WO2010104079A1 - Composition destinée à réduire le risque de fractures osseuses et/ou à prévenir des fractures osseuses - Google Patents

Composition destinée à réduire le risque de fractures osseuses et/ou à prévenir des fractures osseuses Download PDF

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Publication number
WO2010104079A1
WO2010104079A1 PCT/JP2010/053907 JP2010053907W WO2010104079A1 WO 2010104079 A1 WO2010104079 A1 WO 2010104079A1 JP 2010053907 W JP2010053907 W JP 2010053907W WO 2010104079 A1 WO2010104079 A1 WO 2010104079A1
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zinc
male
bone
fracture
risk
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PCT/JP2010/053907
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English (en)
Japanese (ja)
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長田昌士
原博
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明治乳業株式会社
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Priority to JP2011503829A priority Critical patent/JP5967936B2/ja
Publication of WO2010104079A1 publication Critical patent/WO2010104079A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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 composition for reducing fracture risk and / or preventing fracture. More specifically, the present invention relates to a pharmaceutical composition or a food composition (oral ingestion agent) that can be taken orally effective in reducing fracture risk and / or preventing fracture.
  • a pharmaceutical composition or a food composition oral ingestion agent
  • a fracture is a fracture or a crack in the bone.
  • the main determinants of bone strength include (1) bone mass and density, and (2) bone quality.
  • the characteristics indicating bone quality include structural characteristics and material characteristics. Structural characteristics include macroscopic bone structure and size, microcancellous trabecular structure and cortical bone (compact bone) morphology and porosity.
  • the material characteristics include mineralization degree, crystal size, collagen, and micro damage (Non-Patent Document 1).
  • Osteoporosis is divided into several modes, for example, (1) secondary osteoporosis caused by a specific disease or drug, and (2) primary osteoporosis that is thought to occur due to various causes overlapping. Can do.
  • the main ones of primary osteoporosis can include osteoporosis and senile osteoporosis in postmenopausal women.
  • Osteoporosis in postmenopausal women is caused by a decrease in estrogen.
  • Estrogen is a major regulator of bone metabolism, and it is supposed that osteoporosis is caused by a decrease in bone mass due to a decrease in estrogen.
  • the cause of senile osteoporosis in men and postmenopausal women after the menopause is considered to be caused by a combination of factors, such as decreased sex hormones, changes in systemic hormones and cytokine actions.
  • factors such as decreased sex hormones, changes in systemic hormones and cytokine actions.
  • the proliferative ability and function of osteoblast progenitor cells and mature osteoblasts decrease at the cellular level as a result of aging.
  • bone resorption increases with aging and bone formation declines.
  • the endocrine system changes due to aging, and the concentration of growth hormone and IGF-I decreases, which reduces bone formation. It is said that the decrease in sex hormones causes bone loss even in men.
  • Non-patent Document 2 Active vitamin D, bisphosphate, magnesium, calcium, casein phosphopeptide, and the like are also used for the treatment of osteoporosis.
  • Patent Document 1 the use of vitamin K 2, vitamin K 2 and the combination of zinc is known as an improvement agent or preventive agent for osteoporosis.
  • Patent Document 2 the use of vitamin K 2, vitamin K 2 and the combination of zinc is known as an improvement agent or preventive agent for osteoporosis.
  • Creine and vitamin D As a composition with the effect of increasing bone mass and muscle mass, which helps prevent falls and fractures in the elderly, creatine and vitamin D, glucosamines, glycosaminoglycans are active ingredients, bone and muscle strengthening Food compositions have been developed (Patent Document 2).
  • a pharmaceutical composition or (health) food composition effective for reducing fracture risk and / or preventing fracture, particularly for improving or preventing adult male, elderly male, and male adult osteoporosis and senile osteoporosis Development is the first issue.
  • the risk of fracture of a male male and / or prevention of fracture is reduced.
  • the male of a grown mammal, the male of an old mammal, and the male grown male osteoporosis and old osteoporosis Development of a pharmaceutical composition or feed composition effective for improving or preventing the above is a second problem.
  • Development of a pharmaceutical composition or a (health) food composition or a feed composition is a third problem.
  • a fourth problem is to develop a pharmaceutical composition or a food composition that can reduce the risk of fracture, which has been confirmed or verified to actually improve bone strength.
