present invention was 400 parts by mass of β-glucan with respect to 100 parts by mass of chitosan.

[Example 3] <Production of granular composite (3)>
β-1,3-1,6-glucan (β-glucan derived from Aureobasidium pulullans ADK-34 (FERM BP-8391): manufactured by ADEKA Corporation: weight average molecular weight 300,000) 0 .50 g and chitosan powder (manufactured by Yaizu Suisan Kagaku Kogyo Co., Ltd., trade name: LL-40: deacetylation rate of 80% or more) mixed with 0.15 g suspended in 100 g of water (β-glucan component is water The chitosan component was suspended in the aqueous solution, and a 50% by mass acetic acid aqueous solution was added thereto so as to have a pH of 4.8 to obtain an acidic aqueous solution containing β-glucan and chitosan (pH = 4.8). . This acidic aqueous solution was heated at 121 ° C. and 0.2 MPa for 15 minutes using an autoclave. Thereafter, the solution was filtered, washed, and air-dried to obtain a fibrous composite (0.45 g) (average diameter 100 μm, length 2 mm or less) composed of chitosan and β-glucan.
The obtained fibrous composite was insoluble in acidic aqueous solution and alkaline aqueous solution and had sufficient water resistance and water absorption.
In addition, the ratio of chitosan and β-glucan in the obtained granular composite of the present invention was 400 parts by mass of β-glucan with respect to 100 parts by mass of chitosan.

[Comparative Example 1]
The β-glucan powder used in Example 1 was used as the powder of Comparative Example 1 as it was. This powder was soluble in both acidic and alkaline aqueous solutions. The water absorption was good, but the water resistance was extremely poor.

[Comparative Example 2]
The chitosan powder used in Example 1 was used as the powder of Comparative Example 2 as it was. This powder was soluble in acidic aqueous solution but insoluble in alkaline aqueous solution. The water absorption was good, but the water resistance was extremely poor.

[Comparative Example 3]
The β-glucan powder and chitosan powder used in Example 1 were mixed at a mass ratio of 1: 1 to obtain a powder mixture of Comparative Example 3. This powder mixture was completely dissolved in the acidic aqueous solution and partially dissolved in the alkaline aqueous solution, but a granular precipitate was formed. The water absorption was good, but the water resistance was extremely poor.

<Mouse test of wound dressing>
Using 6 ddy mice (male, 6 weeks old, body weight 25-30 g) as test animals per group, shaved and disinfected under ether anesthesia (soaked in absorbent cotton and aspirated in a desiccator), back A full-thickness skin defect wound having a diameter of 1 cm was created on the skin on the midline with scissors for surgery. Immediately after the creation of the defect, 0.5 g of the powder composite obtained in Examples 1 to 3 is directly applied to the wound surface as a wound dressing, and the outside is covered with a film (Tegaderm: manufactured by Sumitomo 3M). Covered.
On the 7th and 14th days after the creation of the defect, the wound dressing material absorbed and swollen by the film and the exudate was once peeled and removed, and the wound area was measured. As comparative examples, 0.5 g of the powder of Comparative Example 1, 0.5 g of the Powder of Comparative Example 2, 0.5 g of the powder mixture of Comparative Example 3, and no wound dressing (Comparative Example 4) It carried out similarly.

<Evaluation of wound dressing>
Table 1 summarizes the ratio (%) of the wound area measured on each measurement day when the wound area immediately after creation of the defect wound (day 0) is 100 (%).

  From the results of Table 1, when the wound dressing of the present invention of Examples 1 to 3 was used, in the case of control (Comparative Example 4), β-glucan only (Comparative Example 1), chitosan only (Comparative Example 2) Or it turns out that the period required for healing is remarkably shortened compared with the mixture (comparative example 3) of the powder of (beta) glucan and chitosan. In addition, scars after healing were inconspicuous.

Claims (7)

Chitosan and beta -1,3-1,6- glucan Tona is, particulate complex of chitosan and beta-1,3-1,6-glucan is present homogeneously. The granular composite according to claim 1, wherein the β- 1,3-1,6- glucan is derived from a microorganism.   A wound dressing comprising the powdery composite according to claim 1 or 2 as an active ingredient. The chitosan is suspended in a β- 1,3-1,6- glucan aqueous solution, then β- 1,3-1,6- glucan is gelled, and further chitosan is dissolved in an acidic aqueous solution to obtain β −1. , 3-1, 6- glucan infiltrated into a complex gel obtained by infiltrating, and a powdered composite comprising chitosan and β-1, 3-1, 6- glucan Body manufacturing method. A composite gel obtained by gelling an acidic aqueous solution containing β- 1,3-1,6- glucan and chitosan is granulated, and chitosan and β- 1,3-1, A method for producing a granular composite comprising 6- glucan. beta -1,3-1,6- glucan solution and acidic aqueous solution of chitosan by overlaying, characterized in that granular the complex gel formed at the interface, chitosan and beta-1,3 A method for producing a granular composite comprising -1,6- glucan. Production of a granular composite comprising chitosan and β- 1,3-1,6- glucan, characterized in that an acidic aqueous solution containing β- 1,3-1,6- glucan and chitosan is heated under pressure Method.