WO2011105403A1 - Composition having bedsore-relieving effect - Google Patents

Composition having bedsore-relieving effect Download PDF

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Publication number
WO2011105403A1
WO2011105403A1 PCT/JP2011/053920 JP2011053920W WO2011105403A1 WO 2011105403 A1 WO2011105403 A1 WO 2011105403A1 JP 2011053920 W JP2011053920 W JP 2011053920W WO 2011105403 A1 WO2011105403 A1 WO 2011105403A1
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composition
pressure ulcer
lactic acid
composition according
present
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PCT/JP2011/053920
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French (fr)
Japanese (ja)
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卓巳 渡邉
隆充 塚原
薫 山田
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コンビ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to a composition having a pressure ulcer improving action. More specifically, the present invention relates to a composition having a pressure ulcer improving action containing lactic acid bacteria as an active ingredient, and its use as a medicine, reagent, and food and drink.
  • a pressure ulcer is a state in which blood flow to the skin, subcutaneous adipose tissue, and muscle is interrupted by continuous compression, and these tissues are killed.
  • local therapies including nursing, prevention, nutrition management, and skin care for the purpose of dispersion of body pressure are performed in order to secure local blood flow.
  • local treatment of pressure ulcers it is necessary to correctly determine the state of pressure ulcers, select treatments suitable for the state, external medicine, and wound dressing, and apply them to the patient.
  • the conventional local treatment of pressure ulcers since highly specialized knowledge is required, the development of a simpler new treatment method is required.
  • enterobacteria such as lactic acid bacteria
  • attempts have been made to verify the effect of preventing diseases and improving the symptoms of diseases, and can be easily consumed and used as highly safe medicines and foods and drinks. Yes.
  • EC-12 Enterococcus faecalis EC-12 strain
  • EC-12 is a lactic acid bacterium isolated from the human intestinal tract
  • the applicant of the present application has an effect of suppressing the contraction of villi.
  • Patent Document 1 Non-Patent Document 1
  • Patent Document 2 Non-Patent Documents 2 to 4
  • Listeria Protective effect against bacterial infection Non-patent document 5
  • Non-patent document 3 Listeria Protective effect against drug-resistant bacteria
  • Patent document 6 activation effect of innate and acquired immunity
  • Patent Document 4 Type I allergic reaction (asthma, hay fever, atopic dermatitis) alleviating effect
  • Patent Document 5 Non-Patent Document 7
  • Patent Document 6 rheumatoid arthritis improving effect
  • Patent Document 9 have reported such as anti-tumor effects (Non-Patent Document 8), and burns healing promoting effect
  • Non-Patent Document 9 Non-Patent Document 9
  • JP 2008-255080 A JP 2004-51530 A JP 2006-89421 JP 2006-28050 A JP 2007-91694 A JP 2007-254333 A JP 2007-290992 A
  • the present invention has been made in view of such circumstances, and an object of the present invention is a composition having a pressure ulcer improving action, which can be easily administered or ingested, and has a high safety. To provide things.
  • the present inventors examined the effect of lactic acid bacteria in a pressure ulcer model mouse. Specifically, this model mouse was ingested with Enterococcus faecalis (EC-12 strain) as an example of lactic acid bacteria, and its pressure ulcer improving action was evaluated. As a result, in this model mouse, the pressure ulcer area decreased from the early stage after pressure ulcer formation, and high expression of various inflammatory cytokines and growth factors was observed in the early stage after pressure ulcer formation. Turned out to be promoted. Furthermore, it was found that the expression of inflammatory cytokines and growth factors decreased later in the post- pressure ulcer formation, and they were heading toward a normal state faster than the control.
  • Enterococcus faecalis (EC-12 strain) showed its improving action from an early stage after pressure ulcer formation. Furthermore, comparing this with the negative control group and the group that received Enterococcus faecalis (EC-12 strain) on the same day, this effect was especially effective when Enterococcus faecalis (EC-12 strain) was administered prophylactically before the formation of pressure ulcers. It was also found that this was remarkable.
  • Enterococcus faecalis (EC-12 strain) is extremely useful as a medicine or food and drink for the prevention of pressure ulcer and healing at an early stage, thereby completing the present invention. It came to.
  • the present invention provides the following inventions.
  • a composition used for improving pressure ulcer comprising lactic acid bacteria as an active ingredient.
  • the pressure ulcer in the living body can be improved by administering the composition of the present invention as a pharmaceutical or ingesting as a food or drink.
  • the composition of the present invention can obtain a prominent effect by prophylactic administration before pressure ulcer formation.
  • the composition of the present invention is useful in the prevention of pressure ulcer and healing at an early stage of pressure ulcer.
  • the active ingredient of the composition of this invention is a lactic acid bacterium, and its safety is high. For this reason, when used as a medicine, it can be administered orally, and unlike conventional local treatments for pressure ulcers, it is simple and has less burden on pressure ulcer patients.
  • the composition of the present invention can be easily taken by a healthy person on a daily basis as a food or drink such as a health food to prevent pressure ulcers.
  • the present invention provides a composition for improving pressure ulcer comprising lactic acid bacteria as an active ingredient.
  • “decubitus” means a state in which blood flow to the skin, subcutaneous adipose tissue, and muscle is interrupted due to continuous compression, and these tissues are killed.
  • “decubitus ameliorating action” includes that pressure ulcers are less likely to occur by administration or ingestion of lactic acid bacteria, that the resulting pressure ulcers become mild, that pressure ulcer deterioration is suppressed, and that pressure ulcer healing is accelerated. I mean. Moreover, in the process until the formed pressure ulcer is healed, it is meant not only to improve the whole but also to improve a specific stage. The action of improving pressure ulcer can be evaluated, for example, by measuring the pressure ulcer area or measuring the expression of inflammatory cytokines and growth factors, as shown in this Example.
  • Examples of lactic acid bacteria belonging to the genus Enterococcus include Enterococcus faecalis and Enterococcus faecium.
  • Examples of bacteria belonging to the genus Bifidobacterium include, for example, Bifidobacterium longum, Bifidobacterium previ Bifidobacterium bifidum, and bacteria belonging to the genus Lactobacillus include Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivaius, and bacteria belonging to the genus Streptococcus include, for example, Streptococcus thermophilus Examples of bacteria belonging to the genus Lactococcus include Lactococcus cremolith and Lactococcus lactis.
  • the lactic acid bacteria used in the composition of the present invention are preferably those belonging to the genus Enterococcus, and particularly preferably Enterococcus faecalis.
  • Enterococcus faecalis EC-12 strain (EC-12) used in this example was incorporated on February 25, 2005 (original deposit date), National Institute of Advanced Industrial Science and Technology, Patent Biological Depositary Center ( ⁇ 305 -5466 Deposited at Tsukuba City, Ibaraki Prefecture, Japan, 1st Street, 1st Street, 1st Central, 1st 6th (Accession number is FERM BP-10284).
  • strains such as ATCC19433, ATCC14508, ATCC23655, IFO16803, and IFO16804 can be used in addition to the EC-12 strain.
  • lactic acid bacteria can be used as viable bacteria or dead cells.
  • Dead cells are preferred as an active ingredient of the composition of the present invention in that they are excellent in heat resistance, stable in quality, and tasteless and odorless.
  • heat-sterilized cells can be used as dead cells in the composition of the present invention. Heat-sterilized cells are collected from a culture obtained by culturing lactic acid bacteria according to a conventional method, for example, by filtration, centrifugation, or the like, and after washing with water, suspended in water or the like and 120 ° C.
  • composition of the present invention may be in the form of a pharmaceutical composition having a pressure ulcer improving action, a food or drink (including animal feed), or a reagent used for model animal experiments.
  • the composition of the present invention can be suitably used as a pharmaceutical composition that is administered prophylactically or as a food or drink that is taken prophylactically (daily), thereby preventing pressure ulcers or at an early stage. Can be cured.
