WO2015076244A1 - Anti-inflammatory agent using low-molecular-weight polysaccharide from aphanothece sacrum - Google Patents

Anti-inflammatory agent using low-molecular-weight polysaccharide from aphanothece sacrum Download PDF

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WO2015076244A1
WO2015076244A1 PCT/JP2014/080454 JP2014080454W WO2015076244A1 WO 2015076244 A1 WO2015076244 A1 WO 2015076244A1 JP 2014080454 W JP2014080454 W JP 2014080454W WO 2015076244 A1 WO2015076244 A1 WO 2015076244A1
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disaccharide structure
molecular weight
pentose
polysaccharide
deoxyhexose
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PCT/JP2014/080454
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French (fr)
Japanese (ja)
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有馬　英俊
敬一 本山
大志 東
河添　宏
慎一郎 金子
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国立大学法人熊本大学
日立化成株式会社
グリーンサイエンス・マテリアル株式会社
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Priority to JP2015549146A priority Critical patent/JPWO2015076244A1/en
Publication of WO2015076244A1 publication Critical patent/WO2015076244A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to an anti-inflammatory agent containing a low-molecular-weight polysaccharide derived from suizendinori.
  • Inflammation is a reaction that occurs when a living body is damaged, and is a local protective reaction that is caused by the immune system against cell and tissue damage.
  • the signs of inflammation can include five major signs of redness, swelling, heat, pain, and dysfunction.
  • Anti-inflammatory drugs that suppress inflammation are mainly classified into two types: steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs.
  • steroidal anti-inflammatory agents include corticosteroids such as hydrocortisone, prednisolone, and triamcinolone, and have an inhibitory effect on the synthesis of prostaglandins.
  • non-steroidal anti-inflammatory agents include salicylic acid, indomethacin, ibuprofen, etc., and exhibit high anti-inflammatory activity by inhibiting the synthesis of prostaglandins.
  • side effects such as gastrointestinal disorders and renal dysfunction are concerned.
  • an attempt to search for a substance having an anti-inflammatory action from a natural product and use it as a new anti-inflammatory agent is also widely performed.
  • it is obtained from, for example, an anti-inflammatory agent containing, as an active ingredient, an acidic xylo-oligosaccharide obtained from wood or the like
  • Patent Document 1 Japanese Patent Publication No. 2003-221339
  • An anti-inflammatory agent containing an anti-inflammatory substance as an active ingredient Patent Document 2: Japanese Patent Publication No.
  • Patent Document 4 Japanese Patent Application Laid-Open No. 2008-120716.
  • glucosaminoglycans such as hyaluronic acid, dermatan sulfate, and chondroitin sulfate have anti-inflammatory effects, and some are marketed as pharmaceuticals.
  • hyaluronic acid has been reported to suggest the possibility of promoting canceration, and there are concerns about safety.
  • Sakuran is a novel ultra-high molecular weight polysaccharide with a weight average molecular weight of about 20 million, which is extracted from suizendinori, an edible cyanobacteria unique to Japan.
  • Sakuran (Suizendinori polysaccharide) is an ampholyte having many sulfate groups, carboxylic acid groups, and amino groups.
  • the molecular structure of sakuran changes depending on the concentration in the solution, and it exists in the form of nanometer-sized particles in the low concentration region. Form.
  • the weight average molecular weight of cherry is as high as about 20 million, and it becomes highly viscous at high concentration, so that it is expected that the permeability to the skin will decrease.
  • the present inventors have confirmed that the anti-inflammatory action of cherry is attenuated at a high concentration, and there is a problem in using cherry itself as an anti-inflammatory agent.
  • An object of the present invention is to provide a highly safe anti-inflammatory agent that can suppress inflammation.
  • sakuran exhibits an anti-inflammatory action in an inflammation model, and is further sometimes referred to as a low-molecular-weight polysaccharide derived from Suizendinori derived from sakuran having a specific weight average molecular weight (hereinafter simply referred to as a low-molecular-weight polysaccharide). ) Has an excellent anti-inflammatory action, and the present invention has been completed.
  • the present invention includes the following.
  • the weight average molecular weight is about 2,000 or more (preferably about 5,000 or more, more preferably about 10,000 or more) and about 3 million or less (preferably about 2 million or less, more preferably about 1 million or less).
  • An anti-inflammatory agent comprising a low molecular weight polysaccharide derived from a suizendinori or a pharmacologically acceptable salt derivative thereof.
  • the low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
  • R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3
  • the anti-inflammatory agent according to (1) or (2) above which is a sugar derivative containing any of the above.
  • R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3
  • the anti-inflammatory agent according to (1) or (2) above which is a mixture of sugar derivatives containing all of the above.
  • the weight average molecular weight is about 2,000 or more (preferably about 5,000 or more, more preferably about 10,000 or more) and about 3 million or less (preferably about 2 million or less, more preferably about 1 million or less).
  • a therapeutic or prophylactic agent for atopic dermatitis comprising a certain suizendinori-derived polysaccharide low molecular weight product or a pharmacologically acceptable salt derivative thereof as an active ingredient.
  • a weight-average molecular weight of the low molecular weight product of the suizendinori-derived polysaccharide is about 10,000 or more and about 1 million or less (preferably about 30,000 or more and about 1 million or less).
  • a therapeutic or prophylactic agent for dermatitis. contains sulfated muramic acid as a sugar structure, and at least the following formula:
  • R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3
  • the therapeutic or preventive agent for atopic dermatitis according to (7) or (8) above, which is a sugar derivative containing any of the above.
  • R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3
  • the therapeutic or preventive agent for atopic dermatitis according to (7) or (8) above, which is a mixture of sugar derivatives containing all of the
  • an anti-inflammatory agent that can suppress inflammation and has high safety is provided.
  • the low molecular weight polysaccharide-derived polysaccharide having a specific average molecular weight used in the present invention can be obtained from cherry, which is a sulfated polysaccharide having a weight average molecular weight of about 20 million derived from Aphanothece sacrum.
  • Suizenjinori (Aphanothece ⁇ sacrum) is a freshwater cyanobacteria that forms a colony in the state that a large number of single cells (size: 3.5-4.0 ⁇ ⁇ 6-7 ⁇ ) are buried in agar. Growth has been confirmed only in Kumamoto Prefecture and Fukuoka Prefecture in the Kyushu region.
  • Sakuran has a repeating structure of a sugar chain unit in which a sugar structure having a hexose structure and a sugar structure having a pentose structure are linked in a linear or branched manner by ⁇ -glycoside bonds or ⁇ -glycoside bonds, and
  • the chain unit contains sulfated muramic acid as a sugar structure, and in the sugar chain unit, 2.7 or more hydroxyl groups per 100 hydroxyl groups are sulfated, or the sulfur element is 1.5% in all elements. It is characterized by containing a sugar derivative occupying at least% by weight.
  • Sakura has a weight average molecular weight of about 20 million, contains sulfated muramic acid as a sugar structure, and has at least the following formula:
  • a trisaccharide structure having the sequence shown in 1) and the sequences listed in the following 1) to 6): 1) Disaccharide structure of hexose and pentose which is xylose or arabinose, 2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose, 3) Disaccharide structure of pentose and pentose, 4) Disaccharide structure of pentose and deoxyhexose, 5) Disaccharide structure of hexosamine and hexosamine, 6) Disaccharide structure of uronic acid which is glucuronic acid or galacturonic acid and deoxyhexose, It is a sugar derivative containing all of the disaccharide structure having
  • a cherry tree can be extracted from a lily of the valley by adding it to a 0.1N NaOH aqueous solution at 80 ° C. and stirring for several hours.
  • cherry blossoms can be extracted from the water lily by heating an aqueous dispersion of water lily in an autoclave at 135 ° C. for 30 minutes.
  • the extracted cherry may be purified by centrifugation, filtration, alcohol washing or the like.
  • cherry is an acidic polysaccharide and can be extracted from scorpionary using an alkaline solution.
  • the cherry tree extracted from a suizenjinori can be obtained from Daito Kasei Co., Ltd., for example.
  • Examples of the method for reducing the molecular weight of the cherry include acid hydrolysis by heat treatment under acidic conditions, but are not limited thereto.
  • the low molecular weight product of cherry can be used by any method, for example, but not limited to, fractionating a specific molecular weight using gel filtration chromatography.
  • the polysaccharide low molecular weight product contained in the anti-inflammatory agent or the atopic dermatitis treatment / prevention agent of the present invention is a polysaccharide that can be obtained from the above cherry. Is the body.
  • the polysaccharide low-molecular-weight product used in the present invention may be composed of a uniform polysaccharide or a mixture of various polysaccharides. However, since it is usually prepared from natural cherry, It consists of a mixture of polysaccharides.
  • the polysaccharide-reduced product used in the present invention can be obtained by degrading natural cherry, but the method of preparation is not limited thereto.
  • the polysaccharide-reduced product of the polysaccharide of the present invention is a polysaccharide that can be obtained from the above cherry, and has a weight average molecular weight of about 3 million or less, preferably about 2 million or less, more preferably about 1 million or less, Further, the lower limit of the weight average molecular weight is about 2,000 or more, preferably about 5,000 or more, more preferably about 10,000 or more polysaccharides containing sulfated saccharides, or polysaccharides having an equivalent structure thereof, These are various derivatives (for example, salt derivatives of polysaccharides) obtained from polysaccharides by conventional methods.
  • the weight average molecular weight here can be measured by a conventional method, and can be measured, for example, using gel filtration chromatography.
  • the weight average molecular weight of the low molecular weight polysaccharide used in the present invention is, for example, about 2,000 or more and about 3 million or less.
  • a method for measuring an arbitrary weight molecular weight of the low molecular weight polysaccharide used for example, gel filtration chromatography). (Polygraph)), a mixture of polysaccharides derived from Sakuran whose (weight) average molecular weight determined from the distribution is between about 2,000 and about 3 million may be used. Or a mixture thereof).
  • the low molecular weight cherry used in the present invention is preferably a mixture of polysaccharides showing one peak when the molecular weight is measured by gel filtration chromatography, but may be a mixture of polysaccharides showing a plurality of peaks. Good.
  • the polysaccharide low molecular weight product used in the present invention is not limited as long as the polysaccharide low molecular weight product used or a mixture thereof falls within the range of the weight average molecular weight defined in the present invention. More preferably a mixture showing a sharper peak.
  • “Sacran (molecular weight 1,500,000)”, “Sacran (molecular weight 940,000)”, “Sacran (molecular weight 45,000)”, and “Sacran (molecular weight 900)” are decomposed or processed. And a mixture of polysaccharides each having a weight average molecular weight of about 1.5 million, about 940,000, about 45,000, or about 900, respectively. means.
