WO2013137382A1 - Agent améliorant le métabolisme osseux - Google Patents

Agent améliorant le métabolisme osseux Download PDF

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Publication number
WO2013137382A1
WO2013137382A1 PCT/JP2013/057160 JP2013057160W WO2013137382A1 WO 2013137382 A1 WO2013137382 A1 WO 2013137382A1 JP 2013057160 W JP2013057160 W JP 2013057160W WO 2013137382 A1 WO2013137382 A1 WO 2013137382A1
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WO
WIPO (PCT)
Prior art keywords
bone
hydroxyproline
bone metabolism
salt
improving
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PCT/JP2013/057160
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English (en)
Japanese (ja)
Inventor
義宏 野村
一貴 上原
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協和発酵バイオ株式会社
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Publication of WO2013137382A1 publication Critical patent/WO2013137382A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to a bone metabolism improving agent containing an N-acylated derivative of hydroxyproline or a salt thereof as an active ingredient.
  • osteoporosis is a disease that is characterized by loss of bone mass and strength and causes fragile fractures. In osteoporosis, bone formation does not catch up with excessive bone resorption (because the balance between bone formation by osteoblasts and bone resorption by osteoclasts is lost), and it is known that bone loss is caused. ing.
  • N-acylated derivatives of hydroxyproline or salts thereof are effective for improving arthritis (patent document 1), pressure ulcer (patent document 2), dry skin (patent document 3), liver damage (patent document 4), etc.
  • the effect of improving rough skin (Patent Document 5) has been reported.
  • N-acetylhydroxyproline, an N-acylated derivative of hydroxyproline is used as a cosmetic raw material and quasi-drug additive in Japan, and as a drug for wound healing (burn treatment) in Europe as Oxaceprol. Used as a raw material.
  • An object of the present invention is to provide an agent for improving bone metabolism that is effective in improving bone-related diseases.
  • the present invention relates to the following (1) to (5): (1) An agent for improving bone metabolism comprising an N-acylated derivative of hydroxyproline or a salt thereof as an active ingredient. (2) A bone resorption inhibitor containing an N-acylated derivative of hydroxyproline or a salt thereof as an active ingredient. (3) An osteoclast differentiation inhibitor containing an N-acylated derivative of hydroxyproline or a salt thereof as an active ingredient. (4) Use of a salt of an N-acylated derivative of hydroxyproline for the production of a bone metabolism improving agent. (5) A method for improving bone metabolism, wherein a subject in need of improving bone metabolism is provided with a sufficient amount of a salt of an N-acylated derivative of hydroxyproline to improve bone metabolism of the subject. A method for improving bone metabolism comprising the step of administering.
  • a safe and effective bone metabolism improving agent containing an N-acylated derivative of hydroxyproline or a salt thereof as an active ingredient can be provided.
  • the bone metabolism improving agent of the present invention can improve bone metabolism.
  • “improving bone metabolism” means improving the balance between bone formation by osteoblasts and bone resorption by osteoclasts performed in vivo.
  • improving the balance between bone formation and bone resorption means suppressing bone resorption.
  • inhibiting bone resorption means inhibiting osteoclast differentiation.
  • Hydroxyproline an N-acylated derivative of hydroxyproline used in the present invention, is widely present in nature as a major constituent amino acid component in collagen and as a constituent amino acid component of elastin.
  • Naturally-occurring hydroxyproline depends on whether proline is D-form or L-form, whether the position of hydroxyl group is 3-position or 4-position, and whether the stereoisomer is cis-form or trans-form. Eight types of stereoisomers are known.
  • cis-4-hydroxy-L-proline cis-4-hydroxy-D-proline, cis-4-hydroxy-D-proline, cis-3-hydroxy-L-proline, cis-3-hydroxy-D-proline, trans-4-hydroxy -L-proline, trans-4-hydroxy-D-proline, trans-3-hydroxy-L-proline, trans-3-hydroxy-D-proline and the like.
