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WO2012035770A1 - Agent d'activation de l'ostéogenèse contenant du glycogène - Google Patents

Agent d'activation de l'ostéogenèse contenant du glycogène Download PDF

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WO2012035770A1
WO2012035770A1 PCT/JP2011/005183 JP2011005183W WO2012035770A1 WO 2012035770 A1 WO2012035770 A1 WO 2012035770A1 JP 2011005183 W JP2011005183 W JP 2011005183W WO 2012035770 A1 WO2012035770 A1 WO 2012035770A1
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promotion
glycogen
kda
bone formation
bone
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Japanese (ja)
Inventor
浩子 依田
勇人 大島
英蔵 中川
みか子 田中
洋樹 高田
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Ezaki Glico Co Ltd
Niigata University NUC
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Ezaki Glico Co Ltd
Niigata University NUC
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Priority to JP2012533869A priority Critical patent/JP5885206B2/ja
Publication of WO2012035770A1 publication Critical patent/WO2012035770A1/fr
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    • 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
    • A61K31/716—Glucans
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to a bone forming agent, an osteogenesis promoting agent, a tooth germ growth promoting agent, a tooth root formation promoting agent, a periodontal tissue regeneration promoting agent and the like containing glycogen as an active ingredient.
  • the present invention relates to an osteogenesis agent, an osteogenesis promoter, tooth germ development promotion, tooth root formation promotion, periodontal tissue regeneration promotion, and the like, and relates to a novel use of glycogen.
  • the bone tissue regeneration therapy currently performed in regenerative medicine includes a method of transplanting autologous bone or bone substitute material, a method of promoting bone formation by locally administering a factor such as cytokine.
  • the former is a general method as a bone augmentation method.
  • a cytokine therapy a platelet-derived growth factor (PDGF), a bone morphogenetic protein (BMP).
  • BMP bone morphogenetic protein
  • bFGF basic fibroblast growth factor
  • BMP is a proteinous factor that differentiates undifferentiated mesenchymal cells into osteoblasts.
  • bFGF has a potent angiogenic action and proliferation-inducing ability of mesenchymal cells, promotes the production of extracellular matrix and has a bone-increasing action. Therefore, it is expected to be clinically applied as a fracture healing promoter and periodontal tissue regenerative drug.
  • each factor requires a large amount for actual bone defect treatment, but the safety problem of the gene transfer method that is effective for mass production has not been completely cleared at present.
  • cost there are many problems when widely used in general medical and dental clinics. Accordingly, there has been a demand for the development of an osteogenesis promoter that can be mass-produced and can be provided to clinical sites at low cost and has high safety.
  • Glycogen is the main storage polysaccharide in animals, fungi, yeasts and bacteria. Glycogen is soluble in water and becomes a milky white solution. The molecular structure of animal glycogen is well studied. Natural glycogen is branched from ⁇ - 1,6-glucoside bonds from sugar chains that are linearly linked via ⁇ -1,4-glucoside bonds of glucose (glucose), and is also branched into a network. It is a homoglucan that forms a structure. Natural glycogen is composed of ⁇ -1,4-glucoside-linked chains having an average degree of polymerization of about 10 to about 14 linked by ⁇ -1,6-glucoside bonds.
  • Natural glycogen exists as particles having a molecular weight of about 10 7 ( ⁇ particles) or larger particles ( ⁇ particles) formed by aggregation of ⁇ particles.
  • the structure of bacterial glycogen is thought to be similar to that of animal glycogen.
  • a certain kind of plant for example, sweet corn also has a glucan having a structure similar to glycogen, and is called plant glycogen (phytoglycogen).
  • Non-Patent Document 1 it is reported that glycogen is present in osteoblast progenitor cells, and glycogen disappears when differentiated into osteoblasts. However, it is not known that administration of glycogen can contribute to bone formation.
  • Non-Patent Document 1 and Non-Patent Document 2 describe that a glycogen positive site and an alkaline phosphatase (differentiation marker for osteoblast) positive site almost coincide. In vivo, it has been suggested that "the appearance of cells containing glycogen may be involved in bone formation". However, there is no description of the event when glycogen is applied externally.
  • Non-Patent Document 3 describes that 5000-6500 kDa glycogen activates immune cells. However, it does not describe promoting proliferation. However, there is no description regarding osteoblasts.
  • Patent Document 1 discloses a fibroblast proliferating agent and an external preparation for skin containing the same, and describes that glycogen has a fibroblast proliferating effect. Only what is used as a coating agent is described. However, there is no description regarding osteoblasts.
  • Patent Document 2 discloses an epidermal cell activator and an ATP production promoter, and discloses that glycogen promotes ATP production of epidermal cells. However, there is no description regarding osteoblasts.
  • glycogen is a polysaccharide consisting of glucose, stored in the liver and muscles of animals, and plays an important role as an energy source for cells.
  • enzyme-synthesized glycogen has almost the same chemical structure and physical properties as natural glycogen, but is less susceptible to degradation by ⁇ -amylase (Non-Patent Document 5), and further has an immunostimulatory function (Non-Patent Document 3) and moisturizing. It is becoming clear that there exists an effect
  • Hayato Oshima “Functional significance of glycogen in tooth development” Niigata Dental Society 29 (2) 185-186: 1999 Yoda et al., “Localization of glycogen and glucose transporter during mouse tooth germ development” 51st Annual Meeting of the Dental Society of Japan (Niigata) R. Kakutani, et al. (2007) Carbohydrr Res 342, 2371-2379. H. Kajiura, et al. (2008) Biocatal. Biotransform. 26, 133-140. H. Takata, et al. (2009) Carbohydr. Res. 344, 654-659.
  • the present invention finds that a specific type of glycogen promotes bone formation, and provides a novel bone formation agent, bone formation promoter, tooth germ growth promoter, tooth root formation promoter, and periodontal tissue regeneration promoter. Completed.
  • the present invention solves the problem of side effects of active ingredients relating to therapeutic agents or preventive agents for diseases that require bone formation or bone formation proliferation such as osteoporosis currently on the market, and has an effective osteogenesis promoting effect, To provide a safe compound or composition with reduced side effects and to provide a biocompatible material to promote bone formation.
  • the present invention provides the following.
  • ESG enzyme-synthesized glycogen
  • the glycogen is ESG-5M (enzymatic synthetic glycogen having a weight average molecular weight of about 5200 kDa), ESG-3M (enzymatic synthetic glycogen having a weight average molecular weight of about 3200 kDa), ESGB (enzymatic synthetic glycogen having a weight average molecular weight of about 5000 kDa), 6.
  • the composition is a food, an additive, a medical device, or a medicine.
  • the medicament according to item 9 or 10 further comprising a drug for bone formation.
  • the medical device according to item 13 which is a bone cement, a stent, a catheter, a bone filling material or an implant.
  • a method for producing a medicament for at least one selected from the group consisting of bone formation, bone formation promotion, tooth germ development promotion, tooth root formation promotion, and periodontal tissue regeneration promotion wherein the weight average molecular weight is Mixing a glycogen that is less than about 8700 kDa with a pharmaceutically acceptable excipient.
  • a method wherein a glycogen having a weight average molecular weight less than about 8700 kDa is delivered to a site in need of bone formation or promotion of bone formation to a patient in need of bone formation or promotion of bone formation. Administering the step of administering.
  • the present invention proved that a specific glycogen is useful for bone formation.
  • the finding that such a material compatible with a living body is useful for bone formation is expected to be applied in the pharmaceutical industry and can achieve an effect not found in the prior art.
  • FIG. 1 is a graph showing the growth curve of osteoblasts (MC3T3-E1) after glycogen addition. Black squares indicate glycogen (ESM-5M), and diamonds indicate controls. * Indicates statistical significance (p ⁇ 0.05). It turns out that the glycogen addition group has increased significantly compared with control by the 5th day. The concentration of glycogen used is 300 ⁇ g / ml. The result of an osteoblast (MC3T3-E1) proliferation promotion effect test of various glycogen is shown. Cell growth was observed over time using various types of glycogen (300 ⁇ g / ml) or control, and the cell number was recorded. The left group shows the first day and the right group shows the third day.