  • the polysaccharide low molecular weight product of the present invention can be expressed not only by the weight average molecular weight but also by the average number of sugars (in such a case, the weight average molecular weight of the monosaccharide can be estimated to be about 180).
  • the polysaccharide low molecular weight product of the present invention is a polysaccharide that can be obtained from the above sakuran, and the upper limit of the average number of sugars is about 10 4 or less, preferably about 10 3 or less, and the average number of sugars
  • the lower limit of the polysaccharide is about 10 or more, preferably about 20 or more, more preferably about 50 or more, more preferably about 10 2 or more of a polysaccharide containing a sulfated sugar, or a polysaccharide having an equivalent structure,
  • the average number of sugars referred to here is a value obtained by converting the size of a sugar derivative into the number of sugars constituting the sugar derivative.
  • a cherry derivative composed of a sugar derivative having an average sugar number of 10 4 is an aggregate of sugar derivatives having a sugar number between about 10 3 and about 10 5 (a sugar number on the order of 10 4 (ie, around the derivatives of sugars several tens of thousand-hundred thousand) means confusion induced composed distributed), and confusion induced composed average number sugar from 10 3 sugar derivative is from about 10 2 to about 10
  • Sakura derivatives composed of 10 2 sugar derivatives are aggregates of sugar derivatives having a sugar number between about 10 1 and about 10 3 (number of sugars on the order of 10 2 (that is, hundreds to thousands of sugars). ), Which is distributed around the derivative).
  • “Sacran (molecular weight: 1,500,000)”, “Sacran (molecular weight: 940,000)”, “Sacran (molecular weight: 45,000)”, and “Sacran (molecular weight: 900)” indicated by the weight average molecular weight are indicated by the average number of sugars. These can be expressed as “Sacran (10 4 )”, “Sakuran (10 3 )”, “Sakuran (10 2 )”, and “Sakuran (4)”, respectively.
  • the above polysaccharide having an equivalent sugar structure includes, for example, sulfated muramic acid as the sugar structure, and at least the following formula:
  • R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3
  • the sugar structure contains sulfated muramic acid, and at least the following formula:
  • R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3
  • a suizendinori-derived polysaccharide low molecular weight product having a desired weight average molecular weight can be obtained from Sakuran by a combination of known methods. For example, it can be obtained by heat treatment under acidic conditions and acid hydrolysis.
  • a sugar chain can be randomly cleaved using a known sugar chain cleavage method, for example, an enzyme, and a mixture of sugar derivatives having a desired weight average molecular weight can be isolated based on the molecular weight.
  • Examples of enzymes that can cleave the sugar chain of cherry include ⁇ -galactosidase, hexosaminidase A, hexosaminidase B, ⁇ -galactosidase A, ⁇ -glucosidase, ⁇ -L-iduronidase, N-acetyl- ⁇ .
  • the end of the cleaved sugar chain can be arbitrarily modified.
  • functional groups that can be used for modification include, but are not limited to, a carboxy group, an amino group, and a sulfate group.
  • Derivatives in which these cleaved sugar chains are modified or substituted are also included in the polysaccharide low molecular weight product of the present invention.
  • a hydroxyl group or a hydrogen group of a sugar constituting sakuran, or a carboxy group an amino group or other group bonded to the sugar is substituted or It is also possible to modify these derivatives, and these modified or substituted derivatives are also included in the polysaccharide low molecular weight product of the present invention.
  • the low molecular weight polysaccharide of the present invention can also be used in the form of a pharmacologically acceptable salt.
  • the pharmacologically acceptable salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include inorganic salts such as hydrochloride and sulfate, and organic acid salts such as citric acid. Can do.
  • the content of the low-molecular-weight polysaccharide in the pharmaceutical composition of the present invention can be appropriately selected according to the use and purpose.
  • the content of the polysaccharide can be 0.0001 to It is 20% by weight, preferably 0.001 to 10% by weight, and more preferably 0.01 to 5% by weight.
  • the pharmaceutical composition of the present invention can be used in any form and is not limited thereto, and examples thereof include oral preparations, injection preparations, external preparations for skin, topical preparations, eye drops and the like.
  • the polysaccharide low-molecular-weight product of the present invention has a moisturizing action in addition to an anti-inflammatory action, it is preferably used in an embodiment as a topical administration agent or an injection or an eye drop for external preparations for skin and arthritis.
  • the dosage form When used as an external preparation for skin, the dosage form is arbitrary, and for example, it can be used in various forms such as liquids, ointments, patches, aerosols, haps, tapes, and powders.
  • the dosage form When used as an oral preparation, the dosage form is arbitrary, and can be used in various forms such as tablets, capsules, granules, powders and the like.
  • the pharmaceutical composition of the present invention can contain components appropriately selected according to the purpose, in addition to the polysaccharide low molecular weight product of the present invention.
  • auxiliary ingredients for formulation include bases, stabilizers, preservatives, preservatives, emulsifiers, suspending agents, solubilizers, solubilizers, lubricants, flavoring agents, colorants, fragrances , Soothing agents, excipients, binders, thickeners, buffers, and the like.
  • the auxiliary components may be appropriately selected and used.
  • assistant component should just be suitably selected according to a dosage form etc. in the range accept
  • excipients when used as an external preparation for skin, for example, excipients, binders, flavoring agents, emulsifiers, surfactants, solubilizing agents, suspending agents , And can be formulated by appropriately combining isotonic agents, preservatives, antioxidants, stabilizers or absorption promoters.
  • an emulsifier, a surfactant, a solubilizer, a suspending agent, a tonicity agent, a buffer, an antiseptic, an antioxidant, a stabilizer, or an absorption enhancer is appropriately used. It can be formulated in combination.
  • the pharmaceutical composition containing the polysaccharide low molecular weight product of the present invention can be widely used for diseases accompanied by inflammation, for example, infection, rheumatoid arthritis, collagen disease, gout, allergic disease, atopic dermatitis, inflammatory bowel
  • diseases accompanied by inflammation for example, infection, rheumatoid arthritis, collagen disease, gout, allergic disease, atopic dermatitis, inflammatory bowel
  • the polysaccharide low molecular weight product of the present invention is an anionic polysaccharide derived from a natural product, it is excellent in safety.
  • the polysaccharide low-molecular-weight product of the present invention is relatively stable against heat, can be sterilized by autoclave, is easy to handle, and has an advantage of being suitable for pharmaceutical use.
  • Example 1 Preparation of Sakura Water Solution and Inflammation Model (1) Preparation of Sakura Water Solution
  • a low molecular weight polysaccharide derived from Suizendinori a low molecular weight polysaccharide derived from sakuran having a weight average molecular weight of about 800 to 1000 (sakuran (molecular weight 900)), a low molecular weight polysaccharide having a weight average molecular weight of about 45,000 (Sakuran (molecular weight 45,000)), and a low molecular weight polysaccharide having a weight average molecular weight of about 940,000 (Sakuran (molecular weight 940,000)).
  • a low molecular weight polysaccharide having a weight average molecular weight of about 1,500,000 (Sakuran (molecular weight 1,500,000)) (all manufactured by Hitachi Chemical Co., Ltd.).
  • the molecular weight of each low-molecular-weight polysaccharide is measured by connecting a GPC column (GL-W560, Hitachi High-Technologies Corporation) to an HPLC system equipped with a differential refractometer (Shimadzu Corporation, RID-10A) as a detector.
  • the carrageenin-induced rat footpad edema model was prepared by injecting 100 ⁇ L of carrageenin ( ⁇ -carrageenin (SIGMA, Lot No.0001408463) 1% aqueous solution) into the rat footpad in accordance with a conventional method. Created with edema.
  • ⁇ -carrageenin SIGMA, Lot No.0001408463
  • Example 2 Anti-inflammatory effect by repeated administration of low molecular weight polysaccharide-derived polysaccharides from Suizendinori Immediately after carrageenin administration to the footpad of rats, 100 ⁇ L of an aqueous solution containing various low-molecular-weight polysaccharides derived from Suizendinori was applied once every hour. did. Application was repeated 6 times. The concentration of the polysaccharide low molecular weight aqueous solution used was 0.0005% (w / v) for cherry (molecular weight 1,500,000), cherry (molecular weight 940,000), and cherry (molecular weight 45,000), and cherry (molecular weight). 900) was 0.02% (w / v).
  • the low molecular weight polysaccharide derived from Suizen Ginori has an anti-inflammatory effect equivalent to or higher than that of Sakuran in an amount of 1/100, and strong anti-inflammatory even at a low concentration of 0.0005% (w / v). The effect was shown.
  • Example 3 Anti-inflammatory action by pretreatment of low molecular weight polysaccharide-derived polysaccharide derived from suizendinori
  • low molecular weight polysaccharide-derived polysaccharide derived from suizendinori was applied to the rat footpad before inducing inflammation by carrageenan The anti-inflammatory effect was confirmed.
  • the polysaccharide low molecular weight product was applied 1 hour before carrageenan administration.
  • the concentration of the polysaccharide low molecular weight product aqueous solution used was 0.0005% (w / v) for cherry (molecular weight 1,500,000), cherry (molecular weight 940,000), and cherry (molecular weight 45,000).
  • Example 4 Concentration dependence of anti-inflammatory action of low molecular weight polysaccharide derived from Suizendinori
  • concentration of the polysaccharide low-molecular-weight aqueous solution used was 0.0005% (w / v), 0.005% (w / v), and 0.01% (w / v). .05% (w / v)) and physiological saline.
  • FIG. 3 shows the results of cherry (molecular weight 1,500,000)
  • FIG. 4 shows the results of cherry (molecular weight 940,000)
  • FIG. 5 shows the results of cherry (molecular weight 45,000). All of the low molecular weight cherries showed a concentration-dependent anti-inflammatory effect.
  • Comparative Example 1 Concentration dependence of anti-inflammatory action by cherry (natural cherry)
  • an aqueous solution containing various concentrations of cherry (natural cherry) immediately after administration of carrageenan to the rat footpad 100 ⁇ L was applied once every hour. Application was repeated 6 times.
  • the concentration of the sakura aqueous solution used was 0.01% (w / v), 0.05% (w / v), 0.1% (w / v), and 0.2% (w / v).
  • Saline was used as the subject.
  • the increase in paw volume was measured using a plethysmometer, and the rat footpad was protected with a lap after each measurement. The results are shown in FIG. In natural cherries, the anti-inflammatory effect was found to decrease with increasing concentration.
  • the low molecular weight product derived from Suizendinori has a strong and concentration-dependent anti-inflammatory effect compared to natural sakuran (non-decreased sakuran). It was found that it can be used as an inflammatory drug. Moreover, in the case of a polysaccharide low molecular weight product derived from Suizendinori, it is possible to set a wide range of administration concentrations, unlike a natural type cherry.
