WO2003004011A1 - Calcium l-threonate for preventing or treating bone facture - Google Patents
Calcium l-threonate for preventing or treating bone facture Download PDFInfo
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- WO2003004011A1 WO2003004011A1 PCT/CN2002/000468 CN0200468W WO03004011A1 WO 2003004011 A1 WO2003004011 A1 WO 2003004011A1 CN 0200468 W CN0200468 W CN 0200468W WO 03004011 A1 WO03004011 A1 WO 03004011A1
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- Prior art keywords
- calcium
- threonate
- fracture
- bone
- bone fracture
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- ZJXGOFZGZFVRHK-BALCVSAKSA-L calcium;(2r,3s)-2,3,4-trihydroxybutanoate Chemical compound [Ca+2].OC[C@H](O)[C@@H](O)C([O-])=O.OC[C@H](O)[C@@H](O)C([O-])=O ZJXGOFZGZFVRHK-BALCVSAKSA-L 0.000 title claims abstract description 79
- 210000000988 bone and bone Anatomy 0.000 title description 23
- 208000010392 Bone Fractures Diseases 0.000 claims abstract description 57
- 239000000203 mixture Substances 0.000 claims abstract description 11
- -1 calcium L-threonate compound Chemical class 0.000 claims abstract description 4
- 206010049514 Traumatic fracture Diseases 0.000 claims description 12
- 206010034156 Pathological fracture Diseases 0.000 claims description 10
- 208000005250 Spontaneous Fractures Diseases 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000000963 osteoblast Anatomy 0.000 abstract description 35
- 230000035755 proliferation Effects 0.000 abstract description 18
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- 238000000338 in vitro Methods 0.000 abstract description 10
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- 102000012422 Collagen Type I Human genes 0.000 description 8
- 108010022452 Collagen Type I Proteins 0.000 description 8
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 8
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- 206010017076 Fracture Diseases 0.000 description 6
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- 229910021641 deionized water Inorganic materials 0.000 description 6
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- 102000008186 Collagen Human genes 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 239000004227 calcium gluconate Substances 0.000 description 5
- 229960004494 calcium gluconate Drugs 0.000 description 5
- 235000013927 calcium gluconate Nutrition 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010018852 Haematoma Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
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- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
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- 208000038016 acute inflammation Diseases 0.000 description 1
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- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
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- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
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- 235000010216 calcium carbonate Nutrition 0.000 description 1
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- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
-
- 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
Definitions
- the present invention relates to calcium L-threonate compound for preventing or treating bone fracture, in particular relates to calcium L-threonate compound for preventing or treating traumatic fracture or pathological fracture, and a composition comprising the same and use of the same.
- Bone fracture is a disruption of structure continuity of a bone, and it is a common surgical disease. Bone fracture can be classified into traumatic fracture and pathological fracture. Traumatic fracture is caused by external force, and pathological fracture is due to the pathological change of bone itself, such as senile osteoporosis, along with a certain degree of external force on the bone.
- Inflammation phase is an immediate response following bone fracture. At that time, a hematoma occurs at fracture site and the adjacent tissues, and an acute inflammation response occurs immediately, which is manifested by blood vessels dilating, and the effusing of plasma and leukocytes.
- Soft callus phase is a period from the disappearance of swelling and pain to the connection of fibers or cartilage tissue at the fracture site, during which hematoma is organized, osteoclasts remove residual necrotic bone, intramembranous ossification begins to form. Its characteristic is that blood vessels increase greatly, capillary vessels grow into callus, and cells are very abundant.
- Hard callus phase is a period from the adhesion of soft callus at the fracture site to the formation of new bone. This phase corresponds to the period of bone fracture healing in clinic or X-ray representation. It generally takes three to four months, during which callus changes to fibrous bone from f ⁇ brocartilage tissue, membranous bone forms between the fracture sites. Remolding phase is a process when the fracture sites are connected by newly bora bones and gradually adapt to new functions.
- Bone fracture healing is a very unique process of tissue repair program. It is different from the repair of other tissues, since the result of other tissue repair is cicatrization, whereas bone repair is not by cicatrization but by regeneration of bone. Therefore the proliferation of osteoblasts plays a crucial role in bone fracture healing.
