WO2012077622A1 - Therapeutic or prophylactic agent for keloid or hypertrophic scar, and agent for inhibiting tissue hypertrophy in injured part of airway - Google Patents

Therapeutic or prophylactic agent for keloid or hypertrophic scar, and agent for inhibiting tissue hypertrophy in injured part of airway Download PDF

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Publication number
WO2012077622A1
WO2012077622A1 PCT/JP2011/078040 JP2011078040W WO2012077622A1 WO 2012077622 A1 WO2012077622 A1 WO 2012077622A1 JP 2011078040 W JP2011078040 W JP 2011078040W WO 2012077622 A1 WO2012077622 A1 WO 2012077622A1
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trehalose
agent
keloid
therapeutic
derivative
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PCT/JP2011/078040
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French (fr)
Japanese (ja)
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伸雄 佐々木
雄一 鄭
鈴木　茂樹
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株式会社ネクスト２１
国立大学法人東京大学
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Priority to JP2012547840A priority Critical patent/JPWO2012077622A1/en
Publication of WO2012077622A1 publication Critical patent/WO2012077622A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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 preventive / therapeutic agent for keloids or hypertrophic scars containing trehalose or trehalose derivatives.
  • Keloids and hypertrophic scars are scars that form after wounds such as trauma, burns, and surgery.
  • Tranilast (trade name “Rizaben (registered trademark)”) is known as a keloid and hypertrophic scar treatment. However, tranilast may cause hemorrhagic cystitis-like symptoms as a side effect.
  • An erythropoietin antagonist is also said to be effective in suppressing the formation of keloids and hypertrophic scars (see, for example, Patent Document 2).
  • erythropoietin antagonists are protein preparations and are difficult to handle.
  • TGF- ⁇ transforming growth factor
  • Non-patent Document 2 NF- ⁇ B activation by TNF- ⁇
  • Non-patent Document 3 IL-1 ⁇ and IL-1 ⁇ are involved in the sterile inflammatory reaction accompanying cell death caused by trauma or the like.
  • Patent Document 8 discloses a tracheal tube made of a thermoplastic material.
  • the tracheal tube disclosed in Japanese Patent Application Laid-Open No. 2003-102827 has low repulsion. For this reason, the pain which arises when an endotracheal tube is inserted in a trachea can be suppressed.
  • the respiratory assistance tube has high adhesion to the tissue mucosa. For this reason, when the respiratory assistance tube is removed, the cells on the tissue surface to which the respiratory assistance tube has adhered are peeled off. Difficulty in sputation of sputum and inflammation of tracheal tissue after use of respiratory aid tube.
  • cilia peel off in addition to the cells on the tracheal wall. This prevents the patient from discharging sputum. And there was a problem that sputum caused pneumonia by flowing back into the lungs.
  • An object of the present invention is to provide a therapeutic or preventive agent for preventing excessive granulation.
  • An object of the present invention is to provide a therapeutic or preventive agent for keloids or hypertrophic scars with few side effects.
  • the object of the present invention is to provide an effective tissue thickening inhibitor for airway damage sites with few side effects.
  • a drug containing trehalose or a derivative of trehalose by using a drug containing trehalose or a derivative of trehalose, excessive granulation can be prevented, and a therapeutic or preventive agent for keloid or hypertrophic scar, or suppression of tissue thickening in an airway injury site. Based on the knowledge that the agent can be provided.
  • the first aspect of the present invention relates to a therapeutic or preventive agent for keloid or hypertrophic scar containing trehalose or a derivative of trehalose as an active ingredient.
  • trehalose or a derivative of trehalose can prevent excessive granulation, so that an agent containing an effective amount of trehalose or a derivative of trehalose as an active ingredient is used for the treatment or prevention of keloid or hypertrophic scar. It is effective for.
  • this agent is preferably an agent administered to the treatment site after the treatment.
  • An example of the dosage form of this agent is a liquid agent. A spray is preferred as the liquid.
  • the second aspect of the present invention relates to a tissue thickening inhibitor for respiratory tract lesions containing trehalose or a derivative of trehalose as an active ingredient.
  • trehalose or a derivative of trehalose can prevent excessive granulation, so that the agent of the present invention is effective as a tissue thickening inhibitor in airway damage sites.
  • This agent can also be used as an agent for preventing airway obstruction due to thickening of tissues in damaged airways.
  • the drug of the present invention containing trehalose or a derivative of trehalose as an active ingredient was effective in the treatment and prevention of keloid or hypertrophic scar because it can prevent excessive granulation. . Therefore, according to the present invention, a therapeutic or prophylactic agent for keloid or hypertrophic scar can be provided.
  • the agent of the present invention containing trehalose or a trehalose derivative as an active ingredient has few side effects and effectively prevents thickening of an effective airway injury tissue.
  • FIG. 1 is a graph showing the amount of TGF- ⁇ 1 produced.
  • FIG. 2 is a graph showing the amount of TNF- ⁇ produced.
  • FIG. 3 is a graph showing the amount of IL-1 ⁇ produced.
  • FIG. 4 is a graph showing the amount of PGE 2 produced.
  • FIG. 5 is a graph showing the amount of TNF- ⁇ produced.
  • the first aspect of the present invention relates to a therapeutic or preventive agent for keloids or hypertrophic scars.
  • the therapeutic or preventive agent for keloids or hypertrophic scars of the present invention contains an effective amount of trehalose or a derivative of trehalose as an active ingredient, thereby preventing excessive granulation and preventing or preventing keloids or hypertrophic scars. It is effective as.
  • the agent for preventing keloid or hypertrophic scar is a drug for preventing the occurrence of keloid or hypertrophic scar.
  • the agent for preventing keloid or hypertrophic scar of the present invention is used for, for example, orthopedic surgery, plastic surgery, surgical operation, incision line marking of mammary surgery, confirmation of fistula, pressure ulcer.
  • Keloid or hypertrophic scar therapeutics are used to treat keloid or hypertrophic scars in patients who have already developed.
  • the therapeutic or preventive agent for keloids or hypertrophic scars may contain not only the active ingredient trehalose or a derivative of trehalose but also a drug having an anesthetic action, a drug for preventing inflammation, and the like.
  • trehalose derivatives are ⁇ -glucosyl trehalose, ⁇ -maltosyl trehalose, ⁇ -maltotriosyl trehalose, ⁇ -maltotetraosyl trehalose and ⁇ -maltopentaosyl trehalose. Of these, ⁇ -maltosyl trehalose is preferable.
  • drugs having anesthetic action are cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, propitocaine, bupivacaine, dipcaine, ethyl alcohol, and xylocaine.
  • drugs that prevent inflammation are steroidal anti-inflammatory drugs (eg, hydrocortisone) or non-steroidal anti-inflammatory drugs (NSAIDs).
  • the non-steroidal anti-inflammatory agent is preferably one in which NSAIDs and trehalose form an intermolecular compound.
  • NSAIDs examples include indomethacin, ibuprofen, aspirin, diclofenac sodium, mefenamic acid, piroxicam, felbinac, loxoprofen, ketoprofen, flurbibrofen, salicylate glycol, glycyrrhetinic acid, loxonin, suprofen, bufexamac, ufenoxalate, 5-profixate , Bufexamac, glycyrrhetinic acid, carbenoxolone and their derivatives.
  • steroidal anti-inflammatory agents are hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, prednisolone, prednisolone acetate, prednisolone acetate valerate, triamcinolone acetonide, fluocinolone acetonide, betamethasone valerate, and beclomethasone propionate These derivatives.
  • the therapeutic or prophylactic agent for keloid or hypertrophic scar may include an opioid.
  • opioids are morphine sulfate, morphine hydrochloride, oxycodone hydrochloride, fentanyl, codeine, pentazocine hydrochloride, and buprenorphine hydrochloride.
  • antibiotics and antibacterial agents may be added to the therapeutic or preventive agent for keloid or hypertrophic scar.
  • antibiotics are penicillins, cephems, carbapenems, tetracyclines, and aminoglycosides.
  • antibacterial agents are polylysine, 2- (4-thiocyanomethylthio) benzimidazole, polyhexamethylene biguanide and chlorhexidine glucuronate, triclosan, bis- (2-pyridylthio-1-oxide) zinc, 2,4,5, 6-tetrachloroisophthalonitrile, trichlorocarbanilide, 8-oxyquinoline, dehydroacetic acid, benzoates, chlorocresols, chlorothymol, chlorophene, dichlorophen, bromochlorophene, hexachlorophene.
  • the agent of the present invention may contain a glycosaminoglycan such as hyaluronic acid.
  • Examples of dosage forms of keloid or hypertrophic scar treatment or prevention agents are coating agents, sprays, injections, injections, ointments (cream-containing agents, gels), and patches.
  • the therapeutic or preventive agent for keloid or hypertrophic scars preferably contains one or more of phosphatidylcholine (lecithin), 2-methacryloyloxyethyl phosphorylcholine (MPC) and hyaluronic acid in the base.
  • Phosphatidylcholine (lecithin) is a major component of biological membranes.
  • 2-Methacryloyloxyethyl phosphorylcholine is effective as a component that protects the living body from dryness irritation, and can be used particularly as an ointment base or a gel material.
  • Hyaluronic acid can be used as a moisturizing ingredient.
  • “Applicant” is an agent for applying a liquid to a target part during use.
  • the “spraying agent” is an agent for administration by spraying a liquid on a target part.
  • the amount of trehalose used for application or spraying is not particularly limited.
  • the amount of trehalose used is, for example, 1 g or more and 100 g or less.
  • the coating agent and the spray can be produced by mixing a known solvent with trehalose. Examples of the solvent are physiological saline, distilled water and purified water.
  • injection is a preparation used by dissolving or suspending in a solution, suspension, emulsion, or solvent of a pharmaceutical that is directly applied to the body through the skin or through the skin or mucous membrane. Can be granted. Since an appropriate amount can be administered at an appropriate position, for example, even when a drug having a tissue necrosis effect is included, the tissue necrosis effect can be minimized.
  • the injection site can be injected directly into a site such as a tumor or keloid, or into the base of the tumor or keloid.
  • the tumor basal portion refers to the boundary region between the tumor portion and the normal cell portion, and the basal portion such as keloid refers to the boundary region between the keloid or the like and the normal cell portion.
  • an example of the number of local injections to the tumor site is 1 to 5 times a day, or 1 to 10 days a day.
  • the example of the amount of local injections per time is 0.1 to 10 g, preferably 0.1 to 1 g.