  • the low molecular weight polysaccharide-derived polysaccharide of the Suizendinori of the present invention is useful as an active ingredient of an anti-inflammatory agent.

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Abstract

　The purpose of the present invention is to provide an anti-inflammatory agent containing a novel component capable of suppressing inflammation and having high safety. The present invention provides an anti-inflammatory agent using a low-molecular-weight polysaccharide from Aphanothece sacrum, the polysaccharide being derived from sacran extracted from Aphanothece sacrum. The low-molecular-weight polysaccharide from Aphanothece sacrum is a sugar derivative containing a sulfated sugar having a weight average molecular weight of approximately 3,000,000 or less, the sugar derivative being derived from sacran. The present invention provides a pharmaceutical composition, especially a dermal topical anti-inflammatory, containing a low-molecular-weight polysaccharide from Aphanothece sacrum.

Description

スイゼンジノリ由来多糖体低分子化物を用いた抗炎症剤Anti-inflammatory agents using polysaccharides derived from suizendinori
　本発明は、スイゼンジノリ由来多糖体低分子化物を含む抗炎症剤に関する。 The present invention relates to an anti-inflammatory agent containing a low-molecular-weight polysaccharide derived from suizendinori.
　炎症とは生体が障害を受けた際に起こす反応であり、細胞や組織の障害に対して免疫系が引き起こす局所的な防御反応である。炎症の兆候として、発赤、腫脹、熱感、疼痛、および機能障害の５大徴候をあげることができる。炎症を抑える抗炎症剤は、主にステロイド系抗炎症薬と非ステロイド系抗炎症薬の2種類に分類される。
　ステロイド系抗炎症剤としては、ヒドロコルチゾン、プレドニゾロン、トリアムシノロン等の副腎皮質ホルモンが挙げられ、プロスタグランジン類の合成阻害作用をもつ。しかし、プロスタグランジン類合成阻害のために消化性潰瘍等の副作用、過剰な免疫抑制作用による副作用、副腎皮質機能不全などの副作用を生じる恐れがあるという問題がある。
　一方、非ステロイド系抗炎症剤としては、例えば、サリチル酸、インドメタシン、イブプロフェン等が挙げられ、プロスタグランジン類の合成を阻害することにより高い抗炎症活性を示す。しかしながら、その強いプロスタグランジン類合成阻害のために、特に胃腸障害や腎機能障害等の副作用が懸念されるという問題がある。 Inflammation is a reaction that occurs when a living body is damaged, and is a local protective reaction that is caused by the immune system against cell and tissue damage. The signs of inflammation can include five major signs of redness, swelling, heat, pain, and dysfunction. Anti-inflammatory drugs that suppress inflammation are mainly classified into two types: steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs.
Examples of steroidal anti-inflammatory agents include corticosteroids such as hydrocortisone, prednisolone, and triamcinolone, and have an inhibitory effect on the synthesis of prostaglandins. However, there is a problem that side effects such as peptic ulcer, side effects due to excessive immunosuppressive action, side effects such as adrenal cortex dysfunction may occur due to inhibition of prostaglandin synthesis.
On the other hand, examples of non-steroidal anti-inflammatory agents include salicylic acid, indomethacin, ibuprofen, etc., and exhibit high anti-inflammatory activity by inhibiting the synthesis of prostaglandins. However, due to the strong inhibition of prostaglandin synthesis, there is a problem that side effects such as gastrointestinal disorders and renal dysfunction are concerned.
　一方、前記したような従来の抗炎症剤の副作用の問題を解消する目的から、天然物から抗炎症作用を有する物質を探索し、新たな抗炎症剤として利用しようとする試みも広く行われている。具体的には、例えば、木材等から得られる酸性キシロオリゴ糖を有効成分とする抗炎症剤（特許文献１：特許公開２００３－２２１３３９号公報）；ヒャクジツセイ、コウカツツジ、モウボクジュ、サラソウジュ、コウザンレキ等から得られる抗炎症性物質を有効成分とする抗炎症剤（特許文献２：特許公開２００１－２２６２７３号公報）；黄杞等から得られるアスチルビン類を有効成分とする抗炎症剤（特許文献３：特許公開平６－２５６１９４号公報）などが提案されている。さらには、天然物であるヒドロキシチロソールと、グルコサミン、ガラクトサミン、グルコサミノグリカンのいずれかを組み合わせた抗炎症剤が提案されている（特許文献４：特開２００８－１２０７１６号公報）。 On the other hand, for the purpose of solving the problems of the side effects of the conventional anti-inflammatory agents as described above, an attempt to search for a substance having an anti-inflammatory action from a natural product and use it as a new anti-inflammatory agent is also widely performed. Yes. Specifically, it is obtained from, for example, an anti-inflammatory agent containing, as an active ingredient, an acidic xylo-oligosaccharide obtained from wood or the like (Patent Document 1: Japanese Patent Publication No. 2003-221339); obtained from dipper, kotsutsuji, mobokuju, sarasouju, kozanreki An anti-inflammatory agent containing an anti-inflammatory substance as an active ingredient (Patent Document 2: Japanese Patent Publication No. 2001-226273); an anti-inflammatory agent containing astilbins obtained from jaundice etc. 6-256194) has been proposed. Furthermore, an anti-inflammatory agent in which a natural product, hydroxytyrosol, and any of glucosamine, galactosamine, and glucosaminoglycan are combined has been proposed (Patent Document 4: Japanese Patent Application Laid-Open No. 2008-120716).
　また、ヒアルロン酸、デルマタン硫酸、コンドロイチン硫酸などのグルコサミノグリカンは、抗炎症作用を有しており、医薬品として上市されているものもある。しかし、その効果は十分とはいえず、また、ヒアルロン酸においては、癌化促進に働く可能性を示唆する報告がなされており、安全性に懸念がある。 In addition, glucosaminoglycans such as hyaluronic acid, dermatan sulfate, and chondroitin sulfate have anti-inflammatory effects, and some are marketed as pharmaceuticals. However, the effect is not sufficient, and hyaluronic acid has been reported to suggest the possibility of promoting canceration, and there are concerns about safety.
　サクランは、日本固有の食用藍藻であるスイゼンジノリから抽出される、重量平均分子量約2000万の新規超高分子多糖体である。サクラン（スイゼンジノリ多糖体）は多くの硫酸基とカルボン酸基、アミノ基を有する両性電解質である。また、サクランは溶液中で濃度に応じて分子構造が変化し、低濃度領域ではナノメートルサイズの粒子状で存在するが、濃度の上昇に伴い、サクラン分子鎖が互いに相互作用し、液晶構造を形成する。 Sakuran is a novel ultra-high molecular weight polysaccharide with a weight average molecular weight of about 20 million, which is extracted from suizendinori, an edible cyanobacteria unique to Japan. Sakuran (Suizendinori polysaccharide) is an ampholyte having many sulfate groups, carboxylic acid groups, and amino groups. In addition, the molecular structure of sakuran changes depending on the concentration in the solution, and it exists in the form of nanometer-sized particles in the low concentration region. Form.
　一方、サクランの化学構造は、抗炎症作用を含む様々な生理活性を有するグルコサミノグリカンと類似していることから、抗炎症作用および抗アレルギー作用を示す可能性が考えられている。スイゼンジノリからのエタノール抽出物を有効成分とする抗炎症剤が提案されている（特許文献５：特開２００８－２０１６９４号公報）。また、Nagatsuらは、アトピー性皮膚炎モデルマウスにおいて、サクラン水溶液が抗かゆみ・抗アレルギー作用を有することを報告した（非特許文献１：Nagatu et al., Ann. Allergy Asthma Immunol., 108, 117-122, 2012）。さらに、三価金属低減スイゼンジノリ由来多糖類を含む抗アレルギー性皮膚炎剤が提案されている（特許文献６：ＷＯ２０１１／０１３９６号公報）。 On the other hand, the chemical structure of cherry is similar to that of glucosaminoglycans having various physiological activities including anti-inflammatory effects, and therefore, the possibility of exhibiting anti-inflammatory and anti-allergic effects is considered. An anti-inflammatory agent comprising an ethanol extract from suizendinori as an active ingredient has been proposed (Patent Document 5: Japanese Patent Application Laid-Open No. 2008-201694). Moreover, Nagatsu et al. Reported that an aqueous solution of Sakuran has anti-itch and anti-allergic effects in atopic dermatitis model mice (Non-patent document 1: Nagatu et al., Ann. Allergy Asthma Immunol., 108, 117). -122, 2012). Furthermore, an antiallergic dermatitis agent containing a trivalent metal-reduced Suizendinori-derived polysaccharide has been proposed (Patent Document 6: WO2011 / 01396).
特許公開２００３－２２１３３９号公報Japanese Patent Publication No. 2003-221339 特許公開２００１－２２６２７３号公報Japanese Patent Publication No. 2001-226273 特許公開平６－２５６１９４号公報Japanese Patent Publication No. 6-256194 特開２００８－１２０７１６号公報JP 2008-120716 A 特開２００８－２０１６９４号公報JP 2008-201694 A ＷＯ２０１１／０１３９６号公報WO2011 / 01396 Publication
　しかし、サクランの重量平均分子量は約2000万と大きく、高濃度では高粘性となるため、皮膚への浸透性が低下することが予想される。実際、本発明者らは、サクランの抗炎症作用が高濃度にて減弱することが確認しており、サクランそのものを抗炎症剤として用いることは問題があった。
　本発明は、炎症を抑制でき、かつ安全性の高い抗炎症剤を提供することを目的とする。 However, the weight average molecular weight of cherry is as high as about 20 million, and it becomes highly viscous at high concentration, so that it is expected that the permeability to the skin will decrease. In fact, the present inventors have confirmed that the anti-inflammatory action of cherry is attenuated at a high concentration, and there is a problem in using cherry itself as an anti-inflammatory agent.
An object of the present invention is to provide a highly safe anti-inflammatory agent that can suppress inflammation.