  • the inventor of the present application can administer an effective amount of zinc to a woman or a mother of a mammal by giving it an effective amount of zinc to a woman or a mammal mother during the period before pregnancy and during pregnancy and breastfeeding, or at least during pregnancy.
  • the present invention was completed by finding that the risk of fracture when a boy or male offspring born from an animal mother reached adulthood was significantly reduced.
  • the male when zinc is administered to a woman, a boy born from the woman reaches adulthood (hereinafter also referred to as “adult”, “adult”, “after growth”, etc.) or old age
  • adulthood hereinafter also referred to as “adult”, “adult”, “after growth”, etc.
  • old age the male has a particularly excellent effect of reducing fracture risk and / or preventing fracture.
  • the present invention provides a method for administering a fracture to a male when a male offspring born from the mother grows (hereinafter also referred to as an “adult”) or reaches an old age by administering zinc to a mammalian mother. It has a particularly excellent effect of enabling risk reduction and / or prevention of fractures.
  • Cortical bone thickness (cm) of the pup mouse by X-ray CT imaging * p ⁇ 0.05 mm there is a significant difference Cortical bone area ratio (%), which is the ratio of cortical bone area to total bone area * p ⁇ 0.05 mm, there is a significant difference Minimum moment of inertia (mg ⁇ cm) showing the bone strength against bending * p ⁇ 0.05mm, there is a significant difference Cross-sectional second-order moment (mg ⁇ cm) showing bone strength against torsion * p ⁇ 0.05 mm, significant difference Maximum bending energy (mJ) from the three-point fracture test of the right femur Tissue volume of cancellous bone (mm 3 ) * p ⁇ 0.05, significant difference Total bone mass of cortical bone (mg) * p ⁇ 0.05 mm with significant difference 25 (OH) vitamin D3 concentration in blood (nmol / L) * p ⁇ 0.05, there is a significant difference
  • Osteoporosis has conventionally been regarded as a disease involving a fracture caused by a decrease in bone mass, but is now regarded as a disease with an increased risk of fracture. And it has been widely recognized that therapeutic agents for osteoporosis require preventive treatment of fractures.
  • Zinc is said to play catalytic, structural and regulatory functions in vivo.
  • RNA polymerase and alkaline phatase.
  • proteins in the living body whose structure is maintained by zinc bonding such as Zinc-finger protein.
  • Zinc-finger protein proteins in the human body.
  • zinc deficiency includes growth disorder, hypogonadism, taste / olfactory disturbance, hair loss, immune decline, and the like.
  • the recommended amount of zinc consumed by Japanese is 3 mg per day for pregnant women, compared to the recommended amount of 7 mg per day at the age of pregnancy. In the period, the recommended amount per day is 10 mg.
  • the 2005 National Health and Nutrition Survey about 90% of pregnant women do not meet the daily required intake of zinc, which includes additional amounts.
  • Bone strength is an integration of bone density and bone quality.
  • particular attention has been directed to bone mass and bone density as an assessment of fracture risk.
  • the burden on the patient is small and clinically excellent, but there are various problems in evaluating the risk of fracture.
  • treatment with fluorine has little effect on preventing fractures despite an increase in bone mass.
  • raloxifene treatment it is said that the incidence of fracture is lower when the bone mass decreases than when the bone mass increases in the control group.
  • Characteristics that represent bone quality include macroscopic bone structure and bone dimensions, microscopic trabecular bone trabecular structure and bone dimensions, microscopic trabecular bone trabecular structure and cortical bone morphology and porosity, etc. And “material properties” such as mineralization degree, crystal size, and micro damage.
  • a macroscopic bone structure evaluation method a method using dual-Xray-absorptiometry (eg, femoral neck length), a method using cross-sectional CT (eg, long bone), or a method using micro CT (A trabecular bone trabecular structure, fine bone).
  • Bone material evaluation methods include quantitative backscattered electron imaging (quantative backscattered imaging qBEI), scanning electron microscope, and synchrotron radiation CT (Clinical). Calcium IV Vol.14, No.12, pages 27-32).
  • the present invention is a composition containing zinc as an active ingredient, and is administered to a pregnant woman or a mammal mother to reduce the risk of fracture of a male or male offspring that the pregnant woman or mammal mother gave birth.
  • the present invention relates to a composition containing zinc as an active ingredient, which is administered to a pregnant woman or a mother of a mammal so that the pregnant woman or the mother of the mammal gives birth to a male or mammalian male adult osteoporosis And compositions effective for improving or preventing senile osteoporosis.