  • the composition of the present invention contains inflammatory cytokines and growth factors (eg, IL-1 ⁇ gene, TNF- ⁇ gene, TGF- ⁇ gene, FGF-7 gene, FGF-10 gene) in the early stage after pressure ulcer formation.
  • inflammatory cytokines and growth factors eg, IL-1 ⁇ gene, TNF- ⁇ gene, TGF- ⁇ gene, FGF-7 gene, FGF-10 gene
  • composition for promoting expression suppression and inflammatory cytokines and growth factors (for example, IL-1 ⁇ gene, IL-8 gene, TNF- ⁇ gene, TGF- ⁇ gene, FGF- It can also be used as a composition for promoting suppression of expression of 10 genes).
  • inflammatory cytokines and growth factors for example, IL-1 ⁇ gene, IL-8 gene, TNF- ⁇ gene, TGF- ⁇ gene, FGF- It can also be used as a composition for promoting suppression of expression of 10 genes).
  • the composition in the present invention can be formulated by a known pharmaceutical method.
  • a known pharmaceutical method for example, capsule, tablet, pill, liquid, powder, granule, fine granule, film coating, pellet, troche, sublingual, chewing agent, buccal, paste, syrup, suspension, To be used orally or parenterally as elixirs, emulsions, coatings, ointments, plasters, cataplasms, transdermal preparations, lotions, inhalants, aerosols, injections, suppositories, etc. Can do.
  • the present invention is a composition comprising a lactic acid bacterium which is an enteric bacterium as an active ingredient, and can be easily administered or ingested orally. That is, the preferred method of administration or ingestion of the composition of the present invention is oral administration or ingestion.
  • carriers that are acceptable pharmacologically or as foods and beverages, specifically, sterile water and physiological saline, vegetable oils, solvents, bases, emulsifiers, suspensions, surfactants, stabilizers, Flavoring agent, fragrance, excipient, vehicle, preservative, binder, diluent, tonicity agent, soothing agent, extender, disintegrant, buffering agent, coating agent, lubricant, colorant, sweetness Can be suitably combined with an agent, a thickening agent, a flavoring agent, a solubilizing agent or other additives.
  • composition of the present invention when used as a pharmaceutical composition, it may be used in combination with a known pharmaceutical composition used for the prevention or treatment of pressure ulcers.
  • the food or drink can be, for example, a health food, a functional food, a food for specified health use, a nutritional supplement, a food for a sick person, or an animal feed.
  • the food / beverage products of this invention can be ingested as a composition as described above, and can also be ingested as various food / beverage products.
  • food and drink include juices, soft drinks, tea drinks, drinks, jelly-like drinks, functional drinks and other drinks; beer and other alcoholic drinks; rice, noodles, breads and pasta Carbohydrate-containing foods; paste products such as fish ham, sausage and fish paste products; retort products such as curry, sauce, and Chinese soup; soups; dairy products such as milk, milk drinks, ice cream, cheese, and yogurt; Fermented products such as lactic acid bacteria, fermented beverages and pickles; Bean products; Western confectionery such as biscuits and cookies; Japanese confectionery such as buns and sheep candy; Kinds: Instant foods such as instant soup and instant miso soup, foods compatible with microwave ovens, and the like.
  • health foods and drinks prepared in the form of powder, granules, tablets, capsules, liquid, paste or jelly are also included.
  • composition of the present invention can be used for animals including humans, but is not particularly limited as animals other than humans, and may be used for various domestic animals, poultry, pets, laboratory animals, and the like. it can. Specific examples include but are not limited to pigs, cows, horses, sheep, goats, chickens, ducks, ostriches, ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like.
  • the production of food and drink in the present invention can be performed by a production technique known in the technical field.
  • one or more components for example, nutrients
  • the dose or ingestion is appropriately determined according to the age, weight, pressure ulcer symptoms, health condition, type of composition (pharmaceuticals, food and drink, etc.), etc. Selected.
  • the dose or intake of lactic acid bacteria per dose is generally 0.01 mg / kg body weight to 100 mg / kg body weight, preferably 1 mg / kg body weight to 10 mg / kg body weight.
  • the present invention also provides a method for improving pressure ulcers in a subject, characterized by administering or ingesting lactic acid bacteria to the subject.
  • the product of the composition of the present invention may be labeled with an indication that it is used to improve pressure ulcers.
  • labeled product or instructions means that the product body, container, packaging, etc. are marked, or instructions, package inserts, promotional materials, or other printed materials that disclose product information. It means that the display is attached to.
  • the indication that it is used to improve pressure ulcers can include information on the mechanism by which the pressure ulcer is improved by administering or ingesting lactic acid bacteria.
  • Mechanisms include, for example, inflammatory cytokines and growth factors associated with pressure ulcers (eg, IL-1 ⁇ gene, IL-8 gene, TNF- ⁇ gene, TGF- ⁇ gene, FGF-7 gene, FGF-10 gene) Information on its action and expression.
  • inflammatory cytokines and growth factors associated with pressure ulcers eg, IL-1 ⁇ gene, IL-8 gene, TNF- ⁇ gene, TGF- ⁇ gene, FGF-7 gene, FGF-10 gene
  • Example 1 Examination of the pressure ulcer improvement effect of EC-12 in a mouse model BALB / c 10-week-old male mice were used as test animals. “Saline administration group (control group)”, “Prophylactic EC-12 administration group” and “Same day EC-12 administration group” were set as test groups, and 15 mice (45 in total) were assigned to each group. Using.
  • mice are suspended daily so that EC-12 is suspended in physiological saline and EC-12 is 10 mg / kg (body weight).
  • Sterile saline was orally administered to the “saline administration group”.
  • Administration of EC-12 to the “preventive EC-12 administration group” and the administration of physiological saline to the “saline administration group” started 7 days before the start of pressure ulcer and once a day until necropsy in the morning I went at 9 o'clock.
  • EC-12 administration to the “same day EC-12 administration group” started from the day of pressure ulcer preparation and was performed once a day at 9:00 am until autopsy.
  • the condition of the wound part was observed daily and photographed, and the area of the wound part was measured by image analysis of the photograph.
  • 5 autopsies were performed in each group. Somnopentyl (Schering plow) was intraperitoneally administered, and after deep anesthesia, it was sacrificed by exsanguination.
  • the wound area reduction rate was calculated as a value when the maximum pressure ulcer area of the “preventive EC-12 administration group” was 100.
  • the wound area reduction rate was lower in the “prophylactic EC-12 administration group” than the “same day EC-12 administration group” and the “saline administration group” from the fourth day after pressure ulcer formation. Values are shown (FIG. 1).
  • the present inventors further confirmed the mRNA expression of cytokines and growth factors for the wound sample.
  • IL-8 is a leukocyte chemotactic factor that is produced from various cells such as leukocytes, fibroblasts and endothelial cells by stimulation of inflammatory cytokines such as IL-1 and TNF. factor).
  • IL-1 ⁇ has various physiological activities in various immunocompetent cells, but its most important function is to induce IL-2 production of helper T cells and to differentiate T cells via IL-2.
  • -It is known to promote proliferation.
  • TNF- ⁇ is considered to be one of mediators in inflammatory reactions because it induces fever and various inflammatory reactions through the production of IL-1, PGE2, collagenase and the like.
  • TGF- ⁇ is known to promote the migration of macrophages to the damaged site when the tissue is damaged. Since macrophages themselves also secrete TGF- ⁇ , this secretion increases fibroblasts and synergistically accelerates the wound healing process.
  • FGF-7 is a multifunctional signal molecule that exhibits activities such as proliferation and differentiation to various cells as well as fibroblasts, and is also called KGF (keratinocyte growth factor).
  • FGF-10 is a family of fibroblast growth factors and is located in the FGF-7 subfamily.
  • IL-1 ⁇ , IL-8, and TNF- ⁇ as cytokines and the above-described TGF- ⁇ , FGF-7, and FGF-10 as growth factors were examined. .
  • cDNA was synthesized by reverse transcription, and the cDNA was used as a template and real-time PCR (Rotor-Gene 6200 (Qiagen)) using the primers shown in Table 1 was done.