  • injection is a preparation used by dissolving or suspending in a solution, suspension, emulsion or solvent of a pharmaceutical directly applied to the skin, and the drug can be appropriately administered locally.
  • a therapeutic agent such as a tumor or keloid can be injected in the form of an injection, and the injection site can be injected directly into the tumor or keloid or the like, or into the base of the tumor.
  • “Ointment” refers to a semi-solid topical preparation with an appropriate consistency and full quality, and unlike an injection, it can cover the entire affected area, so it can be used regardless of the size of the affected area. Ointments are based on fat, fatty oil, lanolin, petrolatum, paraffin, wax, resin, plastic, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents, or other suitable additives, or Using these as base materials, trehalose is added and mixed to equalize the whole quality. Note that a preservative, an antioxidant, a wetting agent, and the like may be added to the ointment. There are kneading methods, melting methods, etc.
  • Ointments are classified into oily, emulsion, water-soluble, and suspension ointments depending on the base material, and any of these may be used. Oil-in-water type (burnishing cream) and water-in-oil type (cold cream) using emulsion base are called creams, but are included in ointments.
  • a drug capable of promoting percutaneous absorption in addition to trehalose which is an active ingredient, a drug capable of promoting percutaneous absorption may be added.
  • agents that promote percutaneous absorption include surfactants such as sodium lauryl sulfate and polyoxyethylene ether, alcohols such as oleyl alcohol, sorbitan esters such as sorbitan monolaurate, and the like. Instead, a known percutaneous absorption enhancer is used.
  • an anesthetic, an anti-inflammatory agent, an antibacterial agent, etc. may be added.
  • the ointment can be applied by simply rubbing it, applying it on a gauze or lint cloth, applying it in layers, overlaying two or more ointments on top of each other, applying ointment to the lesion, and slightly overcoating it.
  • There is a sealing bandage method that covers with a wide plastic and fixes the surrounding area with adhesive bandages, etc., and can be used depending on the condition of the affected area.
  • “Patches” include cataplasms and plasters that can be used easily.
  • the drug used for the patch the same drug as the ointment is used.
  • silicone gel sheets and polyethylene gel sheets are used for the treatment of keloids and hypertrophic scars.
  • compositions The drug of the present invention is combined with trehalose or a derivative of trehalose, which is an active ingredient, and one or more pharmaceutically acceptable carriers, excipients and diluents. It can be a thing.
  • trehalose a derivative of trehalose
  • each of the above-mentioned concomitant agents may be appropriately contained.
  • Carriers, excipients or diluents include, for example, physiological saline, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, silicic acid.
  • oils such as calcium, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like can be mentioned. Of these, physiological saline is preferable.
  • the agent of the present invention may contain a ceramide-like polymer as an active ingredient.
  • This polymer is obtained by polymerizing a monomer raw material containing a monomer having a high structural similarity with ceramide.
  • the polymer of the present invention have the formula (1) glycerol represented by (meth) acrylate (hereinafter, to monomer M 1), isobornyl represented by the formula (2) (meth) acrylate, benzyl (meth) acrylate , 2-methyl-2-adamantyl (meth) acrylate, 2-ethyl-2-adamantyl (meth) acrylate (hereinafter referred to as monomer M 2) and a cationic group-containing monomer represented by the formula (3) body is a polymer having a specific weight average molecular weight obtained by polymerizing at a specific ratio (hereinafter, the monomer M 3).
  • the polymer and the monomer M 1 5-90 mol% of the formula (1), a monomer M 2 of the formula (2) 5 to 90 mol% And a polymer obtained by polymerizing a monomer composition consisting of 3 to 80 mol% of the monomer M 3 represented by the formula (3) and M 1 + M 2 + M 3 of 100 mol%. is there.
  • the average molecular weight of the polymer is preferably 5,000 to 5,000,000.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents an alkyl group having 1 to 4 carbon atoms
  • R 3 represents an alkyl group having 1 to 8 carbon atoms.
  • (AO) represents the number of carbon atoms. Represents 2 to 4 oxyalkylene groups, and X is an integer of 0 to 1000.
  • R 4 represents a hydrogen atom or a methyl group
  • B represents an isobornyl group, a benzyl group, a phenoxyethyl group, a 2-methyl-2-adamantyl group, or a 2-ethyl-2-adamantyl group.
  • R 5 represents a hydrogen atom or a methyl group
  • L represents — (CH 2 ) n —L 1 , — (C ⁇ O) O— (CH 2 ) n —L 1 , — (C ⁇ O) O — ((CH 2 ) m —O) n —L 1 or —CH 2 CH (OH) CH 2 —L 1 , where n is 0 to 24, m is an integer of 2 to 5, L 1 represents an amino group, an ammonium base, a pyridyl group or a pyridinium base.
  • R 1 represents a hydrogen atom or a methyl group, and a methyl group is preferable from the viewpoint of high stability.
  • R 2 represents an alkylene group having 1 to 4 carbon atoms.
  • R 2 is specifically -CH 2 -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 - are either, -CH 2 CH 2 - is preferable.
  • R 3 represents an alkylene group having 1 to 8 carbon atoms.
  • R 3 is specifically -CH 2 -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 - can be mentioned, -CH 2 - are preferred.
  • (AO) represents an oxyalkylene group
  • A is an alkylene group having 2 to 4 carbon atoms.
  • the alkylene group of the oxyalkylene group is preferably an ethylene group.
  • X is an integer of 0 to 1000, and X is preferably 0 to 500.
  • the monomer of formula (1) is preferably glyceryl-1-methacryloyloxyethylurethane.
  • a monomeric M 1 5-90 mol% of the formula (1), and 5 to 90 mol% of the monomer M 2 of the formula (2) , 3 to 80 mol% of the monomer M 3 represented by the formula (3) and 50 mol% or less of the monomer M 4 other than the monomers M1 to M3, and M 1 + M 2 + M 3 + M 4 may be a polymer obtained by polymerizing a monomer composition is 100 mol%.
  • excessive granulation can be more effectively prevented by including the above-mentioned polymer having a high structural similarity with ceramide as an active ingredient.
  • An agent comprising an effective amount of the above-described polymer having a high structural similarity to ceramide as an active ingredient is effective for the treatment or prevention of keloid or hypertrophic scar.
  • trehalose or a derivative of trehalose and the above-mentioned copolymer can be mixed to obtain an agent containing an effective amount.
  • the pharmaceutical composition of the present invention can be used for oral or non-oral such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, skin patches, etc., depending on the pharmaceutical technology normally used. Prepared as an oral medicine.
  • a liquid or an injection is preferable, and specifically, an injection or a perfusate is more preferable.
  • a liquid agent may be obtained by mixing and stirring trehalose, a concomitant drug, and a diluent as appropriate. The obtained liquid agent may be enclosed in an ampoule, a prefilled syringe or a drug pack.
  • an administration method of the drug of the present invention one which applies or sprays 1 g or more and 10 g or less of trehalose or a derivative of trehalose once or several times a day to an adult patient (60 kg). It is done.
  • This specification also provides use of the agent of the present invention for producing a therapeutic agent and a preventive agent for keloid or hypertrophic scar.
  • the drug of the present invention each of the above drugs can be appropriately employed.
  • This specification also provides treatment and prevention of keloids or hypertrophic scars, including the step of administering the agent of the present invention to a subject.
  • the subject include humans or non-human mammals.
  • the “step of administering the drug of the present invention to a subject” includes a method of administering the drug of the present invention by applying or spraying the drug of the present invention to the affected area of the subject.
  • each of the above drugs can be appropriately employed.
  • the second aspect of the present invention relates to a tissue thickening inhibitor for respiratory tract lesions containing trehalose or a derivative of trehalose as an active ingredient.
  • This agent can also be used as an agent for preventing airway obstruction due to thickening of tissues in damaged airways.
  • Trehalose and trehalose derivatives are as described above.
  • trehalose or a derivative of trehalose can prevent excessive granulation, and thus can prevent airway obstruction due to thickening of the tissue of the damaged airway.
  • the tissue thickening inhibitor in the airway damage part may be applied to a medical instrument inserted into the airway as a gel or a coating agent, for example.
  • a medical instrument inserted into the airway as a gel or a coating agent, for example.
  • the tissue thickening caused by the medical device is prevented, and the situation where the airway is blocked due to the damage is effectively prevented.
  • a preferred embodiment of the tissue thickening inhibitor for this airway injury is a lubricating gel.
  • the tissue thickening inhibitor is a lubricating gel, it preferably contains 5% by weight or more and 20% by weight or less of trehalose or a derivative of trehalose.
  • the specific content of trehalose or trehalose derivative is 10% by weight.
  • a biocompatible gel can be used as appropriate. That is, a tissue thickening inhibitor that is a lubricating gel can be obtained by forming a gel as a carrier based on a known method and mixing trehalose or a derivative of trehalose as an active ingredient into the gel.
  • the tissue thickening inhibitor which is a lubricating gel
  • a medical device inserted into the respiratory tract.
  • a medical device with a tissue thickening inhibitor attached is inserted into the airway.
  • the gel surrounding the medical device protects the tissue and trehalose or a derivative of trehalose contained in the gel accumulates in the tracheal mucosa.
  • Accumulated trehalose or trehalose derivatives prevent complications after removing a medical device.
  • An example of this complication is airway obstruction due to tissue damage.
  • medical devices inserted into the airway are cuffed tubes, endotracheal tubes, bronchial tubes, tracheostomy tubes, laryngotracheal tubes, or esophageal tubes.
  • a cell disruption solution disrupted with a homogenizer was used as a model for cell disruption caused by trauma (including surgery). Macrophage cells were treated with a cell lysate to examine whether trehalose suppresses the induced TGF- ⁇ 1 production.
  • FIG. 1 is a graph showing the amount of TGF- ⁇ 1 produced.
  • the cell disruption solution prepared in physiological saline strongly induced the production of TGF- ⁇ 1 in a concentration-dependent manner, but the production of TGF- ⁇ 1 decreased under the conditions using trehalose. It was revealed that trehalose suppresses TGF- ⁇ 1 production.
  • FIGS. 1 and 3 are shown in FIGS.
  • FIG. 2 is a graph showing the amount of TNF- ⁇ produced.
  • FIG. 3 is a graph showing the amount of IL-1 ⁇ produced.
  • the cell disruption solution prepared in physiological saline strongly induces the production of TNF- ⁇ and IL-1 ⁇ in a concentration-dependent manner, but under conditions using trehalose, TNF- ⁇ Production and IL-1 ⁇ production were decreased. It was revealed that trehalose suppresses TNF- ⁇ production and IL-1 ⁇ production.