  • the above composition may be any of a pharmaceutical (for) composition, a food (for) composition, or a feed (for) composition.
  • Mammals include humans, but also include livestock, pets, and laboratory animals.
  • the effect of taking zinc during pregnancy and breastfeeding from the time when the mother can become pregnant is the effect of reducing the risk of fracture and improving the prevention of fracture in boys born from that mother. As it appeared prominently. In other words, when the mother ingested and did not ingest the zinc experimentally, the mother was born with a significant difference in the effectiveness in reducing fracture risk and preventing fracture. When zinc was ingested, it was excellent.
  • the effect of taking zinc during pregnancy and breastfeeding from the time when the mother can become pregnant is not only for boys but also for girls, as it reduces the risk of fracture and improves the effectiveness of fracture prevention. It can be expected.
  • compositions a pharmaceutical composition containing zinc as an active ingredient, and a male or a male born from a pregnant woman or a mother of a mammal has become an adult by administering to the mother of the pregnant woman or a mammal. And a pharmaceutical composition that is effective in reducing fracture risk and improving or preventing adult osteoporosis and senile osteoporosis.
  • the pharmaceutical composition of the present invention may be any zinc composition including zinc-containing compounds and compositions, such as zinc sulfate, zinc chloride, inorganic zinc, zinc gluconate, chelate zinc, and picolinic acid. Zinc etc. are mentioned, Furthermore, zinc binding protein, a zinc binding peptide, etc. are mentioned.
  • the pharmaceutical composition of the present invention can be made into appropriate dosage forms such as powders, granules, tablets, capsules, and liquids.
  • adjuvants commonly used for formulation such as excipients, binders, disintegrants, and lubricants, can be added.
  • excipients include starch, lactose, sucrose, methylcellulose, carboxymethylcellulose, sodium alginate, calcium hydrogen phosphate, synthetic aluminum silicate, microcrystalline cellulose, polyvinylpyrrolidone (PVP), and hydroxypropyl starch (HPS).
  • Binders include aqueous solutions of starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), gum arabic powder, gelatin, glucose, sucrose, or water / ethanol solutions thereof.
  • Disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, microcrystalline cellulose, hydroxypropyl starch, calcium phosphate and the like.
  • lubricants carnauba wax, light anhydrous silicic acid, synthetic aluminum silicate, natural aluminum silicate, synthetic magnesium silicate, hardened oil, hardened vegetable oil derivative (Sterotex HM), sesame oil, white beeswax, titanium oxide, dry hydroxide
  • lubricants carnauba wax, light anhydrous silicic acid, synthetic aluminum silicate, natural aluminum silicate, synthetic magnesium silicate, hardened oil, hardened vegetable oil derivative (Sterotex HM), sesame oil, white beeswax, titanium oxide, dry hydroxide
  • Aluminum gel stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, and sodium lauryl sulfate for lubricants, carnauba wax, light anhydrous silicic acid, synthetic aluminum silicate, natural aluminum silicate, synthetic magnesium silicate, hardened oil, hardened vegetable oil derivative (Sterotex HM), sesame oil, white beeswax, titanium oxide, dry hydro
  • the pharmaceutical composition of the present invention can take various forms of administration depending on the form of zinc, but can preferably be in the form of oral administration.
  • the pharmaceutical composition of the present invention contains an effective amount of zinc capable of reducing the risk of fractures during adulthood and old age, or reducing the risk of suffering from osteoporosis when a boy born from an administered mother is an adult. More specifically, it can be administered so that the intake amount is 7 to 40 mg per day in terms of zinc. Taking into account the intake of zinc by a method such as a meal, administration can be made so that the intake is 7 to 40 mg per day in terms of zinc. More specifically, it can be administered at an intake of 1 to 40 mg, preferably 4 to 30 mg, more preferably 6 to 30 mg, more preferably more than 10 mg and less than 30 mg per day in terms of zinc.
  • the pharmaceutical composition of the present invention can be administered during a period from the time when pregnancy is possible until pregnancy and breastfeeding. In addition, it is desirable to administer during the above-mentioned period, but administration during pregnancy is considered to be necessary at a minimum.
  • the pharmaceutical composition of the present invention is also referred to as a fracture risk reducing agent, an adult osteoporosis and senile osteoporosis improving agent or preventing agent.