  • RNA extraction QuickGene 810 system and QuickGene RNA tissue kit SII (Fujifilm) were used, and for reverse transcription, PrimeScript RT RT reagent kit (Perfect Real Time; Takara Bio) was used. The work was performed in accordance with the instruction manual. The measured value was corrected with GAPDH.
  • the process from pressure ulcer development to healing is generally classified into four stages: (1) bleeding coagulation phase, (2) inflammation phase, (3) proliferative phase, and (4) mature phase.
  • a significant decrease in the pressure ulcer area was observed on the fourth day of the pressure ulcer compared with the “same day EC-12 administration group” and the “saline administration group”.
  • high expression of inflammatory cytokines and growth factors was observed on the 3rd day of the pressure ulcer development, and thereafter, their expression was dramatically decreased on the 6th day of the pressure ulcer development. From these facts, it was shown that administration of EC-12 before the pressure ulcer formation was effective in healing pressure ulcers at the early stage of pressure ulcer development. These facts also suggested that EC-12 is useful for preventing pressure ulcers.
  • pressure ulcers in a living body can be improved by administering the composition of the present invention as a pharmaceutical or ingesting as a food or drink.
  • Lactic acid bacteria which are active ingredients of the composition of the present invention, are enteric bacteria and can be administered or taken orally. Since the composition of the present invention is highly safe and can be easily administered or ingested, it is expected to be used as a new medicine or health food having an action to improve pressure ulcers.

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Abstract

When administered to bedsore model mice to examine the bedsore-relieving effect, an Enterococcus faecalis strain (EC-12 strain), which is an example of lactic acid bacteria, exhibited a significant effect of relieving bedsore from the early stage after the formation of the bedsore in the mice. Thus, it is clarified that the Enterococcus faecalis strain (EC-12 strain) is very advantageously usable in drugs, foods and drinks for preventing bedsore or healing the same at the early stage.

Description

褥瘡改善作用を有する組成物Composition having pressure ulcer improving action
　本発明は、褥瘡改善作用を有する組成物に関する。より詳しくは、乳酸菌を有効成分として含む褥瘡改善作用を有する組成物、並びに、その医薬、試薬、および飲食品としての用途に関する。 The present invention relates to a composition having a pressure ulcer improving action. More specifically, the present invention relates to a composition having a pressure ulcer improving action containing lactic acid bacteria as an active ingredient, and its use as a medicine, reagent, and food and drink.
　褥瘡は、持続的圧迫により皮膚、皮下脂肪組織、筋肉への血流が途絶え、これらの組織が死滅した状態である。褥瘡の予防または治療においては、局所の血流を確保するために、体圧分散を目的とした看護、予防、栄養管理、スキンケアを含めた局所療法が実施されている。褥瘡の局所療法においては、褥瘡の状態を正しく判断し、その状態に適した処置、外用薬、および創傷被覆材を選択し、患者に適用する必要がある。これまでの褥瘡の局所療法においては、高度な専門的知識が必要であったことから、より簡便な新たな治療法の開発が求められている。 A pressure ulcer is a state in which blood flow to the skin, subcutaneous adipose tissue, and muscle is interrupted by continuous compression, and these tissues are killed. In the prevention or treatment of pressure ulcers, local therapies including nursing, prevention, nutrition management, and skin care for the purpose of dispersion of body pressure are performed in order to secure local blood flow. In local treatment of pressure ulcers, it is necessary to correctly determine the state of pressure ulcers, select treatments suitable for the state, external medicine, and wound dressing, and apply them to the patient. In the conventional local treatment of pressure ulcers, since highly specialized knowledge is required, the development of a simpler new treatment method is required.
　ところで、近年、乳酸菌などの腸内細菌について、疾病の予防効果や疾病の症状の改善効果などを検証し、簡便に摂取でき、安全性の高い医薬や飲食品として利用しようとする試みがなされている。 By the way, in recent years, with regard to enterobacteria such as lactic acid bacteria, attempts have been made to verify the effect of preventing diseases and improving the symptoms of diseases, and can be easily consumed and used as highly safe medicines and foods and drinks. Yes.
　例えば、ヒト腸管から単離された乳酸菌であるエンテロコッカス・フェカリス・EC-12株（以下、単に「EC-12」と略することがある）について、本願出願人は、絨毛の委縮を抑制する効果および腸管上皮細胞増殖抑制効果（特許文献１、非特許文献１）、腸内細菌叢の改善効果、便通促進効果、および便通改善作用のメカニズム（特許文献２、非特許文献２～４）、リステリア菌感染に対する生体防御効果（非特許文献５）、薬剤耐性菌の排除効果（特許文献３）、自然免疫および獲得免疫の活性化効果（非特許文献６）、接触性皮膚炎に対する炎症抑制効果（特許文献４）、I型アレルギー反応（喘息、花粉症、アトピー性皮膚炎）の軽減効果（特許文献５、非特許文献７）、リウマチ性関節炎の改善効果（特許文献６）、ハンセン病（らい病）の予防効果（特許文献７）、抗腫瘍効果（非特許文献８）、および火傷の治癒促進効果（非特許文献９）などを報告している。 For example, regarding the Enterococcus faecalis EC-12 strain (hereinafter sometimes simply referred to as “EC-12”), which is a lactic acid bacterium isolated from the human intestinal tract, the applicant of the present application has an effect of suppressing the contraction of villi. And intestinal epithelial cell proliferation inhibitory effect (Patent Document 1, Non-Patent Document 1), intestinal bacterial flora improving effect, bowel movement promoting effect, mechanism of bowel movement improving action (Patent Document 2, Non-Patent Documents 2 to 4), Listeria Protective effect against bacterial infection (Non-patent document 5), exclusion effect of drug-resistant bacteria (Patent document 3), activation effect of innate and acquired immunity (Non-patent document 6), anti-inflammatory effect on contact dermatitis ( Patent Document 4), Type I allergic reaction (asthma, hay fever, atopic dermatitis) alleviating effect (Patent Document 5, Non-Patent Document 7), rheumatoid arthritis improving effect (Patent Document 6), leprosy Preventive effect of) (Patent Document 7), have reported such as anti-tumor effects (Non-Patent Document 8), and burns healing promoting effect (Non-Patent Document 9).
　上記報告も含め、これまで、乳酸菌などの腸内細菌について様々な疾患に対する症状改善効果が報告されてきたが、いまだ褥瘡改善に応用した例は報告されていない。 Up to now, including the above reports, symptom-improving effects on various diseases have been reported for intestinal bacteria such as lactic acid bacteria, but no examples of application to pressure ulcer improvement have been reported yet.
特開2008-255080号公報JP 2008-255080 A 特開2004－51530号公報JP 2004-51530 A 特開2006-89421号公報JP 2006-89421 特開2006-28050号公報JP 2006-28050 A 特開2007-91694号公報JP 2007-91694 A 特開2007-254333号公報JP 2007-254333 A 特開2007-290992号公報JP 2007-290992 A
　本発明は、このような状況に鑑みてなされたものであり、その目的は、褥瘡改善作用を有する組成物であって、簡便に投与または摂取することができ、かつ、高い安全性を有する組成物を提供することにある。 The present invention has been made in view of such circumstances, and an object of the present invention is a composition having a pressure ulcer improving action, which can be easily administered or ingested, and has a high safety. To provide things.