  • FIG. 3 shows the MC3T3-E1 cell proliferation test. Cell growth was observed over time using various glycogens (500 ⁇ g / ml) or controls, and the number of cells was recorded. For NSG (mussel), statistical significance (p ⁇ 0.05) was also observed. Each group shows the results on the 3rd, 5th, 7th and 10th days from the left.
  • Each lane has no glycogen stimulation on the first day (1 day) from the left (-), glycogen stimulation on the first day (+; 300 ⁇ g / ml), no glycogen stimulation on the third day (-), 3 Glycogen stimulation on day (+; 300 ⁇ g / ml), no glycogen stimulation on day 5 ( ⁇ ), glycogen stimulation on day 5 (+; 300 ⁇ g / ml), glycogen stimulation on day 7 None ( ⁇ ) and glycogen stimulation on day 7 (+; 300 ⁇ g / ml).
  • FIG. 6 is a photograph showing the effect of enzyme-synthesized glycogen on bone regeneration: in vivo experiments. A hole was made in the skull of a mouse, and it was examined whether or not bone regeneration was promoted by injecting ESG and applying CT-Scan several days later. The left shows control, and the right shows addition of glycogen (ESG 070223-5M). The arrow indicates the location where glycogen was added. Significant promotion of bone regeneration is observed when glycogen is added.
  • the concentration of glycogen used is 300 ⁇ g / ml. It is a photograph which shows the influence on tooth-germ development by the enzyme synthesis glycogen addition in an organ culture system. Mandibular first and second molar tooth germs were collected from mouse fetuses at 16.5 days of gestation and cultured in vitro. Enzyme-synthesized glycogen (5000 kDa) was added to 500 ⁇ g / ml and cultured for 4 days, and then the state of tooth germ development was observed. The addition of glycogen clearly promoted growth, and large and well-differentiated tooth germs were formed.
  • glycogen is a sugar having D-glucose as a structural unit, which is linked only by ⁇ -1,4-glucoside bond and ⁇ -1,6-glucoside bond, and has a molecular weight. The thing which is 1 million Da or more.
  • the product used in the present invention has a Mw of 500,000 Da when a product obtained by allowing pullulanase of 50 U / g substrate to act under the following conditions (see Japanese Patent No. 4086312) by the MALLS method.
  • Mw is 500,000 Da or more when the product obtained when ⁇ -amylase of 300 U / g substrate is allowed to act under the following conditions (see Japanese Patent No. 4086312) by the MALLS method.
  • Say sugar see Japanese Patent No. 4086312
  • the activity of pullulanase is expressed as 1 U in an amount necessary to generate a reducing power corresponding to 1 ⁇ mol of glucose per minute using pullulan as a substrate.
  • the pullulanase for example, the enzyme agent derived from Bacillus brevis manufactured by Daiwa Kasei Co., Ltd., or the crystallase PL45, the pullulanase derived from Bacillus acidopullulyticus manufactured by SigmaAldrich, or the pullulanase derived from Klebilla pneumoniae manufactured by the same company is used. it can.
  • the reaction temperature and reaction pH a temperature and pH most suitable for the reaction of each enzyme are selected.
  • ⁇ -amylase includes ⁇ -amylase derived from human salivary gland (for example, Sigma Aldrich Type XIII-A) and porcine pancreatic ⁇ -amylase (for example, Sigma Aldrich Type). IA can be used, 1U of ⁇ -amylase activity is defined as the amount of enzyme that liberates 1.0 mg maltose in 3 minutes at 20 ° C., pH 6.9, using starch as a substrate.
  • Glycogen used in the present invention is known to be stored in animal liver and skeletal muscle, and is not particularly limited. The origin is exemplified by animals, but it is also known that plants or microorganisms produce glycogen or a substance having a structure similar to glycogen, and these can all be used as glycogen of the present invention. Furthermore, glycogen used in the present invention can be synthesized using an enzyme. For example, sucrose phosphorylase (EC 2.4.1.7), ⁇ -glucan phosphorylase (EC 2.4.1.1), and branching enzyme (EC 2.4.1.18) are added to sugar and primer molecules (malto-oligo and the like and dextrin).
  • sucrose phosphorylase EC 2.4.1.7
  • ⁇ -glucan phosphorylase EC 2.4.1.1
  • branching enzyme EC 2.4.1.1
  • a branching enzyme EC 2.4.1.18
  • Glycogen synthesized by these methods is also known to have the same chemical structure and physical structure as natural glycogen, and these enzymatically synthesized glycogens can also be used in the stabilization method of the present invention.
  • derivatives thereof or equivalents thereof may be used. Such derivatives or equivalents can be produced, for example, by the following method.
  • the glycogen of the present invention can be separated into fractions having an appropriate molecular weight distribution by separation methods well known to those skilled in the art, for example, chromatographic separation (for example, gel filtration chromatography, HPLC), membrane separation, and the like.
  • chromatographic separation for example, gel filtration chromatography, HPLC
  • membrane separation for example, membrane separation, and the like.
  • a method such as precipitation using a solvent (for example, methanol or ethanol) may be used alone or in combination to separate into fractions having an appropriate molecular weight distribution.
  • Natural or synthetic glycogen obtained by etherification, esterification, cross-linking and grafting by methods well known to those skilled in the art can be used.
  • phosphorylated glycogen can be obtained by reacting the glycogen of the present invention with phosphorus oxychloride in dimethylformamide.
  • bone formation refers to the formation of new bone by osteoblasts. Bone formation can be actually observed with the naked eye, confirmed by X-ray photography or the like, and can be evaluated based on an index. As an index of bone formation, increase in expression of alkaline phosphatase, promotion of osteoblast proliferation, mineralization, and the like can be mentioned. It is understood that “bone formation” in the present specification includes not only bone formation but also tooth formation and the like, as normally understood by those skilled in the art.
  • promoting bone formation includes both making a state without bone formation a certain state and accelerating the existing bone formation state.
  • the activity of promoting bone formation is 0.1 to 10.0 ⁇ M in the medium concentration in the cultured 2.0 ⁇ 10 4 cells / well osteoblast cell line MC3T3-E1.
  • ALP alkaline phosphatase
  • the osteogenesis promoting activity can be determined for 4 weeks by administering a gastric sonde to a laboratory animal such as a rat (including a disease model animal) or feeding a test feed in addition to the calcification experiment described in the Examples.
  • the animals are reared as described above and can be determined by measuring changes in bone components of the diaphysis and metaphyseal tissue of the animal's femur using the calcium content, alkaline phosphatase activity, and DNA content as indicators.
  • the amount of calcium in the bone tissue was determined by washing the bone tissue with a 0.25M sucrose solution and drying at 100 ° C. for 6 hours, measuring the dry weight, adding concentrated nitric acid and decomposing at 120 ° C. for 24 hours.
  • Alkaline phosphatase activity was determined by washing bone tissue with a cold 0.25M sucrose solution, crushing in 6.5 mM barbital buffer (pH 7.4), sonicating for 60 seconds, centrifuging at 3000 rpm, and supernatant fraction. Can be measured by a known method (Methods of Enzymatic Analysis, Vol. 1-2, Academic Press, New York, pp 856-860, 1965).
  • the amount of DNA was determined by washing bone tissue with cold 0.25M sucrose solution, removing water, crushing in 0.1N sodium hydroxide solution, extracting, centrifuging at 3000 rpm, and measuring the supernatant fraction with DNA
  • the sample can be measured by a known method (J. Biol. Chem. 214: 39-77, 1955).
  • tooth germ refers to a cell population that becomes the basis of teeth and periodontal tissues, and includes enamel organs, tooth papilla and dental follicles. Therefore, in this specification, “promoting tooth germ development” means that tooth germ development is promoted. In addition to those exemplified in the examples described later, (1) tooth germ development is fast (the whole tooth germ The developmental stage is progressing, the individual differentiation of the tooth germ epithelium and mesenchymal cells is progressing), and (2) whether the size of the tooth germ is large can be evaluated as an index.
  • the average tooth size can be referred to, for example, Fujita Tsunetaro, 22nd Edition, Dental Anatomy (ISBN4-307-45007-8).