　本発明者らは上記課題を解決するために鋭意研究をした結果、カラゲニン誘発性ラット足蹠浮腫モデルおよび 12-O-テトラデカノイルホルボールエステル-13-アセタート (TPA) 誘発性マウス耳介皮膚炎症モデルにおいてサクランが抗炎症作用を示すことを明らかにし、さらに、特定の重量平均分子量を有するサクランから由来するスイゼンジノリ由来多糖体低分子化物（以下、単に多糖体低分子化物ともいうことがある。）が、優れた抗炎症作用を有することを見出し、本発明を完成した。
　本発明は、以下のものを含む。
（１）重量平均分子量が、約２千以上（好ましくは約５千以上、より好ましくは約１万以上）かつ約３００万以下（好ましくは約２００万以下、より好ましくは約１００万以下）であるスイゼンジノリ由来多糖体低分子化物またはそれらの薬理学的に許容される塩誘導体を含む抗炎症剤。
（２）前記スイゼンジノリ由来多糖体低分子化物の重量平均分子量が、約１万以上かつ約１００万以下（好ましくは、約３万以上かつ約１００万以下）である上記（１）に記載の抗炎症剤。
（３）前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式： As a result of intensive studies to solve the above problems, the present inventors have found that carrageenin-induced rat footpad edema model and 12-O-tetradecanoylphorbol ester-13-acetate (TPA) -induced mouse ear skin It has been clarified that sakuran exhibits an anti-inflammatory action in an inflammation model, and is further sometimes referred to as a low-molecular-weight polysaccharide derived from Suizendinori derived from sakuran having a specific weight average molecular weight (hereinafter simply referred to as a low-molecular-weight polysaccharide). ) Has an excellent anti-inflammatory action, and the present invention has been completed.
The present invention includes the following.
(1) The weight average molecular weight is about 2,000 or more (preferably about 5,000 or more, more preferably about 10,000 or more) and about 3 million or less (preferably about 2 million or less, more preferably about 1 million or less). An anti-inflammatory agent comprising a low molecular weight polysaccharide derived from a suizendinori or a pharmacologically acceptable salt derivative thereof.
(2) The anti-wetting agent according to (1) above, wherein a weight average molecular weight of the low molecular weight product of the suizendinori-derived polysaccharide is about 10,000 or more and about 1 million or less (preferably about 30,000 or more and about 1 million or less). Inflammatory agent.
(3) The low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
Figure JPOXMLDOC01-appb-C000005
 （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、および
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
のいずれかを含む糖誘導体である、前記（１）または（２）に記載の抗炎症剤。
（４）前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式：
Figure JPOXMLDOC01-appb-C000005
 (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
And a disaccharide structure represented by the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
The anti-inflammatory agent according to (1) or (2) above, which is a sugar derivative containing any of the above.
(4) The suizendinori-derived polysaccharide low molecular weight product contains sulfated muramic acid as a sugar structure, and at least the following formula:
Figure JPOXMLDOC01-appb-C000006
 （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、および
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
の全てを含む糖誘導体の混合物である、前記（１）または（２）に記載の抗炎症剤。
（５）前記（１）～（４）のいずれか一つに記載の抗炎症剤を含有する皮膚外用炎症治療剤または予防剤。
（６）前記（１）～（４）のいずれか一つに記載の抗炎症剤を含有する局所投与炎症治療剤または予防剤。
Figure JPOXMLDOC01-appb-C000006
 (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
And a disaccharide structure represented by the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
The anti-inflammatory agent according to (1) or (2) above, which is a mixture of sugar derivatives containing all of the above.
(5) A therapeutic or preventive agent for external skin inflammation containing the anti-inflammatory agent according to any one of (1) to (4).
(6) A locally administered inflammatory treatment or prevention agent comprising the anti-inflammatory agent according to any one of (1) to (4).
（７）重量平均分子量が、約２千以上（好ましくは約５千以上、より好ましくは約１万以上）かつ約３００万以下（好ましくは約２００万以下、より好ましくは約１００万以下）であるスイゼンジノリ由来多糖体低分子化物またはそれらの薬理学的に許容される塩誘導体を有効成分として含むアトピー性皮膚炎の治療剤または予防剤。
（８）前記スイゼンジノリ由来多糖体低分子化物の重量平均分子量が、約１万以上かつ約１００万以下（好ましくは、約３万以上かつ約１００万以下）である上記（７）に記載のアトピー性皮膚炎の治療剤または予防剤。
（９）前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式： (7) The weight average molecular weight is about 2,000 or more (preferably about 5,000 or more, more preferably about 10,000 or more) and about 3 million or less (preferably about 2 million or less, more preferably about 1 million or less). A therapeutic or prophylactic agent for atopic dermatitis comprising a certain suizendinori-derived polysaccharide low molecular weight product or a pharmacologically acceptable salt derivative thereof as an active ingredient.
(8) The atopy according to (7) above, wherein a weight-average molecular weight of the low molecular weight product of the suizendinori-derived polysaccharide is about 10,000 or more and about 1 million or less (preferably about 30,000 or more and about 1 million or less). A therapeutic or prophylactic agent for dermatitis.
(9) The Suizendinori-derived polysaccharide low molecular weight product contains sulfated muramic acid as a sugar structure, and at least the following formula:
Figure JPOXMLDOC01-appb-C000007
 （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、および
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
のいずれかを含む糖誘導体である、前記（７）または（８）に記載のアトピー性皮膚炎の治療剤または予防剤。
（１０）前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式：
Figure JPOXMLDOC01-appb-C000007
 (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
And a disaccharide structure represented by the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
The therapeutic or preventive agent for atopic dermatitis according to (7) or (8) above, which is a sugar derivative containing any of the above.
(10) The low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
Figure JPOXMLDOC01-appb-C000008
 （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、および
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
の全てを含む糖誘導体の混合物である、前記（７）または（８）に記載のアトピー性皮膚炎の治療剤または予防剤。
Figure JPOXMLDOC01-appb-C000008
 (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
And a disaccharide structure represented by the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
The therapeutic or preventive agent for atopic dermatitis according to (7) or (8) above, which is a mixture of sugar derivatives containing all of the above.
　本発明によれば、炎症を抑制でき、かつ安全性の高い抗炎症剤が提供される。 According to the present invention, an anti-inflammatory agent that can suppress inflammation and has high safety is provided.
カラゲニン誘発性ラット足蹠浮腫モデルを用いた、スイゼンジノリ由来多糖体低分子化物の反復投与による抗炎症作用を確認した結果である。It is the result of having confirmed the anti-inflammatory effect by the repeated administration of the polysaccharide low molecular weight substance derived from Suizendinori using the carrageenin-induced rat footpad edema model. カラゲニン誘発性ラット足蹠浮腫モデルを用いた、スイゼンジノリ由来多糖体低分子化物の前処理による抗炎症作用を確認した結果である。It is the result of having confirmed the anti-inflammatory effect by the pretreatment of the low molecular weight polysaccharide derived from Suizendinori using the carrageenin-induced rat footpad edema model. カラゲニン誘発性ラット足蹠浮腫モデルを用いた、スイゼンジノリ由来多糖体低分子化物（サクラン（重量平均分子量150万））の前処理による抗炎症作用の濃度依存性を確認した結果である。It is the result of having confirmed the concentration dependence of the anti-inflammatory effect by the pre-treatment of the low molecular weight polysaccharide derived from Suizendinori (Sakuran (weight average molecular weight 1,500,000)) using a carrageenin-induced rat footpad edema model. カラゲニン誘発性ラット足蹠浮腫モデルを用いた、スイゼンジノリ由来多糖体低分子化物（サクラン（重量平均分子量94万））の前処理による抗炎症作用の濃度依存性を確認した結果である。It is the result of having confirmed the concentration dependence of the anti-inflammatory effect by the pretreatment of the polysaccharide low molecular weight substance (Sacran (weight average molecular weight 940,000)) derived from Suizendinori using the carrageenin-induced rat footpad edema model. カラゲニン誘発性ラット足蹠浮腫モデルを用いた、スイゼンジノリ由来多糖体低分子化物（サクラン（重量平均分子量4.5万）の前処理による抗炎症作用の濃度依存性を確認した結果である。It is the result of having confirmed the concentration dependence of the anti-inflammatory effect by the pre-treatment of the low molecular weight polysaccharide derived from Suizendinori (Sakuran (weight average molecular weight 45,000)) using a carrageenin-induced rat footpad edema model. カラゲニン誘発性ラット足蹠浮腫モデルを用いた、天然型サクランの反復投与による抗炎症作用の濃度依存性を確認した結果である。It is the result of having confirmed the concentration dependence of the anti-inflammatory effect by the repeated administration of a natural type | mold cherry using the carrageenin induced rat footpad edema model.
　本発明で用いられる特定の平均分子量を有するスイゼンジノリ由来多糖体低分子化物とは、スイゼンジノリ（Aphanothece sacrum）由来の重量平均分子量が約２０００万の硫酸化多糖類であるサクランから得ることができる。 The low molecular weight polysaccharide-derived polysaccharide having a specific average molecular weight used in the present invention can be obtained from cherry, which is a sulfated polysaccharide having a weight average molecular weight of about 20 million derived from Aphanothece sacrum.
　スイゼンジノリ（Aphanothece sacrum）は、多数のマユ型（大きさ：３．５～４．０μ×６～７μ）の単細胞が寒天質の中に埋没する状態で群体を形成する淡水性藍藻類であり、九州地方の熊本県、福岡県にのみ生育が確認されている。サクランは、ヘキソース構造を持つ糖構造体およびペントース構造を持つ糖構造体がα－グリコシド結合またはβ－グリコシド結合により直鎖状または分岐鎖状に連結した糖鎖ユニットの繰り返し構造を持ち、前記糖鎖ユニットが糖構造体として硫酸化ムラミン酸を含み、かつ、前記糖鎖ユニットにおいては、水酸基１００個当たり２．７個以上の水酸基が硫酸化され、あるいは全元素中で硫黄元素が１．５重量％以上を占める糖誘導体を含むことに特徴を有する。 Suizenjinori (Aphanothece 淡 sacrum) is a freshwater cyanobacteria that forms a colony in the state that a large number of single cells (size: 3.5-4.0μ × 6-7μ) are buried in agar. Growth has been confirmed only in Kumamoto Prefecture and Fukuoka Prefecture in the Kyushu region. Sakuran has a repeating structure of a sugar chain unit in which a sugar structure having a hexose structure and a sugar structure having a pentose structure are linked in a linear or branched manner by α-glycoside bonds or β-glycoside bonds, and The chain unit contains sulfated muramic acid as a sugar structure, and in the sugar chain unit, 2.7 or more hydroxyl groups per 100 hydroxyl groups are sulfated, or the sulfur element is 1.5% in all elements. It is characterized by containing a sugar derivative occupying at least% by weight.