　本発明者らは、上記課題を解決すべく、褥瘡のモデルマウスにおける、乳酸菌の効果を検討した。具体的には、このモデルマウスに、乳酸菌の一例としてエンテロコッカス・フェカリス（EC-12株）を摂取させ、その褥瘡改善作用を評価した。その結果、このモデルマウスでは、褥瘡形成後早期から褥瘡面積の減少が認められ、また、褥瘡形成後の初期において、種々の炎症性サイトカインや成長因子の高発現が認められたことから、創傷治癒が促進されていることが判明した。さらに、褥瘡形成後の後期では、炎症性サイトカインや成長因子の発現が減少し、対照と比較して正常な状態に早く向かっていることが判明した。このように、エンテロコッカス・フェカリス（EC-12株）は、褥瘡形成後の早期の段階から、その改善作用を示した。さらに、陰性対照群およびエンテロコッカス・フェカリス（EC-12株）を同日投与した群との比較により、この効果は、特に、エンテロコッカス・フェカリス（EC-12株）を褥瘡の形成前から予防的に投与した場合に顕著であることも判明した。 In order to solve the above problems, the present inventors examined the effect of lactic acid bacteria in a pressure ulcer model mouse. Specifically, this model mouse was ingested with Enterococcus faecalis (EC-12 strain) as an example of lactic acid bacteria, and its pressure ulcer improving action was evaluated. As a result, in this model mouse, the pressure ulcer area decreased from the early stage after pressure ulcer formation, and high expression of various inflammatory cytokines and growth factors was observed in the early stage after pressure ulcer formation. Turned out to be promoted. Furthermore, it was found that the expression of inflammatory cytokines and growth factors decreased later in the post- pressure ulcer formation, and they were heading toward a normal state faster than the control. Thus, Enterococcus faecalis (EC-12 strain) showed its improving action from an early stage after pressure ulcer formation. Furthermore, comparing this with the negative control group and the group that received Enterococcus faecalis (EC-12 strain) on the same day, this effect was especially effective when Enterococcus faecalis (EC-12 strain) was administered prophylactically before the formation of pressure ulcers. It was also found that this was remarkable.
　以上から、本発明者らは、エンテロコッカス・フェカリス（EC-12株）が、褥瘡の予防や早期段階での治癒のための医薬や飲食品として極めて有用であることを見出し、本発明を完成するに至った。 From the above, the present inventors have found that Enterococcus faecalis (EC-12 strain) is extremely useful as a medicine or food and drink for the prevention of pressure ulcer and healing at an early stage, thereby completing the present invention. It came to.
　本発明は、より詳しくは、以下の発明を提供するものである。
（１）乳酸菌を有効成分として含んでなる、褥瘡の改善に用いられる組成物。
（２）乳酸菌が、エンテロコッカス属に属するものである、（１）に記載の組成物。
（３）乳酸菌が、エンテロコッカス・フェカリスである、（１）に記載の組成物。
（４）医薬組成物である、（１）から（３）のいずれかに記載の組成物。
（５）経口的に投与されるものである、（４）に記載の組成物。
（６）褥瘡が形成される前に予防的に投与される、（４）または（５）に記載の組成物。
（７）飲食品である、（１）から（３）のいずれかに記載の組成物。
（８）経口的に摂取されるものである、（７）に記載の組成物。
（９）褥瘡が形成される前に摂取される、（７）または（８）に記載の組成物。
（１０）褥瘡を改善するために用いられる旨の表示を付した、（４）から（９）のいずれかに記載の組成物。 More specifically, the present invention provides the following inventions.
(1) A composition used for improving pressure ulcer, comprising lactic acid bacteria as an active ingredient.
(2) The composition according to (1), wherein the lactic acid bacteria belong to the genus Enterococcus.
(3) The composition according to (1), wherein the lactic acid bacterium is Enterococcus faecalis.
(4) The composition according to any one of (1) to (3), which is a pharmaceutical composition.
(5) The composition according to (4), which is administered orally.
(6) The composition according to (4) or (5), which is administered prophylactically before the pressure ulcer is formed.
(7) The composition according to any one of (1) to (3), which is a food or drink.
(8) The composition according to (7), which is taken orally.
(9) The composition according to (7) or (8), which is taken before pressure ulcer is formed.
(10) The composition according to any one of (4) to (9), which is labeled to be used for improving pressure ulcer.
　本発明の組成物を医薬品として投与あるいは飲食品として摂取することによって、生体における褥瘡の改善を図ることができる。特に、本発明の組成物は、褥瘡形成前に予防的に投与することにより、顕著な効果を得ることができる。本発明の組成物は、褥瘡の予防や褥瘡の早期段階での治癒において有用である。また、本発明の組成物の有効成分は、乳酸菌であり、安全性が高い。このため、医薬として用いた場合には経口投与することができ、これまでの褥瘡の局所療法と異なり、簡便で、しかも、褥瘡の患者への負担も少ない。また、本発明の組成物は、健康食品などの飲食品として、健常者が日常的に容易に摂取して、褥瘡の予防を図ることができる。 The pressure ulcer in the living body can be improved by administering the composition of the present invention as a pharmaceutical or ingesting as a food or drink. In particular, the composition of the present invention can obtain a prominent effect by prophylactic administration before pressure ulcer formation. The composition of the present invention is useful in the prevention of pressure ulcer and healing at an early stage of pressure ulcer. Moreover, the active ingredient of the composition of this invention is a lactic acid bacterium, and its safety is high. For this reason, when used as a medicine, it can be administered orally, and unlike conventional local treatments for pressure ulcers, it is simple and has less burden on pressure ulcer patients. In addition, the composition of the present invention can be easily taken by a healthy person on a daily basis as a food or drink such as a health food to prevent pressure ulcers.
「予防的EC-12投与群」、「同日EC-12投与群」、「生理食塩水投与群」における、褥瘡形成後3日目から11日目の褥瘡面積縮小率を示す図である。「予防的EC-12投与群」の最大褥瘡面積を100として、傷面積縮小率を算出した。It is a figure which shows the pressure-reduction area reduction rate from the 3rd day after the pressure sore formation to the 11th day in the "prophylactic EC-12 administration group", the "same day EC-12 administration group", and the "saline administration group". The wound area reduction rate was calculated with the maximum pressure ulcer area of the “preventive EC-12 administration group” as 100.
　本発明は、乳酸菌を有効成分として含んでなる、褥瘡の改善に用いられる組成物を提供する。 The present invention provides a composition for improving pressure ulcer comprising lactic acid bacteria as an active ingredient.
　本発明において「褥瘡」とは、持続的圧迫により皮膚、皮下脂肪組織、筋肉への血流が途絶え、これらの組織が死滅した状態を意味する。本発明において「褥瘡の改善作用」とは、乳酸菌の投与もしくは摂取により、褥瘡が生じにくくなること、生じる褥瘡が軽度となること、褥瘡の悪化を抑制すること、褥瘡の治癒が早まることを含む意である。また、形成された褥瘡が治癒に至るまでの過程において、全体を改善する場合のみならず、特定のステージを改善することも含む意である。褥瘡の改善作用は、例えば、本実施例に示すように、褥瘡面積の測定や炎症性サイトカインや成長因子の発現の測定により評価することができる。 In the present invention, “decubitus” means a state in which blood flow to the skin, subcutaneous adipose tissue, and muscle is interrupted due to continuous compression, and these tissues are killed. In the present invention, “decubitus ameliorating action” includes that pressure ulcers are less likely to occur by administration or ingestion of lactic acid bacteria, that the resulting pressure ulcers become mild, that pressure ulcer deterioration is suppressed, and that pressure ulcer healing is accelerated. I mean. Moreover, in the process until the formed pressure ulcer is healed, it is meant not only to improve the whole but also to improve a specific stage. The action of improving pressure ulcer can be evaluated, for example, by measuring the pressure ulcer area or measuring the expression of inflammatory cytokines and growth factors, as shown in this Example.
　本発明の組成物の有効成分である「乳酸菌」としては、エンテロコッカス属、ビフィドバクテリウム属、ラクトバシルス属、ストレプトコッカス属、および、ラクトコッカス属に属するものが例示されるが、褥瘡改善作用を有する限り、特に制限されない。 Examples of the “lactic acid bacterium” that is an active ingredient of the composition of the present invention include those belonging to the genus Enterococcus, Bifidobacterium, Lactobacillus, Streptococcus, and Lactococcus, which have an action to improve pressure ulcers. As long as it is not particularly limited.