- the object of the present invention is to provide a method for preventing or treating bone fracture, which comprises administering an effective amount of calcium L-threonate to a subject suffering from bone fracture.
- the present inventor studied the stimulation effects of calcium L-threonate on proliferation, differentiation of osteoblasts and bone formation, as well as the effects of calcium L-threonate on promoting synthesis of collagen I. The result is astonishing that calcium L-threonate can not only facilitate the proliferation, differentiation and mineralization of osteoblasts, but also can enhance niRNA expression of collagen I in osteoblasts cultured in vitro.
- calcium L-threonate can increase bone density and mechanical property, so as to prevent bone fracture, especially pathological fracture, such as the fracture caused by senile osteoporosis.
- the present invention relates to a method for treating bone fracture, which comprises administering an effective amount of calcium L-threonate to a subject suffering from bone fracture.
- bone fracture includes but is not limited to traumatic fracture and pathological fracture.
- the present invention also includes a method for preventing bone fracture, preferably traumatic fracture and pathological fracture, more preferably traumatic fracture, which comprises administering an effective amount of calcium L- threonate to a subject suffering from bone fracture.
- the present invention also relates to a pharmaceutical composition for preventing or treating bone fracture, comprising an effective amount of calcium L-threonate.
- the present invention further includes the use of calcium L-threonate in the preparation of a pharmaceutical composition for treating or preventing bone fracture.
- the present invention still relates to calcium L-threonate usable for preventing or treating bone fracture.
- the present invention still includes use of calcium L-threonate for preventing or treating bone fracture.
- the calcium L-threonate of the present invention is white powder, scarcely with odor, it is soluble in water but insoluble in alcohol, ether and chloroform and has a formula C 8 H 14 O 10 Ca and a chemical structural formula represented by:
- the compound can be prepared by: a certain amount of L-ascorbic acid (Vc) was added to water and dissolved, then calcium carbonate was slowly added into the mixture with stirring. To the above mixture, hydrogen peroxide was added dropwise at a temperature between 10°C and 60°C and maintained the temperature for 1-4 hours at 40-80°C. After active charcoal being added, the mixture was filtered. The filtrate was concentrated at a temperature between 30°C and 90°C and crystallized at ambient temperature. The crystal was dried at a temperature of 50-100°C.
- the addition of calcium carbonate must be carried out very slowly to avoid that the content rushed out of the container due to the dash of the produced carbon dioxide gas.
- the above process of preparing calcium L-threonate may further comprise the operation of washing the cake obtained by filtering the mixture that had been treated with active charcoal, twice with hot water of 80°C and the operation of concentrating the combined washes and filtrate.
- the calcium L-threonate of the present invention may be administered orally.
- the calcium L-threonate of the present invention may be used in various forms of formulations, such as tablets, capsules and other forms of pharmaceutically acceptable compositions.
- the pharmaceutical composition according to the present invention contains a certain amount of calcium L-threonate as an active ingredient, along with a pharmaceutically acceptable carrier, which can be various carriers that have been widely used in medicaments in the prior art such as excipients.
- the pharmaceutical composition of the present invention can be prepared by the methods known in the art, such as mixing, pelleting and tabletting.
- the pharmaceutical composition of the present invention may also contain other optional ingredients that can be used in pharmacology, such as perfumes, colorants and sweetening agents, etc..
- the preferred pharmaceutical composition of the present invention contains 60%, preferably 80%, more preferably 90% by weight of calcium L-threonate with other excipients and optional components as make-ups.
- the dosage of calcium L-threonate may vary depending on the age of patients. As guidance, the dosage of calcium L-threonate for an adult is typically between 0.5 g and 12 g per day, preferably between 3 g and 7 g per day. For children, the dosage may be decreased according to their weights
- the present test studied the effect of calcium L-threonate on stimulation of bone formation function of osteoblast by using the method of culturing osteoblasts in vitro.
- the calvaria of newborn SD rat were excised, and osteoblasts were isolated and seeded at a cell concentration of lxlOVml in the culture medium containing 10wt% of NCS-MEM.
- the second generation of secondary cells were tested for pharmacodynamics.
- the calvaria were predigested by 0.25% trypsin for 10-15 minutes firstly, then oscillated and digested by 0.1% collagenase II at 37 ° C for 60 minutes. The cells were collected by centrifugation at 1000 rpm.
