JP2024063317A - Cell migration promoter - Google Patents

Abstract

[Problem] To provide a cell migration promoter that has higher activity than honey, which has already been reported to have a wound healing effect. Furthermore, to provide a wound healing agent and wound dressing agent containing said cell migration promoter. [Solution] A cell migration promoter that contains at least one honey selected from the group consisting of bee honey, soybean honey, and black glutinous honey, and a wound healing agent and wound dressing agent that contain said cell migration promoter. [Selected Figure] Figure 1

Description

The present invention relates to a cell migration promoter, and more specifically, to a cell migration promoter containing honey. Furthermore, the present invention relates to a wound healing agent and a wound dressing agent containing the cell migration promoter.

Honey is a sweet substance collected by bees, and its main components are sugars such as glucose, fructose, and sucrose, but it is also rich in nutrients essential to humans, such as vitamins, essential amino acids, and minerals, and is widely loved as a food for restoring physical strength and as a highly nutritious health food. Honey is not only edible, but is also known to have various health and beauty benefits. For example, honey can be used for a variety of purposes, such as as an antibacterial agent, a wound treatment composition, and a cosmetic composition.

As such, honey has long been known to have wound-healing effects. In Europe, it has been approved as a medical device by the UK's National Health Service (NHS), and in the US it has been approved as a medical device by the US Food and Drug Administration (FDA). Also, in New Zealand, a gel-type preparation containing manuka honey (antibacterial wound gel: Medihoney) has been commercialized.

The components of honey are influenced by the type and blending ratio of the source plant from which it is made, so it is known that the type and amount of active ingredients contained in honey, as well as their physiological activity, vary greatly depending on the source plant. The wound healing effects of various honeys like these have been reported in Non-Patent Documents 1 and 2.

Non-patent literature 1 reports that manuka honey, honeydew honey, and acacia honey have healing effects on excision wounds in mice.

In addition, Non-Patent Document 2 reports that an in vitro test was conducted on re-epithelialization of HaCaT keratinocytes using manuka honey, acacia honey, and buckwheat honey to investigate the mechanism.

Manuka (Leptospermum scoparium) is a woody plant of the Myrtaceae family that grows mainly in New Zealand. Among honeys, manuka honey is known to have particularly high antibacterial properties.

Honeydew honey, known as "forest honey" in Europe, is made when insects first ingest the sap from various trees (oak, pine, fir, spruce, etc.), and then the sugar content remains as droplets on the leaves and trunks of the trees, which are then collected by bees and turned into honey. Like manuka honey, it is known to have strong antibacterial properties.

Wounds a Compendium of Clinical Research and Practice, 30(7), 197-204 Wound Repair Regen. 2012 Sep-Oct_20(5)778-85.

The present invention aims to provide a cell migration promoter that has higher activity than honey, which has already been reported to have a wound healing effect. Furthermore, the present invention aims to provide a wound healing agent and a wound dressing agent that contain the cell migration promoter.

The above-mentioned Non-Patent Documents 1 and 2 report that manuka honey, honeydew honey, acacia honey, and buckwheat honey have wound healing properties. As honey is made from plants harvested by bees, the ingredients vary depending on the source plant, and it is expected that the effects will vary depending on the source plant. Therefore, the inventors of the present invention have conducted extensive research to achieve the above-mentioned objective, and as a result, they have found that horsetail honey, soyogo honey, and kuroganemochi honey have higher cell migration properties than manuka honey, honeydew honey, acacia honey, and buckwheat honey.

The present invention was completed based on these findings and through further investigation, and provides the following cell migration promoter, wound healing agent, and wound covering agent.

[1] A cell migration promoter comprising at least one honey selected from the group consisting of bee honey, soybean honey, and black glutinous honey.
[2] A wound-healing agent comprising the cell migration promoter described in [1].
[3] A wound covering agent comprising the cell migration promoter according to [1].
[4] The agent described in [2], which is a food or beverage, cosmetic, pharmaceutical or quasi-drug.
[5] The agent according to [3], which is a cosmetic, a medicine or a quasi-drug.

Bee honey, Soyogo honey, and Kuroganemochi honey have excellent cell migration activity, and are therefore useful as active ingredients in cell migration promoters. Furthermore, because these honeys have excellent cell migration activity, they are also useful as wound dressings and as active ingredients in wound dressings.