  • any hydroxyproline can be used, but trans-4-hydroxy-L-proline is preferably used.
  • Hydroxyproline can be obtained by acid hydrolysis of animal-derived collagen such as pigs and cows and purification by conventional methods, but hydroxyproline produced using microorganisms is more preferably used.
  • the microorganism includes a microorganism belonging to the genus selected from the genus Amycolatopsis, the genus Dactylosporangium and the genus Streptomyces, or the proline 3-hydroxylase or proline 4-position derived from the microorganism.
  • a microorganism into which a hydroxylase gene has been introduced can be used.
  • proline 3-hydroxylase or proline 4-hydroxylase gene derived from a microorganism belonging to the genus selected from the genus Amycolatopsis, Dactyrosporandium and Streptomyces to Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in Molecular Biology, John Wiley & Sons (1987-1997), etc.
  • trans-4-hydroxy-L-proline is obtained by using proline 4-hydroxylase (Japanese Patent Laid-Open No. 7-313179) isolated from a microorganism belonging to the genus Amycolatopsis or Dactyrosporandium.
  • Cis-3-hydroxy-L-proline can be produced using a proline 3-hydroxylase isolated from a microorganism belonging to the genus Streptomyces (Japanese Patent Laid-Open No. 7-322885).
  • cis-4-hydroxyproline can be produced using proline 4-hydroxylase (WO2009 / 139365) isolated by a microorganism belonging to the genus Mesozobium.
  • acyl moiety of the N-acylated derivative of hydroxyproline used in the present invention examples include linear or branched acyl having 2 to 23 carbon atoms, and more specifically, acetyl, propionyl, butyryl, isobutyryl. Valeryl, hexanoyl, heptanoyl, octanoyl, decanoyl, eicosanoyl, etc., among which acetyl and propionyl are preferred.
  • the N-acylated derivative of hydroxyproline can be produced by a known method. That is, it is preferably prepared by N-acylation of hydroxyproline in an aqueous medium or an organic solvent using an active derivative (an acid anhydride, acid chloride, etc.) of a fatty acid having an alkyl group having 1 to 22 carbon atoms. it can.
  • the obtained N-acylated derivative of hydroxyproline can be purified using a conventional purification method such as crystallization or chromatography.
  • salts of N-acylated derivatives of hydroxyproline include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salts such as ammonium and tetramethylammonium, morpholine And organic amine addition salts such as piperidine.
  • a salt of an N-acylated derivative of hydroxyproline can be administered as it is, but it is usually desirable to provide it as various preparations.
  • Preparations can be produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.
  • the preparation may further contain any other active ingredient for treatment.
  • additives such as excipients, binders, disintegrants, lubricants, dispersants, suspending agents, emulsifiers, diluents, buffers, antioxidants, and bacterial inhibitors should be used. it can.
  • dosage forms include tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, fluid extracts, and other oral preparations. Any of parenteral agents such as injections, drops, creams, suppositories and the like may be used.
  • the dosage forms suitable for oral administration are tablets, powders and granules, sugars such as lactose, glucose, sucrose, mannitol, sorbitol, starches such as potato, wheat, corn, calcium carbonate, calcium sulfate , Inorganic substances such as sodium hydrogen carbonate, sodium chloride, excipients such as crystalline cellulose, licorice powder, gentian powder, etc., starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, Disintegrants such as sodium bicarbonate and sodium alginate, magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and other lubricants, polyvinyl alcohol, hydroxypropylcellulose, methylcellulose, ethylcellulose, carmellose, gelatin Binders starch glue solution and the like, surfactants such as fatty acid esters can be formulated by adding a plasticizer such as glycerin.
  • a plasticizer
  • the dosage form suitable for oral administration is a liquid preparation such as syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil, etc. Oils, p-hydroxybenzoic acid esters and other preservatives, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint. can do.
  • a liquid preparation such as syrup, water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil, etc.
  • Oils, p-hydroxybenzoic acid esters and other preservatives, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint. can do.