- Cell culture The isolated cells were inoculated into culture flask at a concentration of lxlO 4 /cm 2 , wherein the culture solution is 10%o of NCS-MEM.
- the cells were cultured in an incubator with 5% C0 2 at 37 ° C , then passaged until half confluence.
- the second generation of secondary cells (OB 2 ) were tested for pharmacodynamics.
- OB 2 were inoculated into 24 well COSTOR culture plate at a density of 6x10 3 per well. 24 hours later, the above culture solution was replaced by culture solution containing varying concentrations of medicines ranging from 10 "9 to 10 "3 mol/L. 72 hours after adding medicines, the cells were tested through Labsystems Multiskan MS (Finland) )ELISA analyzer by MTT method. OD value at 570 nm was used to reflect cell proliferation. The result was compared with that of control group.
- OB 2 was inoculated into 24 well COSTOR culture plate at a density of 2x10 4 per well. 24 hours later, the above culture solution was replaced by medium containing medicines. Then the culture solution was changed every 48 hours until confluence of cells was reached. ALP activity of cell lysates was measured by para-nitrobenzene phosphate method. Content of protein in cell lysates was measured by Coomassie brilliant blue method. ALP acitivity was represented by U/mg of protein and the result was compared with that of control group.
- Tables 1-3 list the results of the test that medicines have influences on cell proliferation.
- n 4, in comparison with control group: * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 in comparison with calcium L-threonate group of the same concentration: & P ⁇ 0.05, # P ⁇ 0.01
- n 4, in comparison with control group: *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001 in comparison with calcium L-threonate group of the same concentration: & P ⁇ 0.05, # P ⁇ 0.01
- n 4, in comparison with control group: *P ⁇ 0.05, **P ⁇ 0.01 in comparison with calcium L-threonate group of the same concentration:
- ALP activity of OB 2 in calcium L-threonate group was higher than that of control group, among which the increase in test I and test II was significant (P ⁇ 0.05).
- the ALP activity of OB 2 in calcium L-threonate group was increased, however the increase was not significant.
- n 4, in comparison with control group: *P ⁇ 0.05; in comparison with calcium L-threonate group: & P ⁇ 0.05.
- Table 5 the number of mineralization nodules formed by osteoblasts within two weeks in calcium L-threonate group was the largest, and the increase was significant (PO.05).
- Osteoblasts are bone-forming cells. During bone remolding process, osteoblasts proliferated and differentiated, synthesized and secreted collagen or non-collagen protein which were related with bone formation, thus producing osteoid and promoting mineralization of osteoid.
- the newly formed bones repaired bone lacuna that was caused by resorbing of osteoclasts. Decline of osteoblast function causes the amount of newly formed bone to decrease, and its ability of repairing bone lacuna attenuates. As a result, bone trabecula becomes thin, weak and perforated, and cortical bone shows porous change.
- proliferation rate, ALP activity and mineralization nodules were often used as indexes. These indexes represented the ability of proliferation, differentiation and mineralization of osteoblast respectively. Therefore, these indexes could comprehensively evaluate the stimulation of medicines on the bone formation function of osteoblasts.
- RNA was extracted with TRIzol reagent (Gibco Co.) method. Two bands at 18s and 28s were visualized in formaldehyde denaturing agarose gel electrophoresis. The concentration and purity of the RNA were measured by ultraviolet spectrophotometer (the value of A260/A280 falls between 1.7 and 2.0).
- RT-PCR Reverse transcriptase polymerase chain reaction
- Each test medicine was formulated at the concentration of 0.1 mol/L, and sterilized by high pressure for later use.
- Calcium L-threonate provided by Beijing Juneng Asia Pacific Research Center of Life Science, 1.55 g was dissolved in 50 ml deionized water by heating. Calcium gluconate, Shanghai Huanghai Pharmaceutical Factory, 2.24 g was dissolved in 50 ml deionized water.
- osteoblasts synthesized a large amount of procollagen I in cytoplasm, which was secreted into matrix, which constituted the main component of bone-collagen, thereby promoting the healing of bone fracture.
- the content of bone mass was also an important factor that determined bone strength.