In addition, honey has a long history of use as a food ingredient, making it highly safe.

1 is a graph showing the results of a cell migration test for various honeys in a test example.

The following describes in detail the mode for carrying out the present invention, but the present invention is not limited to the following embodiment.

The cell migration promoter of the present invention contains at least one honey selected from the group consisting of haze honey, soyogo honey, and Kuroganemochi honey (hereinafter, sometimes referred to as "the honey of the present invention") as an active ingredient, and may consist of at least one honey selected from the group consisting of haze honey, soyogo honey, and Kuroganemochi honey. In addition, the wound healing agent and wound dressing agent of the present invention are characterized by containing the above cell migration promoter, which contains at least one honey selected from the group consisting of haze honey, soyogo honey, and Kuroganemochi honey as an ingredient for promoting cell migration.

In the present invention, the term "wound healing agent" refers to an "internal agent" or "external agent (dressing agent)" for treating a wound. In addition, in the present invention, the term "wound dressing agent" refers to a gel, foam, or liquid preparation for covering a wound site, or a dressing sheet onto which these are applied.

Honey is produced by bees using nectar collected from plant nectar, tree sap, and secretions from insects that parasitize plants as the main ingredient. There are no particular limitations on the type of bees used to collect honey, or on the place where the honey is produced. In the present invention, refined honey or sweetened honey can also be used as honey. Two or more types of honey can also be mixed and used. Refined honey is honey from which odor, color, etc. have been removed, and sweetened honey is honey to which isomerized liquid sugar and other sugars have been added, and contains 60% or more honey by weight.

Toxicodendron succedaneum honey is honey made from nectar extracted from the flowers of the Toxicodendron succedaneum plant, which belongs to the Anacardiaceae family.

Ilex pedunculosa honey is honey made from nectar extracted from the flowers of the Ilex pedunculosa plant, which belongs to the Ilex genus of the Ilex family.

Kuroganemochi honey is honey derived from nectar extracted from the flowers of Ilex rotunda, a plant of the Ilex genus in the Ilex family.

The cell migration promoter of the present invention preferably contains at least one honey selected from the group consisting of soyogo honey and kuroganemochi honey as an active ingredient.

The cell migration promoter of the present invention may contain other honeys in addition to horsetail honey, soyogo honey, and Kuroganemochi honey. Examples of such honeys include manuka honey, honeydew honey, flower honey, acacia honey, clover honey, orange honey, astragalus honey, rosemary honey, sunflower honey, rapeseed honey, coffee honey, linden honey, coriander honey, horse chestnut honey, buckwheat honey, and karasusansho honey.

While honey is stored in a beehive, it is generally kept at around 35°C by the body temperature of the bees. Honey collected from the beehive is generally heated as needed to reduce the viscosity and make transportation, packing, and other operations easier, and to melt any crystals.

The honey heating temperature may be 59°C or less, 58°C or less, 57°C or less, 56°C or less, 55°C or less, 54°C or less, 53°C or less, 52°C or less, 51°C or less, 50°C or less, 49°C or less, 48°C or less, 47°C or less, 46°C or less, 45°C or less, 44°C or less, 43°C or less, 42°C or less, 41°C or less, 40°C or less, 39°C or less, 38°C or less, 37°C or less, or 36°C or less. The honey heating temperature may be, for example, 35°C or more, 36°C or more, or 37°C or more. A honey heating temperature of 35°C or more is preferable in terms of the ease of handling of the honey, as it reduces the viscosity of the honey and makes it easier to reduce crystallization in the honey.

After harvesting, the honey may be left as it is, or before or after heating, it may be subjected to purification processes such as removal of proteins, wax, debris, beehive residues, filtration, extraction with organic solvents, fractionation, sterilization, concentration, etc.

Honey is composed of approximately 80% carbohydrates, with other healthy components such as vitamins, minerals, flavonoids, organic acids, and fatty acids, and the remainder is water. Most of the carbohydrates in honey are glucose and fructose, with small amounts of oligosaccharides and maltose also included. The mechanism by which honey promotes cell migration is not yet clear, but active ingredients may include sugars, vitamins, minerals, flavonoids, organic acids, fatty acids, amino acids, peptides, proteins, and glycoproteins. It may also be due to the synergistic effect of multiple ingredients.