  • the dosage form suitable for parenteral administration is an injection
  • it preferably comprises a sterile aqueous preparation containing an N-acylated derivative of hydroxyproline or a salt thereof that is isotonic with the blood of the recipient.
  • a solution for injection can be prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
  • preparations suitable for oral administration include additives generally used in foods and drinks such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, gum bases.
  • Sweeteners such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color formers, bleaches, fungicides, gum bases.
  • Bitterings enzymes, brighteners, acidulants, seasonings, emulsifiers, fortifiers, manufacturing agents, fragrances, spice extracts and the like may be added.
  • the ingestion form of the preparation is desirably the most effective in improving bone metabolism, and examples thereof include oral administration and parenteral administration such as intravenous, intraperitoneal or subcutaneous administration.
  • the concentration of the salt of the hydroxyproline N-acylated derivative in the bone metabolism-improving agent of the present invention is appropriately selected according to the type of preparation, the effect expected by administration of the preparation, etc.
  • the salt of the N-acylated derivative of hydroxyproline is usually 0.1 to 100% by weight, preferably 0.5 to 80% by weight, particularly preferably 1 to 70% by weight.
  • the dose and frequency of administration of the bone metabolism-improving agent of the present invention vary depending on the administration form, patient age, body weight, nature or severity of the condition to be treated, but usually N-acyl of hydroxyproline per adult day.
  • the salt of the derivatized derivative is usually administered once to several times a day so as to be 50 mg to 30 g, preferably 100 mg to 10 g, particularly preferably 200 mg to 3 g.
  • the administration period is not particularly limited, but is usually 1 day to 2 years, preferably 1 month to 12 months.
  • improvement means that by taking the above-mentioned improving agent, the onset of bone metabolism is prevented, the onset rate is reduced, or the symptoms at the time of onset are suppressed or treated.
  • the bone metabolism improving agent of the present invention can be used for improving bone metabolism.
  • the bone metabolism improving agent of the present invention can be used for the effects expected from the improvement of bone metabolism.
  • diseases related to bone include, for example, osteoporosis, juvenile osteoporosis, bone dysplasia, hypercalcemia, decreased bone mass associated with hyperparathyroidism, osteomalacia, osteocalcinosis, osteolytic bone disease, bone Necrosis, Paget's disease of bone, osteoarthritis, fracture, bone loss due to prosthesis fixation, periodontal bone loss, metastatic bone disease, bone loss due to cancer, bone loss due to aging, Examples include bone loss due to side effects of other medications (such as steroids), bone loss due to weightlessness, and other conditions involving bone abnormalities or bone damage.
  • other medications such as steroids
  • a salt of an N-acylated derivative of hydroxyproline can be used for producing a bone metabolism improving agent.
  • the present invention includes a method for improving bone metabolism.
  • the method of the invention comprises administering to a subject in need of improving bone metabolism an amount of a salt of an N-acylated derivative of hydroxyproline sufficient to improve the subject's bone metabolism.
  • the following is a test example for examining the bone metabolism improving effect of a salt of an N-acylated derivative of hydroxyproline.
  • Osteoclast Differentiation Inhibition RAW264 cells an ascites-derived macrophage cell line of BALB / c mice, which are osteoclast-like cells, were treated with 10% fetal bovine serum (FBS: GIBCO) and 1% antibiotics (PNS Antibiotic Mixture). : GIBCO) in an ⁇ -MEM medium (SIGMA) and used for the experiment. The cells were cultured in a 37 ° C., 5% CO 2 incubator.
  • RAW264 cells were seeded in a 96-well plate by 8 ⁇ 10 2 cells / well and cultured in a medium of 200 ⁇ L / Well.
  • RANKL receptor activator of NF- ⁇ B ligand: SIGMA
  • SIGMA receptor activator of NF- ⁇ B ligand
  • N-acetylhydroxyproline with a final concentration of 1.15 ⁇ 10-2 mol / L (Kyowa Hakko Bio) was added.