- the determination of degradation fragments of collagen I was usually used as one of the indexes to reflect bone-forming function. Therefore it showed that calcium L- threonate was very important in preventing or treating bone fracture.
- Quantitative RT-PCR method used in the present study to detect the level of ⁇ -COLI mRNA could reflect the gene expression in OB more accurately than detection of ⁇ - COLI protein molecule.
- calcium L-threonate could not only promote proliferation, differentiation and mineralization functions of osteoblast, but also could promote the expression of mRNA procollagen I in osteoblasts cultured in vitro. By these functions, calcium L-threonate could facilitate bone fracture healing, and could increase bone density and mechanical performance as well, so as to prevent bone fracture, especially pathological fracture (such as caused by senile osteoporosis).
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003510022A JP2005519856A (en) | 2001-07-03 | 2002-07-02 | Calcium L-threonate for preventing or treating fractures |
EP02748548A EP1443918B1 (en) | 2001-07-03 | 2002-07-02 | Calcium l-threonate for treating bone facture |
DE02748548T DE02748548T1 (en) | 2001-07-03 | 2002-07-02 | CALCIUM-L-THREONATE FOR PREVENTING OR TREATING BONE FRACTURES |
KR1020037016574A KR100737278B1 (en) | 2001-07-03 | 2002-07-02 | Method for treating bone fracture, comprising step of administering calcium l-threonate compound and calcium l-threonate compound for treating bone fracture |
DE60223707T DE60223707T2 (en) | 2001-07-03 | 2002-07-02 | CALCIUM-L-THREONATE FOR THE TREATMENT OF BONE FRACTURES |
CA002471232A CA2471232A1 (en) | 2001-07-03 | 2002-07-02 | Calcium l-threonate for preventing or treating bone fracture |
HK04106351A HK1063603A1 (en) | 2001-07-03 | 2004-08-25 | Calcium l-threonate for treating bone facture |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN01119870.2 | 2001-07-03 | ||
CNB011198702A CN1196480C (en) | 2001-07-03 | 2001-07-03 | Application of calcium L-threonate for curing fracture |
Publications (1)
Publication Number | Publication Date |
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WO2003004011A1 true WO2003004011A1 (en) | 2003-01-16 |
Family
ID=4663771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2002/000468 WO2003004011A1 (en) | 2001-07-03 | 2002-07-02 | Calcium l-threonate for preventing or treating bone facture |
Country Status (9)
Country | Link |
---|---|
US (1) | US6727288B2 (en) |
EP (1) | EP1443918B1 (en) |
JP (1) | JP2005519856A (en) |
KR (1) | KR100737278B1 (en) |
CN (1) | CN1196480C (en) |
CA (1) | CA2471232A1 (en) |
DE (2) | DE02748548T1 (en) |
HK (1) | HK1063603A1 (en) |
WO (1) | WO2003004011A1 (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1197561C (en) * | 2001-07-03 | 2005-04-20 | 北京巨能亚太生命科学研究中心 | Application of calcium L-threonate in treating cartilage related diseases |
CN100367952C (en) * | 2003-09-30 | 2008-02-13 | 戴向国 | Calcium L-Threonate and soy bean isoflavone containing combination |
US20050244499A1 (en) * | 2004-05-03 | 2005-11-03 | Robert Diaz | Method and device for reducing susceptibility to fractures in long bones |
US20050244451A1 (en) * | 2004-05-03 | 2005-11-03 | Robert Diaz | Method and device for reducing susceptibility to fractures in vertebral bodies |
EP1782805A4 (en) * | 2004-08-05 | 2007-08-08 | Godo Shusei Kk | Composition for accelerating calcium absorption |
US20060089642A1 (en) * | 2004-10-27 | 2006-04-27 | Diaz Robert L | Prefracture spinal implant for osteoporotic unfractured bone |
US20060223730A1 (en) * | 2005-04-04 | 2006-10-05 | Hl Distribution Company | Calcium supplements |