  • tooth germ development In the tooth germ organ culture system, a case where the tooth size is large compared to the size of the tooth germ of the group not added with glycogen simultaneously cultured can be referred to as “promoting tooth germ development”.
  • tooth germ For the development of tooth germ, reference can be made, for example, to the 7th edition of Antonio Nanci edited by TenCate's Oral Histology: Development, Structure, and Function (ISBN4-263-45444-8). Strictly speaking, tooth germ growth promotion includes bone formation or actions that are not included in the bone formation action. However, when considering the action in vivo, the tooth germ is synchronized with the surrounding alveolar bone. Since it grows up, it can be said that it is substantially included in the promotion of bone formation.
  • periodontal tissue is a general term for surrounding tissues that support teeth. It includes four tissues: soft tissue gingiva and periodontal ligament, and hard tissues, cementum and alveolar bone. Therefore, in this specification, “periodontal tissue regeneration” means regeneration of periodontal tissue. Evaluation of “periodontal tissue regeneration” is not limited to those exemplified in the examples described later, and the regeneration level of individual components can be evaluated with an animal experimental model for the regeneration of gingiva, periodontal ligament, cementum and alveolar bone. it can. As an example of such an evaluation method, for example, S. Murakami, et al. J Periodont Res 2003; 38; 97-103 (for example, see FIG. 4 on page 101) can be performed. Regarding bFGF and periodontal tissue regeneration, S. Murakami, “Periodontology” 2000, “Vol.” 56, “2011”, “188-208” and the like can be referred to.
  • tooth root refers to a portion in the alveolar bone at the lower part of the tooth. Therefore, in this specification, “protrusion of tooth root formation” means that the formation of tooth root is promoted in an arbitrary form.
  • the evaluation of the promotion of tooth root formation can be performed by using, for example, (1) a fast root elongation rate and (2) a long tooth root as an index.
  • OhshimaOH., J.Oral.Biosci.50 (3), 147-153 (2008), etc. can be referred to.
  • tooth root formation promotion includes bone formation or actions that are not included in bone formation. However, when considering the action in vivo, the root grows in synchronization with the surrounding alveolar bone. Therefore, it can be said that it is substantially included in the promotion of bone formation.
  • enzyme synthetic glycogen refers to glycogen synthesized by an enzyme.
  • a method of synthesizing glycogen using an enzyme is described in, for example, WO2006 / 035848 and Patent 4086312.
  • the obtained enzyme-synthesized glycogen is highly pure and has a controlled molecular weight and degree of branching.
  • enzyme-synthesized glycogen has an excellent feature that it has higher resistance to various digestive enzymes than natural glycogen.
  • This enzyme-synthesized glycogen also has a moisturizing effect, skin function improving effect, and prevention of skin aging that are equal to or higher than those of natural glycogen.
  • Enzyme-synthetic glycogen as used herein includes enzyme-synthetic glycogen described in WO2006 / 035848. That is, this is produced by a step of producing glycogen by allowing a branching enzyme having the ability to synthesize glycogen to act on a substrate in a solution, and the substrate is mainly ⁇ -1,4-glucoside bond ⁇ -glucan having a degree of polymerization of 4 or more linked in the above, the substrate is starch debris, dextrin debranches or enzyme-synthesized amylose, and the weight average molecular weight of the glycogen is 1 million Da or more. When a pullulanase of 50 U / g substrate is allowed to act at 60 ° C.
  • the product obtained by the MALLS method has a weight average molecular weight of 500,000 Da or more, and the glycogen contains 300 U / g substrate.
  • the product obtained when ⁇ -amylase was allowed to act at 37 ° C. for 30 minutes was analyzed using the MALLS method. Average molecular weight of glycogen is 500,000 Da or more.
  • ESG is quantified to be about 20% “Resistant Starch content” when quantified with a Resistant Starch assay kit from Megazymes. This is because there is a relatively large portion that is resistant to ⁇ -amylase in the molecular core portion of ESG. In the case of NSG, since the ratio of molecules having such a resistant core portion is small, the quantitative value of this kit can be identified by being very low.
  • the MALLS method is an HPLC gel filtration analysis method using a multi-angle light scattering detector and a differential refractometer as a detector. Takata et al. Appl. Glycosci. 50, pages 15-20, described in 2003.
  • the weight average molecular weight of the glycogen is 1 million to 100 million Da, more preferably 1 million to 50 million Da, more preferably 2 million to 30 million Da, and even more preferably 3 million to 2000 Can be tens of thousands.
  • Branching enzyme having the ability to synthesize glycogen Aquifex aeolicus, Aquifex pyrophilus, Rhodothermus obamensis, Rhodothermus marinus, Bacillus stearothermophilus, Bacillus caldovelox, Bacillus thermocatenulatus, Bacillus caldolyticus, Bacillus flavothermus, Bacillus acidocaldarius, Bacillus caldotenax, Bacillus Smithii, Thermosynechococcus elongatus and It can be derived from a bacterium selected from the group consisting of Escherichia coli.
  • the enzyme-synthesized glycogen that can be used in the present invention is a polymer having substantially the same size and shape as natural glycogen. Furthermore, the enzyme-synthesized glycogen used in the present invention has a lower content of impurities such as electrolytes and higher safety to the skin than natural glycogen. In addition, since the arrangement of branched bonds in the molecule is slightly different, the solution has high stability over time, high resistance to biological decomposition of enzymes, microorganisms, and the like, and high resistance to chemical and physical decomposition. From such characteristics, the combined use with various auxiliary components can synergistically enhance the original effect.
  • the amount of the enzyme-synthesized glycogen can be any amount.
  • osteoblast is an osteogenic cell made of mesenchymal tissue, and is divided from an undifferentiated mesenchymal cell into a precursor osteoblast and a young osteoblast to a mature osteoblast. Formed.
  • the bone matrix is formed from osteoblasts, which are encapsulated in the bone matrix as bone cells.
  • Type I collagen, alkaline phosphatase (ALP), and osteonectin are produced between the precursor cell stage and the mature cell stage, and osteopontin when differentiated to young osteoblasts, bone sialoprotein (BSP) when differentiated to mature cells, Osteocalcin (BGP) begins to be produced (H. Komori, The Bone 12: 49-59, 1998).
  • Osteoblasts exist on the surface of bone tissue and actively secrete bone matrix proteins such as collagen. Crystals of calcium phosphate and hydroxyapatite are deposited on the matrix protein, resulting in a hard bone tissue. The deposition of calcium phosphate crystals is called “calcification”. Osteoblasts on the bone surface and the bone matrix immediately after the start of calcification are called osteoids, and osteoids increase when there are calcification disorders such as osteomalacia. Osteoblasts are embedded in this matrix and eventually become bone cells.
  • the cell nucleus is located on the opposite side of the bone, the Golgi and the rough endoplasmic reticulum are developed in the cytoplasm, and the matrix is actively synthesized and secreted on the side of the bone.
  • Osteoblasts show high alkaline phosphatase activity (ALP) and are used as histochemical biochemical markers for osteoblasts.
  • ALP alkaline phosphatase activity
  • any of the cell markers described above can be used.
  • osteoblast proliferation can be observed using osteoblast cell lines such as MC3T3-E1.
  • composition of the present invention is used as an additive for the purpose of culture, medical devices, foods, health foods, functional foods, etc. in addition to pharmaceuticals.
  • the term “medicament” is interpreted in the broadest sense in the art, and includes any drug, including any drug under the Pharmaceutical Affairs Law, quasi-drug, etc. It is understood to encompass drugs, compositions, etc. of use. Examples thereof include applications in the medical field, dental field, etc., for example, treatment adjuvants (for example, those administered to affected areas), bone fillers (for example, directly filling bone defects), bones, etc. Use as a main component or subcomponent in a filling material or the like, or application to a membrane, a tooth extraction wound protective agent, and the like can also be mentioned.
  • the medicine contains solid or liquid excipients, and may contain additives such as disintegrants, flavoring agents, delayed release agents, lubricants, binders, coloring agents and the like as necessary.
  • additives such as disintegrants, flavoring agents, delayed release agents, lubricants, binders, coloring agents and the like as necessary.