  • FIG. 4 is a graph showing the amount of PGE 2 produced.
  • the cell disruption solution prepared in physiological saline strongly induced PGE 2 production in a concentration-dependent manner, but PGE 2 production was decreased under conditions using trehalose. It was revealed that trehalose suppresses PGE 2 production.
  • FIG. 5 is a graph showing the amount of TNF- ⁇ produced.
  • TNF- ⁇ production decreased as the concentration of trehalose increased under the conditions using trehalose. That is, it was also confirmed that trehalose suppresses TNF- ⁇ production.
  • a keloid tissue is transplanted into a nude mouse, and the effect of trehalose inhibiting keloid growth is confirmed.
  • a transplant material in the culture solution (MEM + 10%) until transplanted with a tissue fragment removed from a keloid patient FCS + PC + SM) and stored in a cool dark place.
  • nude mice are 6 weeks old, and under anesthesia, finely sliced keloid tissue pieces are transplanted subcutaneously between the scapulae into 10 mice, one piece per mouse.
  • the size of the tumor in which the keloid tissue has grown three times a week is measured with a caliper.
  • the trehalose solution is injected three times at 0.1 g 1 hour intervals into 4 mouse tumors in the third month when the tumor size is stable.
  • Two control mice are injected three times in the same manner with 0.1 g each of physiological saline or mouse total serum.
  • For two mouse tumors apply trehalose solution three times.
  • Two mouse tumors are sprayed with trehalose solution three times and injected with trehalose solution three times at 0.1 g 1 hour intervals.
  • the tumor is removed from the mouse and fixed.
  • the present invention can be used in fields such as the pharmaceutical industry.

Abstract

[Problem] To provide a therapeutic and prophylactic agent for keloid or hypertrophic scar. [Solution] A therapeutic and prophylactic agent for keloid or hypertrophic scar, said agent comprising trehalose as the active ingredient. The aforesaid prophylactic agent for keloid or hypertrophic scar can be preferably used as an agent which is to be administered to a surgical site after surgery. As Example shows, the agent according to the present invention can effectively cure keloid or hypertrophic scar and prevent the same due to trehalose that is contained therein as the active ingredient.

Description

ケロイド又は肥厚性瘢痕の治療剤又は予防剤，気道損傷部の組織肥厚抑制剤Therapeutic or preventive agent for keloid or hypertrophic scar, tissue thickening inhibitor for airway injury
　本発明は，トレハロース又はトレハロースの誘導体を含有するケロイド又は肥厚性瘢痕の予防・治療剤などに関する。 The present invention relates to a preventive / therapeutic agent for keloids or hypertrophic scars containing trehalose or trehalose derivatives.
　創傷や組織損傷によって，血液凝固カスケードが活性化し，炎症反応が昂進する。その後，繊維芽細胞によって組織再生の土台となる肉芽形成が行われ，アクチンフィラメントに富む筋繊維芽細胞により創傷の最終的な修復がなされる。このとき，創部の大きさ，体質，感染などの影響によって，肥厚性瘢痕やケロイドが生じる。ケロイド及び肥厚性瘢痕は，外傷・熱傷・手術等の創傷後に形成される瘢痕である。 Wound and tissue damage activates the blood coagulation cascade and promotes inflammatory reaction. Thereafter, granulation forms the basis for tissue regeneration by fibroblasts, and the wound is finally repaired by myofibroblasts rich in actin filaments. At this time, hypertrophic scars and keloids are produced due to the influence of the size, constitution, and infection of the wound. Keloids and hypertrophic scars are scars that form after wounds such as trauma, burns, and surgery.
　ケロイド，肥厚性瘢痕治療薬として，トラニラスト（商品名「リザベン（登録商標）」）が知られている。しかしながら，トラニラストは，副作用として出血性膀胱炎様症状を惹起することがある。 ト ラ Tranilast (trade name “Rizaben (registered trademark)”) is known as a keloid and hypertrophic scar treatment. However, tranilast may cause hemorrhagic cystitis-like symptoms as a side effect.
　また，保湿クリームや保湿剤がケロイドの治療に有効であるとされている（特許文献１）。しかしながら，保湿クリームや保湿剤によるケロイドの治療効果はそれほど強力ではない。 Moreover, it is said that moisturizing creams and moisturizing agents are effective for the treatment of keloids (Patent Document 1). However, the therapeutic effect of keloids by moisturizing creams and moisturizers is not so strong.
　エリスロポエチン拮抗物質もケロイド，肥厚性瘢痕の形成抑制に効果があるとされている（例えば，特許文献２を参照）。しかしながら，エリスロポエチン拮抗物質はタンパク製剤であり，取り扱いが困難である。 An erythropoietin antagonist is also said to be effective in suppressing the formation of keloids and hypertrophic scars (see, for example, Patent Document 2). However, erythropoietin antagonists are protein preparations and are difficult to handle.
　瘢痕形成や組織の線維化は，損傷組織の病理的修復の結果であり，その過程において，損傷部位や線維細胞の異常な増殖およびコラ－ゲンの大量合成や沈着が見られる。この修復過程においてトランスフォ－ミング成長因子（ＴＧＦ－β）は重要な役割を果たしている（例えば，特許文献３，特許文献４，特許文献５を参照）。すなわち，肥厚性瘢痕やケロイドが生じる上で重要な働きをするものは，ＴＧＦ－β及びＭＡＰカイネースパスウェイによる炎症性サイトカイン産生の上昇(非特許文献１)である。 Scar formation and tissue fibrosis are the result of pathological repair of damaged tissue, and in the process, abnormal growth of damaged sites and fiber cells and mass synthesis and deposition of collagen are observed. In this repair process, transforming growth factor (TGF-β) plays an important role (see, for example, Patent Document 3, Patent Document 4, and Patent Document 5). That is, what plays an important role in producing hypertrophic scars and keloids is an increase in inflammatory cytokine production by TGF-β and MAP kinase pathway (Non-patent Document 1).
　このような観点からＴＧＦ－βの阻害剤を用いたケロイド又は肥厚性瘢痕の治療剤又は予防剤が提案されている（特許文献６を参照）。 From such a viewpoint, a therapeutic or preventive agent for keloids or hypertrophic scars using an inhibitor of TGF-β has been proposed (see Patent Document 6).
　また，肥厚性瘢痕やケロイドが生じる上で重要な働きをするものとして,ＴＮＦ－αによるＮＦ-κＢの活性化 (非特許文献２)があげられる。また，近年，外傷などによって生じる細胞死に伴う無菌性炎症反応に，ＩＬ－1α及びＩＬ－1βが関わっているという報告がある (非特許文献３及び非特許文献４) Also, as an important function in producing hypertrophic scars and keloids, NF-κB activation by TNF-α (Non-patent Document 2) can be mentioned. In recent years, there have been reports that IL-1α and IL-1β are involved in the sterile inflammatory reaction accompanying cell death caused by trauma or the like (Non-patent Document 3 and Non-patent Document 4).
　さらに，ＰＰＡＲγのアゴニストを用いたケロイド又は肥厚性瘢痕の治療剤又は予防剤も提案されている（特許文献７を参照）。 Furthermore, a therapeutic or prophylactic agent for keloids or hypertrophic scars using an agonist of PPARγ has also been proposed (see Patent Document 7).
　一方，医療用樹脂製製品は広く知られており，様々な医療現場で用いられている。しかし，特に塩化ビニル製の医療用樹脂製製品を使用すると原因不明の炎症を惹起するなどの問題がある。医療用樹脂製製品の例は，呼吸補助チューブである。 On the other hand, medical resin products are widely known and used in various medical settings. However, the use of medical resin products made of vinyl chloride, in particular, causes problems such as causing unexplained inflammation. An example of a medical plastic product is a breathing assistance tube.
　従来，呼吸補助チューブは，手術の際に広く使用されている。例えば，特開２００３－１０２８２７号(特許文献８)には，熱可塑性材料で製造された気管チューブが開示されている。特開２００３－１０２８２７号に開示された気管チューブは，反撥性が小さい。このため，気管内チューブを気管に挿入した際に生ずる痛みを抑えることができる。 Conventionally, breathing assistance tubes have been widely used during surgery. For example, Japanese Patent Application Laid-Open No. 2003-102827 (Patent Document 8) discloses a tracheal tube made of a thermoplastic material. The tracheal tube disclosed in Japanese Patent Application Laid-Open No. 2003-102827 has low repulsion. For this reason, the pain which arises when an endotracheal tube is inserted in a trachea can be suppressed.
　しかし，呼吸補助チューブは，組織粘膜との接着性が高い。このため，呼吸補助チューブを取り外すとき，呼吸補助チューブが接着していた組織表面の細胞がはがれてしまう。痰の喀出困難や，呼吸補助チューブ使用後に，気管組織への炎症が生じるという問題がある。 However, the respiratory assistance tube has high adhesion to the tissue mucosa. For this reason, when the respiratory assistance tube is removed, the cells on the tissue surface to which the respiratory assistance tube has adhered are peeled off. Difficulty in sputation of sputum and inflammation of tracheal tissue after use of respiratory aid tube.
　また，呼吸補助チューブを取り外すときに気管壁の細胞に加え，繊毛が剥離してしまう。これにより，患者は痰を排出することができなくなる。そして，痰が肺に逆流することで，肺炎を惹き起こすという問題もあった。 Also, when removing the breathing assistance tube, cilia peel off in addition to the cells on the tracheal wall. This prevents the patient from discharging sputum. And there was a problem that sputum caused pneumonia by flowing back into the lungs.
　さらには，気道に損傷が生ずると，気道損傷部の組織が肥厚化し，その結果気道を閉塞するという問題もあった。 Furthermore, when the airway is damaged, the tissue of the damaged airway becomes thickened, resulting in a problem that the airway is blocked.
特開平７－１４９６２７号公報Japanese Patent Laid-Open No. 7-149627 特開２００２－３２６９５８号公報JP 2002-326958 A 特表２００３－５０９０３０号公報Special table 2003-509030 gazette 特表２０００－５００６４３号公報Special Table 2000-500643 特表平０８－５０４５７７号公報Japanese National Patent Publication No. 08-504577 特開２００７－０８４４４６号公報JP 2007-084446 A 特開２００９－０９６８０５号公報JP 2009-096805 A 特開２００３－１０２８２７JP 2003-102827 A
　本発明は，過剰な肉芽形成を防止するための治療剤又は予防剤を提供することを目的とする。本発明は，副作用が少なく，ケロイド又は肥厚性瘢痕の治療剤又は予防剤を提供することを目的とする。 An object of the present invention is to provide a therapeutic or preventive agent for preventing excessive granulation. An object of the present invention is to provide a therapeutic or preventive agent for keloids or hypertrophic scars with few side effects.