　エンテロコッカス属に属する乳酸菌としては、例えば、エンテロコッカス・フェカリス、エンテロコツカス・フェシウムが挙げられ、ビフィドバクテリウム属に属する細菌としては、例えば、ビフィドバクテリウム・ロンガム、ビフィドバクテリウム・プレーべ、ビフィドバクテリウム・ビフィダムが挙げられ、ラクトバシルス属に属する細菌としては、ラクトバシルス・アシドフィラス、ラクトバシルス・カゼイ、ラクトバシルス・サリバリウスが挙げられ、ストレプトコッカス属に属する細菌としては、例えば、ストレプトコッカス・サーモフィラス等が挙げられ、ラクトコッカス属に属する細菌としては、例えば、ラクトコッカス・クレモリス、ラクトコッカス・ラクティス等が挙げられる。本発明の組成物に用いる乳酸菌は、好ましくは、エンテロコッカス属に属するものであり、特に好ましくは、エンテロコッカス・フェカリスである。 Examples of lactic acid bacteria belonging to the genus Enterococcus include Enterococcus faecalis and Enterococcus faecium. Examples of bacteria belonging to the genus Bifidobacterium include, for example, Bifidobacterium longum, Bifidobacterium previ Bifidobacterium bifidum, and bacteria belonging to the genus Lactobacillus include Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivaius, and bacteria belonging to the genus Streptococcus include, for example, Streptococcus thermophilus Examples of bacteria belonging to the genus Lactococcus include Lactococcus cremolith and Lactococcus lactis. The lactic acid bacteria used in the composition of the present invention are preferably those belonging to the genus Enterococcus, and particularly preferably Enterococcus faecalis.
　なお、本実施例において用いたエンテロコッカス・フェカリス・EC-12株（EC-12）は、2005年2月25日（原寄託日）、独立行政法人産業技術総合研究所特許生物寄託センター（〒305-5466　日本国茨城県つくば市東1丁目1番地1中央第6）に寄託された（受託番号は、FERM　BP-10284）。エンテロコッカス・フェカリスとしては、EC-12株の他、ATCC19433、ATCC14508、ATCC23655、IFO16803、IFO16804等の菌株を利用することができる。 In addition, Enterococcus faecalis EC-12 strain (EC-12) used in this example was incorporated on February 25, 2005 (original deposit date), National Institute of Advanced Industrial Science and Technology, Patent Biological Depositary Center (〒305 -5466 Deposited at Tsukuba City, Ibaraki Prefecture, Japan, 1st Street, 1st Street, 1st Central, 1st 6th (Accession number is FERM BP-10284). As the Enterococcus faecalis, strains such as ATCC19433, ATCC14508, ATCC23655, IFO16803, and IFO16804 can be used in addition to the EC-12 strain.
　これらの乳酸菌は、1種のみを本発明の組成物に用いることもできるが、2種以上の菌種を配合して本発明の組成物に用いることもできる。また、本発明の組成物において、乳酸菌は、生菌として、また、死菌体として用いることができる。死菌体は、耐熱性に優れ、品質が安定しており、無味無臭である点で、本発明の組成物の有効成分として好ましい。本発明の組成物における死菌体としては、加熱殺菌した菌体を用いることができる。加熱殺菌した菌体は、乳酸菌を常法に従って培養して得られた培養物から、例えば、濾過、遠心分離等の方法により菌体を回収し、水洗後、水等に懸濁して120℃以下（好ましくは80～120℃）、30分以内（3秒～30分間）加熱処理した後、必要に応じて濃縮、乾燥することにより調製できる。なお、エンテロコッカス・フェカリス・EC-12株の加熱殺菌菌体の微細粉末は、商品名「EC-12（イーエフパワー）」（コンビ株式会社製）として市販されている。 Only one of these lactic acid bacteria can be used in the composition of the present invention, but two or more kinds of lactic acid bacteria can be blended and used in the composition of the present invention. In the composition of the present invention, lactic acid bacteria can be used as viable bacteria or dead cells. Dead cells are preferred as an active ingredient of the composition of the present invention in that they are excellent in heat resistance, stable in quality, and tasteless and odorless. As dead cells in the composition of the present invention, heat-sterilized cells can be used. Heat-sterilized cells are collected from a culture obtained by culturing lactic acid bacteria according to a conventional method, for example, by filtration, centrifugation, or the like, and after washing with water, suspended in water or the like and 120 ° C. or lower (Preferably 80 to 120 ° C.) Heat treatment within 30 minutes (3 seconds to 30 minutes), followed by concentration and drying as necessary. The fine powder of heat-sterilized cells of Enterococcus faecalis EC-12 strain is commercially available under the trade name “EC-12 (Efpower)” (manufactured by Combi Corporation).
　本発明の組成物は、褥瘡改善作用を有する医薬組成物、飲食品（動物用飼料を含む）、あるいはモデル動物実験などに用いられる試薬の形態であり得る。 The composition of the present invention may be in the form of a pharmaceutical composition having a pressure ulcer improving action, a food or drink (including animal feed), or a reagent used for model animal experiments.
　本実施例において、エンテロコッカス・フェカリス（EC-12株）を褥瘡のマウスモデルに摂取させると、褥瘡形成後早期から褥瘡面積の有意な減少が認められた。また、この効果は、特に、エンテロコッカス・フェカリス（EC-12株）を褥瘡の形成前から予防的に投与した場合に大きかった。従って、本発明の組成物は、特に予防的に投与される医薬組成物または予防的に（日常的に）摂取される飲食品として好適に用いることができ、これにより褥瘡の予防や早期段階での治癒を行うことができる。 In this example, when Enterococcus faecalis (EC-12 strain) was ingested by a mouse model of pressure ulcer, a significant decrease in the pressure ulcer area was observed from the early stage after pressure ulcer formation. This effect was particularly great when Enterococcus faecalis (EC-12 strain) was administered prophylactically before the formation of pressure ulcers. Therefore, the composition of the present invention can be suitably used as a pharmaceutical composition that is administered prophylactically or as a food or drink that is taken prophylactically (daily), thereby preventing pressure ulcers or at an early stage. Can be cured.
　また、本実施例におけるマウスモデルでは、エンテロコッカス・フェカリス（EC-12株）を摂取させると、褥瘡形成後の初期において、対照と比較して、炎症性サイトカインや成長因子が高発現し、創傷治癒が促進されていることが認められ、さらに、褥瘡形成後の後期になると、対照と比較して炎症性サイトカインや成長因子の発現が減少し、対照よりも正常な状態に早く向かっていることが認められた。従って、本発明の組成物は、褥瘡形成後の初期における炎症性サイトカインや成長因子（例えば、IL-1α遺伝子、TNF-α遺伝子、TGF-β遺伝子、FGF-7遺伝子、FGF-10遺伝子）の発現抑制を促進するための組成物として、また、褥瘡形成後の後期における炎症性サイトカインや成長因子（例えば、IL-1α遺伝子、IL-8遺伝子、TNF-α遺伝子、TGF-β遺伝子、FGF-10遺伝子）の発現抑制を促進するための組成物として用いることもできる。 In addition, in the mouse model of this example, when Enterococcus faecalis (EC-12 strain) was ingested, inflammatory cytokines and growth factors were highly expressed in the initial stage after pressure ulcer formation, compared to the control, and wound healing. In addition, in later stages of pressure ulcer formation, the expression of inflammatory cytokines and growth factors is decreased compared to controls, and may be moving faster to normal than controls. Admitted. Therefore, the composition of the present invention contains inflammatory cytokines and growth factors (eg, IL-1α gene, TNF-α gene, TGF-β gene, FGF-7 gene, FGF-10 gene) in the early stage after pressure ulcer formation. As a composition for promoting expression suppression, and inflammatory cytokines and growth factors (for example, IL-1α gene, IL-8 gene, TNF-α gene, TGF-β gene, FGF- It can also be used as a composition for promoting suppression of expression of 10 genes).