  • the control group was examined in three groups: RANKL-stimulated, RANKL-stimulated group, and RANKL-stimulated + N-acetylhydroxyproline group. Thereafter, the medium of 100 ⁇ L / well was changed every other day and cultured for 6 days.
  • TRAP thyroid-resistant acid phosphatase
  • Primary Cell a staining kit (Primary Cell). The number of mature osteoclasts, which are multinucleated osteoclasts having three or more nuclei, was counted among the stained osteoclasts.
  • N-acetylhydroxyproline has an osteoclast differentiation inhibitory action, and it was shown to be a bone resorption inhibitor in osteoclasts and a bone metabolism improver in vivo.
  • N-acetylhydroxyproline was manufactured by Kyowa Hakko Bio.
  • composition (component; blending ratio% by weight) N-acetylhydroxyproline; 20%, lactose; 40%, calcium lactate; 10%, magnesium stearate; 25%, calcium carbonate; 5%
  • composition (component; blending g) N-acetylhydroxyproline: 30 g, vitamin C: 1 g, vitamin B1: 0.005 g, vitamin B2: 0.01 g, vitamin B6: 0.025 g, liquid sugar: 150 g, citric acid: 3 g , Fragrance; 1 g
  • hard capsules 360 mg per capsule
  • Composition component; formulation mg
  • N-acetylhydroxyproline 250 mg
  • lactose 60 mg
  • corn starch 30 mg
  • hydroxypropylcellulose 20 mg
  • Lactose and corn starch are added to N-acetylhydroxyproline and mixed, and an aqueous solution of hydroxypropylcellulose is added thereto and kneaded.
  • granules are produced by an ordinary method using an extrusion granulator.
  • a hard capsule is produced by filling the granule into a gelatin hard capsule.
  • soft capsules (170 mg per capsule) are produced by the following method.
  • Composition component; compounding mg) N-acetylhydroxyproline; 25 mg, soybean oil; 120 mg, glucosamine; 25 mg
  • soft capsules are produced by filling the soft capsules using a rotary soybean automatic molding machine according to a conventional method.
  • cream phase component Squalane 5.0 g, olive oil 3.0 g, hydrogenated lanolin 2.0 g, beeswax 2.5 g, monoglyceryl stearate 2.0 g, polyoxyethylene stearyl ether 2.5 g, propylparaben 1 .5 g, 1,3-butylene glycol 5.0 g, perfume, (water phase component) N-acetyl-trans-4-hydroxy-L-proline 5.0 g, methylparaben 0.5 g, carbopol 9400.03 g, tri Ethanolamine 0.3g, refined starch syrup 70.97g (Preparation method) Heat the oil phase component and water phase component to 80 ° C to homogenize them, add the water phase to the oil phase with stirring, emulsify and cool to obtain cream It was.
  • ointment 0.2 g white petrolatum, 1.0 g stearyl alcohol, 0.3 g sodium lauryl sulfate, (aqueous phase component) 5.0 g N-acetyl-trans-4-hydroxy-L-proline, propylene Glycol 5.0 g ⁇ ⁇ ⁇ ethyl paraoxybenzoate, 0.02 g ⁇ ⁇ ⁇ butyl paraoxybenzoate 1.0 g purified water tank 81.45 g (preparation method) The phase component and the aqueous phase component were each heated to 80 ° C. to make the water phase oil phase While stirring, the mixture was cooled after emulsification to obtain an ointment.