US8163301B2 (en) * | 2007-03-22 | 2012-04-24 | Magceutics, Inc. | Magnesium compositions and uses thereof for metabolic disorders |
US8377473B2 (en) * | 2009-07-01 | 2013-02-19 | Magceutics, Inc. | Slow release magnesium composition and uses thereof |
RU2548776C2 (en) * | 2013-01-11 | 2015-04-20 | Общество С Ограниченной Ответственностью "Парафарм" | Method and medication for acceleration of bone fracture consolidation |
AU2015254267B2 (en) * | 2014-05-01 | 2018-03-08 | Shimadzu Corporation | Method for assessing state of differentiation of cells |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1240647A (en) * | 1998-07-08 | 2000-01-12 | 北京巨能亚太生命科学研究中心 | Use of calcium L-threonate in prevention and inhibition of osteoporosis and rickets |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07126181A (en) * | 1993-11-05 | 1995-05-16 | Hoechst Japan Ltd | Preventive and therapeutic agent for fracture |
US5656598A (en) * | 1994-03-08 | 1997-08-12 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Use of fibroblast growth factors to stimulate bone growth |
WO1996025165A1 (en) * | 1995-02-17 | 1996-08-22 | Merck & Co., Inc. | Method of lessening the risk of non-vertebral bone fractures |
CN1039571C (en) * | 1996-06-13 | 1998-08-26 | 北京巨能经贸发展有限责任公司 | Calcium L-threonate for food additives and preparing process and use thereof |
CN1053653C (en) * | 1997-08-29 | 2000-06-21 | 北京巨能亚太生命科学研究中心 | Neo-L-threonic acid derivatives |
CN1215592A (en) * | 1997-10-28 | 1999-05-05 | 马斐文 | Oral calcium L-threonate liquid |
CN1074762C (en) * | 1998-08-18 | 2001-11-14 | 北京巨能亚太生命科学研究中心 | Process for preparing chromium L-threonate, its preparing process and application |
CN1133379C (en) * | 2001-02-20 | 2004-01-07 | 北京巨能亚太生命科学研究中心 | Isotonic sports beverage and its preparing process |
-
2001
- 2001-07-03 CN CNB011198702A patent/CN1196480C/en not_active Expired - Fee Related
- 2001-12-31 US US10/039,194 patent/US6727288B2/en not_active Expired - Lifetime
-
2002
- 2002-07-02 WO PCT/CN2002/000468 patent/WO2003004011A1/en active IP Right Grant
- 2002-07-02 JP JP2003510022A patent/JP2005519856A/en active Pending
- 2002-07-02 EP EP02748548A patent/EP1443918B1/en not_active Expired - Lifetime
- 2002-07-02 DE DE02748548T patent/DE02748548T1/en active Pending
- 2002-07-02 KR KR1020037016574A patent/KR100737278B1/en not_active IP Right Cessation
- 2002-07-02 CA CA002471232A patent/CA2471232A1/en not_active Abandoned
- 2002-07-02 DE DE60223707T patent/DE60223707T2/en not_active Expired - Fee Related
-
2004
- 2004-08-25 HK HK04106351A patent/HK1063603A1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1240647A (en) * | 1998-07-08 | 2000-01-12 | 北京巨能亚太生命科学研究中心 | Use of calcium L-threonate in prevention and inhibition of osteoporosis and rickets |
Non-Patent Citations (3)
Title |
---|
DATABASE EMBASE [online] RECKER R.R. ET AL.: "Prevention of osteoporosis: Calcium nutrition", XP002904903, Database accession no. 93099921 * |
DRUG & PHARMACOLOGY, OSTEOPOROSIS-INT., vol. 3, no. SUPPL. 1, 1993, pages 163 - 165 * |
See also references of EP1443918A4 * |
Also Published As
Publication number | Publication date |
---|---|
KR20040011541A (en) | 2004-02-05 |
JP2005519856A (en) | 2005-07-07 |
HK1063603A1 (en) | 2005-01-07 |
CN1196480C (en) | 2005-04-13 |
US6727288B2 (en) | 2004-04-27 |
DE60223707T2 (en) | 2008-10-30 |
KR100737278B1 (en) | 2007-07-09 |
CA2471232A1 (en) | 2003-01-16 |
DE60223707D1 (en) | 2008-01-03 |
EP1443918B1 (en) | 2007-11-21 |
EP1443918A4 (en) | 2004-11-24 |
US20020169210A1 (en) | 2002-11-14 |
EP1443918A1 (en) | 2004-08-11 |
CN1328820A (en) | 2002-01-02 |
DE02748548T1 (en) | 2004-11-11 |
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