　サクランは、重量平均分子量が約２０００万であり、糖構造体として硫酸化ムラミン酸を含み、且つ、少なくとも下記式： Sakura has a weight average molecular weight of about 20 million, contains sulfated muramic acid as a sugar structure, and has at least the following formula:
Figure JPOXMLDOC01-appb-C000009
 （式はヘキソースと、ヘキソースと、Ｎ－アセチルムラミン酸との３糖構造であることを示し、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨが－ＯＳＯ3またはＯＣＨ3となっているものを含む。）で示される配列を持つ３糖構造と、下記１）～６）に列挙する配列：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
を持つ２糖構造の全てを含む糖誘導体である。
Figure JPOXMLDOC01-appb-C000009
 (The formula indicates a trisaccharide structure of hexose, hexose, and N-acetylmuramic acid, R and R ′ indicate sugars, and any —OH in the formula is —OSO 3 or OCH 3 . And a trisaccharide structure having the sequence shown in 1) and the sequences listed in the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine,
6) Disaccharide structure of uronic acid which is glucuronic acid or galacturonic acid and deoxyhexose,
It is a sugar derivative containing all of the disaccharide structure having
　スイゼンジノリからサクランを抽出する方法の一例は、例えば、国際公開ＷＯ２００８／０６２５７４号に記載されている。例えば、８０℃の０．１Ｎ－ＮａＯＨ水溶液にスイゼンジノリを入れて数時間攪拌することによってスイゼンジノリからサクランを抽出できる。また、他の一例としては、スイゼンジノリの水分散液をオートクレーブ中において１３５℃で３０分間加熱することによってスイゼンジノリからサクランを抽出できる。抽出されたサクランは、遠心分離、ろ過、アルコール洗浄などによって精製してもよい。また、スイゼンジノリからサクランを抽出する前に、スイゼンジノリを凍結したのち融解させ、その後に色素を除去する工程を行ってもよい。 An example of a method for extracting cherries from Suizenjinori is described in, for example, International Publication WO2008 / 062574. For example, a cherry tree can be extracted from a lily of the valley by adding it to a 0.1N NaOH aqueous solution at 80 ° C. and stirring for several hours. As another example, cherry blossoms can be extracted from the water lily by heating an aqueous dispersion of water lily in an autoclave at 135 ° C. for 30 minutes. The extracted cherry may be purified by centrifugation, filtration, alcohol washing or the like. Moreover, before extracting a cherry tree from a sardine sardine, you may freeze and melt | dissolve a sardine sardine, and may remove the pigment | dye after that.
　このように、サクランは、酸性多糖類であり、アルカリ溶液を用いることでスイゼンジノリから抽出できる。スイゼンジノリから抽出されるサクランは、例えば、大東化成(株)から入手することができる。
　また、前記サクランを低分子量化する方法としては、例えば、酸性条件化で加熱処理することによる酸加水分解等が挙げられるが、これに限定されるものではない。
　また、サクランの低分子量化物は、任意の方法にて、例えばこれに限定されないがゲル濾過クロマトグラフィーを用いて、特定の分子量のものを分画して用いることもできる。 Thus, cherry is an acidic polysaccharide and can be extracted from scorpionary using an alkaline solution. The cherry tree extracted from a suizenjinori can be obtained from Daito Kasei Co., Ltd., for example.
Examples of the method for reducing the molecular weight of the cherry include acid hydrolysis by heat treatment under acidic conditions, but are not limited thereto.
In addition, the low molecular weight product of cherry can be used by any method, for example, but not limited to, fractionating a specific molecular weight using gel filtration chromatography.
　本発明の抗炎症剤またはアトピー性皮膚炎治療・予防剤（以下、これらをまとめて「医薬組成物」という場合がある）に含まれる多糖体低分子化物は、上記サクランから得ることができる多糖体である。本発明で用いる多糖体低分子化物とは、均一な多糖体から構成されてもよくまた種々の多糖体の混合物から構成されてもよいが、通常は、天然のサクランから調製されるので種々の多糖体の混合物からなる。本発明で用いる多糖体低分子化物は、天然のサクランを分解して得ることができるが、調製する方法はそれに限定されない。 The polysaccharide low molecular weight product contained in the anti-inflammatory agent or the atopic dermatitis treatment / prevention agent of the present invention (hereinafter sometimes collectively referred to as “pharmaceutical composition”) is a polysaccharide that can be obtained from the above cherry. Is the body. The polysaccharide low-molecular-weight product used in the present invention may be composed of a uniform polysaccharide or a mixture of various polysaccharides. However, since it is usually prepared from natural cherry, It consists of a mixture of polysaccharides. The polysaccharide-reduced product used in the present invention can be obtained by degrading natural cherry, but the method of preparation is not limited thereto.
　本発明の多糖体低分子化物は、上記サクランから得ることができる多糖体であって、重量平均分子量が、約３００万以下、好ましくは約２００万以下、さらに好ましくは約１００万以下であり、また、重量平均分子量の下限は、約２千以上、好ましくは約５千以上、より好ましくは約１万以上の硫酸化糖を含む多糖体、またはそれと同等の構造を持つ多糖体、さらには、多糖体から常法により得られる各種誘導化物（例えば、多糖体の塩誘導体）である。ここでいう重量平均分子量は、常法により測定することができ、例えば、ゲル濾過クロマトグラフィーを用いて測定することができる。 The polysaccharide-reduced product of the polysaccharide of the present invention is a polysaccharide that can be obtained from the above cherry, and has a weight average molecular weight of about 3 million or less, preferably about 2 million or less, more preferably about 1 million or less, Further, the lower limit of the weight average molecular weight is about 2,000 or more, preferably about 5,000 or more, more preferably about 10,000 or more polysaccharides containing sulfated saccharides, or polysaccharides having an equivalent structure thereof, These are various derivatives (for example, salt derivatives of polysaccharides) obtained from polysaccharides by conventional methods. The weight average molecular weight here can be measured by a conventional method, and can be measured, for example, using gel filtration chromatography.
　本発明で用いる多糖体低分子化物の重量平均分子量が、例えば、約２千以上かつ約３００万以下とは、用いる多糖体低分子化物を任意の重量分子量を測定する方法（例えば、ゲル濾過クロマトグラフィー）で測定した場合に、その分布から求められる（重量）平均分子量が、約２千～約３００万の間にはいるサクラン由来の多糖体の混合物であればよく、それら全ての多糖体（またはその混合物）を含む意味で用いられる。本発明で用いる低分子サクランとは、ゲル濾過クロマトグラフィーで分子量を測定した際に、好ましくは一つのピークを示す多糖体の混合物であるが、複数のピークを示す多糖体の混合物であってもよい。また、本発明で用いる多糖体低分子化物とは、用いる多糖体低分子化物またはその混合物が、本発明で規定する重量平均分子量の範囲に入る限り制限がないが、好ましくは、一つのピークを示す混合物であり、より好ましくは、よりシャープな一つのピークを示す混合物である。 The weight average molecular weight of the low molecular weight polysaccharide used in the present invention is, for example, about 2,000 or more and about 3 million or less. A method for measuring an arbitrary weight molecular weight of the low molecular weight polysaccharide used (for example, gel filtration chromatography). (Polygraph)), a mixture of polysaccharides derived from Sakuran whose (weight) average molecular weight determined from the distribution is between about 2,000 and about 3 million may be used. Or a mixture thereof). The low molecular weight cherry used in the present invention is preferably a mixture of polysaccharides showing one peak when the molecular weight is measured by gel filtration chromatography, but may be a mixture of polysaccharides showing a plurality of peaks. Good. In addition, the polysaccharide low molecular weight product used in the present invention is not limited as long as the polysaccharide low molecular weight product used or a mixture thereof falls within the range of the weight average molecular weight defined in the present invention. More preferably a mixture showing a sharper peak.
　本明細書において、例えば、「サクラン（分子量１５０万）」、「サクラン（分子量９４万）、「サクラン（分子量４．５万）」、「サクラン（分子量９００）」とは、サクランを分解または処理することにより得ることができる多糖体低分子化物またはその混合物であって、それぞれ、重量平均分子量が、約１５０万、約９４万、約４．５万、または約９００である多糖体の混合物を意味する。 In this specification, for example, “Sacran (molecular weight 1,500,000)”, “Sacran (molecular weight 940,000)”, “Sacran (molecular weight 45,000)”, and “Sacran (molecular weight 900)” are decomposed or processed. And a mixture of polysaccharides each having a weight average molecular weight of about 1.5 million, about 940,000, about 45,000, or about 900, respectively. means.
　本発明の多糖体低分子化物は、重量平均分子量の他、平均糖数でも表すことができる（かかる場合は、単糖の重量平均分子量を約１８０と推定することができる）。つまり、本発明の多糖体低分子化物は、上記サクランから得ることができる多糖体であって、平均糖数の上限が、約104以下、好ましくは約103以下であり、また平均糖数の下限は、約10以上、好ましくは約20以上、より好ましくは約50以上、さらに好ましくは約102以上の硫酸化糖を含む多糖体、またはそれと同等の構造を持つ多糖体、さらには、多糖体から常法により得られる各種誘導化物（例えば、多糖体の塩誘導体）である。ここでいう平均糖数とは、糖誘導体の大きさを、それを構成する糖の数に換算して表したものである。例えば、平均糖数が104の糖誘導体から構成されるサクラン誘導物とは、約103～約105の間の糖数を有する糖誘導体の集合体（104オーダーの糖数（つまり、糖数万～十万）の誘導体を中心にして分布する）からなるサクラン誘導物を意味し、平均糖数が103の糖誘導体から構成されるサクラン誘導物とは、約102～約104の間の糖数を有する糖誘導体の集合体（103オーダーの糖数（つまり、糖数千～万）の誘導体を中心にして分布する）からなるサクラン誘導物を意味し、平均糖数が102の糖誘導体から構成されるサクラン誘導物とは、約101～約103の間の糖数を有する糖誘導体の集合体（102オーダーの糖数（つまり、糖数百～千）の誘導体を中心にして分布する）からなるサクラン誘導物を意味する。
　上記した重量平均分子量で示した「サクラン（分子量１５０万）」、「サクラン（分子量９４万）、「サクラン（分子量４．５万）」、「サクラン（分子量９００）」は、平均糖数で示すと、それぞれ、「サクラン（104）」、「サクラン(103)」、「サクラン(102)」、「サクラン(4)」と表すことができる。 The polysaccharide low molecular weight product of the present invention can be expressed not only by the weight average molecular weight but also by the average number of sugars (in such a case, the weight average molecular weight of the monosaccharide can be estimated to be about 180). That is, the polysaccharide low molecular weight product of the present invention is a polysaccharide that can be obtained from the above sakuran, and the upper limit of the average number of sugars is about 10 4 or less, preferably about 10 3 or less, and the average number of sugars The lower limit of the polysaccharide is about 10 or more, preferably about 20 or more, more preferably about 50 or more, more preferably about 10 2 or more of a polysaccharide containing a sulfated sugar, or a polysaccharide having an equivalent structure, These are various derivatives (for example, salt derivatives of polysaccharides) obtained from polysaccharides by conventional methods. The average number of sugars referred to here is a value obtained by converting the size of a sugar derivative into the number of sugars constituting the sugar derivative. For example, a cherry derivative composed of a sugar derivative having an average sugar number of 10 4 is an aggregate of sugar derivatives having a sugar number between about 10 3 and about 10 5 (a sugar number on the order of 10 4 (ie, around the derivatives of sugars several tens of thousand-hundred thousand) means confusion induced composed distributed), and confusion induced composed average number sugar from 10 3 sugar derivative is from about 10 2 to about 10 Means the number of sugar derivatives, consisting of a collection of sugar derivatives having a number of sugars between 4 (distributed centering on derivatives of 10 3 order sugars (ie, thousands to thousands of sugars)). Sakura derivatives composed of 10 2 sugar derivatives are aggregates of sugar derivatives having a sugar number between about 10 1 and about 10 3 (number of sugars on the order of 10 2 (that is, hundreds to thousands of sugars). ), Which is distributed around the derivative).