  • pharmaceutical forms include, but are not limited to, tablets, injections, capsules, granules, powders, fine granules, sustained release formulations and the like.
  • the term “medical device” is interpreted in the broadest sense in the art, and includes any device or device. In addition to medical devices under the Pharmaceutical Affairs Law, devices, devices for any application intended for bone formation, It is understood to encompass instruments. Examples of the medical device include bone cement, a stent, a catheter, a bone filling material, and an implant.
  • “food” has a meaning that is routinely used in the field, refers to all foods that can be eaten by humans, and an embodiment includes processed products.
  • components such as glycogen of the present invention can be mixed in processed foods such as confectionery, dairy products, and processed cereal products.
  • “health food” and “functional food” have the meanings commonly used in the industry, and are specially used to prevent bone loss and bone fragility that show symptoms or signs of osteoporosis.
  • additive refers to any drug added for some purpose to the main component.
  • an additive for promoting growth can be exemplified.
  • the additive of the present invention include, but are not limited to, an additive for promoting growth (culture additive and the like) in dental embryo organ culture for research use.
  • treatment means to significantly improve, alleviate or prevent bone loss and bone vulnerability before and after the onset of osteoporosis by promoting bone formation.
  • the present invention promotes osteoblast differentiation by promoting the formation of mature osteoblasts, which in turn promotes bone formation and improves or alleviates the imbalance between bone formation and bone resorption by osteoclasts. Is done.
  • the present invention provides a composition for promoting bone formation or osteogenesis comprising glycogen having a weight average molecular weight of less than about 8700 kDa (wherein the weight average molecular weight is a significant figure) Is displayed in two digits.)
  • the present invention provides for bone formation, bone formation promotion such as treatment of bone diseases, fractures, bone damage, and other bone abnormalities (these may be promoted calcification, osteoblast proliferation, indicators), bone formation Methods, compositions, foods, additives, medical devices, pharmaceuticals, and the like for promoting, promoting tooth germ development, promoting root formation, and / or promoting periodontal tissue regeneration are provided.
  • glycogen This is accomplished by administering glycogen to a subject, such as a mammal, resulting in stimulation or enhancement of calcification.
  • a subject such as a mammal
  • Specific examples of such methods include, for example, food to be ingested by a patient for a certain period of time before treatment of teeth and bones, therapeutic adjuvants to be administered to affected areas, and growth promotion in tooth germ organ culture for research purposes.
  • it is not limited to these.
  • any glycogen having a weight average molecular weight of less than about 8700 kDa can be used. It has not been conventionally known that glycogen having a specific molecular weight has osteogenic activity, and it can be said that this is an unexpected effect.
  • the upper limit of the weight average molecular weight of glycogen used in the present invention is about 8700 kDa, about 8600 kDa, about 8500 kDa, about 8400 kDa, about 8300 kDa, about 8200 kDa, about 8100 kDa, about 8000 kDa, about 7900 kDa, about 7800 kDa.
  • the upper limit of the weight average molecular weight of glycogen used in the present invention can be preferably about 8000 kDa or more.
  • the lower limit of the weight average molecular weight of glycogen used in the present invention is about 1000 kDa, about 1100 kDa, about 1200 kDa, about 1300 kDa, about 1400 kDa, about 1500 kDa, about 1600 kDa, about 1700 kDa, about 1800 kDa, about 1900 kDa, which is the lower limit of glycogen itself.
  • the weight average molecular weight used in the present invention is about 3000 kDa or more and about 8000 kDa or less.
  • Each of these weight average molecular weight glycogens has been demonstrated to promote osteoblast proliferation and ALP expression and actual animal experiments, or promote dental healing, and such effects are It has been found that other glycogens (for example, glycogen of Patent Document 1 (Kuppie phytoglycogen)) are not recognized, and it can be said that this is an unexpected effect.
  • the weight average molecular weight used in the present invention is from about 4900 to about 7000 kDa. Although not wishing to be bound by theory, this range is preferable because calcification in animal experiments, promotion of formation of tooth germ or promotion of tooth healing in organ culture, etc. have been confirmed. is there.
  • the glycogen used in the present invention comprises enzymatically synthesized glycogen (ESG).
  • ESG enzymatically synthesized glycogen
  • glycogen used in the present invention can be synthesized based on the method of Japanese Patent No. 4086312, for example, ESG-5M (enzymatic synthetic glycogen having a weight average molecular weight of about 5200 kDa) used in Examples, ESG-3M (enzymatic synthetic glycogen having a weight average molecular weight of about 3200 kDa), ESGB (enzymatic synthetic glycogen having a weight average molecular weight of about 5000 kDa), ESG-7M (enzymatic synthetic glycogen having a weight average degree of polymerization of about 7000 kDa), mussel glycogen (Laboratoires, France) Manufactured by Serobi unanimouss, imported by Yamakawa Trading Co., Ltd.
  • ESG-5M enzyme synthetic glycogen having a weight average molecular weight of about 5200 kDa
  • ESG-3M enzyme synthetic glycogen having a weight average molecular weight of about 3200 kDa
  • ESGB enzymatic synthetic glycogen having a weight
  • glycogen of the present invention is achieved at least in part by promoting osteoblast proliferation.
  • the invention includes osteogenesis, osteogenesis promotion (which can be promoted calcification, osteoblast proliferation, indicator), glycogen comprising a glycogen having a weight average molecular weight of less than about 8700 kDa.
  • the present invention provides a medicament for promoting tooth germ development, promoting root formation, and / or promoting periodontal tissue regeneration.
  • glycogen contained in the medicament of the present invention those used for a composition for promoting osteogenesis or osteogenesis, such as those described in the section of these compositions in the present specification, are described. Any of those described can be used.
  • the medicament of the present invention can be used in the form of a treatment adjuvant or the like administered to the affected area, but is not limited thereto.
  • the medicament of the present invention further comprises a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient examples include tablets, powders, fine granules, granules, coated tablets, sustained-release preparations, capsules, injections and the like.
  • the medicinal product may contain additives such as excipients, if necessary, binders, disintegrants, lubricants, flavoring agents, coloring agents, delayed release agents and the like.
  • excipients such as lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, etc.
  • binders such as polyvinyl alcohol, polyvinyl ether, methylcellulose, hydroxypropylcellulose, gum arabic, tragacanth, gelatin , Shellac, polyvinylpyrrolidone, block copolymer, etc., as a disintegrating agent, such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, etc., as a lubricant, eg, magnesium stearate
  • cocoa powder, mint oil, cinnamon powder and the like can be used as flavoring agents such as talc, polyethylene glycol, silica and hydrogenated vegetable oil, but are not limited thereto.
  • a coating for obtaining a sustained release or enteric preparation can be applied.
  • medicaments which may be contained are variously considered depending on the purpose.
  • a therapeutic agent for osteoporosis such as a calcium agent (trade name aspara CA, carticol) , Calcium lactate, etc.), vitamin D preparations (trade names such as alpha roll, one alpha, locartrol, and high titrol), female hormone preparations (trade name such as estreol), ipriflavones (trade names such as osten and asost), vitamin K2 preparations (For example, Graque etc.), bisphosphonates (trade name Fasax, risedronate, tiludronate, ibandronate, etc.) and the like can be mentioned, but are not limited thereto.
  • osteoporosis and other diseases including osteogenesis promoters have been reported.
  • pterocarpan [(5 ⁇ R, 11 ⁇ R) -3-hydroxy-9,10-dimethoxypterocarpan] (Japanese Patent Laid-Open No. 2003-155236) (pterocarpan is a leguminous plant belonging to the genus Astragrass.
  • estrogen agonists / antagonists such as droloxifene, or drugs that promote bone formation and increase bone mass (such as sodium fluoride, parathyroid hormone, growth hormone or growth hormone secretory), or the like
  • drugs that promote bone formation and increase bone mass such as sodium fluoride, parathyroid hormone, growth hormone or growth hormone secretory
  • polyphosphonates alendronade, cimadronade, etc.
  • statins statin, bravastatin, cerivastatin, etc.