　本発明は，副作用が少なく，有効な気道損傷部の組織肥厚抑制剤を提供することを目的とする。 The object of the present invention is to provide an effective tissue thickening inhibitor for airway damage sites with few side effects.
　本発明は，基本的には，トレハロース又はトレハロースの誘導体を含有した薬剤を用いることで，過剰な肉芽形成を防止でき，ケロイド又は肥厚性瘢痕の治療剤又は予防剤や気道損傷部の組織肥厚抑制剤を提供できるという知見に基づく。 In the present invention, by using a drug containing trehalose or a derivative of trehalose, excessive granulation can be prevented, and a therapeutic or preventive agent for keloid or hypertrophic scar, or suppression of tissue thickening in an airway injury site. Based on the knowledge that the agent can be provided.
　本発明の第一の側面は，トレハロース又はトレハロースの誘導体を有効成分として含有するケロイド又は肥厚性瘢痕の治療剤又は予防剤に関する。後述する実施例により示された通り，トレハロース又はトレハロースの誘導体は，過剰な肉芽形成を防止できるので，トレハロース又はトレハロースの誘導体を有効成分として有効量含む剤は，ケロイド又は肥厚性瘢痕の治療又は予防に有効である。 The first aspect of the present invention relates to a therapeutic or preventive agent for keloid or hypertrophic scar containing trehalose or a derivative of trehalose as an active ingredient. As shown by the examples described later, trehalose or a derivative of trehalose can prevent excessive granulation, so that an agent containing an effective amount of trehalose or a derivative of trehalose as an active ingredient is used for the treatment or prevention of keloid or hypertrophic scar. It is effective for.
　また，この剤は，施術後の施術部に投与される剤であることが好ましい。この剤の剤型の例は，液剤である。液剤として噴霧剤が好ましい。 In addition, this agent is preferably an agent administered to the treatment site after the treatment. An example of the dosage form of this agent is a liquid agent. A spray is preferred as the liquid.
　本発明の第二の側面は，トレハロース又はトレハロースの誘導体を有効成分として含有する気道損傷部の組織肥厚抑制剤に関する。後述する実施例により示された通り，トレハロース又はトレハロースの誘導体は，過剰な肉芽形成を防止できるので，本発明の剤は，気道損傷部の組織肥厚抑制剤として有効である。この剤は，気道損傷部の組織が肥厚することによる気道閉塞を防止するための剤としても利用されうる。 The second aspect of the present invention relates to a tissue thickening inhibitor for respiratory tract lesions containing trehalose or a derivative of trehalose as an active ingredient. As shown in the examples described later, trehalose or a derivative of trehalose can prevent excessive granulation, so that the agent of the present invention is effective as a tissue thickening inhibitor in airway damage sites. This agent can also be used as an agent for preventing airway obstruction due to thickening of tissues in damaged airways.
　後述する実施例により実証されたとおり，有効成分としてトレハロース又はトレハロースの誘導体を含有する本発明の薬剤は，過剰な肉芽形成を防止できるので，ケロイド又は肥厚性瘢痕の治療及び予防に有効であった。よって，本発明によれば，ケロイド又は肥厚性瘢痕の治療剤又は予防剤を提供できる。 As demonstrated by the examples described below, the drug of the present invention containing trehalose or a derivative of trehalose as an active ingredient was effective in the treatment and prevention of keloid or hypertrophic scar because it can prevent excessive granulation. . Therefore, according to the present invention, a therapeutic or prophylactic agent for keloid or hypertrophic scar can be provided.
　有効成分としてトレハロース又はトレハロースの誘導体を含有する本発明の薬剤は，副作用が少なく，有効な気道損傷部の組織が肥厚することを有効に防止する。 The agent of the present invention containing trehalose or a trehalose derivative as an active ingredient has few side effects and effectively prevents thickening of an effective airway injury tissue.
図１は，ＴＧＦ－β１の産生量を示すグラフである。FIG. 1 is a graph showing the amount of TGF-β1 produced. 図２は，ＴＮＦ－αの産生量を示すグラフである。FIG. 2 is a graph showing the amount of TNF-α produced. 図３は，ＩＬ－１αの産生量を示すグラフである。FIG. 3 is a graph showing the amount of IL-1α produced. 図４は，ＰＧＥ２の産生量を示すグラフである。FIG. 4 is a graph showing the amount of PGE 2 produced. 図５は，ＴＮＦ－αの産生量を示すグラフである。FIG. 5 is a graph showing the amount of TNF-α produced.
　先に説明したとおり，本発明の第１の側面は，ケロイド又は肥厚性瘢痕の治療剤又は予防剤に関する。この発明のケロイド又は肥厚性瘢痕の治療剤又は予防剤は，トレハロース又はトレハロースの誘導体を有効成分として有効量含むことで，過剰な肉芽形成を防止し，ケロイド又は肥厚性瘢痕の治療剤又は予防剤として有効であるというものである。 As described above, the first aspect of the present invention relates to a therapeutic or preventive agent for keloids or hypertrophic scars. The therapeutic or preventive agent for keloids or hypertrophic scars of the present invention contains an effective amount of trehalose or a derivative of trehalose as an active ingredient, thereby preventing excessive granulation and preventing or preventing keloids or hypertrophic scars. It is effective as.
　ケロイド又は肥厚性瘢痕の予防剤はケロイド又は肥厚性瘢痕が生じる事態を予防するための薬剤である。本発明のケロイド又は肥厚性瘢痕の予防剤は，たとえば整形外科，形成外科，外科の手術や，乳腺外科の切開線のマーキング，瘻孔の確認，褥瘡に用いられる。ケロイド又は肥厚性瘢痕の治療剤は，すでに生じてしまった患者のケロイド又は肥厚性瘢痕を治療するために用いられる。 The agent for preventing keloid or hypertrophic scar is a drug for preventing the occurrence of keloid or hypertrophic scar. The agent for preventing keloid or hypertrophic scar of the present invention is used for, for example, orthopedic surgery, plastic surgery, surgical operation, incision line marking of mammary surgery, confirmation of fistula, pressure ulcer. Keloid or hypertrophic scar therapeutics are used to treat keloid or hypertrophic scars in patients who have already developed.
　ケロイド又は肥厚性瘢痕の治療剤又は予防剤には，有効成分であるトレハロース又はトレハロースの誘導体のみならず，麻酔作用を有する薬剤や，炎症を防止する薬剤等が添加されていてもよい。 The therapeutic or preventive agent for keloids or hypertrophic scars may contain not only the active ingredient trehalose or a derivative of trehalose but also a drug having an anesthetic action, a drug for preventing inflammation, and the like.
　トレハロース誘導体の例は，α－グルコシルトレハロース，α－マルトシルトレハロース，α－マルトトリオシルトレハロース，α－マルトテトラオシルトレハロース及びα－マルトペンタオシルトレハロースである。これらの中では，α－マルトシルトレハロースが好ましい。 Examples of trehalose derivatives are α-glucosyl trehalose, α-maltosyl trehalose, α-maltotriosyl trehalose, α-maltotetraosyl trehalose and α-maltopentaosyl trehalose. Of these, α-maltosyl trehalose is preferable.
　麻酔作用を有する薬剤の例は，コカイン，プロカイン，クロロプロカイン，テトラカイン，リドカイン，メピバカイン，プロピトカイン，ブピバカイン，ジプカイン，エチルアルコール，キシロカインである。また，炎症を防止する薬剤の例は，ステロイド性抗炎症剤（たとえば，ヒドロコルチゾン），又は非ステロイド性抗炎症剤（ＮＳＡＩＤｓ）である。ここで，非ステロイド性抗炎症剤は，ＮＳＡＩＤｓとトレハロースとが分子間化合物を形成したものが好ましい。ＮＳＡＩＤｓの例は，インドメタシン，イブプロフェン，アスピリン，ジクロフェナクナトリウム，メフェナム酸，ピロキシカム，フェルビナク，ロキソプロフェン，ケトプロフェン，フルルビブロフェン，サリチル酸グリコール，グリチルレチン酸，ロキソニン，スプロフェン，ブフェキサマク，ウフェナマート，５－アミノサルチル酸，ナプロキセン，ブフェキサマク，グリチルレチン酸，カルベノキソロン及びこれらの誘導体である。ステロイド性抗炎症剤の例は，ヒドロコルチゾン，酢酸ヒドロコルチゾン，酪酸ヒドロコルチゾン，デキサメタゾン，酢酸デキサメタゾン，プレドニゾロン，酢酸プレドニゾロン，吉草酸酢酸プレドニゾロン，トリアムシノロンアセトニド，フルオシノロンアセトニド，吉草酸ベタメタゾン，プロピオン酸ベクロメタゾン及びこれらの誘導体である。ケロイド又は肥厚性瘢痕の治療剤又は予防剤には，オピオイドが含まれていてもよい。オピオイドの例は，硫酸モルヒネ，塩酸モルヒネ，塩酸オキシコドン，フェンタニル，コデイン，塩酸ペンタゾシン，及びブプレノルフィン塩酸塩である。 Examples of drugs having anesthetic action are cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, propitocaine, bupivacaine, dipcaine, ethyl alcohol, and xylocaine. Examples of drugs that prevent inflammation are steroidal anti-inflammatory drugs (eg, hydrocortisone) or non-steroidal anti-inflammatory drugs (NSAIDs). Here, the non-steroidal anti-inflammatory agent is preferably one in which NSAIDs and trehalose form an intermolecular compound. Examples of NSAIDs are indomethacin, ibuprofen, aspirin, diclofenac sodium, mefenamic acid, piroxicam, felbinac, loxoprofen, ketoprofen, flurbibrofen, salicylate glycol, glycyrrhetinic acid, loxonin, suprofen, bufexamac, ufenoxalate, 5-profixate , Bufexamac, glycyrrhetinic acid, carbenoxolone and their derivatives. Examples of steroidal anti-inflammatory agents are hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, prednisolone, prednisolone acetate, prednisolone acetate valerate, triamcinolone acetonide, fluocinolone acetonide, betamethasone valerate, and beclomethasone propionate These derivatives. The therapeutic or prophylactic agent for keloid or hypertrophic scar may include an opioid. Examples of opioids are morphine sulfate, morphine hydrochloride, oxycodone hydrochloride, fentanyl, codeine, pentazocine hydrochloride, and buprenorphine hydrochloride.