In this embodiment, the content of the honey of the present invention in the cell migration promoter, wound healing agent and wound covering agent may be an amount that can exert a cell migration effect and a wound healing effect, and may be, for example, 0.1% by mass or more, 1% by mass or more, 3% by mass or more, 5% by mass or more, 7% by mass or more, 10% by mass or more, 15% by mass or more, 20% by mass or more, 25% by mass or more, 30% by mass or more, 35% by mass or more, 40% by mass or more, 45% by mass or more, 50% by mass or more, 55% by mass or more, 60% by mass or more, 65% by mass or more, 70% by mass or more, 75% by mass or more, 80% by mass or more, 85% by mass or more, 90% by mass or more, 95% by mass or more, 97% by mass or more, 98% by mass or more, 99% by mass or more, 99.5% by mass or more, or 100% by mass. The content of sedge honey, soyogo honey, and black glutinous honey in the wound healing agent and wound covering agent may be, for example, 99.5% by mass or less, 99% by mass or less, 98% by mass or less, 97% by mass or less, 95% by mass or less, 90% by mass or less, 85% by mass or less, 80% by mass or less, 75% by mass or less, 70% by mass or less, 65% by mass or less, 60% by mass or less, 55% by mass or less, 50% by mass or less, 45% by mass or less, 40% by mass or less, 35% by mass or less, 30% by mass or less, 25% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 7% by mass or less, 5% by mass or less, 3% by mass or less, 2% by mass or less, or 1% by mass or less.

In this embodiment, the daily intake amount of the honey of the present invention contained in the cell migration promoter and wound healing agent is not particularly limited as long as the cell migration promoting effect and wound healing effect are obtained, and may be, for example, 0.01 to 70 g/day, and more preferably 4 to 70 g/day. The cell migration promoter and wound healing agent of this embodiment may be taken once a day, or may be taken in multiple divided doses, such as twice a day or three times a day. In addition, the timing of intake is not particularly limited, and may be before meals, after meals, between meals, or before going to bed. The intake amount can be appropriately set within the above range depending on factors such as the health condition of the person to be administered, the administration method, and the combination with other agents.

In this embodiment, the daily dosage of the honey of the present invention contained in the cell migration promoter, wound healing agent, and wound dressing when used as an external preparation is not particularly limited as long as the cell migration promoting effect and wound healing effect are obtained, and may be, for example, 0.01 to 1000 mg/ ^cm2 , and more preferably 10 to 100 mg/ ^cm2 . The cell migration promoter, wound healing agent, and wound dressing according to this embodiment may be administered once a day, or may be administered in multiple divided doses, such as twice a day or three times a day. The dosage can be appropriately set within the above range depending on factors such as the health condition of the person to be administered, the administration method, and the combination with other agents.

In one embodiment, the cell migration promoter, wound healing agent, and wound dressing agent may further contain, in addition to honey, other known components, such as components having a cell migration or wound healing effect. Known components having a cell migration or wound healing effect include, for example, lactoferrin, collagen, aluminum chloride, tannin, cyclodextrin, etc.

The cell migration and wound healing effects can be evaluated by measuring the rate of decrease in the cell-free zone after addition of a test substance using human epidermal keratinocyte membranes that have a cell-free zone in the center, i.e., cell migration.

The cell migration promoter and wound healing agent of the present invention can be used as a food composition (food or drink), a pharmaceutical composition (drug), a quasi-drug, a cosmetic, a cosmetic ingredient, etc. The cell migration promoter and wound healing agent of the present invention also include the meaning of additives that impart a cell migration promoting effect and a wound healing effect, respectively. The wound dressing agent of the present invention can be used as an external agent such as a pharmaceutical composition (drug), a quasi-drug, or a cosmetic.

It is preferable that the food composition (food or drink) is one in which the tertiary function of the food (function to regulate physical condition) is emphasized. Examples of foods in which the tertiary function of the food is emphasized include health foods, functional foods, nutritional compositions, dietary supplements, supplements, health foods, foods for specified health uses, foods with nutrient functions, and foods with functional claims.