  • the present invention includes a food composition effective for reducing the risk of fracture when a male or male born from the pregnant woman or the mother of a mammal becomes an adult and for improving or preventing adult osteoporosis and senile osteoporosis.
  • the food composition of the present invention may be any zinc composition including zinc-containing compounds and compositions, such as zinc sulfate, zinc chloride, inorganic zinc, zinc gluconate, chelate zinc, and picolinic acid.
  • Zinc etc. are mentioned, and also zinc binding protein, zinc binding peptide etc. are mentioned, and these zinc or a compound or composition containing zinc can be added to food in a required amount.
  • the food composition of the present invention can be prepared by adding a food containing a large amount of zinc, such as cheese, yeast, liver, meat, and natto, as it is or after processing it to other foods or food materials.
  • a food containing a large amount of zinc such as cheese, yeast, liver, meat, and natto
  • Examples of the treatment include treatment that is easy to add to other food ingredients such as drying, pulverization, and cutting.
  • the other foods or food materials may be any foods including processed foods, beverages, edible materials, and drinking materials.
  • the food composition of the present invention contains an effective amount of zinc capable of reducing the risk of fractures during adulthood and old age, or reducing the risk of suffering from osteoporosis when a boy born from an administered mother is an adult. More specifically, zinc is contained so that the intake amount is 7 to 40 mg per day in terms of zinc. In consideration of the amount of zinc intake by a method such as a meal, zinc is contained so as to be 7 to 40 mg per day in terms of zinc. More specifically, it can be contained in an amount of 1 to 40 mg, preferably 4 to 30 mg, more preferably 6 to 30 mg, more preferably more than 10 mg and less than 30 mg per day in terms of zinc.
  • the food composition of the present invention can be ingested during a period from the time when pregnancy is possible until pregnancy and breastfeeding. In addition, it is desirable to take it during the aforementioned period, but it is considered necessary to take it during pregnancy.
  • the amount of zinc ingested by meals can be calculated using, for example, the 5th edition supplemented Japanese food standard ingredient table and the food composition table, or using the 5th edition Japanese food standard component table analysis manual. It is obtained by actually measuring the amount.
  • the food composition of the present invention can be a health food, a food for specified health use, a special use food for pregnant women, or a dietary supplement.
  • the food composition may be solid (powder, granule, etc.), paste, liquid or suspension.
  • sweetener, acidulant, vitamin Other additives that are commonly used in the manufacture of drinks can also be added.
  • special-purpose foods for pregnant women or dietary supplements powders, granules, tablets, capsules It is also possible to use supplements in appropriate dosage forms such as agents and liquids.
  • the food composition of the present invention is also described as a fracture risk reducing agent, an adult osteoporosis and senile osteoporosis improving agent or preventive agent.
  • the present invention can also be used as a food additive for preparing health foods, foods for specified health use, special-purpose foods for pregnant women or dietary supplements containing zinc as an active ingredient.
  • an age-related osteoporosis model SAM (Senescence-Accelerated Mouse) P6 was used. It has been reported that SAMP6 (mouse) is about 16 weeks of age and significantly decreases bone mass compared to the control SAMR1. SAMP6 (mouse) is about 20 weeks old and can sufficiently evaluate osteoporosis in the elderly. Further, in this example, a zinc level of 7 ppm was set as an intermediate zinc deficiency state in the case of rodents with zinc deficiency. In the past, a number of experiments with extremely low zinc levels such as 1 ppm have been reported as zinc-deficient conditions, but if you continue to consume such extremely low zinc levels, your intake will be significantly reduced, Daily fluctuations in food intake increase. In the experiment with intake of extremely low zinc levels, we simply observed (confirmed) the phenomenon (effect) due to a decrease in calorie intake and abnormal eating, and it was completely a test to confirm the effect of pure zinc deficiency. Is inappropriate.
  • SAMP6 female (8 weeks old) containing 7 ppm zinc (medium low zinc level feed, hereinafter also referred to as “low level group”) or 35 ppm feed (appropriate zinc level feed, below) (Also called “appropriate level group”). Two weeks after ingestion of these zinc diets, the female mice were mated with syngeneic male mice to become pregnant.
  • the female mice were fed the same feed as before mating during pregnancy.