　本発明における組成物は、公知の製剤学的方法により製剤化することができる。例えば、カプセル剤、錠剤、丸剤、液剤、散剤、顆粒剤、細粒剤、フィルムコーティング剤、ペレット剤、トローチ剤、舌下剤、咀嚼剤、バッカル剤、ペースト剤、シロップ剤、懸濁剤、エリキシル剤、乳剤、塗布剤、軟膏剤、硬膏剤、パップ剤、経皮吸収型製剤、ローション剤、吸引剤、エアゾール剤、注射剤、坐剤などとして、経口的または非経口的に使用することができる。本発明は、腸内細菌である乳酸菌を有効成分とする組成物であり、経口により、簡便に投与もしくは摂取することができる。すなわち、本発明の組成物の好ましい投与もしくは摂取の方法は、経口による投与もしくは摂取である。 The composition in the present invention can be formulated by a known pharmaceutical method. For example, capsule, tablet, pill, liquid, powder, granule, fine granule, film coating, pellet, troche, sublingual, chewing agent, buccal, paste, syrup, suspension, To be used orally or parenterally as elixirs, emulsions, coatings, ointments, plasters, cataplasms, transdermal preparations, lotions, inhalants, aerosols, injections, suppositories, etc. Can do. The present invention is a composition comprising a lactic acid bacterium which is an enteric bacterium as an active ingredient, and can be easily administered or ingested orally. That is, the preferred method of administration or ingestion of the composition of the present invention is oral administration or ingestion.
　これら製剤化においては、薬理学上もしくは飲食品として許容される担体、具体的には、滅菌水や生理食塩水、植物油、溶剤、基剤、乳化剤、懸濁剤、界面活性剤、安定剤、香味剤、芳香剤、賦形剤、ベヒクル、防腐剤、結合剤、希釈剤、等張化剤、無痛化剤、増量剤、崩壊剤、緩衝剤、コーティング剤、滑沢剤、着色剤、甘味剤、粘稠剤、矯味矯臭剤、溶解補助剤あるいはその他の添加剤等と適宜組み合わせることができる。 In these preparations, carriers that are acceptable pharmacologically or as foods and beverages, specifically, sterile water and physiological saline, vegetable oils, solvents, bases, emulsifiers, suspensions, surfactants, stabilizers, Flavoring agent, fragrance, excipient, vehicle, preservative, binder, diluent, tonicity agent, soothing agent, extender, disintegrant, buffering agent, coating agent, lubricant, colorant, sweetness Can be suitably combined with an agent, a thickening agent, a flavoring agent, a solubilizing agent or other additives.
　本発明の組成物を医薬組成物として用いる場合には、褥瘡の予防や治療に用いられる公知の医薬組成物と併用してもよい。 When the composition of the present invention is used as a pharmaceutical composition, it may be used in combination with a known pharmaceutical composition used for the prevention or treatment of pressure ulcers.
　本発明の組成物を飲食品として用いる場合、当該飲食品は、例えば、健康食品、機能性食品、特定保健用食品、栄養補助食品、病者用食品、あるいは動物用飼料であり得る。本発明の飲食品は、上記のような組成物として摂取することができる他、種々の飲食品として摂取することもできる。飲食品の具体例としては、ジュース、清涼飲料水、茶飲料、ドリンク剤、ゼリー状飲料、機能性飲料等の各種飲料；ビール等のアルコール飲料；飯類、麺類、パン類およびパスタ類等の炭水化物含有食品；魚肉ハム、ソーセージ、水産練り製品等の練製品；カレー、あんかけ、中華スープ等のレトルト製品；スープ類；牛乳、乳飲料、アイスクリーム、チーズ、ヨーグルト等の乳製品；みそ、ヨーグルト、乳酸菌、発酵飲料、漬け物等の発酵物；豆製品；ビスケット、クッキーなどの洋菓子類、饅頭や羊羹等の和菓子類、キャンディー類、ガム類、グミ、ゼリー、プリンなどの冷菓や氷菓などの各種菓子類；インスタントスープ、インスタントみそ汁等のインスタント食品、電子レンジ対応食品等が挙げられる。さらには、粉末、穎粒、錠剤、カプセル剤、液状、ペースト状またはゼリー状に調製された健康飲食品も挙げられる。 When the composition of the present invention is used as a food or drink, the food or drink can be, for example, a health food, a functional food, a food for specified health use, a nutritional supplement, a food for a sick person, or an animal feed. The food / beverage products of this invention can be ingested as a composition as described above, and can also be ingested as various food / beverage products. Specific examples of food and drink include juices, soft drinks, tea drinks, drinks, jelly-like drinks, functional drinks and other drinks; beer and other alcoholic drinks; rice, noodles, breads and pasta Carbohydrate-containing foods; paste products such as fish ham, sausage and fish paste products; retort products such as curry, sauce, and Chinese soup; soups; dairy products such as milk, milk drinks, ice cream, cheese, and yogurt; Fermented products such as lactic acid bacteria, fermented beverages and pickles; Bean products; Western confectionery such as biscuits and cookies; Japanese confectionery such as buns and sheep candy; Kinds: Instant foods such as instant soup and instant miso soup, foods compatible with microwave ovens, and the like. Furthermore, health foods and drinks prepared in the form of powder, granules, tablets, capsules, liquid, paste or jelly are also included.
　本発明の組成物は、ヒトを含む動物を対象として使用することができるが、ヒト以外の動物としては特に制限はなく、種々の家畜、家禽、ペット、実験用動物などを対象とすることができる。具体的には、ブタ、ウシ、ウマ、ヒツジ、ヤギ、ニワトリ、カモ、ダチョウ、アヒル、イヌ、ネコ、ウサギ、ハムスター、マウス、ラット、サルなどが挙げられるが、これらに制限されない。 The composition of the present invention can be used for animals including humans, but is not particularly limited as animals other than humans, and may be used for various domestic animals, poultry, pets, laboratory animals, and the like. it can. Specific examples include but are not limited to pigs, cows, horses, sheep, goats, chickens, ducks, ostriches, ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like.
　本発明における飲食品の製造は、当該技術分野に公知の製造技術により実施することができる。当該飲食品においては、褥瘡の改善に有効な1種もしくは2種以上の成分（例えば、栄養素など）を添加してもよい。また、褥瘡の改善以外の機能を発揮する他の成分あるいは他の機能性食品と組み合わせることによって、多機能性の飲食品としてもよい。 The production of food and drink in the present invention can be performed by a production technique known in the technical field. In the food and drink, one or more components (for example, nutrients) effective for improving pressure ulcers may be added. Moreover, it is good also as multifunctional food-drinks by combining with the other component which exhibits functions other than the pressure ulcer improvement, or another functional food.
　本発明の組成物を投与または摂取する場合、その投与量または摂取量は、対象の年齢、体重、褥瘡の症状、健康状態、組成物の種類（医薬品、飲食品など）などに応じて、適宜選択される。例えば、1回当たりの乳酸菌の投与量または摂取量は、一般に、0.01mg/kg体重～100mg/kg体重であり、好ましくは、1mg/kg体重～10mg/kg体重である。本発明は、このように、乳酸菌を対象に投与もしくは摂取させることを特徴とする、対象における褥瘡の改善方法をも提供するものである。 When the composition of the present invention is administered or ingested, the dose or ingestion is appropriately determined according to the age, weight, pressure ulcer symptoms, health condition, type of composition (pharmaceuticals, food and drink, etc.), etc. Selected. For example, the dose or intake of lactic acid bacteria per dose is generally 0.01 mg / kg body weight to 100 mg / kg body weight, preferably 1 mg / kg body weight to 10 mg / kg body weight. Thus, the present invention also provides a method for improving pressure ulcers in a subject, characterized by administering or ingesting lactic acid bacteria to the subject.