When the honey of the present invention is added to a food composition, the food composition may contain ingredients acceptable for use as food. Examples of ingredients acceptable for use as food compositions include minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, colorants, flavorings, stabilizers, preservatives, sustained-release regulators, surfactants, solubilizers, humectants, etc.

When the food composition is a nutritional supplement or a supplement, it may be in any form, such as a solid, liquid, or paste, and may be in the form of a tablet (including plain tablets, sugar-coated tablets, effervescent tablets, film-coated tablets, chewable tablets, troches, etc.), capsule, pill, powder (dispersed medicine), fine granules, granules, liquid, suspension, emulsion, syrup, paste, drink, gummies, etc. These can be prepared, for example, by mixing and formulating haze honey, soyogo honey, and kuroganemochi honey with other ingredients as necessary.

The food composition may be obtained by adding the honey of the present invention to food. Examples of the food include the following, and an effective amount of honey can be mixed with intermediate products in the manufacturing process or final products to obtain a food composition for the above purpose: beverages such as soft drinks such as coffee, juice, and tea drinks, milk drinks, lactic acid bacteria drinks, yogurt drinks, carbonated drinks, and alcoholic beverages such as sake, Western liquor, fruit wine, and mead; spreads such as custard cream; pastes such as fruit paste; Western confectionery such as chocolate, donuts, pies, cream puffs, gum, jelly, candy, cookies, cakes, and puddings; Japanese confectionery such as daifuku, mochi, manju, castella, anmitsu, and yokan; frozen desserts such as ice cream, popsicles, and sorbet; cooked foods such as curry, beef bowl, porridge, miso soup, soup, meat sauce, pasta, pickles, and jam; and seasonings such as dressings, furikake, umami seasonings, and soup bases.

The content of the honey of the present invention in the food composition is not particularly limited and may be the same as the content of the honey of the present invention in the cell migration promoter and wound healing agent, for example. The method for producing the above food composition is not particularly limited and may follow any known method as appropriate. For example, the honey of the present invention may be mixed with an intermediate product or a final product in the manufacturing process of the food composition to obtain a food composition to be used for the above purpose.

In addition to the honey of the present invention, the pharmaceutical composition may contain pharma- ceutically acceptable ingredients such as excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizers, suspending agents, etc. It may also be mixed with other medicinal ingredients described in the Japanese Pharmacopoeia, such as vitamins and herbal medicines. The pharmaceutical composition may be in any form, such as a solid, liquid, or paste, and may be in the form of a tablet (including plain tablets, sugar-coated tablets, effervescent tablets, film-coated tablets, chewable tablets, troches, etc.), capsule, pill, powder (powder), fine granules, granules, liquid, suspension, emulsion, syrup, paste, injection (including the case where it is mixed with distilled water or an infusion such as an amino acid infusion or an electrolyte infusion at the time of use to prepare a liquid), topical formulation such as a liniment or patch, etc.

The pharmaceutical composition may be administered locally or systemically. There are no particular limitations on the administration method, and the composition may be administered orally or parenterally. Parenteral administration routes include subcutaneous, intradermal, intramuscular, intraperitoneal, intravenous or intraarterial administration, and transdermal administration.

The content of the honey of the present invention in the pharmaceutical composition is not particularly limited and may be the same as the content of the honey of the present invention in, for example, a cell migration promoter, a wound healing agent, and a wound covering agent.

The cosmetic raw material may be in any form, such as a solid, liquid, or paste. The cosmetic may be a medicated cosmetic (i.e., a quasi-drug). Cosmetics include any cosmetic that can be applied to the skin, mucous membranes, body hair, head hair, scalp, nails, teeth, facial skin, lips, and other parts of animals (especially humans).

The cosmetic product may contain, in addition to the honey of the present invention, ingredients that are acceptable as cosmetics. Examples of ingredients that are acceptable as cosmetics include whitening agents, moisturizing agents, antioxidants, oily ingredients, UV absorbers, surfactants, thickeners, alcohols, powdered ingredients, coloring materials, aqueous ingredients, water, and various skin nutrients.