　ケロイド又は肥厚性瘢痕の治療剤又は予防剤には，細菌感染を防止するために，抗生物質や抗菌剤が添加されていてもよい。抗生物質の例は，ペニシリン系薬剤，セフェム系薬剤，カルバペネム系薬剤，テトラサイクリン系薬剤，及びアミノグリコシド系薬剤である。抗菌剤の例は，ポリリジン，2-(4-チオシアノメチルチオ)ベンズイミダゾール，ポリヘキサメチレンビグアニド及びグルクロン酸クロルヘキシジン，トリクロサン，ビス-(2-ピリジルチオ－１－オキシド）亜鉛，2,4,5,6-テトラクロロイソフタロニトリル，トリクロロカルバニリド，8-オキシキノリン，デヒドロ酢酸，安息香酸エステル類，クロロクレゾール類，クロロチモール，クロロフェン，ジクロロフェン，ブロモクロロフェン，ヘキサクロロフェンである。さらに，本発明の剤は，ヒアルロン酸などのグリコサミノグリカンを含んでもよい。 In order to prevent bacterial infection, antibiotics and antibacterial agents may be added to the therapeutic or preventive agent for keloid or hypertrophic scar. Examples of antibiotics are penicillins, cephems, carbapenems, tetracyclines, and aminoglycosides. Examples of antibacterial agents are polylysine, 2- (4-thiocyanomethylthio) benzimidazole, polyhexamethylene biguanide and chlorhexidine glucuronate, triclosan, bis- (2-pyridylthio-1-oxide) zinc, 2,4,5, 6-tetrachloroisophthalonitrile, trichlorocarbanilide, 8-oxyquinoline, dehydroacetic acid, benzoates, chlorocresols, chlorothymol, chlorophene, dichlorophen, bromochlorophene, hexachlorophene. Furthermore, the agent of the present invention may contain a glycosaminoglycan such as hyaluronic acid.
　ケロイド又は肥厚性瘢痕の治療剤又は予防剤の剤型の例は，塗布剤，噴霧剤，注射剤，注入剤，軟膏剤（含クリーム剤，ゲル剤），貼付剤である。ケロイド又は肥厚性瘢痕の治療剤又は予防剤は，基剤中に，ホスファチジルコリン（レシチン），２－メタクリロイルオキシエチルホスホリルコリン（ＭＰＣ）及びヒアルロン酸のいずれか１つ以上含むものが好ましい。ホスファチジルコリン（レシチン）は，生体膜の主要成分である。２－メタクリロイルオキシエチルホスホリルコリンは，乾燥刺激から生体を守る成分として有効であり，特に軟膏基材やゲル材料として使用できる。ヒアルロン酸は，保湿成分として利用できる。 Examples of dosage forms of keloid or hypertrophic scar treatment or prevention agents are coating agents, sprays, injections, injections, ointments (cream-containing agents, gels), and patches. The therapeutic or preventive agent for keloid or hypertrophic scars preferably contains one or more of phosphatidylcholine (lecithin), 2-methacryloyloxyethyl phosphorylcholine (MPC) and hyaluronic acid in the base. Phosphatidylcholine (lecithin) is a major component of biological membranes. 2-Methacryloyloxyethyl phosphorylcholine is effective as a component that protects the living body from dryness irritation, and can be used particularly as an ointment base or a gel material. Hyaluronic acid can be used as a moisturizing ingredient.
　「塗布剤」とは，使用に際して対象部に液体を塗布するための剤である。「噴霧剤」とは，対象部に液体を噴霧することにより投与するための剤である。塗布又は噴霧に用いられるトレハロースの量は特に限定されない。トレハロースの使用量は，たとえば１ｇ以上１００ｇ以下である。塗布剤及び噴霧剤は，トレハロースに公知の溶媒を混合することで製造できる。溶媒の例は，生理食塩水，蒸留水及び精製水である。 “Applicant” is an agent for applying a liquid to a target part during use. The “spraying agent” is an agent for administration by spraying a liquid on a target part. The amount of trehalose used for application or spraying is not particularly limited. The amount of trehalose used is, for example, 1 g or more and 100 g or less. The coating agent and the spray can be produced by mixing a known solvent with trehalose. Examples of the solvent are physiological saline, distilled water and purified water.
　「注射剤」とは，皮膚内又は皮膚若しくは粘膜を通して体内に直接適用する医薬品の溶液，懸濁液，乳濁液または溶剤に溶解もしくは懸濁して用いる製剤であり，局所に適量の当該薬剤を付与することができる。適所に適量投与しうることから，たとえば，組織壊死作用を有する薬剤を含む場合であっても，組織壊死作用を最小限とすることができる。注射部位は腫瘍・ケロイド等部位に直接，又は腫瘍・ケロイド等の基底部等に注射することができる。なお，腫瘍基底部とは，腫瘍部と正常細胞部の境界領域を，ケロイド等の基底部とは，ケロイド等と正常細胞部の境界領域をいう。 An “injection” is a preparation used by dissolving or suspending in a solution, suspension, emulsion, or solvent of a pharmaceutical that is directly applied to the body through the skin or through the skin or mucous membrane. Can be granted. Since an appropriate amount can be administered at an appropriate position, for example, even when a drug having a tissue necrosis effect is included, the tissue necrosis effect can be minimized. The injection site can be injected directly into a site such as a tumor or keloid, or into the base of the tumor or keloid. The tumor basal portion refers to the boundary region between the tumor portion and the normal cell portion, and the basal portion such as keloid refers to the boundary region between the keloid or the like and the normal cell portion.
　注射剤を使用する場合にあっては，腫瘍部位への局所注射回数の例は，１日１回以上５回以下，又は１日以上１０日以下に１回の割合である。また，１回当たりの局所注射剤量の例は０．１ｇ以上１０ｇ以下，好ましくは０．１ｇ以上１ｇ以下である。 In the case of using an injection, an example of the number of local injections to the tumor site is 1 to 5 times a day, or 1 to 10 days a day. Moreover, the example of the amount of local injections per time is 0.1 to 10 g, preferably 0.1 to 1 g.
　「注入剤」とは，皮膚内に直接適用する医薬品の溶液，懸濁液，乳濁液又は溶剤に溶解もしくは懸濁して用いる製剤であり，局所に当該薬剤を適切に投与しうる。腫瘍・ケロイド等治療剤を注入剤の形で，注入部位は腫瘍・ケロイド等部位に直接，又は腫瘍の基底部に注入することができる。 “Injection” is a preparation used by dissolving or suspending in a solution, suspension, emulsion or solvent of a pharmaceutical directly applied to the skin, and the drug can be appropriately administered locally. A therapeutic agent such as a tumor or keloid can be injected in the form of an injection, and the injection site can be injected directly into the tumor or keloid or the like, or into the base of the tumor.
　「軟膏剤」とは，適当な稠度の全質均等な半固形状の外用剤をいい，注入剤とは異なり，患部全体を覆い得ることから，患部の大小に係わらず対応することができる。軟膏剤は，脂肪，脂肪油，ラノリン，ワセリン，パラフィン，ろう，樹脂，プラスティック，グリコール類，高級アルコール，グリセリン，水，乳化剤，懸濁化剤，または他の適当な添加剤を原料とし，またはこれらを基材とし，トレハロースを加え，混和して全質を均等にしたものである。なお，軟膏剤には，保存剤，酸化防止剤，湿潤剤等が添加されていてもよい。また，軟膏の調剤法としては練合法，溶融法等があるが，そのいずれを用いるかは，基材により適合した方法が採られる。軟膏は，基材により油脂性，乳剤性，水溶性，懸濁性軟膏に分類されるが，これらのいずれであってもよい。なお，乳剤性基剤を用いた，水中油滴型（バニシングクリーム）・油中水滴型（コールドクリーム）はクリーム剤と称されるが，軟膏剤に含まれる。 “Ointment” refers to a semi-solid topical preparation with an appropriate consistency and full quality, and unlike an injection, it can cover the entire affected area, so it can be used regardless of the size of the affected area. Ointments are based on fat, fatty oil, lanolin, petrolatum, paraffin, wax, resin, plastic, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents, or other suitable additives, or Using these as base materials, trehalose is added and mixed to equalize the whole quality. Note that a preservative, an antioxidant, a wetting agent, and the like may be added to the ointment. There are kneading methods, melting methods, etc. as methods for dispensing ointments. Whichever method is used, a method suited to the base material is adopted. Ointments are classified into oily, emulsion, water-soluble, and suspension ointments depending on the base material, and any of these may be used. Oil-in-water type (burnishing cream) and water-in-oil type (cold cream) using emulsion base are called creams, but are included in ointments.
　軟膏剤にあっては，有効成分であるトレハロース以外にも，経皮吸収を促進させうる薬剤を添加してもよい。経皮吸収を促進させる薬剤としては，たとえば，ラウリル硫酸ナトリウム，ポリオキシエチレンエーテル等の界面活性剤，オレイルアルコール等のアルコール類，モノラウリン酸ソルビタン等のソルビタンエステル類等が挙げられるが，これらに制限されるものではなく，公知の経皮吸収促進剤が用いられる。
また，麻酔剤や抗炎症剤，抗菌剤等が添加されていてもよい。 In the case of an ointment, in addition to trehalose which is an active ingredient, a drug capable of promoting percutaneous absorption may be added. Examples of agents that promote percutaneous absorption include surfactants such as sodium lauryl sulfate and polyoxyethylene ether, alcohols such as oleyl alcohol, sorbitan esters such as sorbitan monolaurate, and the like. Instead, a known percutaneous absorption enhancer is used.
Moreover, an anesthetic, an anti-inflammatory agent, an antibacterial agent, etc. may be added.
　また，軟膏剤の使用方法は，単純に擦りこむ塗布法，ガーゼ又はリント布などに厚めにのばして貼り付ける貼付法，２種類以上の軟膏を重ねる重層法，病巣に軟膏を塗りその上をやや広めのプラスティックで覆い，周囲を絆創膏などで固定する密封包帯法などがあり，患部の状態に応じて使い分けられる。 The ointment can be applied by simply rubbing it, applying it on a gauze or lint cloth, applying it in layers, overlaying two or more ointments on top of each other, applying ointment to the lesion, and slightly overcoating it. There is a sealing bandage method that covers with a wide plastic and fixes the surrounding area with adhesive bandages, etc., and can be used depending on the condition of the affected area.
