WO1998008877A1 - Derives de chitosane, procedes permettant de produire ceux-ci et leur utilisation - Google Patents

Derives de chitosane, procedes permettant de produire ceux-ci et leur utilisation Download PDF

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Publication number
WO1998008877A1
WO1998008877A1 PCT/JP1997/002998 JP9702998W WO9808877A1 WO 1998008877 A1 WO1998008877 A1 WO 1998008877A1 JP 9702998 W JP9702998 W JP 9702998W WO 9808877 A1 WO9808877 A1 WO 9808877A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
chitosan derivative
present
group
derivative according
Prior art date
Application number
PCT/JP1997/002998
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English (en)
Japanese (ja)
Inventor
Masanori Kakimoto
Mitsuyasu Ushijima
Shigeo Kasuga
Sumihiro Shiraishi
Youichi Itakura
Original Assignee
Wakunaga Seiyaku Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wakunaga Seiyaku Kabushiki Kaisha filed Critical Wakunaga Seiyaku Kabushiki Kaisha
Publication of WO1998008877A1 publication Critical patent/WO1998008877A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention relates to a novel chitosan derivative, a method for producing the same, and a medicament or food comprising the same. More specifically, the present invention relates to a chitosan derivative obtained by subjecting a partially deacetylated chitosan to a reduction treatment, a method for producing the same, and a medicament or food comprising this and an indigestible dextrin having an effect of improving constipation.
  • chitosan which is obtained by deacetylating chitin, a constituent of shells such as Rikiji and Eze, interacts with cholesterol bile acid to inhibit absorption. Its effective use has attracted attention [M Sugan 0 et a1: Lipid, 23, 187 (1988), Y. Maejima et al: Biosci. Biotech. Biochem., 57, 1439 (1993)].
  • chitosan has already been commercialized in the form of powders, tablets, and soft capsules, but chitosan used in these products hardly dissolves in water. Organic acids such as acids must be used.
  • chitosan is known to form complex salts with minerals such as iron, magnesium, and calcium. ⁇ It is known that if taken in large amounts, it may inhibit the absorption of nutrient minerals. Furthermore, chitosan has an astringent non-astringent taste, and is not desirable to be incorporated into drinks, powders, and »j.
  • the present inventors have recently reported that, by further reducing the partially deacetylated chitosan, it is possible to obtain an extremely stable chitosan derivative which has high solubility and almost no astringent ego taste. Obtained knowledge. Further, they have found that this chitosan derivative has an activity equivalent to that of chitosan known hitherto, and also has an excellent defecation ⁇ 3 ⁇ 4! Effect when combined with indigestible dextrin. The present invention is based on such findings.
  • an object of the present invention is to provide a chitosan derivative which is stable, has no taste and is effective, and a method for producing the same.
  • Another object of the present invention is to provide a medicament or food containing the chitosan derivative, particularly a medicament or food having a constipation improving effect.
  • the chitosan derivative according to the present invention can be obtained by partially deacetylating chitin and then subjecting the chitin to a reduction treatment.
  • the medicament or food according to the present invention especially a medicament or food having an effect of improving constipation, comprises the chitosan derivative according to the present invention and, in some cases, dietary fiber.
  • the chitosan derivative according to the present invention can be obtained by partially deacetylating chitin and then subjecting the chitin to a reduction treatment. More specifically, the chitosan derivative according to the present invention is obtained by treating purified chitin with an alkali at a low temperature to partially deacetylate, and then treating the terminal aldehyde with a ⁇ -terminal component.
  • the reduction is with a borohydride reducing agent such as sodium borohydride.
  • this reduction is based on other reduction methods However, it is preferable that the degree of the reduction is the same as that obtained by sodium hydrogen boron.
  • the chitosan derivative according to the present invention has the same water solubility as the partially deacetylated chitosan derivative before being subjected to the reduction treatment. Furthermore, it has the advantage that it has almost no taste and odor, is excellent in stability, and hardly discolors even when heated and stored.
  • the degree of deacetylation is preferably from 20 to 80%, more preferably from 40 to 60%.
  • the average amount of the chitosan derivative is preferably 50,000 to 500,000 ⁇ , more preferably 100,000 to 300. 0, 0 0 0.
  • the structure of the chitosan derivative according to the present invention is considered to be a mixture of chitosan derivatives having a structure of ⁇ [type].
  • the chitosan derivative obtained by partial deacetylation and then subjected to a reduction treatment is used. If so, it may be understood that specifying the structure is not essential for practicing the present invention since it has the above advantages.
  • the chitosan derivative according to the present invention is considered to be a compound represented by the following formula (I).
  • n represents an integer of 20 to 140 °
  • R represents a hydrogen atom or a group COCH 3 , wherein 20 to 80% of all Rs in the molecule represent a group COCH 3 ).
  • the compound represented by the above formula (I) may be further reduced by the above-mentioned reduction treatment, to give a structure of a chitosan derivative represented by the following formula (11).
  • n represents an integer of 20 to 1400
  • R represents a hydrogen atom or a group C ⁇ CH 3 , wherein 20 to 80% of all R in the group represents a group COCH 3
  • the method for producing a chitosan derivative according to the present invention comprises a step of partially deacetylating chitin and a step of reducing the partially deacetylated product.
  • the reduction step S is specifically a step of reducing the terminal aldehyde of the partially deacetylinated product.
  • the partial deacetylation step and the reduction step S may be respectively carried out according to known reactions. That is, partial deacetylation of chitin may be carried out by a known de-N-acetylation method, and can be preferably carried out by hydrolysis with heating with an acid or an acid.