  • phosphodiesterase I Xanthines having V inhibitory activity Japanese Patent Laid-Open No.
  • examples of the bone forming component include bone morphogenetic proteins (BMP and the like).
  • BMP bone morphogenetic proteins
  • the BMP in the present invention is not particularly limited as long as it has an activity of promoting osteogenesis by inducing differentiation into undifferentiated mesenchymal cells into osteoblasts.
  • BMP-1 , BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-12 (above, homodimers) or heterodimers of these BMPs
  • a variant ie, a protein having an amino acid sequence in which one or more amino acids are deleted, substituted and / or added in the amino acid sequence of a naturally occurring BMP and having the same activity as that of a naturally occurring BMP
  • Etc ie, a protein having an amino acid sequence in which one or more amino acids are deleted, substituted and / or added in the amino acid sequence of a naturally occurring BMP and having the same activity as that of a naturally occurring BMP
  • the nucleic acid which codes it may be sufficient.
  • the base sequence encoding naturally occurring BMP may be the same as the base sequence encoding naturally occurring BMP, or one having one or more bases deleted, substituted and / or added in the base sequence encoding naturally occurring BMP. Moreover, you may make it use these things combining 1 type (s) or 2 or more types.
  • the medicament of the present invention is administered over 1 day to 10 days, or 3 to 10 days.
  • it is because it is a period in which the proliferation effect of osteoblasts is well promoted. It is understood that this period depends on the number of cells present at the site where glycogen is administered, and those skilled in the art can appropriately determine depending on the state of the site to be administered (for example, the state of cell confluence). This can be changed.
  • the “effective amount” of a drug or the like means an amount capable of exerting the intended drug effect of the drug.
  • the minimum concentration may be referred to as the minimum effective amount.
  • Such minimum effective amounts are well known in the art, and usually the minimum effective amount of a drug is determined by those skilled in the art or can be determined as appropriate by those skilled in the art.
  • an animal model or the like can be used in addition to actual administration. The present invention is also useful in determining such effective amounts.
  • pharmaceutically acceptable carrier refers to a substance that is used when producing an agrochemical such as a pharmaceutical or veterinary drug, and that does not adversely affect active ingredients.
  • Such pharmaceutically acceptable carriers include, for example, antioxidants, preservatives, colorants, flavors, and diluents, emulsifiers, suspending agents, solvents, fillers, bulking agents, buffering agents, delivery agents.
  • Vehicles, excipients and / or agricultural or pharmaceutical adjuvants include, but are not limited to:
  • the invention includes osteogenesis, osteogenesis promotion (these can be promoted calcification, osteoblast proliferation, an indicator), osteogenesis comprising glycogen having a weight average molecular weight of less than about 8700 kDa
  • the present invention provides a medical device for promoting tooth germ development, promoting root formation, and / or promoting periodontal tissue regeneration.
  • the composition used for osteogenesis or osteogenesis, a pharmaceutical, etc. for example, these compositions or Any of those described in the pharmaceutical section can be used.
  • the medical device of the present invention may be, but is not limited to, bone cement, stent, catheter, bone prosthesis or implant.
  • the medical device of the present invention is intended to be applied to a bone defect site, eg, a site resulting from an injury, a defect caused during surgery, an infection, a malignant tumor or a developmental malformation.
  • a bone defect site eg, a site resulting from an injury, a defect caused during surgery, an infection, a malignant tumor or a developmental malformation.
  • Implants that are appropriately sized and shaped as needed can be used to repair simple and complex fractures and poor fusion, external and internal fixation, joint remodeling like arthrodesis, general arthroplasty, Hip cup arthroplasty, femoral head replacement and total joint replacement, spinal repair including spinal fusion and internal fixation, eg defect filling, isolated resection, laminectomy, spinal tumor resection, anterior neck Tumor surgery such as head and chest surgery, spinal cord injury repair, scoliosis, lordosis and kyphosis treatment, fracture intermaxillary fixation, orthognathic surgery, temporomandib
  • Specific bones that can be repaired or replaced with bone-derived implants in this specification include ethmoid bone, frontal bone, nasal bone, occipital bone, parietal bone, temporal bone, mandible, maxilla, cheekbone, cervical vertebra, Thoracic vertebrae, lumbar vertebrae, sacrum, ribs, sternum, clavicle, scapula, humerus, calcaneus, ulna, carpal, palmar, phalange, iliac, sciatic, pubic, femur, tibia, rib, patella, rib, Includes tarsal and metatarsal bones.
  • the device of the present invention may have a biocompatible substrate (matrix).
  • This substrate can be used as a bone formation field (scaffold) for osteogenesis differentiated from undifferentiated mesenchymal cells, or as a field for healing or tooth germ formation (scaffold).
  • the form of the substrate is preferably a block body (lump).
  • the block body (for example, a sintered body) has shape stability, and when an osteogenesis treatment device is implanted in a living body, the osteogenesis treatment device can be prevented from dissipating from the implantation site at an early stage.
  • bone formation can proceed along the shape of the block body, it is particularly effective when the transplant site is a relatively large bone defect or the like.
  • the form of the substrate may be appropriately selected according to the application site (transplantation site) of the osteogenesis treatment device.
  • the application site for example, powder, granule, pellet (small block) Or the like.
  • a composition mixed with an active ingredient such as glycogen can be used as an osteogenic treatment device, and the osteogenic treatment device is filled (stuffed) into the bone defect portion. Can be used.
  • the substrate is preferably porous (porous body).
  • a porous body By using a porous body as a substrate, an active ingredient such as glycogen can be more easily and reliably supported on the substrate, and cells involved in bone formation can easily enter the substrate, which is advantageous for bone formation. It is.
  • the porosity is not particularly limited, but is preferably about 30 to 95%, more preferably about 55 to 90%. By setting the porosity within the above range, cells that are involved in bone formation can be more easily penetrated into the substrate while maintaining the mechanical strength of the substrate suitably. can do.
  • the constituent material of the substrate is not particularly limited as long as it has biocompatibility.
  • the constituent material of the substrate is preferably a ceramic material (so-called bioceramics) such as a calcium phosphate compound, alumina, zirconia, and particularly, a material mainly composed of hydroxyapatite or tricalcium phosphate is frequently used. Is done.
  • a ceramic material such as a calcium phosphate compound, alumina, zirconia, and particularly, a material mainly composed of hydroxyapatite or tricalcium phosphate is frequently used. Is done.
  • Hydroxyapatite and tricalcium phosphate have a particularly excellent biocompatibility because they have the same structure as the mineral main component of bone. Moreover, since it has both positive and negative charges, particularly when liposomes are used as carriers, the liposomes can be stably supported on a substrate for a long time. As a result, an active ingredient such as glycogen adsorbed or encapsulated in the liposome is also stably held on the substrate for a long time, contributing to more rapid bone formation. Moreover, since it has high affinity with osteoblasts, it is preferable for maintaining new bone.
  • Such a substrate can be manufactured (manufactured) by various methods.
  • a porous block body made of a ceramic material is produced as an example will be described as an example.
  • Such a porous block body is made of, for example, a slurry containing a ceramic material powder and transplanted into a bone defect or the like. It can be produced by obtaining a molded body formed into a shape corresponding to a part by, for example, compression molding or the like, and sintering (firing) the molded body.
  • the osteogenic treatment device as described above can be produced (manufactured) by mixing glycogen with a substrate.
  • a bone-forming device is produced by molding a kneaded material obtained by kneading the substrate, a binder and the liquid as described above. You can also
  • the invention includes osteogenesis, osteogenesis promotion (which can be promoted calcification, osteoblast proliferation, indicator), glycogen comprising a glycogen having a weight average molecular weight of less than about 8700 kDa.
  • the present invention provides an additive, a food, a health food, or a functional food for promoting tooth germ development, promoting root formation, and / or promoting periodontal tissue regeneration.
  • the glycogen contained in the additive, food, health food or functional food of the present invention it is used for a composition for forming bone or promoting bone formation, a medicine, a medical device, etc.
  • Such additives, foods, health foods or functional foods include, for example, foods to be ingested by patients for a certain period of time before treatment of teeth and bones, or for growth promotion in tooth germ organ culture for research purposes. However, it is not limited to these.