“Sacran (molecular weight: 1,500,000)”, “Sacran (molecular weight: 940,000)”, “Sacran (molecular weight: 45,000)”, and “Sacran (molecular weight: 900)” indicated by the weight average molecular weight are indicated by the average number of sugars. These can be expressed as “Sacran (10 4 )”, “Sakuran (10 3 )”, “Sakuran (10 2 )”, and “Sakuran (4)”, respectively.
　上記の同等の糖構造を有する多糖体とは、一例としては、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式： The above polysaccharide having an equivalent sugar structure includes, for example, sulfated muramic acid as the sugar structure, and at least the following formula:
Figure JPOXMLDOC01-appb-C000010
 （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、および
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
の全てを含む糖誘導体である。
Figure JPOXMLDOC01-appb-C000010
 (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
And a disaccharide structure represented by the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
It is a sugar derivative containing all of the above.
　上記の同等の糖構造を有する多糖体の別の例としては、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式： As another example of the polysaccharide having the same sugar structure as described above, the sugar structure contains sulfated muramic acid, and at least the following formula:
Figure JPOXMLDOC01-appb-C000011
 （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
１）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
３）ペントースとペントースとの２糖構造、
４）ペントースとデオキシヘキソースとの２糖構造、
５）ヘキソサミンとヘキソサミンとの２糖構造、および
６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
のいずれかを含む糖誘導体である。
Figure JPOXMLDOC01-appb-C000011
 (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
And a disaccharide structure represented by the following 1) to 6):
1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
3) Disaccharide structure of pentose and pentose,
4) Disaccharide structure of pentose and deoxyhexose,
5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
It is a sugar derivative containing any of these.
　所望の重量平均分子量を有するスイゼンジノリ由来多糖体低分子化物は、サクランから公知の方法を組み合わせて得ることができる。例えば、酸性条件下で加熱処理して酸加水分解することにより得ることができる。あるいは、公知の糖鎖の切断方法、例えば酵素を用いて糖鎖をランダムに切断し、所望の重量平均分子量を有する糖誘導体の混合物を分子量に基づいて単離できる。サクランの糖鎖を切断可能な酵素としては、例えば、β－ガラクトシダーゼ、ヘキソサミニダーゼＡ、ヘキソサミニダーゼＢ、α－ガラクトシダーゼＡ、β－グルコシダーゼ、α－Ｌ－イズロニダーゼ、Ｎ－アセチル－α－グルコサミニダーゼ、β－グルクロニダーゼ、ヒアルロニダーゼ、Ｎ－アセチル－β－グルコサミニダーゼ、α－フコシダーゼ、α－マンノシダーゼ、β－マンノシダーゼ、α－Ｎ－アセチルガラクトサミニダーゼ、α－ノイラミニダーゼ、α－１，４－グルコシダーゼを挙げることができるが、これらに限定されるものではない。 A suizendinori-derived polysaccharide low molecular weight product having a desired weight average molecular weight can be obtained from Sakuran by a combination of known methods. For example, it can be obtained by heat treatment under acidic conditions and acid hydrolysis. Alternatively, a sugar chain can be randomly cleaved using a known sugar chain cleavage method, for example, an enzyme, and a mixture of sugar derivatives having a desired weight average molecular weight can be isolated based on the molecular weight. Examples of enzymes that can cleave the sugar chain of cherry include β-galactosidase, hexosaminidase A, hexosaminidase B, α-galactosidase A, β-glucosidase, α-L-iduronidase, N-acetyl-α. -Glucosaminidase, β-glucuronidase, hyaluronidase, N-acetyl-β-glucosaminidase, α-fucosidase, α-mannosidase, β-mannosidase, α-N-acetylgalactosaminidase, α-neuraminidase, α-1,4-glucosidase It can be mentioned, but is not limited to these.
　所望の重量平均分子量を有するサクラン誘導物を調製するに際し、切断された糖鎖末端は、任意に修飾することも可能である。修飾に用いることができる官能基としては、カルボキシ基、アミノ基、硫酸基、などをあげることができるが、これらに限定されるものではない。これらの切断糖鎖が修飾または置換された誘導物も本発明の多糖体低分子化物に含まれる。
　また、所望の重量平均分子量を有するスイゼンジノリ由来多糖体低分子化物を調製するに際し、サクランを構成する糖の水酸基または水素基、あるいは糖に結合しているカルボキシ基、アミノ基その他の基を置換または修飾することも可能であり、これらの修飾または置換された誘導物も本発明の多糖体低分子化物に含まれる。 In preparing a cherry derivative having a desired weight average molecular weight, the end of the cleaved sugar chain can be arbitrarily modified. Examples of functional groups that can be used for modification include, but are not limited to, a carboxy group, an amino group, and a sulfate group. Derivatives in which these cleaved sugar chains are modified or substituted are also included in the polysaccharide low molecular weight product of the present invention.
Further, when preparing a low molecular weight product of a suizendinori-derived polysaccharide having a desired weight average molecular weight, a hydroxyl group or a hydrogen group of a sugar constituting sakuran, or a carboxy group, an amino group or other group bonded to the sugar is substituted or It is also possible to modify these derivatives, and these modified or substituted derivatives are also included in the polysaccharide low molecular weight product of the present invention.
　本発明の多糖体低分子化物は、薬理学的に許容できる塩の形で用いることもできる。薬理学的に許容できる塩としては、特に制限がなく、目的に応じて適宜選択をすることができ、例えば、塩酸塩、硫酸塩などの無機塩、クエン酸などの有機酸塩などをあげることができる。 The low molecular weight polysaccharide of the present invention can also be used in the form of a pharmacologically acceptable salt. The pharmacologically acceptable salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include inorganic salts such as hydrochloride and sulfate, and organic acid salts such as citric acid. Can do.
　本発明の医薬組成物中の多糖体低分子化物の含有量は、用途・目的に応じて適宜選択することができ、例えば、医薬組成物の全量に対して固形分換算で、０．０００１～２０重量％、好ましくは０．００１～１０重量％、さらに好ましくは、０．０１～５重量％である。
　本発明の医薬組成物は、いずれの形態でも用いることができ、これらに限定されないが、例えば、経口剤、注射剤、皮膚外用剤、局所投与剤、点眼剤等をあげることができる。本発明の多糖体低分子化物は、抗炎症作用に加えて保湿作用を有しているので、皮膚外用剤、関節炎などの対する局所投与剤または注射剤、点眼剤としての態様において好ましく用いられる。 The content of the low-molecular-weight polysaccharide in the pharmaceutical composition of the present invention can be appropriately selected according to the use and purpose. For example, the content of the polysaccharide can be 0.0001 to It is 20% by weight, preferably 0.001 to 10% by weight, and more preferably 0.01 to 5% by weight.
The pharmaceutical composition of the present invention can be used in any form and is not limited thereto, and examples thereof include oral preparations, injection preparations, external preparations for skin, topical preparations, eye drops and the like. Since the polysaccharide low-molecular-weight product of the present invention has a moisturizing action in addition to an anti-inflammatory action, it is preferably used in an embodiment as a topical administration agent or an injection or an eye drop for external preparations for skin and arthritis.
　皮膚外用剤として用いる場合は、その剤形は任意であり、例えば、液剤、軟膏、貼付剤、エアゾール形態、ハップ剤、テープ剤、粉末等様々な形態で用いることができる。
　経口剤として用いる場合は、その剤形は任意であり、例えば、錠剤、カプセル剤、顆粒剤、散剤等様々な形態で用いることができる。 When used as an external preparation for skin, the dosage form is arbitrary, and for example, it can be used in various forms such as liquids, ointments, patches, aerosols, haps, tapes, and powders.
When used as an oral preparation, the dosage form is arbitrary, and can be used in various forms such as tablets, capsules, granules, powders and the like.
　本発明の医薬組成物は、本発明の多糖体低分子化物に加え、目的に応じて適宜選択した成分を含むことができる。例えば、製剤化のための補助成分としては、基剤、安定剤、防腐剤、保存剤、乳化剤、懸濁化剤、溶解剤、溶解補助剤、滑沢剤、矯味剤、着色剤、芳香剤、無痛化剤、賦形剤、結合剤、粘稠剤、緩衝剤などがあげることができる。これらの補助成分を用いて、本発明の薬剤を調製する場合には、当該補助成分を適宜選択して使用すればよい。また、補助成分の使用量は、製剤学的に許容されうる範囲内において、剤形などに応じ、適宜選択すればよい。
　より具体的には、例えば、これに制限はされないが、皮膚外用剤として用いる場合は、例えば、賦形剤、結合剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、防腐剤、抗酸化剤、安定化剤または吸収促進剤を適宜組み合わせて製剤化することができる。
　例えば、注射剤として用いる場合は、例えば、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤または吸収促進剤を適宜組み合わせて製剤化することができる。 The pharmaceutical composition of the present invention can contain components appropriately selected according to the purpose, in addition to the polysaccharide low molecular weight product of the present invention. For example, auxiliary ingredients for formulation include bases, stabilizers, preservatives, preservatives, emulsifiers, suspending agents, solubilizers, solubilizers, lubricants, flavoring agents, colorants, fragrances , Soothing agents, excipients, binders, thickeners, buffers, and the like. In preparing the drug of the present invention using these auxiliary components, the auxiliary components may be appropriately selected and used. Moreover, the usage-amount of an auxiliary | assistant component should just be suitably selected according to a dosage form etc. in the range accept | permitted pharmaceutically.
More specifically, for example, although not limited thereto, when used as an external preparation for skin, for example, excipients, binders, flavoring agents, emulsifiers, surfactants, solubilizing agents, suspending agents , And can be formulated by appropriately combining isotonic agents, preservatives, antioxidants, stabilizers or absorption promoters.
For example, when used as an injection, for example, an emulsifier, a surfactant, a solubilizer, a suspending agent, a tonicity agent, a buffer, an antiseptic, an antioxidant, a stabilizer, or an absorption enhancer is appropriately used. It can be formulated in combination.