The formulation of the cosmetic product may be, for example, a solubilized system, an emulsion system, a powder system, an oil liquid system, a gel system, an ointment system, an aerosol system, a water-oil two-layer system, a water-oil-powder three-layer system, etc. The cosmetic product may be, for example, a face wash, a lotion, a milky lotion, a cream, a gel, an essence, a beauty serum, a pack, a mask, a mist, a basic cosmetic product such as a UV protection cosmetic product, a make-up cosmetic product such as a foundation, a lipstick, a blusher, an eye shadow, an eyeliner, a mascara, etc., a face wash, a massage agent, a cleansing agent, an aftershave lotion, a preshave lotion, a shaving cream, a body soap, a soap, a shampoo, a rinse, a hair treatment, a hair styling product, a hair tonic agent, a hair mist, a hair foam, a hair liquid, a hair gel, a hair spray, a hair growth agent, an antiperspirant, a bath agent, a mouth rinse, an oral cosmetic product, a dentifrice, a hand cream, a hand soap, etc.

The amount of the honey of the present invention contained in the cosmetic product is not particularly limited, and may be the same as the amount of the honey of the present invention contained in the cell migration promoter, wound healing agent, and wound dressing agent, for example. The method of producing the above cosmetic product is not particularly limited, and may follow any known method as appropriate. For example, the honey of the present invention may be mixed with an intermediate product or a final product in the cosmetic product manufacturing process to obtain a cosmetic product used for the above purpose.

The cosmetic and pharmaceutical compositions of the present invention also include quasi-drugs.

The cell migration promoter, wound healing agent, and wound covering agent described above are intended to be applied to mammals, including humans (preferably humans).

In this embodiment, the method of administration of the cell migration promoter and the wound healing agent is not particularly limited, and may be either oral or parenteral, such as transdermal, administration. From the viewpoint of cell migration promoting action and wound healing action, however, transdermal administration is preferred. In other words, the cell migration promoter and the wound healing agent are preferably used as external preparations for the skin that can be applied directly to the affected area of a skin wound.

In this embodiment, the wound covering agent is administered transdermally, and the wound covering agent is preferably an external preparation for the skin, such as a liniment or patch, that can be applied directly to the affected area of the skin wound.

As shown in the examples below, the honey of the present invention promotes the migration of skin keratinocytes, and therefore can exert a healing effect on skin wounds. Therefore, since the honey of the present invention has an excellent cell migration effect, it is useful as an active ingredient of a cell migration promoter, and furthermore, it is useful as an active ingredient of a wound treatment agent (wound healing agent) for burns, wounds, bedsores, acne, heat rash, chilblains, etc. The honey of the present invention is also useful as an active ingredient of a wound dressing agent.

In addition, honey has been used as a food ingredient for a long time, so it is highly safe.

In this specification, the word "comprise" includes the meanings "essentially consisting of" and "consisting only of."

The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples.

Test example (cell migration test)
(1) DMEM medium was added to a 96-well plate, and human epidermal keratinocytes (HaCaT) were cultured with an insert placed therein to form a human epidermal keratinocyte membrane having a cell-free zone in the center.
(2) 10 ng/ml EGF (Epidermal Growth Factor) or 0.1% honey solution was added to the plate prepared in (1) and cultured at 37°C for 44 hours. The results were imaged using a confocal high-content imaging system to confirm the reduction rate of the cell-free zone (migration). The reduction rate of the cell-free zone (migration) (%) was calculated using the following formula. The results are shown in Table 1 and Figure 1.
Migration (%) = area of migratory cells in the cell-free zone when honey was added ÷ area of migratory cells in the cell-free zone when EGF was added × 100

From Table 1 and Figure 1, we compared the activity of buckwheat honey, manuka honey, acacia honey, and honeydew honey, which have already been reported to have wound healing effects, and confirmed that the migration activity of bee honey, soyogo honey, and black mochi honey is higher than that of buckwheat honey, manuka honey, acacia honey, and honeydew honey.

Claims (5)

A cell migration promoter comprising at least one honey selected from the group consisting of horsetail honey, Japanese laurel honey, and Japanese laurel honey. A wound healing agent comprising the cell migration promoter according to claim 1. A wound covering agent comprising the cell migration promoter according to claim 1. The agent according to claim 2, which is a food or drink, a cosmetic, a medicine, or a quasi-drug. The agent according to claim 3, which is a cosmetic, a medicine or a quasi-drug.

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