  • the present invention When the present invention is used as an additive, food, health food or functional food, these are used for promoting osteogenesis for the prevention of diseases or conditions requiring osteogenic growth activity such as osteoporosis.
  • ingredients such as glycogen of the present invention are added to processed foods such as confectionery, dairy products and processed cereals together with appropriate excipients, and additives such as flavoring agents and coloring agents are added as necessary. Can be mixed.
  • a compound of the present invention or a mixture thereof is enclosed in a gelatin capsule, or a drink containing the compound of the present invention or a mixture thereof is prepared, and osteoporosis symptoms or It can be used as a health maintenance food for preventing bone loss and fragility of bone showing signs, that is, for promoting bone formation.
  • the amount of the active ingredient added is usually an amount corresponding to about 0.1 mg to about 5,000 mg per day for an adult, but is not limited to this range.
  • capsules containing the compound of the present invention or a mixture thereof, or a beverage containing the compound of the present invention or a mixture thereof can be prepared and used, and
  • the growth promoting additive is prepared by, for example, dissolving the compound of the present invention directly in the culture solution or adding a separately dissolved product to the culture solution.
  • it can be enclosed in a capsule together with an excipient or a lubricant.
  • sweeteners, acidulants, pH adjusters, fragrances, colorants and the like can be mixed.
  • the method of the present invention comprises bone formation, bone formation promotion (these may be promoted calcification, osteoblast proliferation, index), bone formation promotion, tooth germ development promotion, tooth root formation promotion, And a method of producing a medicament for promoting periodontal tissue regeneration, comprising the step of mixing glycogen having a weight average molecular weight of less than about 8700 kDa with a pharmaceutically acceptable excipient.
  • Additives, foods, health foods, functional foods and the like can be produced in the same manner. In that case, it can replace with a pharmaceutically acceptable excipient
  • glycogen included in the present invention include bone formation, bone formation promotion (these can be used as calcification promotion, osteoblast proliferation promotion, and index), bone formation promotion, tooth germ development promotion.
  • used in compositions, medicaments, medical devices, etc. for promoting root formation and / or promoting periodontal tissue regeneration, for example, as described in the section of these compositions, medicaments or medical devices herein Any that are present can be used.
  • the present invention relates to bone formation, bone formation promotion (which can be used as calcification promotion, osteoblast proliferation promotion, index), bone formation promotion, tooth germ development promotion, tooth root formation promotion, and / or periodontal tissue regeneration promotion.
  • a method for producing a medical device for use in which a glycogen having a weight average molecular weight of less than about 8700 kDa is included in the medical device or the material of the medical device.
  • a glycogen having a weight average molecular weight of less than about 8700 kDa is included in the medical device or the material of the medical device.
  • any material known in the art can be used.
  • a secondary component according to the purpose can be used instead of a pharmaceutically acceptable excipient as in the case of a medicine.
  • glycogen included in the present invention include bone formation, bone formation promotion (these can be used as calcification promotion, osteoblast proliferation promotion, and index), bone formation promotion, tooth germ development promotion.
  • used in compositions, medicaments, medical devices, etc. for promoting root formation and / or promoting periodontal tissue regeneration, for example, as described in the section of these compositions, medicaments or medical devices herein Any that are present can be used.
  • the present invention is from the group consisting of forming bone, promoting bone formation, promoting tooth germ development, promoting tooth root formation, and promoting periodontal tissue regeneration.
  • a method for at least one selected, which comprises bone formation, bone formation promotion (these may be calcification promotion, osteoblast proliferation promotion, indicator), bone formation promotion, tooth germ development promotion Glycogen having a weight average molecular weight of less than about 8700 kDa is used to promote bone formation, bone formation (promoting mineralization, promoting osteoblast proliferation,
  • a method comprising administering to be delivered to a site in need of bone formation promotion, tooth germ development promotion, tooth root formation promotion, and / or periodontal tissue regeneration promotion.
  • glycogen included in the present invention include bone formation, bone formation promotion (these can be used as calcification promotion, osteoblast proliferation promotion, and index), bone formation promotion, tooth germ development promotion.
  • used in compositions, medicaments, medical devices, etc. for promoting root formation and / or promoting periodontal tissue regeneration, for example, as described in the section of these compositions, medicaments or medical devices herein Any that are present can be used.
  • the present invention provides methods and compositions for the treatment of bone diseases, fractures, bone damage, and other bone abnormalities.
  • glycogen is administered to a subject such as a mammal, and bone formation, bone formation promotion (these can be used as calcification promotion, osteoblast proliferation promotion, index), bone formation promotion, tooth germ It is achieved by a process that leads to the promotion of events associated with promotion of growth, promotion of root formation, and / or promotion of periodontal tissue regeneration, eg stimulation or enhancement of calcification.
  • a patient who needs treatment, treatment or prevention such as a disease or treatment requiring bone formation such as fracture, osteoporosis, and the like can be targeted.
  • the administration method such as oral administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, and rectal administration is appropriately selected according to the patient's condition, age, sex and the like.
  • the dose of the active ingredient is usually about 0.1 mg to about 5,000 mg per day for an adult, and is not limited to this range, but is appropriately selected according to the patient's condition, age, sex and the like.
  • Glycogen used in the present invention is considered to be non-toxic or low-toxic.
  • an administration method such as oral administration and intravenous administration is appropriately selected according to the patient's condition, age, sex and the like.
  • the dose of the active ingredient is usually about 0.1 mg to about 5,000 mg per day for an adult, and is not limited to this range, but is appropriately selected according to the patient's condition, age, sex and the like.
  • Glycogen used in the present invention is considered to be non-toxic or low-toxic.
  • glycogen is applied during the treatment to heal the pulp and periodontal tissues.
  • the usage method of promoting is considered. Therefore, promotion of tooth germ development, promotion of tooth root formation, and / or promotion of periodontal tissue regeneration is expected to be positioned as a combined therapy in implant or tooth replantation or transplantation.
  • the present invention relates to bone formation, bone formation promotion (these may be promoted calcification, osteoblast proliferation, indication), bone formation, tooth germ development, tooth root formation promotion, and / or Provided is the use of glycogen having a weight average molecular weight of less than about 8700 kDa for the manufacture of a food, additive, medical device or medicament for promoting periodontal tissue regeneration.
  • the present invention provides glycogen having a weight average molecular weight of less than about 8700 kDa for bone formation or promoting bone formation.
  • the amount of the active ingredient used in the treatment method or prevention method of the present invention depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, sex, medical history, cell form or type, etc. In view of this, it can be easily determined by those skilled in the art.
  • the frequency with which the treatment method of the present invention is applied to a subject (or patient) also depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, sex, medical history, treatment course, etc. In view of this, it can be easily determined by those skilled in the art. Examples of the frequency include administration every day to once every several months (for example, once a week to once a month). It is preferable to administer once a week to once a month while observing the course.
  • the type and amount of the drug used in the treatment or prevention method of the present invention is determined based on the purpose of use, target disease (type, severity) based on information obtained by the method of the present invention (for example, information on the disease). Etc.) can be easily determined by those skilled in the art in consideration of the patient's age, weight, sex, medical history, the form or type of the site of the subject to be administered, and the like.
  • the frequency with which the monitoring method of the present invention is applied to a subject (or patient) also depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, gender, medical history, treatment course, etc. In view of this, it can be easily determined by those skilled in the art.
  • the frequency of monitoring the disease state includes, for example, daily-once every several months (eg, once a week-once a month). It is preferable to perform monitoring once a week to once a month while monitoring the progress.
  • the present invention may be used as a kit or the like, in which case it may be accompanied by instructions.
  • the “instruction” describes the treatment method of the present invention and the like for a person who performs administration such as a doctor or a patient.
  • This instruction describes a word that instructs to administer the medicine of the present invention to an appropriate site (for example, a bone defect) at an appropriate amount and at an appropriate time.
  • This instruction is prepared in accordance with the format prescribed by the national supervisory authority (for example, the Ministry of Health, Labor and Welfare in Japan and the Food and Drug Administration (FDA) in the United States, etc. in the United States) where the present invention is implemented, and is approved by the supervisory authority. It is clearly stated that it has been received.