　本発明の多糖体低分子化物を含む医薬組成物は、炎症を伴う疾患に広く用いることができ、例えば、感染症、関節リウマチ、膠原病、痛風、アレルギー疾患、アトピー性皮膚炎、炎症性腸疾患、間質性肺炎等を患う対象（例えば、患者や動物）に投与することにより、前記患者の炎症を効果的に抑制することができる。 The pharmaceutical composition containing the polysaccharide low molecular weight product of the present invention can be widely used for diseases accompanied by inflammation, for example, infection, rheumatoid arthritis, collagen disease, gout, allergic disease, atopic dermatitis, inflammatory bowel By administering to a subject (for example, a patient or an animal) suffering from a disease, interstitial pneumonia, etc., the inflammation of the patient can be effectively suppressed.
　本発明の多糖体低分子化物は、天然物由来のアニオン性多糖体であるので、安全性に優れている。加えて、本発明の多糖体低分子化物は熱に対して比較的安定であり、オートクレーブ滅菌処理を行うことが可能であり、扱いやすく、医薬用途等に適しているという利点を有する。 Since the polysaccharide low molecular weight product of the present invention is an anionic polysaccharide derived from a natural product, it is excellent in safety. In addition, the polysaccharide low-molecular-weight product of the present invention is relatively stable against heat, can be sterilized by autoclave, is easy to handle, and has an advantage of being suitable for pharmaceutical use.
　以下、実施例により、本発明を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。
　スイゼンジノリ由来多糖体低分子化物の抗炎症作用を、炎症モデルを用いて確認を行った。
実施例１：サクラン水溶液の調製および炎症モデル
（１）サクラン水溶液の調製
　スイゼンジノリ由来多糖体低分子化物としては、サクラン由来の、重量平均分子量が約８００～１０００の多糖体低分子化物（サクラン（分子量９００））、重量平均分子量が約４．５万の多糖体低分子化物（サクラン（分子量４．５万））、重量平均分子量が約９４万の多糖体低分子化物（サクラン（分子量９４万））、重量平均分子量が約１５０万の多糖体低分子化物（サクラン（分子量１５０万））（いずれも日立化成（株）製）を用いた。各多糖体低分子化物の分子量は、検出器として示差屈折計（株式会社島津製作所製、ＲＩＤ－１０Ａ）を備えたＨＰＬＣシステムにＧＰＣカラム（株式会社日立ハイテクノロジーズ製、ＧＬ－Ｗ５６０）を接続し、溶離液として０．２Ｍ ＮａＣｌ水溶液を用い、流量を１．０ｍＬ／分にて測定を行い、標準物質としてプルランを用いた検量線から重量平均分子量を算出した。各多糖体低分子化物をそれぞれ生理食塩水に溶解して、種々の濃度のサクラン水溶液を調製した
　対象としてサクラン（天然型のサクラン）（グリーンサイエンス・マテリアル社製）を用いた。
（２）炎症モデル
　炎症モデルとして、カラゲニン誘発性ラット足蹠浮腫モデルを用いた。カラゲニン誘発性ラット足蹠浮腫モデルは、常法に従い、ラットの足蹠皮内に起炎物質であるカラゲニン（λ-カラゲニン（SIGMA社、Lot No.0001408463）の１％水溶液）を１００μL注射して浮腫を起こさせて作成した。 EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to a following example.
The anti-inflammatory action of the low molecular weight polysaccharide derived from Suizendinori was confirmed using an inflammation model.
Example 1 : Preparation of Sakura Water Solution and Inflammation Model (1) Preparation of Sakura Water Solution As a low molecular weight polysaccharide derived from Suizendinori, a low molecular weight polysaccharide derived from sakuran having a weight average molecular weight of about 800 to 1000 (sakuran (molecular weight 900)), a low molecular weight polysaccharide having a weight average molecular weight of about 45,000 (Sakuran (molecular weight 45,000)), and a low molecular weight polysaccharide having a weight average molecular weight of about 940,000 (Sakuran (molecular weight 940,000)). ), A low molecular weight polysaccharide having a weight average molecular weight of about 1,500,000 (Sakuran (molecular weight 1,500,000)) (all manufactured by Hitachi Chemical Co., Ltd.). The molecular weight of each low-molecular-weight polysaccharide is measured by connecting a GPC column (GL-W560, Hitachi High-Technologies Corporation) to an HPLC system equipped with a differential refractometer (Shimadzu Corporation, RID-10A) as a detector. Then, a 0.2 M NaCl aqueous solution was used as an eluent, the flow rate was measured at 1.0 mL / min, and the weight average molecular weight was calculated from a calibration curve using pullulan as a standard substance. Sakuran (natural cherry) (manufactured by Green Science Materials Co., Ltd.) was used as a target for dissolving each polysaccharide low molecular weight product in physiological saline and preparing various concentrations of Sakuran aqueous solution.
(2) Inflammation Model A carrageenin-induced rat footpad edema model was used as an inflammation model. The carrageenin-induced rat footpad edema model was prepared by injecting 100 μL of carrageenin (λ-carrageenin (SIGMA, Lot No.0001408463) 1% aqueous solution) into the rat footpad in accordance with a conventional method. Created with edema.
実施例２：スイゼンジノリ由来多糖体低分子化物の反復投与による抗炎症作用
　ラットの足蹠へのカラゲニン投与直後より、各種スイゼンジノリ由来多糖体低分子化物を含有する水溶液１００μLを１時間毎に１回塗布した。塗布は、６回繰り返した。用いた多糖体低分子化物水溶液の濃度は、サクラン（分子量１５０万）、サクラン（分子量９４万）、およびサクラン（分子量４．５万）が、０．０００５％（w/v）、サクラン（分子量９００）が０．０２％（w/v）とした。対象として、サクラン（０．０５％（w/v））と、生理食塩水を用いた。カラゲニン投与時およびその後は１時間毎に、足容積の増加をプレチスモメーター（plethysmometer）を用いて測定し、測定後はラットの足蹠を毎回ラップで保護した。結果を図１に示す。
　その結果、スイゼンジノリ由来多糖体低分子化物（分子量１５０万、９４万、および４．５万）において、抗炎症作用が確認できた。またスイゼンジノリ由来多糖体低分子化物は、サクランに比べ、１／１００の量にて同等またはそれ以上の抗炎症効果を有し、０．０００5%（w/v）の低濃度でも強力な抗炎症作用を示した。 Example 2: Anti-inflammatory effect by repeated administration of low molecular weight polysaccharide-derived polysaccharides from Suizendinori Immediately after carrageenin administration to the footpad of rats, 100 μL of an aqueous solution containing various low-molecular-weight polysaccharides derived from Suizendinori was applied once every hour. did. Application was repeated 6 times. The concentration of the polysaccharide low molecular weight aqueous solution used was 0.0005% (w / v) for cherry (molecular weight 1,500,000), cherry (molecular weight 940,000), and cherry (molecular weight 45,000), and cherry (molecular weight). 900) was 0.02% (w / v). As a subject, cherry (0.05% (w / v)) and physiological saline were used. At the time of carrageenin administration and every hour thereafter, the increase in paw volume was measured using a plethysmometer, and the rat footpad was protected with a lap after each measurement. The results are shown in FIG.
As a result, anti-inflammatory action was confirmed in the low molecular weight polysaccharides derived from Suizendinori (molecular weights of 1.5 million, 940,000 and 45,000). In addition, the low molecular weight polysaccharide derived from Suizen Ginori has an anti-inflammatory effect equivalent to or higher than that of Sakuran in an amount of 1/100, and strong anti-inflammatory even at a low concentration of 0.0005% (w / v). The effect was shown.
実施例３：スイゼンジノリ由来多糖体低分子化物の前処置による抗炎症作用
　カラゲニン誘発性足蹠浮腫ラットモデルにおいて、カラゲニンにより炎症を誘発する前のラットの足蹠にスイゼンジノリ由来多糖体低分子化物を塗布し、抗炎症効果を確認した。多糖体低分子化物の塗布は、カラゲニン投与の１時間前に行った。用いた多糖体低分子化物水溶液の濃度は、サクラン（分子量１５０万）、サクラン（分子量９４万）、サクラン（分子量４．５万）ともに０．０００５％（w/v）とした。対象として、サクラン（０．０５％（ｗ／ｖ））と、生理食塩水を用いた。カラゲニン投与開始時およびその後の１時間毎に、足容積の増加をプレチスモメーターにより測定し、測定後はラットの足蹠を毎回ラップで保護した。結果を図２に示す。
　その結果、スイゼンジノリ由来多糖体低分子化物（分子量１５０万、９４万および４．５万）において、カラゲニン投与１時間前に１回投与した際にも抗炎症効果が確認できた。またスイゼンジノリ由来多糖体低分子化物は、サクランに比べ、１／１００の量にて同等またはそれ以上の抗炎症効果を示した。 Example 3: Anti-inflammatory action by pretreatment of low molecular weight polysaccharide-derived polysaccharide derived from suizendinori In the rat model of carrageenin-induced footpad edema, low molecular weight polysaccharide-derived polysaccharide derived from suizendinori was applied to the rat footpad before inducing inflammation by carrageenan The anti-inflammatory effect was confirmed. The polysaccharide low molecular weight product was applied 1 hour before carrageenan administration. The concentration of the polysaccharide low molecular weight product aqueous solution used was 0.0005% (w / v) for cherry (molecular weight 1,500,000), cherry (molecular weight 940,000), and cherry (molecular weight 45,000). As a subject, cherry (0.05% (w / v)) and physiological saline were used. At the start of carrageenin administration and every hour thereafter, the increase in paw volume was measured with a plethysmometer, and the rat footpad was protected with a lap after each measurement. The results are shown in FIG.
As a result, the anti-inflammatory effect could be confirmed even when the low molecular weight polysaccharide derived from suizendinori (molecular weight 1.5 million, 940,000 and 45,000) was administered once 1 hour before carrageenan administration. Moreover, the low molecular weight polysaccharide derived from Suizenjinori showed an anti-inflammatory effect equivalent to or higher than that of Sakuran in an amount of 1/100.