　本発明の組成物の製品（医薬品、飲食品、試薬）またはその説明書は、褥瘡を改善するために用いられる旨の表示を付したものであり得る。ここで「製品または説明書に表示を付した」とは、製品の本体、容器、包装などに表示を付したこと、あるいは製品の情報を開示する説明書、添付文書、宣伝物、その他の印刷物などに表示を付したことを意味する。褥瘡を改善するために用いられる旨の表示においては、乳酸菌を投与もしくは摂取することにより褥瘡が改善される機序についての情報を含むことができる。機序としては、例えば、褥瘡に関連する炎症性サイトカインや成長因子（例えば、IL-1α遺伝子、IL-8遺伝子、TNF-α遺伝子、TGF-β遺伝子、FGF-7遺伝子、FGF-10遺伝子）についての、その作用や発現に関する情報が挙げられる。 The product of the composition of the present invention (pharmaceutical product, food and drink, reagent) or its instructions may be labeled with an indication that it is used to improve pressure ulcers. Here, “labeled product or instructions” means that the product body, container, packaging, etc. are marked, or instructions, package inserts, promotional materials, or other printed materials that disclose product information. It means that the display is attached to. The indication that it is used to improve pressure ulcers can include information on the mechanism by which the pressure ulcer is improved by administering or ingesting lactic acid bacteria. Mechanisms include, for example, inflammatory cytokines and growth factors associated with pressure ulcers (eg, IL-1α gene, IL-8 gene, TNF-α gene, TGF-β gene, FGF-7 gene, FGF-10 gene) Information on its action and expression.
　以下、実施例及び比較例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。 Hereinafter, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples.
　[実施例１]　マウスモデルにおける、EC-12の褥瘡改善効果の検討
　供試動物として、BALB/c系10週齢マウスオスを用いた。「生理食塩水投与群（コントロール群）」、「予防的EC-12投与群」、「同日EC-12投与群」を試験群として設定し、各群について15頭（計45頭）のマウスを用いた。 [Example 1] Examination of the pressure ulcer improvement effect of EC-12 in a mouse model BALB / c 10-week-old male mice were used as test animals. “Saline administration group (control group)”, “Prophylactic EC-12 administration group” and “Same day EC-12 administration group” were set as test groups, and 15 mice (45 in total) were assigned to each group. Using.
　マウスを馴化後、麻酔下において、市販バリカンを用いて背部正中の毛刈りを行った後、除毛クリームにて除毛を行った。除毛部は、蒸留水で丁寧に拭った。毛刈りの翌日、背部正中皮膚を持ち上げて、マグネットプレート（直径12mm×厚さ5mm，1180G）2個で挟み、12時間保持した後、12時間マグネットを外した（装着9時；脱着21時）。このサイクルを3日間連続して繰り返し、褥瘡を作成した。なお、褥瘡作成時のみ個別飼育を行った。褥瘡作成時、鎮痛剤としてブプレノルフィン（2mg/kg）を皮下投与した。褥瘡作成方法については、Stadler　et　al.(J.　Invest.　Surg.　2004.　17:221-227)に準拠して行った。 After acclimatization of the mouse, under the anesthesia, the hair was cut in the midline of the back using a commercially available clipper, and then the hair was removed with a hair removal cream. The hair removal part was carefully wiped with distilled water. The day after shaving, lift the midline back skin, pinch it with 2 magnet plates (diameter 12mm x thickness 5mm, 1180G), hold it for 12 hours, then remove the magnet for 12 hours (installation 9 o'clock; desorption 21 o'clock) . This cycle was repeated for 3 consecutive days to create pressure ulcers. Individual breeding was carried out only at the time of pressure ulcer creation. When preparing pressure sores, buprenorphine (2 mg / kg) was administered subcutaneously as an analgesic. The pressure ulcer preparation method was performed according to Stadler et al. (J. Invest. Surg. 2004. 17: 221-227).
　「予防的EC-12投与群」および「同日EC-12投与群」においては、EC-12を生理食塩水で懸濁し、EC-12が10mg/kg（体重）となるように、毎日、マウスに強制経口投与した。「生理食塩水投与群」には、滅菌生理食塩水を経口投与した。「予防的EC-12投与群」へのEC-12の投与、および「生理食塩水投与群」への生理食塩水の投与は、褥瘡開始の7日前から開始し、剖検まで1日1回朝9時に行った。「同日EC-12投与群」へのEC-12投与は、褥瘡作成日から開始し，剖検まで1日1回朝9時に行った。 In the "prophylactic EC-12 administration group" and the "same day EC-12 administration group", mice are suspended daily so that EC-12 is suspended in physiological saline and EC-12 is 10 mg / kg (body weight). Was administered by oral gavage. Sterile saline was orally administered to the “saline administration group”. Administration of EC-12 to the “preventive EC-12 administration group” and the administration of physiological saline to the “saline administration group” started 7 days before the start of pressure ulcer and once a day until necropsy in the morning I went at 9 o'clock. EC-12 administration to the “same day EC-12 administration group” started from the day of pressure ulcer preparation and was performed once a day at 9:00 am until autopsy.
　創傷部の状態は、毎日観察して写真撮影を行い、創傷部面積を写真の画像解析により測定した。褥瘡作成後、3日、6日、11日に各群5頭ずつ剖検を行った。ソムノペンチル（シェリングプラウ）を腹腔投与し、深麻酔後、放血にて屠殺した。傷面積縮小率を、「予防的EC-12投与群」の最大褥瘡面積を100とした時の値として算出した。 The condition of the wound part was observed daily and photographed, and the area of the wound part was measured by image analysis of the photograph. On the 3rd, 6th, and 11th days after the pressure ulcer was made, 5 autopsies were performed in each group. Somnopentyl (Schering plow) was intraperitoneally administered, and after deep anesthesia, it was sacrificed by exsanguination. The wound area reduction rate was calculated as a value when the maximum pressure ulcer area of the “preventive EC-12 administration group” was 100.
　その結果、傷面積縮小率については、褥瘡形成後4日目より、「予防的EC-12投与群」が、「同日EC-12投与群」および「生理食塩水投与群」と比較して低値を示した（図１）。 As a result, the wound area reduction rate was lower in the “prophylactic EC-12 administration group” than the “same day EC-12 administration group” and the “saline administration group” from the fourth day after pressure ulcer formation. Values are shown (FIG. 1).
　本発明者らは、さらに、創傷部サンプルについて、サイトカインおよび成長因子のmRNA発現を確認した。 The present inventors further confirmed the mRNA expression of cytokines and growth factors for the wound sample.
　公知のサイトカインのうち、IL-8は、IL-1やTNFなどの炎症性サイトカインの刺激により、白血球をはじめ、繊維芽細胞や内皮細胞などの種々の細胞から産生される白血球遊走因子（leukocyte　chemotactic　factor）である。また、IL-1αは、種々の免疫担当細胞に多彩な生理活性を有するが、その最も重要な働きとして、ヘルパーT細胞のIL-2産生を誘導し、IL-2を介してT細胞の分化・増殖を促進させることが知られている。また、TNF-αは、IL-1やPGE2、コラゲナーゼなどの産生を介して発熱や種々の炎症反応を惹起することから、炎症反応におけるメディエーターの一つであると考えられている。 Among known cytokines, IL-8 is a leukocyte chemotactic factor that is produced from various cells such as leukocytes, fibroblasts and endothelial cells by stimulation of inflammatory cytokines such as IL-1 and TNF. factor). In addition, IL-1α has various physiological activities in various immunocompetent cells, but its most important function is to induce IL-2 production of helper T cells and to differentiate T cells via IL-2. -It is known to promote proliferation. TNF-α is considered to be one of mediators in inflammatory reactions because it induces fever and various inflammatory reactions through the production of IL-1, PGE2, collagenase and the like.