  • tape agent adheresive solvent

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  • Health & Medical Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent améliorant le métabolisme osseux qui comprend, comme principe actif, un dérivé N-acylé d'hydroxyproline qui est efficace dans l'amélioration de maladies liées aux os ou bien un sel de celui-ci. Des exemples de maladies osseuses comprennent l'ostéoporose, l'ostéoporose juvénile, la dysostose, l'hypercalcémie, la perte osseuse associée à l'hyperparathyroïdisme, l'ostéomalacie, l'osteohalisteresis, des maladies ostéolytiques, l'ostéonécrose, la maladie osseuse de Paget, l'arthrose, la fracture osseuse, la perte osseuse provoquée par l'implantation de prothèses, la perte osseuse parodontale, les maladies osseuses métastatiques, la perte osseuse provoquée par le cancer, la perte osseuse due au vieillissement, la perte osseuse en tant qu'effet secondaire de la thérapie avec d'autres médicaments (tels que des stéroïdes), la perte osseuse dans un environnement exempt de gravité et d'autres symptômes associés à une anomalie osseuse ou une lésion osseuse.
PCT/JP2013/057160 2012-03-15 2013-03-14 Agent améliorant le métabolisme osseux WO2013137382A1 (fr)

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JP2012-058315 2012-03-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015046484A1 (fr) * 2013-09-30 2015-04-02 国立大学法人東京農工大学 Agent thérapeutique contre l'ostéoporose

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09255588A (ja) * 1996-03-28 1997-09-30 Snow Brand Milk Prod Co Ltd 骨強化用医薬、飲食品及び飼料
WO2000051561A1 (fr) * 1999-03-02 2000-09-08 Kyowa Hakko Kogyo Co., Ltd. Produits cosmetiques
WO2002006225A1 (fr) * 2000-07-19 2002-01-24 Kyowa Hakko Kogyo Co., Ltd. Agents de prevention ou de traitement de la dermite atopique
WO2007111238A1 (fr) * 2006-03-23 2007-10-04 Kyowa Hakko Kogyo Co., Ltd. Agent oral pour favoriser la synthese du collagene tissulaire

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09255588A (ja) * 1996-03-28 1997-09-30 Snow Brand Milk Prod Co Ltd 骨強化用医薬、飲食品及び飼料
WO2000051561A1 (fr) * 1999-03-02 2000-09-08 Kyowa Hakko Kogyo Co., Ltd. Produits cosmetiques
WO2002006225A1 (fr) * 2000-07-19 2002-01-24 Kyowa Hakko Kogyo Co., Ltd. Agents de prevention ou de traitement de la dermite atopique
JP2011079856A (ja) * 2000-07-19 2011-04-21 Kyowa Hakko Bio Co Ltd アトピー性皮膚炎の予防または改善剤
WO2007111238A1 (fr) * 2006-03-23 2007-10-04 Kyowa Hakko Kogyo Co., Ltd. Agent oral pour favoriser la synthese du collagene tissulaire

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KALBHEN DA ET AL.: "Autoradiographische Untersuchungen uber den Einfluss von Oxaceprol auf den Stoffwechsel des Gelenkknorpels in vitro und in vivo", ZEITSCHRIFT FUR RHEUMATOLOGIE, vol. 46, no. 3, 1987, pages 136 - 142 *
MOLIMARD R ET AL.: "Effets de la N acetyl hydroxyproline sur l'evolution des brulures intermediaires experimentales du lapin", REVUE EUROPEENNE D'ETUDES CLINIQUES ET BIOLOGIQUES., vol. 17, no. 6, 1 June 1972 (1972-06-01), pages 625 - 629, XP009104147 *
TAKEDA H ET AL.: "Sphingomyelinase and ceramide inhibit formation of F-actin ring in and bone resorption by rabbit mature osteoclasts.", FEBS LETT., vol. 422, no. 2, 30 January 1998 (1998-01-30), pages 255 - 258, XP004261817, DOI: doi:10.1016/S0014-5793(98)00005-2 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015046484A1 (fr) * 2013-09-30 2015-04-02 国立大学法人東京農工大学 Agent thérapeutique contre l'ostéoporose
JPWO2015046484A1 (ja) * 2013-09-30 2017-03-09 国立大学法人東京農工大学 骨粗鬆症治療剤
EP3053581A4 (fr) * 2013-09-30 2017-04-12 National University Corporation Tokyo University Of Agriculture and Technology Agent thérapeutique contre l'ostéoporose

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