実施例４：スイゼンジノリ由来多糖体低分子化物の抗炎症作用の濃度依存性
　実施例３と同様にして、カラゲニン誘発性足蹠浮腫ラットモデルにおいて、カラゲニンにより炎症を誘発する前のラットの足蹠にスイゼンジノリ由来多糖体低分子化物を塗布し、抗炎症効果の濃度依存性を確認した。用いた多糖体低分子化物水溶液の各濃度は、０．０００５％（w/v）、０．００５％（w/v）、０．０１％（w/v）とし、対象として、サクラン（０．０５％（w/v））と、生理食塩水を用いた。サクラン（分子量１５０万）の結果を図３に、サクラン（分子量９４万）の結果を図４に、サクラン（分子量４．５万）の結果を図５に示す。いずれの低分子サクランにおいても、濃度依存的な抗炎症作用を示した。 Example 4: Concentration dependence of anti-inflammatory action of low molecular weight polysaccharide derived from Suizendinori In the same manner as in Example 3, in a rat model of carrageenin-induced footpad edema, the rat footpad before inducing inflammation by carrageenan The low molecular weight polysaccharide derived from Suizenjinori was applied to confirm the concentration dependence of the anti-inflammatory effect. The concentration of the polysaccharide low-molecular-weight aqueous solution used was 0.0005% (w / v), 0.005% (w / v), and 0.01% (w / v). .05% (w / v)) and physiological saline. FIG. 3 shows the results of cherry (molecular weight 1,500,000), FIG. 4 shows the results of cherry (molecular weight 940,000), and FIG. 5 shows the results of cherry (molecular weight 45,000). All of the low molecular weight cherries showed a concentration-dependent anti-inflammatory effect.
比較例１：サクラン（天然型サクラン）による抗炎症作用の濃度依存性
　実施例２と同様にして、ラットの足蹠へのカラゲニン投与直後より、各種濃度のサクラン（天然型サクラン）を含有する水溶液１００μLを１時間毎に１回塗布した。塗布は、６回繰り返した。用いたサクラン水溶液の濃度は、０．０１％（w/v）、０．０５％（w/v）、０．１％（w/v）、および０．２％（w/v）とした。対象として、生理食塩水を用いた。カラゲニン投与時およびその後は１時間毎に、足容積の増加を、プレシスモメーターを用いて測定し、測定後はラットの足蹠を毎回ラップで保護した。結果を図６に示す。
　天然型サクランでは、その抗炎症効果は、濃度を増大させると減弱することが判った。 Comparative Example 1: Concentration dependence of anti-inflammatory action by cherry (natural cherry) In the same manner as in Example 2, an aqueous solution containing various concentrations of cherry (natural cherry) immediately after administration of carrageenan to the rat footpad 100 μL was applied once every hour. Application was repeated 6 times. The concentration of the sakura aqueous solution used was 0.01% (w / v), 0.05% (w / v), 0.1% (w / v), and 0.2% (w / v). . Saline was used as the subject. At the time of carrageenin administration and every hour thereafter, the increase in paw volume was measured using a plethysmometer, and the rat footpad was protected with a lap after each measurement. The results are shown in FIG.
In natural cherries, the anti-inflammatory effect was found to decrease with increasing concentration.
　以上の結果からわかるように、スイゼンジノリ由来多糖体低分子化物は、天然型サクラン（低分子化していないサクラン）に比べ、強力かつ濃度依存的な抗炎症作用を示すことが示唆され、優れた抗炎症薬としての利用が可能であることが判った。また、スイゼンジノリ由来多糖体低分子化物の場合は、天然型サクランとは異なり、広範な投与濃度の設定が可能である。 As can be seen from the above results, it is suggested that the low molecular weight product derived from Suizendinori has a strong and concentration-dependent anti-inflammatory effect compared to natural sakuran (non-decreased sakuran). It was found that it can be used as an inflammatory drug. Moreover, in the case of a polysaccharide low molecular weight product derived from Suizendinori, it is possible to set a wide range of administration concentrations, unlike a natural type cherry.
　上記の記載は、本発明の目的および対象を単に説明するものであり、添付の特許請求の範囲を限定するものではない。添付の特許請求の範囲から離れることなしに、記載された実施態様に対しての、種々の変更および置換は、本明細書に記載された教示より当業者にとって明らかである。 The above description merely explains the objects and objects of the present invention, and does not limit the scope of the appended claims. Various changes and substitutions to the described embodiments will be apparent to those skilled in the art from the teachings set forth herein without departing from the scope of the appended claims.
　本発明のスイゼンジノリ由来多糖体低分子化物は、抗炎症剤の有効成分として有用である。 The low molecular weight polysaccharide-derived polysaccharide of the Suizendinori of the present invention is useful as an active ingredient of an anti-inflammatory agent.

Claims (10)

  1. 　重量平均分子量が、２千以上かつ３００万以下であるスイゼンジノリ由来多糖体低分子化物またはそれらの薬理学的に許容される塩誘導体を含む抗炎症剤。 An anti-inflammatory agent comprising a Suizendinori-derived polysaccharide low molecular weight product having a weight average molecular weight of 2,000 to 3,000,000 or a pharmacologically acceptable salt derivative thereof.
  2. 　前記スイゼンジノリ由来多糖体低分子化物の重量平均分子量が、１万以上かつ１００万以下である請求項１に記載の抗炎症剤。 The anti-inflammatory agent according to claim 1, wherein a weight average molecular weight of the low molecular weight product of the suizendinori-derived polysaccharide is 10,000 or more and 1,000,000 or less.
  3. 　前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式：
    Figure JPOXMLDOC01-appb-C000001
     （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
    に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
    １）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
    ２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
    ３）ペントースとペントースとの２糖構造、
    ４）ペントースとデオキシヘキソースとの２糖構造、
    ５）ヘキソサミンとヘキソサミンとの２糖構造、および
    ６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
    のいずれかを含む糖誘導体である、請求項１または２に記載の抗炎症剤。     The low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
    Figure JPOXMLDOC01-appb-C000001
     (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
    And a disaccharide structure represented by the following 1) to 6):
    1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
    2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
    3) Disaccharide structure of pentose and pentose,
    4) Disaccharide structure of pentose and deoxyhexose,
    5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
    The anti-inflammatory agent of Claim 1 or 2 which is a sugar derivative containing either of these.
  4. 　前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式：
    Figure JPOXMLDOC01-appb-C000002
     （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
    に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
    １）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
    ２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
    ３）ペントースとペントースとの２糖構造、
    ４）ペントースとデオキシヘキソースとの２糖構造、
    ５）ヘキソサミンとヘキソサミンとの２糖構造、および
    ６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
    の全てを含む糖誘導体の混合物である、請求項１または２に記載の抗炎症剤。     The low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
    Figure JPOXMLDOC01-appb-C000002
     (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
    And a disaccharide structure represented by the following 1) to 6):
    1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
    2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
    3) Disaccharide structure of pentose and pentose,
    4) Disaccharide structure of pentose and deoxyhexose,
    5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
    The anti-inflammatory agent according to claim 1 or 2, which is a mixture of sugar derivatives containing all of the above.
  5. 　請求項１～４のいずれか一つに記載の抗炎症剤を含有する皮膚外用炎症治療剤または予防剤。 A therapeutic or preventive agent for external skin inflammation containing the anti-inflammatory agent according to any one of claims 1 to 4.
  6. 　請求項１～４のいずれか一つに記載の抗炎症剤を含有する局所投与炎症治療剤または予防剤。 A locally administered inflammatory therapeutic or preventive agent comprising the anti-inflammatory agent according to any one of claims 1 to 4.
  7. 　重量平均分子量が、２千以上かつ３００万以下であるスイゼンジノリ由来多糖体低分子化物またはそれらの薬理学的に許容される塩誘導体を有効成分として含むアトピー性皮膚炎の治療剤または予防剤。 A therapeutic or prophylactic agent for atopic dermatitis comprising, as an active ingredient, a low molecular weight product of a suizendinori-derived polysaccharide having a weight average molecular weight of 2,000 to 3,000,000 or a pharmacologically acceptable salt derivative thereof.
  8. 　前記スイゼンジノリ由来多糖体低分子化物の重量平均分子量が、１万以上かつ１００万以下である請求項７に記載のアトピー性皮膚炎の治療剤または予防剤。 The therapeutic agent or preventive agent for atopic dermatitis according to claim 7, wherein the weight-average molecular weight of the low molecular weight polysaccharide derived from Suizendinori is 10,000 or more and 1,000,000 or less.
  9. 　前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式：
    Figure JPOXMLDOC01-appb-C000003
     （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
    に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
    １）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
    ２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
    ３）ペントースとペントースとの２糖構造、
    ４）ペントースとデオキシヘキソースとの２糖構造、
    ５）ヘキソサミンとヘキソサミンとの２糖構造、および
    ６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
    のいずれかを含む糖誘導体である、請求項７または８に記載のアトピー性皮膚炎の治療剤または予防剤。     The low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
    Figure JPOXMLDOC01-appb-C000003
     (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
    And a disaccharide structure represented by the following 1) to 6):
    1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
    2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
    3) Disaccharide structure of pentose and pentose,
    4) Disaccharide structure of pentose and deoxyhexose,
    5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
    The therapeutic or preventive agent for atopic dermatitis according to claim 7 or 8, which is a sugar derivative containing any of the above.
  10. 　前記スイゼンジノリ由来多糖体低分子化物が、糖構造体として硫酸化ムラミン酸を含み、かつ、少なくとも下記式：
    Figure JPOXMLDOC01-appb-C000004
     （ここで、Ｒ、Ｒ’は糖を示し、式中の任意の－ＯＨは、－ＯＳＯ3または－ＯＣＨ3に置換されてもよい。）
    に示す配列を持つ３糖構造と、下記１）～６）で表される２糖構造：
    １）ヘキソースと、キシロースまたはアラビノースであるペントースとの２糖構造、
    ２）ヘキソースと、フコースまたはラムノースであるデオキシヘキソースとの２糖構造、
    ３）ペントースとペントースとの２糖構造、
    ４）ペントースとデオキシヘキソースとの２糖構造、
    ５）ヘキソサミンとヘキソサミンとの２糖構造、および
    ６）グルクロン酸またはガラクツロン酸であるウロン酸と、デオキシヘキソースとの２糖構造、
    の全てを含む糖誘導体の混合物である、請求項７または８に記載のアトピー性皮膚炎の治療剤または予防剤。     The low-molecular-weight polysaccharide derived from Suizendinori contains sulfated muramic acid as a sugar structure, and at least the following formula:
    Figure JPOXMLDOC01-appb-C000004
     (Here, R and R ′ represent a saccharide, and any —OH in the formula may be replaced by —OSO 3 or —OCH 3 )
    And a disaccharide structure represented by the following 1) to 6):
    1) Disaccharide structure of hexose and pentose which is xylose or arabinose,
    2) Disaccharide structure of hexose and deoxyhexose which is fucose or rhamnose,
    3) Disaccharide structure of pentose and pentose,
    4) Disaccharide structure of pentose and deoxyhexose,
    5) Disaccharide structure of hexosamine and hexosamine, and 6) Disaccharide structure of uronic acid, which is glucuronic acid or galacturonic acid, and deoxyhexose,
    The therapeutic or preventive agent for atopic dermatitis according to claim 7 or 8, which is a mixture of sugar derivatives containing all of the above.
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