  • the reduction treatment is preferably performed using a borohydride reducing agent such as sodium borohydride.
  • the chitosan derivative according to the present invention In the method for producing a body, the partial deacetylation and the reduction treatment may be performed simultaneously. Applications of chitosan derivatives
  • the chitosan derivative according to the present invention has the property that its water solubility is improved, its taste and odor are hardly strong, its stability is excellent, and it hardly discolors even when it is heated and stored. In terms of effective activity, it is equivalent to conventionally known chitosan. Therefore, the chitosan derivative according to the present invention can be basically used for conventionally known applications of chitosan and its derivatives. Specifically, the chitosan derivative according to the present invention may be used as it is or as a mixture with a carrier and optionally other biologically active compounds for the following uses.
  • Food preservatives using the antibacterial properties of chitosan
  • health foods for example, utilizing the cholesterol-lowering effect of chitosan
  • drug delivery system (DDS) carriers microcapsules, artificial, sutures, flocculants ( It can be used for applications such as aggregation of chitosan substances), chromatographic carriers (ion exchange, affinity chromatography), and functional membranes.
  • the present inventors have found that the chitosan derivative according to the present invention has a constipation improving effect. This constipation-improving effect was made possible by using it in combination with dietary fiber, preferably indigestible dextrin.
  • a pharmaceutical composition or food comprising the chitosan derivative according to the present invention, specifically, a pharmaceutical composition or food having a constipation improving effect.
  • the inconsistent dextrin used in the present invention is known per se, and for example, it can be synthesized according to Powder Science, 37, 107 (1990), or a commercially available one can be used.
  • the composition of the chitosan derivative and the indigestible dextrin may be appropriately determined within a range where the constipation-improving effect can be obtained.
  • the weight ratio is preferably about 1: 1 to 1: 1000, more preferably 1: 1. : About 2 ⁇ 1: 500 Degrees.
  • Both chitosan derivatives and indigestible dextrins are water-soluble and can be used as liquids or beverages.
  • it can be made into ordinary pharmaceutical and food forms, for example, tablets, capsules, granules, powders and the like according to a conventional method. Further, it may be in a form in which a daily food or a food ingredient is added to the product.
  • binders preservatives, sweeteners, vitamins, flavors, minerals and other auxiliary ingredients may be added.
  • auxiliary ingredients for example, one or a number selected from iron, heme iron, iron lactate, iron citrate, pyrophosphate " ⁇ , calcium, calcium dalconate, calcium lactate, calcium carbonate, magnesium, salt ⁇ magnesium, magnesium sulfate, etc.
  • Different minerals can be incorporated.
  • the amount is the total of the chitosan derivative and the indigestible dextrin per day, and is usually preferably 1 to 20 g / 60 kg body weight.
  • the indigestible dextrins and chitosans mentioned above have already been used as food additives and their safety has been confirmed. Also, the chitosan derivative of the present invention obtained by the reduction treatment has no problem in safety.
  • Part 2 Method for producing chitosan derivatives
  • aqueous solution (1% solution) of the chitosan derivative according to the present invention (degree of deacetylation: 50.2%) is stored at 50 ° C and 60 ° C for 14 days, and its stability is determined based on the change in color difference of the solution.
  • the color difference was measured using a color difference meter (manufactured by Nippon Denshoku Industries) with a 4 ° C storage sample as a control.
  • chitosan derivative according to the present invention did not cause any precipitation due to the formation of a complex salt with iron ion, and was excellent in stability.
  • the chitosan derivative according to the present invention degree of deacetylation: 50.2%
  • low chitosan low chitosan
  • commercially available chitosan deacetyl for healthy persons (5 males and 3 females) (Chemical degree: 88.3%) for powder and solution. I did.
  • the egg taste of each solution was evaluated according to the following criteria, and the average score of each person's evaluation was obtained as an evaluation value.
  • test solution 120 g each of three water-soluble dietary fibers, indigestible dextrin, corn fiber, or polydextrose, and 10 g of partially deacetylated chitosan (degree of deacetylation: 50.2%) was dissolved in purified water to prepare a test solution having a composition as shown in Table 3 below.
  • the test solution was prepared using sodium chloride, potassium chloride, citric acid and sodium citrate so as to be almost isotonic solution (285-295 m0sm).
  • Table 3 Composition of test solution
  • SD male rats (3.5 weeks old) are reared on powdered CE-2 diet (CLEA Japan) for 6 days, and divided into 8 animals per group based on blood total cholesterol, triglyceride, and body weight. did.
  • Example 4 Sample 5 Control feed A Control feed B Sucrose 60.17 49.17 60.17 60.17 Casein 20 20 20 20 Lard 1 ⁇ 10 10 10 Vitamin 1 1 1 1 Mineranore 4 5 4 5 weight Choline tartrate 0.2 0.2 0.2 0.2 0.2 Cholesterol 0.5 0.5 0.5 0.5 0.5 Cholic acid
  • the liver weight of the commercial chitosan-containing diet group showed a tendency to decrease compared to the control diet group.
  • the chitosan derivative feeder according to the present invention the liver weight was clearly reduced.
  • the presence of fatty liver was observed in the control diet group.
  • testis-adhered fat weight which is an indicator of visceral fat, showed a decreasing tendency in the chitosan derivative-containing feed group according to the present invention. From these results, it is clear that the chitosan derivative according to the present invention is a material having a cholesterol lowering action and a fat absorption inhibiting action.
  • Example 6 Formulation example / granules
  • Example 8 Formulation examples / drinks