　「貼付剤」には，パップ剤やプラスター剤があり，簡便に使用することができる。また，貼付剤に用いられる薬剤としては，軟膏剤と同様の薬剤が使用される。特に，ケロイド及び肥厚性瘢痕の治療には，たとえばシリコンジェルシート，及びポリエチレンジェルシートが用いられており “Patches” include cataplasms and plasters that can be used easily. In addition, as the drug used for the patch, the same drug as the ointment is used. In particular, silicone gel sheets and polyethylene gel sheets are used for the treatment of keloids and hypertrophic scars.
　医薬組成物
　本発明の薬剤は，有効成分であるトレハロース又はトレハロースの誘導体と，１種又は２種以上の薬学的に許容される担体，賦形剤及び希釈剤と組み合わされて薬剤又は医薬的組成物とされうる。また，トレハロース以外に，上記した各併用剤を適宜含有してもよい。また，担体，賦形剤又は希釈剤としては，例えば，生理食塩水，水，乳糖，デキストロース，フラクトース，ショ糖，ソルビトール，マンニトール，ポリエチレングリコール，プロピレングリコール，でんぷん，ガム，ゼラチン，アルギネート，ケイ酸カルシウム，リン酸カルシウム，セルロース，水シロップ，メチルセルロース，ポリビニルピロリドン，アルキルパラヒドロキシベンゾエート，タルク，ステアリン酸マグネシウム，ステアリン酸，グリセリン，ゴマ油，オリーブ油，大豆油などの各種油があげられる。これらの中では，生理食塩水が好ましい。 Pharmaceutical composition The drug of the present invention is combined with trehalose or a derivative of trehalose, which is an active ingredient, and one or more pharmaceutically acceptable carriers, excipients and diluents. It can be a thing. In addition to trehalose, each of the above-mentioned concomitant agents may be appropriately contained. Carriers, excipients or diluents include, for example, physiological saline, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, silicic acid. Various oils such as calcium, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like can be mentioned. Of these, physiological saline is preferable.
　本発明の薬剤は，有効成分として，セラミド類似の重合体を含んでも良い。この重合体は，セラミドと高い構造類似性を有する単量体を含む単量体原料を重合したものである。本発明の重合体は，式（１）で示されるグリセロール（メタ）アクリレート（以下，単量体Ｍ１とする）と，式（２）で示されるイソボルニル（メタ）アクリレート，ベンジル（メタ）アクリレート，２－メチル－２－アダマンチル（メタ）アクリレート，２－エチル－２－アダマンチル（メタ）アクリレート（以下，単量体Ｍ２とする）と，式（３）で示されるカチオン性基含有単量体（以下，単量体Ｍ３とする）を特定割合で重合して得られる特定の重量平均分子量を有する重合体である。
　具体的には，この重合体は，式（１）で表される単量体Ｍ１を５～９０モル％と，式（２）で表される単量体Ｍ２を５～９０モル％と，式（３）で表される単量体Ｍ３を３～８０モル％からなり，Ｍ１＋Ｍ２＋Ｍ３が１００モル％である単量体組成物を重合して得られる重合体である。重合体の平均分子量は，５，０００～５，０００，０００であることが好ましい。 The agent of the present invention may contain a ceramide-like polymer as an active ingredient. This polymer is obtained by polymerizing a monomer raw material containing a monomer having a high structural similarity with ceramide. The polymer of the present invention have the formula (1) glycerol represented by (meth) acrylate (hereinafter, to monomer M 1), isobornyl represented by the formula (2) (meth) acrylate, benzyl (meth) acrylate , 2-methyl-2-adamantyl (meth) acrylate, 2-ethyl-2-adamantyl (meth) acrylate (hereinafter referred to as monomer M 2) and a cationic group-containing monomer represented by the formula (3) body is a polymer having a specific weight average molecular weight obtained by polymerizing at a specific ratio (hereinafter, the monomer M 3).
Specifically, the polymer and the monomer M 1 5-90 mol% of the formula (1), a monomer M 2 of the formula (2) 5 to 90 mol% And a polymer obtained by polymerizing a monomer composition consisting of 3 to 80 mol% of the monomer M 3 represented by the formula (3) and M 1 + M 2 + M 3 of 100 mol%. is there. The average molecular weight of the polymer is preferably 5,000 to 5,000,000.
Figure JPOXMLDOC01-appb-C000001
  
（式（１）中，Ｒ１は水素原子またはメチル基を示し，Ｒ２は炭素数１～４のアルキル基，Ｒ３は炭素数１～８のアルキル基を示す。（ＡＯ）は炭素数２～４のオキシアルキレン基を示し，Ｘは０～１０００の整数である。）
Figure JPOXMLDOC01-appb-C000001
(In Formula (1), R 1 represents a hydrogen atom or a methyl group, R 2 represents an alkyl group having 1 to 4 carbon atoms, and R 3 represents an alkyl group having 1 to 8 carbon atoms. (AO) represents the number of carbon atoms. Represents 2 to 4 oxyalkylene groups, and X is an integer of 0 to 1000.)
Figure JPOXMLDOC01-appb-C000002
  
（式（２）中，Ｒ４は水素原子またはメチル基を示し，Ｂはイソボルニル基，ベンジル基，フェノキシエチル基，２－メチル－２－アダマンチル基，２－エチル－２－アダマンチル基が選ばれる基である。）
Figure JPOXMLDOC01-appb-C000002
(In the formula (2), R 4 represents a hydrogen atom or a methyl group, and B represents an isobornyl group, a benzyl group, a phenoxyethyl group, a 2-methyl-2-adamantyl group, or a 2-ethyl-2-adamantyl group. Group.)
Figure JPOXMLDOC01-appb-C000003
  
（式（３）中，Ｒ５は水素原子またはメチル基を示し，Ｌは－（ＣＨ２）ｎ－Ｌ１，－（Ｃ＝Ｏ）Ｏ－（ＣＨ２）ｎ－Ｌ１，－（Ｃ＝Ｏ）Ｏ－（（ＣＨ２）ｍ－Ｏ）ｎ－Ｌ１または－ＣＨ２ＣＨ（ＯＨ）ＣＨ２－Ｌ１である。ｎは０～２４，ｍは２～５の整数を示し，Ｌ１はアミノ基，アンモニウム塩基，ピリジル基またはピリジニウム塩基を示す。）
Figure JPOXMLDOC01-appb-C000003
(In formula (3), R 5 represents a hydrogen atom or a methyl group, and L represents — (CH 2 ) n —L 1 , — (C═O) O— (CH 2 ) n —L 1 , — (C ═O) O — ((CH 2 ) m —O) n —L 1 or —CH 2 CH (OH) CH 2 —L 1 , where n is 0 to 24, m is an integer of 2 to 5, L 1 represents an amino group, an ammonium base, a pyridyl group or a pyridinium base.)
　式（１）において，Ｒ１は水素原子またはメチル基を示し，安定性の高さの観点からはメチル基が好ましい。Ｒ２は炭素数１～４のアルキレン基を示す。Ｒ２は具体的に－ＣＨ２－，－ＣＨ２ＣＨ２－，－ＣＨ２ＣＨ２ＣＨ２－及び－ＣＨ２ＣＨ２ＣＨ２ＣＨ２－のいずれかであり，－ＣＨ２ＣＨ２－が好ましい。Ｒ３は炭素数１～８のアルキレン基を示す。Ｒ３は具体的に－ＣＨ２－，－ＣＨ２ＣＨ２－，－ＣＨ２ＣＨ２ＣＨ２－及び－ＣＨ２ＣＨ２ＣＨ２ＣＨ２－が挙げられ，－ＣＨ２－が好ましい。（ＡＯ）はオキシアルキレン基を示し，Ａは，炭素数２～４のアルキレン基である。オキシアルキレン基のアルキレン基としては，エチレン基が好ましい。Ｘは０～１０００の整数であり，Ｘは０～５００が好ましい。
　式（１）の単量体としては，好ましくはグリセリル－１－メタクリロイルオキシエチルウレタンが挙げられる。 In the formula (1), R 1 represents a hydrogen atom or a methyl group, and a methyl group is preferable from the viewpoint of high stability. R 2 represents an alkylene group having 1 to 4 carbon atoms. R 2 is specifically -CH 2 -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 - are either, -CH 2 CH 2 - is preferable. R 3 represents an alkylene group having 1 to 8 carbon atoms. R 3 is specifically -CH 2 -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 - can be mentioned, -CH 2 - are preferred. (AO) represents an oxyalkylene group, and A is an alkylene group having 2 to 4 carbon atoms. The alkylene group of the oxyalkylene group is preferably an ethylene group. X is an integer of 0 to 1000, and X is preferably 0 to 500.
The monomer of formula (1) is preferably glyceryl-1-methacryloyloxyethylurethane.
　さらに，本発明の重合体は，式（１）で表される単量体Ｍ１を５～９０モル％と，式（２）で表される単量体Ｍ２を５～９０モル％と，式（３）で表される単量体Ｍ３を３～８０モル％と，単量体Ｍ１～Ｍ３以外の単量体Ｍ４を５０モル％以下含んでなり，Ｍ１＋Ｍ２＋Ｍ３＋Ｍ４が１００モル％である単量体組成物を重合して得られる重合体であってもよい。 Further, the polymer of the present invention, a monomeric M 1 5-90 mol% of the formula (1), and 5 to 90 mol% of the monomer M 2 of the formula (2) , 3 to 80 mol% of the monomer M 3 represented by the formula (3) and 50 mol% or less of the monomer M 4 other than the monomers M1 to M3, and M 1 + M 2 + M 3 + M 4 may be a polymer obtained by polymerizing a monomer composition is 100 mol%.
　本発明では，有効成分として，セラミドと高い構造類似性を有する上述した重合体を含むことで，過剰な肉芽形成をより効果的に防止することができる。セラミドと高い構造類似性を有する上述した重合体を有効成分として有効量含む剤は，ケロイド又は肥厚性瘢痕の治療又は予防に有効である。
　さらに，本発明では，トレハロース又はトレハロースの誘導体と，上述した共重合体を混合して有効量含む剤を得ることもできる。２つの有効成分を組み合わせることにより，より，効果的に過剰な肉芽形成防止することができ，ケロイド又は肥厚性瘢痕の治療又は予防に有効に作用する。 In the present invention, excessive granulation can be more effectively prevented by including the above-mentioned polymer having a high structural similarity with ceramide as an active ingredient. An agent comprising an effective amount of the above-described polymer having a high structural similarity to ceramide as an active ingredient is effective for the treatment or prevention of keloid or hypertrophic scar.