　また、公知の成長因子のうち、TGF-βは、組織が傷害を受けた際、マクロファージの傷害部位への遊走を促進することが知られている。マクロファージ自体もTGF-βを分泌するため、この分泌により線維芽細胞が増加し、創傷治癒プロセスが相乗的に促進される。また、FGF-7は、線維芽細胞のみならずさまざまな細胞に対し増殖、分化などの活性を示す多機能性シグナル分子であり、別名、KGF（ケラチノサイト増殖因子）と呼ばれている。また、FGF-10は、繊維芽細胞増殖因子のファミリーで、FGF-7のサブファミリーに位置づけられている。 Of the known growth factors, TGF-β is known to promote the migration of macrophages to the damaged site when the tissue is damaged. Since macrophages themselves also secrete TGF-β, this secretion increases fibroblasts and synergistically accelerates the wound healing process. FGF-7 is a multifunctional signal molecule that exhibits activities such as proliferation and differentiation to various cells as well as fibroblasts, and is also called KGF (keratinocyte growth factor). FGF-10 is a family of fibroblast growth factors and is located in the FGF-7 subfamily.
　本実施例においては、サイトカインとして上記のIL-1α、IL-8、およびTNF-αについて、成長因子として上記のTGF-β、FGF-7、およびFGF-10について、その発現の検討を行った。 In this example, the expression of IL-1α, IL-8, and TNF-α as cytokines and the above-described TGF-β, FGF-7, and FGF-10 as growth factors were examined. .
　具体的には、創傷部サンプルからRNA抽出後、逆転写によりcDNAを合成し、該cDNAを鋳型とし、表１に記載のプライマーを用いてreal-time　PCR（Rotor-Gene　6200　(Qiagen社)）を行なった。 Specifically, after RNA extraction from a wound sample, cDNA was synthesized by reverse transcription, and the cDNA was used as a template and real-time PCR (Rotor-Gene 6200 (Qiagen)) using the primers shown in Table 1 Was done.
　なお、RNA抽出には、QuickGene　810　system及びQuickGene　RNA　tissue　kit　SII(富士フイルム社)を使用し、逆転写にはPrimeScript RT reagent kit (Perfect Real Time; Takara Bio)を使用した。作業は取扱説明書に準拠して実施した。測定値はGAPDHにて補正した。 For RNA extraction, QuickGene 810 system and QuickGene RNA tissue kit SII (Fujifilm) were used, and for reverse transcription, PrimeScript RT RT reagent kit (Perfect Real Time; Takara Bio) was used. The work was performed in accordance with the instruction manual. The measured value was corrected with GAPDH.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　その結果、「予防的EC-12投与群」における皮膚褥瘡組織中のmRNA発現量については、褥瘡作成後3日目では、IL-8以外の炎症性サイトカインおよびすべての成長因子において、「同日EC-12投与群」および「生理食塩水投与群」と比較して上昇していた（表２、表３）。一方、褥瘡作成後6日目では、「予防的EC-12投与群」では、すべて炎症性サイトカインおよびFGF-7以外の成長因子の発現が、「同日EC-12投与群」および「生理食塩水投与群」と比較して低下していた（表２、表３）。 As a result, regarding the expression level of mRNA in cutaneous pressure ulcer tissue in the “preventive EC-12 administration group”, inflammatory cytokines other than IL-8 and all growth factors were observed on the third day after the pressure ulcer was created. -12 administration group ”and“ saline saline administration group ”(Tables 2 and 3). On the other hand, on the 6th day after the pressure ulcer was created, the expression of growth factors other than inflammatory cytokines and FGF-7 was all observed in the “preventive EC-12 administration group”. Compared with the “administered group” (Tables 2 and 3).
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　褥瘡の発生から治癒に至るまでの過程は、一般に、（1）出血凝固期、（2）炎症期、（3）増殖期、（4）成熟期、の4つのステージに分類されるが、「予防的EC-12投与群」においては、「同日EC-12投与群」および「生理食塩水投与群」と比較して、褥瘡発生4日目には、褥瘡面積の有意な減少が認められた。また、褥瘡発生3日目において、炎症性サイトカインおよび成長因子の高い発現が見られ、その後、褥瘡発生6日目においては、これらの発現が劇的に低下していた。これら事実から、特に、EC-12を褥瘡形成前から投与することで、褥瘡発生初期の褥瘡の治癒に効果があることが示された。また、これら事実から、EC-12は、褥瘡の予防にも有用であることが示唆された。 The process from pressure ulcer development to healing is generally classified into four stages: (1) bleeding coagulation phase, (2) inflammation phase, (3) proliferative phase, and (4) mature phase. In the “preventive EC-12 administration group”, a significant decrease in the pressure ulcer area was observed on the fourth day of the pressure ulcer compared with the “same day EC-12 administration group” and the “saline administration group”. . In addition, high expression of inflammatory cytokines and growth factors was observed on the 3rd day of the pressure ulcer development, and thereafter, their expression was dramatically decreased on the 6th day of the pressure ulcer development. From these facts, it was shown that administration of EC-12 before the pressure ulcer formation was effective in healing pressure ulcers at the early stage of pressure ulcer development. These facts also suggested that EC-12 is useful for preventing pressure ulcers.
　以上説明したように、本発明の組成物を医薬品として投与あるいは飲食品として摂取することによって、生体における褥瘡の改善を図ることができる。本発明の組成物の有効成分たる乳酸菌は、腸内細菌であり、経口により投与もしくは摂取することができる。本発明の組成物は、安全性が高く、簡便に投与もしくは摂取できるため、褥瘡の改善作用を有する新たな医薬や健康食品などとしての利用が期待される。 As described above, pressure ulcers in a living body can be improved by administering the composition of the present invention as a pharmaceutical or ingesting as a food or drink. Lactic acid bacteria, which are active ingredients of the composition of the present invention, are enteric bacteria and can be administered or taken orally. Since the composition of the present invention is highly safe and can be easily administered or ingested, it is expected to be used as a new medicine or health food having an action to improve pressure ulcers.
配列番号1～12
<223>　人工的に合成されたプライマーの塩基配列 SEQ ID NO: 1-12
<223> Base sequence of artificially synthesized primer

Claims (10)

  1. 　乳酸菌を有効成分として含んでなる、褥瘡の改善に用いられる組成物。 A composition used for improving pressure ulcers comprising lactic acid bacteria as an active ingredient.
  2. 　乳酸菌が、エンテロコッカス属に属するものである、請求項１に記載の組成物。 The composition according to claim 1, wherein the lactic acid bacteria belong to the genus Enterococcus.
  3. 　乳酸菌が、エンテロコッカス・フェカリスである、請求項１に記載の組成物。 The composition according to claim 1, wherein the lactic acid bacterium is Enterococcus faecalis.
  4. 　医薬組成物である、請求項１から３のいずれかに記載の組成物。 The composition according to any one of claims 1 to 3, which is a pharmaceutical composition.
  5. 　経口的に投与されるものである、請求項４に記載の組成物。 The composition according to claim 4, which is orally administered.
  6. 　褥瘡が形成される前に予防的に投与される、請求項４または５に記載の組成物。 The composition according to claim 4 or 5, which is administered prophylactically before the pressure ulcer is formed.
  7. 　飲食品である、請求項１から３のいずれかに記載の組成物。 The composition according to any one of claims 1 to 3, which is a food or drink.
  8. 　経口的に摂取されるものである、請求項７に記載の組成物。 The composition according to claim 7, which is taken orally.
  9. 　褥瘡が形成される前に摂取される、請求項７または８に記載の組成物。 The composition according to claim 7 or 8, which is taken before the pressure ulcer is formed.
  10. 　褥瘡を改善するために用いられる旨の表示を付した、請求項４から９のいずれかに記載の組成物。 The composition according to any one of claims 4 to 9, which is labeled to be used for improving pressure ulcers.
PCT/JP2011/053920 2010-02-26 2011-02-23 Composition having bedsore-relieving effect WO2011105403A1 (en)

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JP6185041B2 (en) * 2015-12-04 2017-08-23 一丸ファルコス株式会社 Glycerol production promoter derived from Staphylococcus epidermidis, antibacterial peptide production promoter derived from skin epidermis keratinocytes, and their use as an external preparation for skin protection
JP2017128522A (en) * 2016-01-19 2017-07-27 公立大学法人岩手県立大学 Wound healing promoting composition
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