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Materials Engineering (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention concerne des dérivés de chitosane obtenus par désacétylation partielle de chitine, suivie d'une réduction. Ces dérivés sont comparables par leur solubilité dans l'eau aux dérivés de chitosane partiellement désacétylés mais non réduits, et n'ont presque pas de goût ni d'odeur. Ils sont hautement stables et à peine colorés, même lorsqu'ils sont conservés à température élevée. Ces dérivés de chitosane sont comparables par leur activité au chitosane habituellement connu. Lorsqu'ils sont combinés avec de la dextrine peu digeste, ces dérivés montrent une excellente capacité d'amélioration de ce défaut, ce qui les rend utiles en tant que médicaments et aliments.
PCT/JP1997/002998 1996-08-29 1997-08-28 Derives de chitosane, procedes permettant de produire ceux-ci et leur utilisation WO1998008877A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8228817A JPH1067804A (ja) 1996-08-29 1996-08-29 キトサン誘導体およびその製造法並びにその用途
JP8/228817 1996-08-29

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WO1998008877A1 true WO1998008877A1 (fr) 1998-03-05

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JP (1) JPH1067804A (fr)
WO (1) WO1998008877A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9527929B2 (en) 2014-01-30 2016-12-27 Sofradim Production Optimized chitosan reacetylation
US10828149B2 (en) 2007-03-13 2020-11-10 Amo Development, Llc Method for patterned plasma-mediated modification of the crystalline lens

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005272401A (ja) * 2004-03-25 2005-10-06 Tendou Seiyaku Kk チュアブル錠
TWI495646B (zh) * 2012-05-24 2015-08-11 Manufacturing method of medical textiles with high wetness coefficient rayon with chitin

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63270550A (ja) * 1987-04-28 1988-11-08 Fuji Boseki Kk 陰イオン交換基を有する粒状多孔質キトサン誘導体の製造方法
JPH02145602A (ja) * 1988-11-25 1990-06-05 Daicel Chem Ind Ltd キトサン誘導体の製造法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63270550A (ja) * 1987-04-28 1988-11-08 Fuji Boseki Kk 陰イオン交換基を有する粒状多孔質キトサン誘導体の製造方法
JPH02145602A (ja) * 1988-11-25 1990-06-05 Daicel Chem Ind Ltd キトサン誘導体の製造法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10828149B2 (en) 2007-03-13 2020-11-10 Amo Development, Llc Method for patterned plasma-mediated modification of the crystalline lens
US9527929B2 (en) 2014-01-30 2016-12-27 Sofradim Production Optimized chitosan reacetylation

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