Furthermore, in the present invention, trehalose or a derivative of trehalose and the above-mentioned copolymer can be mixed to obtain an agent containing an effective amount. By combining the two active ingredients, it is possible to more effectively prevent excessive granulation and to effectively act on the treatment or prevention of keloid or hypertrophic scar.
　本発明の医薬組成物は，通常用いられる製剤技術によって，錠剤，丸剤，カプセル剤，顆粒剤，粉剤，液剤，乳剤，懸濁剤，軟膏剤，注射剤，皮膚貼付剤などの経口又は非経口用医薬として調製される。本発明における剤型として，液剤又は注射剤が好ましく，具体的には，注射剤又は灌流液がより好ましい。例えば,トレハロース,併用剤，及び希釈剤を適宜混ぜ合わせて攪拌することにより液剤を得ればよい。得られた液剤は，アンプル，プレフィルシリンジあるいは薬剤パックなどに封入してもよい。 The pharmaceutical composition of the present invention can be used for oral or non-oral such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, skin patches, etc., depending on the pharmaceutical technology normally used. Prepared as an oral medicine. As the dosage form in the present invention, a liquid or an injection is preferable, and specifically, an injection or a perfusate is more preferable. For example, a liquid agent may be obtained by mixing and stirring trehalose, a concomitant drug, and a diluent as appropriate. The obtained liquid agent may be enclosed in an ampoule, a prefilled syringe or a drug pack.
　本発明の薬剤の投与方法として，成人患者（６０ｋｇ）に対して，１回当たりトレハロース又はトレハロースの誘導体を，１ｇ以上１０ｇ以下を１日１回又は数回に分けて塗布又は噴霧するものがあげられる。 As an administration method of the drug of the present invention, one which applies or sprays 1 g or more and 10 g or less of trehalose or a derivative of trehalose once or several times a day to an adult patient (60 kg). It is done.
　本明細書は，ケロイド又は肥厚性瘢痕の治療剤及び予防剤を製造するための，本発明の薬剤の使用をも提供する。本発明の薬剤として，上記した各薬剤を適宜採用できる。 This specification also provides use of the agent of the present invention for producing a therapeutic agent and a preventive agent for keloid or hypertrophic scar. As the drug of the present invention, each of the above drugs can be appropriately employed.
　本明細書は，本発明の薬剤を対象に投与する工程を含む，ケロイド又は肥厚性瘢痕の治療及び予防をも提供する。上記の対象として，ヒト又はヒト以外の哺乳動物があげられる。また，「本発明の薬剤を対象に投与する工程」として，本発明の薬剤を対象の患部に塗布又は噴霧することにより本発明の薬剤を投与するものがあげられる。本発明の薬剤として，上記した各薬剤を適宜採用できる。 This specification also provides treatment and prevention of keloids or hypertrophic scars, including the step of administering the agent of the present invention to a subject. Examples of the subject include humans or non-human mammals. In addition, the “step of administering the drug of the present invention to a subject” includes a method of administering the drug of the present invention by applying or spraying the drug of the present invention to the affected area of the subject. As the drug of the present invention, each of the above drugs can be appropriately employed.
　本発明の第二の側面は，トレハロース又はトレハロースの誘導体を有効成分として含有する気道損傷部の組織肥厚抑制剤に関する。この剤は，気道損傷部の組織が肥厚することによる気道閉塞を防止するための剤としても利用されうる。トレハロース及びトレハロースの誘導体は先に説明したとおりである。先述したとおり，トレハロース又はトレハロースの誘導体は，過剰な肉芽形成を防止できるので，気道損傷部の組織が肥厚することによる気道閉塞を防止できる。 The second aspect of the present invention relates to a tissue thickening inhibitor for respiratory tract lesions containing trehalose or a derivative of trehalose as an active ingredient. This agent can also be used as an agent for preventing airway obstruction due to thickening of tissues in damaged airways. Trehalose and trehalose derivatives are as described above. As described above, trehalose or a derivative of trehalose can prevent excessive granulation, and thus can prevent airway obstruction due to thickening of the tissue of the damaged airway.
　この気道損傷部の組織肥厚抑制剤は，たとえば，ゲル剤や塗布剤として気道内に挿入される医療用器具に塗布されてもよい。また，医療用器具が気道に挿入される前に，気道に塗布又は噴霧することで，医療用器具による損傷がもたらす組織肥厚を防止し，損傷により気道が閉塞する事態を効果的に防止する。 The tissue thickening inhibitor in the airway damage part may be applied to a medical instrument inserted into the airway as a gel or a coating agent, for example. In addition, by applying or spraying the medical device on the airway before the medical device is inserted into the airway, the tissue thickening caused by the medical device is prevented, and the situation where the airway is blocked due to the damage is effectively prevented.
　この気道損傷部の組織肥厚抑制剤の好ましい態様は，潤滑ゲル剤である。組織肥厚抑制剤が潤滑ゲル剤である場合，５重量％以上２０重量％以下のトレハロース又はトレハロースの誘導体を含有するものが好ましい。具体的なトレハロース又はトレハロースの誘導体の含有量は１０重量％である。ゲル剤は，生体親和性のあるゲル剤を適宜用いることができる。すなわち，公知の方法に基づいて担体としてのゲル剤を形成し，ゲル剤に有効成分であるトレハロース又はトレハロースの誘導体を混合することで，潤滑ゲル剤である組織肥厚抑制剤を得ることができる。 A preferred embodiment of the tissue thickening inhibitor for this airway injury is a lubricating gel. When the tissue thickening inhibitor is a lubricating gel, it preferably contains 5% by weight or more and 20% by weight or less of trehalose or a derivative of trehalose. The specific content of trehalose or trehalose derivative is 10% by weight. As the gel, a biocompatible gel can be used as appropriate. That is, a tissue thickening inhibitor that is a lubricating gel can be obtained by forming a gel as a carrier based on a known method and mixing trehalose or a derivative of trehalose as an active ingredient into the gel.
　潤滑ゲル剤である組織肥厚抑制剤は，たとえば，気道に挿入される医療用器具に塗布する。そして，組織肥厚抑制剤を付着させた医療用器具を気道に挿入する。すると，医療用器具を取り囲むゲルが組織を保護するほか，ゲルに含まれるトレハロース又はトレハロースの誘導体が，気管粘膜に蓄積する。そして，蓄積したトレハロース又はトレハロースの誘導体は，医療用器具を抜いた後の合併症を防止する。この合併症の例が，組織損傷に起因する気道閉塞である。気道に挿入される医療用器具の例は，カフ付チューブ，気管内チューブ，気管支チューブ，気管切開チューブ，喉頭気管チューブ，又は食道チューブである。 The tissue thickening inhibitor, which is a lubricating gel, is applied to, for example, a medical device inserted into the respiratory tract. Then, a medical device with a tissue thickening inhibitor attached is inserted into the airway. Then, the gel surrounding the medical device protects the tissue and trehalose or a derivative of trehalose contained in the gel accumulates in the tracheal mucosa. Accumulated trehalose or trehalose derivatives prevent complications after removing a medical device. An example of this complication is airway obstruction due to tissue damage. Examples of medical devices inserted into the airway are cuffed tubes, endotracheal tubes, bronchial tubes, tracheostomy tubes, laryngotracheal tubes, or esophageal tubes.
　以下，実施例を用いて本発明を具体的に説明する。しかしながら，本発明は，本明細書に開示された発明から当業者にとって自明な範囲で適宜調整することができるものであり，以下の実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention can be appropriately adjusted within the scope obvious to those skilled in the art from the invention disclosed in this specification, and is not limited to the following examples.
　外傷(外科手術を含む)によって起こる細胞破壊のモデルとして，ホモジェナイザーで破砕した細胞破砕液を使用した。細胞破砕液によってマクロファージ細胞を処理し，誘起されたＴＧＦ－β1産生を，トレハロースが抑制するか検討した。 A cell disruption solution disrupted with a homogenizer was used as a model for cell disruption caused by trauma (including surgery). Macrophage cells were treated with a cell lysate to examine whether trehalose suppresses the induced TGF-β1 production.
　２２５ｃｍ２フラスコで培養したＲＡＷ２６４．７細胞を生理食塩水又は１０％トレハロース中でホモジェナイザーを用いて破砕し，細胞破砕液を調製した。６ウェル中で培養しているＲＡＷ２６４．７細胞に上記細胞破砕液を加えて，８時間培養した。培地を酸処理した後，培地中のＴＧＦ－β1をＥＬＩＳＡ法(Ｒ＆Ｄ社)によって測定した。その結果を図１に示す。図１は，ＴＧＦ－β1の産生量を示すグラフである。 225cm the RAW264.7 cells cultured in 2 flasks were disrupted by using a homogenizer with saline or 10% trehalose in, to prepare a cell lysate. The cell disruption solution was added to RAW264.7 cells cultured in 6 wells and cultured for 8 hours. After the medium was acid-treated, TGF-β1 in the medium was measured by ELISA (R & D). The result is shown in FIG. FIG. 1 is a graph showing the amount of TGF-β1 produced.
　図１に示されるとおり，生理食塩水中で調製した細胞破砕液は，濃度依存的にＴＧＦ－β1の産生を強く誘導するが，トレハロースを用いた条件ではＴＧＦ－β1の産生は減少していた。トレハロースによってＴＧＦ－β1産生が抑制することが明らかとなった。 As shown in FIG. 1, the cell disruption solution prepared in physiological saline strongly induced the production of TGF-β1 in a concentration-dependent manner, but the production of TGF-β1 decreased under the conditions using trehalose. It was revealed that trehalose suppresses TGF-β1 production.
　細胞破砕液によって誘起する炎症性サイトカイン産生 (ＴＮＦ－α，ＩＬ－１α)を，トレハロースが抑制するか検討した。 It was examined whether trehalose suppresses inflammatory cytokine production (TNF-α, IL-1α) induced by cell lysate.