  • the instruction sheet is a so-called package insert and is usually provided as a paper medium, but is not limited thereto, and is in the form of, for example, an electronic medium (for example, a home page or e-mail provided on the Internet). But it can be provided.
  • two or more kinds of drugs can be used in the treatment of the present invention.
  • substances with similar properties or origins may be used, or drugs with different properties or origins may be used.
  • Information regarding disease levels for methods of administering two or more such drugs can also be obtained by the methods of the present invention.
  • Thermus aquaticus-derived amylomaltase (2 units / g substrate) were added and allowed to react for 48 hours.
  • the pH of the reaction solution was adjusted to about 3.5 with hydrochloric acid, and the reaction was stopped by heating at 100 ° C. for 15 minutes.
  • 100 mL of ethanol was added to this reaction solution, and the precipitate was collected by centrifuging at about 10,000 ⁇ g for 5 minutes, and further washed with 100 mL of 50% ethanol three times.
  • the precipitate was dissolved in 50 mL of distilled water and freeze-dried to obtain powdery enzyme-synthesized glycogen (ESG-5M).
  • ESG-7M Manufacture of ESG-7M It was produced in the same manner as ESG-5M except that the reaction time of isoamylase was 4.5 hours.
  • Example 1 osteoblast proliferation promoting effects were examined for various glycogens shown below.
  • Alkaline phosphatase was used as an osteoblast differentiation marker.
  • the bone marrow cell proliferation promoting effect was measured using MC3T3-E1.
  • ESG-5M (Lot 070223-5M) ESG-3M (Lot 070312-3M) ESGB (Lot 050225) (also known as GlyB) ESG-20M (Lot 070312-20M) ESG-8M (Lot 070315-8M) NSG (Corn) (Lot ZG7002) (also known as Phytoglycogen) NSG (Mussel) (Lot 127K3775) (aka Sigma Type VII) NSG (Rabbit river) (Lot 039K3775) (also known as Sigma Type III) (Cell proliferation experiment) The following experiment was performed using an osteoblast-like cell line (MC3T3-E1) established from a mouse skull.
  • M3T3-E1 osteoblast-like cell line
  • the medium was 10% fetal bovine serum, ⁇ -minimum essential medium ( ⁇ -MEM) containing 1% penicillin-streptomycin, and ⁇ -sodium glycerophosphate, L-ascorbic acid, dexamethasone was added to obtain a calcified medium at 37 ° C.
  • Cell culture was performed under 5% CO 2 /95% air conditions.
  • Enzyme-synthesized glycogen average molecular weight of about 5000 kDa
  • 300 ⁇ g / ml was added to the same calcification medium, or cultured under the non-addition condition and used for the experiment. The culture solution was changed every two days.
  • each of 5000 MC3T3-E1 cells was seeded in a 6-well plate, and cells were collected with a trypsin-EDTA solution after 1 day, 3 days, and 5 days, and the total number of cells was measured with a cell count plate. did. Three measurements were performed under each condition, and statistical analysis was performed. As a result, in the glycogen-added medium, a significant increase in the number of cells was confirmed on the fifth day of culture compared with the non-added group (FIG. 1). Therefore, it was shown that the synthetic glycogen in the medium promotes the proliferation of osteoblast-like cells.
  • ALP alkaline phosphatase
  • OC osteocalcin
  • MC3T3-E1 cultured in a 6-well plate was extracted with 1 ml of Trisol (manufactured by Invitrogen) according to the product protocol.
  • CDNA was synthesized from 2 ⁇ g of total RNA using a cDNA synthesis kit (Roche Applied Science).
  • ALP-Forward (5′-CCA GCA GGT TTC TCT CTT GG-3 ′ (SEQ ID NO: 1)) and ALP-Reverse (5′-CTG GGA GTC TCA TCC TGA TGC 3 ′ (SEQ ID NO: 2)), OC-Forward (5′-CTT GGT GCA CAC CTA GCA GA-3 ′ (SEQ ID NO: 3)) and OC-Reverse (5′-ACC TTA TTG CCC TCC TGC TT-3 '(SEQ ID NO: 4) was used for PCR amplification with PTC-100 TM Programmable Thermal Controller (manufactured by MJ Research). First, after heat denaturation at 94 ° C.
  • Example 3 In this example, various glycogens were examined for the presence of a calcification promoting effect.
  • MC3T3-E1 cultured in a medium supplemented with or without synthetic glycogen (ESG-5M) for 7 days (confluent state) was fixed with a 4% paraformaldehyde solution and subjected to Kossa staining as an indicator of calcification.
  • ESG-5M synthetic glycogen
  • the cultured cells after fixation with 4% paraformaldehyde were washed with distilled water and then reacted in 5% silver nitrate solution for 1 hour under indirect light. After washing with distilled water, a fixing reaction was performed with 5% sodium thiosulfate solution for 3 minutes. After washing with distilled water again, nuclear staining was performed with a Cologne Echloth funnel, sealed with a cover glass using a water-soluble mounting agent, and observed with an optical microscope.
  • Enzymatic synthetic glycogen has been shown to promote the growth, differentiation and calcification ability of osteoblast-like cell line MC3T3-E1 in an in vitro experimental system, but the specific molecular mechanism is still unclear. .
  • MC3T3-E1 was incubated for 1 hour with biotinylated enzymatic synthetic glycogen added to the medium, reacted with FITC-streptavidin, and examined with a fluorescence microscope. The cytoplasmic fluorescence reaction was observed. As a result, clear uptake of synthetic glycogen was confirmed.
  • glycogen molecule uptake into cells is a stimulus, which may cause some activation of intracellular signal transduction, promote cell proliferation and differentiation, and lead to bone formation.
  • Example 4 Effect of enzyme-synthesized glycogen on bone regeneration: in vivo experiment
  • glycogen of the present invention two on the left and right sides of the mouse parietal bone.
  • Filled with collagen gel with and without glycogen added and evaluated the bone formation, drilled into the skull of the mouse, injected ESG, and applied CT-Scan several days later, It was investigated whether bone regeneration promotion occurred.
  • a cutaneous periosteal flap was formed on the parietal part of ICR mice subjected to deep anesthesia to expose the parietal bone, and a total of 2 left and right bony cavities were formed with a dental turbine with a 4 mm diameter Lindeman bar.
  • collagen gel Cellmatrix; Nitta Gelatin Co., Ltd.
  • the skin periosteal flap was inserted. It was returned and sutured to finish the operation.
  • mice Two weeks later, the mouse was perfused and fixed with 4% paraformaldehyde, the head was cut off, and micro CT (Elesscan; manufactured by Nippon Steel Elex Co., Ltd.) was photographed with a slice width of 15 ⁇ m.
  • micro CT Elesscan; manufactured by Nippon Steel Elex Co., Ltd.
  • the photographed images were three-dimensionally constructed with NDTView (manufactured by Sony Corporation) and 3D bone (manufactured by Ratok System Engineering Co., Ltd.).
  • glycogen is a natural molecule that is abundant in shellfish such as oysters and scallops, and food such as corn.
  • the enzyme-synthesized glycogen used in the present invention has almost the same chemical structure as natural glycogen and has no cytotoxicity. It is a compound that can be safely used in the human body. Therefore, according to the present invention, a new bone formation promoter containing enzyme-synthesized glycogen as an active ingredient can be provided, and can be widely applied to the treatment of diseases associated with bone defects such as fractures and periodontal diseases.
  • enzyme-synthesized glycogen is expected to be able to be taken orally because it is not easily degraded by ⁇ -amylase, it can be administered not only locally to the bone defect site but also systemically as an osteogenesis promoter. It is expected to be.
  • Example 5 Experimental example showing effectiveness as a beverage for promoting dental healing
  • A. Effects in pups ICR mice ⁇ CLEA Japan> from the 0th day of pregnancy to water (water group) or an enzyme-synthesized glycogen aqueous solution prepared as described in the preparation examples (weight average polymerization degree of about 7000 kDa (ESG-7M (lot 070808-7M )) 2 mg / mL) (ESG group)
  • This aqueous solution was prepared by dissolving 200 mg of enzymatically synthesized glycogen in 100 ml of sterile water. > Was orally administered (free drinking) and born mice were bred until 3 weeks of age.