  • the female mice (mother mice) were fed a diet with an appropriate zinc level after giving birth, and the pups were fed a diet with an appropriate zinc level after weaning.
  • X-ray CT imaging was performed on Lacita LCT-100A (Aloka) at 4, 8 and 12 weeks of age of the pups, and bone-related parameters were measured.
  • male pups male pups
  • DNA methylation and histone acetylation DNA methylation and histone acetylation.
  • other epigenetic phenomena may occur before or during pregnancy. More specifically, due to the low zinc state of the female (mother) before and during pregnancy, it is unique to male pups (male pups) as epigenetic phenomena such as active vitamin D and bone metabolism Is expected to have an impact.
  • Zinc is taken in unconsciously on a daily basis because there are very few foods that can be consumed in large doses, and the use of cereals, vegetables, beans, etc. that are often consumed in daily diets decreases. That itself is difficult. According to the 2005 National Health and Nutrition Survey, about 90% of pregnant women do not meet the daily intake of zinc, which includes additional amounts. In addition, about 80% of pregnant women in the world are not satisfied with zinc (Caulfield et al. (1998) Am J Clin Nutr 68 (Suppl): 499S-508S).
  • the present invention relates to the field of pharmaceutical manufacturing for reducing or preventing osteoporosis in male male mammals, including humans, as well as food production for reducing or preventing male male fracture risk. It can be used in the field of industry or beverage manufacturing industry or the field of feed manufacturing industry.

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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)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition médicinale, une composition alimentaire ou une composition d'aliments pour animaux qui est efficace pour la réduction du risque de fractures osseuses et/ou la prévention de fractures osseuses chez des mammifères mâles ou femelles humains adultes et gériatriques. Les compositions susmentionnées ont été développées en se basant sur la découverte que, grâce à l'administration d'une quantité efficace de zinc à une femme ou à un mammifère femelle durant les périodes de fertilité, grossesse ou lactation de la femelle, le risque de fractures osseuses chez un homme ou un mammifère mâle né de la femme ou du mammifère femelle peut être significativement réduit lorsque l'homme ou le mammifère mâle atteint l'âge adulte ou plus tard.
PCT/JP2010/053907 2009-03-13 2010-03-09 Composition destinée à réduire le risque de fractures osseuses et/ou à prévenir des fractures osseuses WO2010104079A1 (fr)

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JP2011503829A JP5967936B2 (ja) 2009-03-13 2010-03-09 骨折リスクの低減及び／又は骨折の予防のための組成物

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JP2009-061838 2009-03-13

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3459932B2 (ja) * 1996-07-23 2003-10-27 株式会社ホーネンコーポレーション 抗骨粗鬆症組成物
JPH1180107A (ja) * 1997-09-01 1999-03-26 Japan Tobacco Inc 骨形成促進剤及びアミド化合物
ID28460A (id) * 1998-07-08 2001-05-24 Lipogenics Inc Komposisi dan metoda untuk perlakuan dan pencegahan penyakit tulang dengan menggunakan tocotrienol

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GONZALEZ-REIMERS,E. ET AL.: "Effect of zinc supplementation on ethanol-mediated bone alterations", FOOD CHEM TOXICOL, vol. 43, no. 10, 2005, pages 1497 - 1505 *
KIM,J.T. ET AL.: "Zinc-deficient diet decreases fetal long bone growth through decreased bone matrix formation in mice", J MED FOOD, vol. 12, no. 1, 2009, pages 118 - 123 *
MA,Z. ET AL.: "Alternation in bone components with increasing age of newborn rats: Role of zinc in bone growth", JOURNAL OF BONE AND MINERAL METABOLISM, vol. 18, no. 5, 2000, pages 264 - 270 *
MERIALDI,M. ET AL.: "Randomized controlled trial of prenatal zinc supplementation and fetal bone growth", AM J CLIN NUTR, vol. 79, no. 5, 2004, pages 826 - 830 *
SASAHARA,H. ET AL.: "Effects of maternal caffeine with zinc intake during gestation and lactation on bone development in newborn rats", ARCH ORAL BIOL, vol. 35, no. 6, 1990, pages 425 - 430 *
YAMAGUCHI,M. ET AL.: "Preventive effect of zinc acexamate administration in streptozotocin- diabetic rats: Restoration of bone loss", INT J MOL MED, vol. 12, no. 5, 2003, pages 755 - 761 *

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