　２２５ｃｍ２フラスコで培養したＲＡＷ２６４．７細胞を生理食塩水又は１０％トレハロース中でホモジェナイザーを用いて破砕し，細胞破砕液を調製した。６ウェル中で培養しているＲＡＷ２６４．７細胞に上記細胞破砕液を加えて，８時間培養した。培地を酸処理した後，培地中のＴＮＦ－α及びＩＬ－１αをＥＬＩＳＡ法(Ｒ＆Ｄ社)によって測定した。その結果を図２及び図３に示す。図２は，ＴＮＦ－αの産生量を示すグラフである。図３は，ＩＬ－１αの産生量を示すグラフである。 RAW264.7 cells cultured in a 225 cm 2 flask were disrupted using a homogenizer in physiological saline or 10% trehalose to prepare a cell disruption solution. The cell disruption solution was added to RAW264.7 cells cultured in 6 wells and cultured for 8 hours. After acid treatment of the medium, TNF-α and IL-1α in the medium were measured by ELISA (R & D). The results are shown in FIGS. FIG. 2 is a graph showing the amount of TNF-α produced. FIG. 3 is a graph showing the amount of IL-1α produced.
　図２及び図３に示されるとおり，生理食塩水中で調製した細胞破砕液は，濃度依存的にＴＮＦ－α及びＩＬ－１αの産生を強く誘導するが，トレハロースを用いた条件ではＴＮＦ－αの産生及びＩＬ－１αの産生は減少していた。トレハロースによってＴＮＦ－α産生及びＩＬ－１α産生が抑制することが明らかとなった。 As shown in FIG. 2 and FIG. 3, the cell disruption solution prepared in physiological saline strongly induces the production of TNF-α and IL-1α in a concentration-dependent manner, but under conditions using trehalose, TNF-α Production and IL-1α production were decreased. It was revealed that trehalose suppresses TNF-α production and IL-1α production.
　細胞破砕液によって誘起するプロスタグランジン（ｐｒｏｓｔａｇｌａｎｄｉｎ）Ｅ２(ＰＧＥ２)を，トレハロースが抑制するか検討した。 It was examined whether trehalose inhibits prostaglandin E 2 (PGE 2 ) induced by cell lysate.
　２２５ｃｍ２フラスコで培養したＲＡＷ２６４．７細胞を生理食塩水又は１０％トレハロース中でホモジェナイザーを用いて破砕し，細胞破砕液を調製した。６ウェル中で培養しているＲＡＷ２６４．７細胞に上記細胞破砕液を加えて，８時間培養した。培地を酸処理した後，培地中のＰＧＥ２をＥＬＩＳＡ法(Ｒ＆Ｄ社)によって測定した。その結果を図４に示す。図４は，ＰＧＥ２の産生量を示すグラフである。 225cm the RAW264.7 cells cultured in 2 flasks were disrupted by using a homogenizer with saline or 10% trehalose in, to prepare a cell lysate. The cell disruption solution was added to RAW264.7 cells cultured in 6 wells and cultured for 8 hours. After the medium was acid-treated, PGE 2 in the medium was measured by ELISA (R & D). The result is shown in FIG. FIG. 4 is a graph showing the amount of PGE 2 produced.
　図４に示されるとおり，生理食塩水中で調製した細胞破砕液は，濃度依存的にＰＧＥ２の産生を強く誘導するが，トレハロースを用いた条件ではＰＧＥ２の産生は減少していた。トレハロースによってＰＧＥ２産生が抑制することが明らかとなった。 As shown in FIG. 4, the cell disruption solution prepared in physiological saline strongly induced PGE 2 production in a concentration-dependent manner, but PGE 2 production was decreased under conditions using trehalose. It was revealed that trehalose suppresses PGE 2 production.
　火傷による細胞傷害のモデルとして，熱ショックによって誘導される死細胞をモデルとして使用した。熱ショック後の細胞死によって細胞内容物が流出するが，これらの細胞内容物によって誘導される炎症性サイトカイン産生(ＴＮＦ－α)を，トレハロースが抑制するか検討した。 As a model of cell damage due to burns, dead cells induced by heat shock were used as models. Cell contents were released by cell death after heat shock, and it was examined whether trehalose suppresses inflammatory cytokine production (TNF-α) induced by these cell contents.
　２２５ｃｍ２フラスコで培養したＲＡＷ２６４．７細胞を回収し，５３℃１０分間熱ショックを加えた。その後，５時間３７℃で静置して細胞死を誘導し，これらを細胞溶液とした。その後，生理食塩水又は１０％トレハロースを細胞溶液に加え，氷上で３０分間処理した。６ウェル中で培養しているＲＡＷ２６４．７細胞に上記細胞破砕液を加えて，８時間培養した。培地を酸処理した後，培地中のＴＮＦ－αをＥＬＩＳＡ法(Ｒ＆Ｄ社)によって測定した。その結果を図５に示す。図５は，ＴＮＦ－αの産生量を示すグラフである。 RAW264.7 cells cultured in a 225 cm 2 flask were collected and heat shocked at 53 ° C. for 10 minutes. Thereafter, the cells were allowed to stand at 37 ° C. for 5 hours to induce cell death, and these were used as cell solutions. Thereafter, physiological saline or 10% trehalose was added to the cell solution and treated on ice for 30 minutes. The cell disruption solution was added to RAW264.7 cells cultured in 6 wells and cultured for 8 hours. After the medium was acid-treated, TNF-α in the medium was measured by ELISA (R & D). The result is shown in FIG. FIG. 5 is a graph showing the amount of TNF-α produced.
　図５に示されるとおり，細胞死によって流出した細胞内容物がＴＮＦ－α産生を誘導することを確認した。さらに，ＴＮＦ－α産生はトレハロースを用いた条件では，トレハロースの濃度が上昇するに従って減少していた。すなわち，トレハロースによってＴＮＦ－α産生が抑制することも確認した。 As shown in FIG. 5, it was confirmed that the cell contents shed by cell death induce TNF-α production. Furthermore, TNF-α production decreased as the concentration of trehalose increased under the conditions using trehalose. That is, it was also confirmed that trehalose suppresses TNF-α production.
　ヌードマウスにケロイド組織を移植し，トレハロースがケロイド増殖を抑制する効果を確認する。移植材料として，ケロイド患者より摘出した組織片を移植するまで培養液中（ＭＥＭ＋１０％
ＦＣＳ＋ＰＣ＋ＳＭ）に入れて，冷暗所に保存した。次に，ヌードマウスを６週齢で，麻酔下で細切ケロイド組織片を肩甲骨間に皮下に１匹に１片ずつ１０匹のマウスに移植する。移植後，週に３回ケロイド組織の増殖した腫瘍の大きさ（長径×短径×高さ）をノギスで測定する。腫瘍の大きさが安定した３ケ月目に４匹のマウス腫瘍にトレハロース溶液を０．１ｇ１時間間隔で３回注入する。対照マウス２匹には生理食塩水またはマウスの全血清をそれぞれ０．１ｇずつ同様に３回局注する。２匹のマウス腫瘍には，トレハロース溶液を３回塗布する。２匹のマウス腫瘍にはトレハロース溶液を３回噴霧するとともにトレハロース溶液を０．１ｇ１時間間隔で３回注入する。１週間後にマウスより腫瘍を取り出し固定する。そのうえで，トレハロースのケロイド組織治癒効果を検証する。 A keloid tissue is transplanted into a nude mouse, and the effect of trehalose inhibiting keloid growth is confirmed. As a transplant material, in the culture solution (MEM + 10%) until transplanted with a tissue fragment removed from a keloid patient
FCS + PC + SM) and stored in a cool dark place. Next, nude mice are 6 weeks old, and under anesthesia, finely sliced keloid tissue pieces are transplanted subcutaneously between the scapulae into 10 mice, one piece per mouse. After transplantation, the size of the tumor in which the keloid tissue has grown three times a week (major axis x minor axis x height) is measured with a caliper. The trehalose solution is injected three times at 0.1 g 1 hour intervals into 4 mouse tumors in the third month when the tumor size is stable. Two control mice are injected three times in the same manner with 0.1 g each of physiological saline or mouse total serum. For two mouse tumors, apply trehalose solution three times. Two mouse tumors are sprayed with trehalose solution three times and injected with trehalose solution three times at 0.1 g 1 hour intervals. One week later, the tumor is removed from the mouse and fixed. In addition, we examine the healing effect of trehalose on keloid tissue.
　本発明は，医薬産業などの分野において利用されうる。 The present invention can be used in fields such as the pharmaceutical industry.

Claims (6)

  1. トレハロース又はトレハロースの誘導体を有効成分として含有するケロイド又は肥厚性瘢痕の治療剤又は予防剤。 A therapeutic or prophylactic agent for keloid or hypertrophic scar containing trehalose or a derivative of trehalose as an active ingredient.
  2. 請求項１に記載のケロイド又は肥厚性瘢痕の予防剤であって，前記トレハロース又はトレハロースの誘導体が，
    　トレハロース，α－グルコシルトレハロース，α－マルトシルトレハロース，α－マルトトリオシルトレハロース，α－マルトテトラオシルトレハロース及びα－マルトペンタオシルトレハロースからなる群から得らばれる１又は２以上の糖である，
    　肥厚性瘢痕の治療剤又は予防剤。     The agent for preventing keloids or hypertrophic scars according to claim 1, wherein the trehalose or trehalose derivative is:
    One or more sugars obtained from the group consisting of trehalose, α-glucosyl trehalose, α-maltosyl trehalose, α-maltotriosyl trehalose, α-maltotetraosyl trehalose and α-maltopentaosyl trehalose ,
    A therapeutic or prophylactic agent for hypertrophic scars.
  3. 請求項１に記載のケロイド又は肥厚性瘢痕の予防剤であって，前記トレハロース又はトレハロースの誘導体が，
    　トレハロース又はα－マルトシルトレハロースである，
    　肥厚性瘢痕の治療剤又は予防剤。     The agent for preventing keloids or hypertrophic scars according to claim 1, wherein the trehalose or trehalose derivative is:
    Trehalose or α-maltosyl trehalose,
    A therapeutic or prophylactic agent for hypertrophic scars.
  4. 請求項１に記載のケロイド又は肥厚性瘢痕の予防剤であって，前記トレハロース又はトレハロースの誘導体が，
    　トレハロースである，
    　肥厚性瘢痕の治療剤又は予防剤。     The agent for preventing keloids or hypertrophic scars according to claim 1, wherein the trehalose or trehalose derivative is:
    Trehalose,
    A therapeutic or prophylactic agent for hypertrophic scars.
  5. 請求項１に記載のケロイド又は肥厚性瘢痕の予防剤であって，施術後の施術部に投与される剤。 The agent for prevention of keloid or hypertrophic scar according to claim 1, which is administered to a treatment site after treatment.
  6. トレハロース又はトレハロースの誘導体を有効成分として含有する気道損傷部の組織肥厚抑制剤。 A tissue thickening inhibitor for respiratory tract lesions containing trehalose or a derivative of trehalose as an active ingredient.
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