  • As a model for tooth replantation the teeth of pup mice were removed and re-implanted at the same site to examine the healing of dental pulp and the differentiation of odontoblasts.
  • composition of the present invention is effective for promoting tooth germ development.
  • the bone formation or the bone formation promotion shown in the above example it became clear that it also promoted the healing of the dental pulp, and the bone formation or bone around the tooth (alveolar bone) In addition to promoting formation, it has been shown to comprehensively promote tooth germ development.
  • glycogen may be of the order of about 7000 kDa.
  • Example 6 Promotion of formation of tooth germ in organ culture
  • An ICR mouse (CLEA Japan) was made pregnant, and a mouse fetus extracted at 16.5 gestation was used as the fetus of this example. Specifically, the mouse fetus on the 15th day of gestation was obtained from CLEA Japan and used in this example.
  • Mandibular first and second molar tooth germs were collected from the fetus and cultured in vitro. More specifically, tooth germ organ culture was performed using the Trowell method in a DMEM medium containing 10% fetal bovine serum, 1% penicillin-streptomycin, and 100 ⁇ g / ml ascorbic acid.
  • ESGB (5000 kDa) prepared as described in the preparation examples was directly added to the medium so as to be 500 ⁇ g / mL, cultured for 4 days, and then the state of tooth germ formation was observed. ESG clearly promoted growth and formed large tooth germs (see FIG. 7).
  • the present invention has an effect on the promotion of tooth germ development.
  • Example 7 Measurement of molecular weight range, cell level experiment
  • M3T3-E1 an osteoblast-like cell line
  • enzyme-synthesized glycogen having an average molecular weight of about 2000 kDa, about 7000 kDa, and about 12000 kDa Investigate calcification promoting effect. In this way, it can be confirmed whether or not there is a significant effect when enzyme-synthesized glycogen of about 2000 kDa, about 7000 kDa and about 12000 kDa is used.
  • Example 8 Measurement of molecular weight range, animal experiment
  • Experiments similar to Example 4 are performed using enzyme-synthesized glycogen having an average molecular weight of about 2000 kDa, about 7000 kDa, and about 12000 kDa, and the bone regeneration effect is examined. As a result, it can be confirmed whether or not there is a significant bone regeneration effect when enzyme-synthesized glycogen of about 2000 kDa, about 7000 kDa and about 12000 kDa is used.
  • Example 9 Tablet formulation example
  • a tablet having the following composition is produced by a conventional method.
  • 100 mg of the compound of the present invention Lactose 60mg Potato starch 30mg Polyvinyl alcohol 2mg Magnesium stearate 1mg Tar pigment Trace amount.
  • Example 10 Formulation example of injection
  • Sodium chloride 0.9g Enzyme-synthesized glycogen 5g 100 ml of purified water
  • the above solid components are dissolved in purified water to give an injection.
  • Example 11 Dental application example
  • a blood vessel or a cell is drawn from a surrounding tissue by being inserted into a wound, and a dosage form used for regeneration of a new tissue is carried out.
  • the following preparation examples are shown.
  • Enzyme-synthesized glycogen 5mg Saline 0.1ml Collagen gel sponge appropriate amount (Example 12: Application example of medical device)
  • a dosage form of a bone prosthetic material is implemented. The following preparation examples are shown.
  • Enzyme-synthesized glycogen 100mg ⁇ -type tricalcium phosphate ( ⁇ -TCP) 190mg Dextran 100mg Saline 0.4ml
  • Example 13 Example of food to be ingested by a patient for a certain period before treatment of teeth and bones
  • ⁇ -TCP tricalcium phosphate
  • Example 13 Example of food to be ingested by a patient for a certain period before treatment of teeth and bones
  • Enzyme-synthesized glycogen 5g Citric acid 0.03g Sucralose 0.005g Perfume appropriate amount Purified water 100ml.
  • Example 14 Example of treatment adjuvant administered to affected area
  • a treatment auxiliary agent administered to the affected area is carried out as an application example of the treatment auxiliary agent.
  • the following preparation examples are shown.
  • Example 15 Example of growth promoting additive in tooth germ organ culture for research use
  • an additive for promoting growth in tooth germ organ culture is carried out as an application example of the additive. The following preparation examples are shown.
  • Enzyme-synthesized glycogen 5mg DMEM medium 8.9ml Fetal calf serum 1ml Penicillin Streptomycin 0.1ml L ascorbic acid 1 mg.
  • the present invention proved that a specific glycogen is useful for bone formation.
  • the discovery that such a biocompatible material is useful for bone formation is expected to be applied in the pharmaceutical industry, and in the field of medicine and the like that can achieve effects not found in the prior art. There is usability.
  • SEQ ID NO: 1 PCR primer used in Example 2 (ALP-Forward)
  • SEQ ID NO: 2 PCR primer used in Example 2 (ALP-Reverse)
  • SEQ ID NO: 3 PCR primer used in Example 2 (OC-Forward)
  • SEQ ID NO: 4 PCR primer used in Example 2 (OC-Reverse)
  • SEQ ID NO: 5 PCR primer used in Example 2 ( ⁇ -actin-Forward)
  • SEQ ID NO: 6 PCR primer used in Example 2 ( ⁇ -actin-Reverse)

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Abstract

La présente invention concerne un composé ou une composition hautement stable possédant un effet efficace d'activation de l'ostéogenèse, d'activation du développement des germes dentaires, d'activation de la formation des racines dentaires, d'activation de la régénérescence du tissu parodontal, et analogues en plus de présenter des effets secondaires en outre réduits. La présente invention aborde le problème susmentionné par la découverte qu'un type spécifique de glycogène active l'ostéogenèse, le développement des germes dentaires, la formation des racines dentaires, la régénérescence du tissu parodontal, et analogues. La présente invention concerne une composition qui contient un glycogène dont la masse moléculaire moyenne en poids est inférieure à environ 8700 kDa, et qui est destinée à au moins un objectif choisi dans le groupe comprenant l'ostéogenèse, l'activation de l'ostéogenèse, l'activation du développement des germes dentaires, l'activation de la formation des racines dentaires et l'activation de la régénérescence du tissu parodontal.
PCT/JP2011/005183 2010-09-15 2011-09-14 Agent d'activation de l'ostéogenèse contenant du glycogène Ceased WO2012035770A1 (fr)

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JP2016514030A (ja) * 2013-03-14 2016-05-19 ジェンザイム・コーポレーション 感熱性骨成長組成物
CN107106464A (zh) * 2015-01-08 2017-08-29 江崎格力高株式会社 抗氧化剂和抗氧化/防uv化妆品
CN110537987A (zh) * 2018-07-31 2019-12-06 首都医科大学 用于控制恒牙胚发育的方法、支架及其用途

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JP2005519056A (ja) * 2002-01-10 2005-06-30 エフ．ホフマン−ラ　ロシュ　アーゲー 骨形成を増加させるための薬物の製造におけるＧＳＫ−３β阻害剤の使用
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JP2002080380A (ja) * 2000-08-31 2002-03-19 Bizen Chemical Co Ltd 骨形成促進剤
JP2005519056A (ja) * 2002-01-10 2005-06-30 エフ．ホフマン−ラ　ロシュ　アーゲー 骨形成を増加させるための薬物の製造におけるＧＳＫ−３β阻害剤の使用
WO2006035848A1 (fr) * 2004-09-30 2006-04-06 Ezaki Glico Co., Ltd. Méthode de synthèse du glycogène
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Publication number Priority date Publication date Assignee Title
JP2016514030A (ja) * 2013-03-14 2016-05-19 ジェンザイム・コーポレーション 感熱性骨成長組成物
CN107106464A (zh) * 2015-01-08 2017-08-29 江崎格力高株式会社 抗氧化剂和抗氧化/防uv化妆品
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CN110537987A (zh) * 2018-07-31 2019-12-06 首都医科大学 用于控制恒牙胚发育的方法、支架及其用途

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