WO2005041945A1 - 還元型補酵素q含有組成物 - Google Patents
還元型補酵素q含有組成物 Download PDFInfo
- Publication number
- WO2005041945A1 WO2005041945A1 PCT/JP2004/016079 JP2004016079W WO2005041945A1 WO 2005041945 A1 WO2005041945 A1 WO 2005041945A1 JP 2004016079 W JP2004016079 W JP 2004016079W WO 2005041945 A1 WO2005041945 A1 WO 2005041945A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- reduced
- cyclodextrin
- composition
- enzyme
- reduced coenzyme
- Prior art date
Links
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Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention provides a reduced-type capture enzyme Q-containing composition having excellent solubility or dispersibility in water and excellent storage stability without using a commonly used natural or synthetic emulsifier, ribosome, or the like. It relates to the provision of foods, functional foods, drugs or quasi-drugs.
- Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals, and is known as a component of the electron transport system of mitochondria in cells in the living organism. It is known that, by repeatedly oxidizing and reducing in mitochondria, capture enzyme Q not only functions as a transfer component in the electron transport system, but also has reduced antioxidant activity. Yes. In humans, a coenzyme in which the side chain of capture enzyme Q has ten repeating structures. Is the main component, and is usually 40 to 90 ° / in vivo. Degree exists as reduced form. The physiological effects of coenzyme Q include activation of energy production by mitochondrial activation, activation of cardiac function, stabilization of cell membrane, and protection of cells by antioxidation.
- Coenzyme Q is known for use in various applications, for example, oxidized capture enzyme. Is effective for hearts and hearts It is used as a congestive heart failure drug. It is also used as a nutritional supplement and nutritional supplement orally in the form of supplements and drinks as well as vitamins.
- Reduced coenzyme Q is strong by itself! / Since it has an antioxidant effect, it is possible to effectively increase the antioxidant activity in blood by solubilizing and sending a sufficient amount of reduced reductase Q into blood.
- Increasing antioxidant activity in the blood can be used to prevent vascular injury during ischemia reperfusion, prevent restenosis of arteriosclerosis, prevent vascular injury after cerebral infarction, prevent arterial effects, prevent diabetic complications, etc. It has broad utility for many diseases where exacerbations are suggested by reactive oxygen species.
- Oxidized and reduced forms of capture enzyme Q are known. Numerous studies have been conducted on the solubilization method (also called ubidecarenone or ubiquinone). Oxidized coenzyme. As a method for solubilizing liposomes, various methods such as coating with ribosomes, suspension with surfactants or fats and oils, and the like have been reported (for example, JP-A-5-186340, JP-A-7-69874, and 510841).
- Oxidized coenzyme Ql There is to show the antioxidant activity needs to be converted into reduced To ⁇ element Q 10, such as by reductase. Orally ingested oxidized coenzyme Q 10, Keru Contact in vivo NADPH-CoQ reductase, lipoamide dehydrogenase, by Chioredokishin reductase or the like, the converted antioxidant activity to the enzyme Q 10 catching reduction It is presumed to be effective. However, with aging, reduced and oxidized coenzymes by in vivo reductases and the like. There is also concern that the ability to reduce the reduced enzymatic enzyme Qw to Qw may be of concern for elderly or oxidized enzymatic enzymes. For those who have reduced reducing ability, reduced-type capture enzyme is used from outside the body. Administration is significant. '
- Reduced capture enzyme Ql Since the per se have antioxidant activity, autoxidation when is the force properties usefulness is greatly promising material exposed to air for diseases as described above administration of reduced coenzyme Q 10 It is a very unstable substance that advances, and its solubility in water is extremely poor, so it has not been available for industrial use.
- Reduced coenzyme Has been prepared for the study of oxidoreductases as a preparation using a ribosome coating (Kishi et al., 1999, BioFactors, 10, 13). 11-138) The ribosomes used were prepared at the time of use for each experiment, and no solubilization method capable of stably maintaining reduced coenzyme Q was known.
- An object of the present invention is to provide a water-soluble or dispersible water-reducing enzyme, which is poorly soluble or dispersible in water and contains an extremely unstable compound.
- An object of the present invention is to provide a composition that can be stored for a long time.
- the present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, despite the fact that reduced-type capture enzyme Q is extremely unstable physically and almost insoluble in water, reduced-type coenzyme Q And cyclodextrin, the storage stability has been dramatically improved, and at the same time, it has been found that a composition having excellent dispersibility in water can be obtained, and the present invention has been completed.
- the present invention relates to a cyclodextrin, a polar solvent and a compound represented by the general formula (1):
- n an integer from 1 to 12
- the present invention relates to a method for solubilizing reduced-type capture enzyme Q, which comprises mixing cyclodextrin, a polar solvent, and reduced-type coenzyme Q represented by the above formula (1).
- the present invention provides a cyclodextrin, a polar solvent, and a reduced capture enzyme Q, which are characterized by mixing cyclodextrin, a polar solvent, and a reduced coenzyme Q represented by the above (1).
- the present invention relates to a method for producing a composition, comprising reduced coenzyme Q solubilized in the composition.
- the present invention also relates to a method for stabilizing reduced coenzyme Q, comprising mixing cyclodextrin, a polar solvent, and reduced coenzyme Q represented by the above formula (1).
- the present invention also relates to a method for preventing oxidation of reduced capture enzyme Q, comprising mixing cyclodextrin, a polar solvent, and reduced coenzyme Q represented by the formula (1). .
- solubilization means that coenzyme Q is dissolved in the composition and that all or part of the capture enzyme Q is included in cyclodextrin.
- the composition may include coenzyme Q that is not dissolved but dispersed in the composition.
- dispersion means that the capture enzyme Q in the composition does not float or precipitate in the test described below.
- inclusion refers to a state in which molecules constituting the composition are associated with each other so that the composition containing the capture enzyme Q is dissolved in water.
- Whether or not reduced enzyme Q is solubilized in the above composition can be determined by the following test.
- the composition lg was suspended in 500 ml of water and, after 24 hours at 20 ° C., was visually observed. When it was confirmed that the composition was uniformly dispersed, it was determined that the composition was solubilized.
- Whether or not reduced enzyme Q is included in cyclodextrin can be determined by the following test.
- the composition lg was suspended in 500 ml of water, and after 24 hours at 20 ° C., when visually confirmed, it was included when it was confirmed that the composition was uniformly dispersed and a transparent solution state could be confirmed.
- Coenzyme Q has the following formula (1); 4 016079
- n represents an integer of 1 to 12, wherein formula (1) represents reduced coenzyme Q, and formula (2) represents oxidized capture enzyme Q.
- Reduced capture enzyme Q may be crystalline or non-crystalline.
- the composition of the present invention may contain an oxidized capture enzyme Q. When both oxidized enzyme Q and reduced coenzyme Q are contained, reduced coenzyme Q is 50% by weight based on the total amount of coenzyme Q (total amount of oxidized coenzyme Q and reduced coenzyme Q).
- the content is preferably at least 75% by weight, more preferably at least 75% by weight.
- the method for obtaining the reduced form of the enzyme Q is not particularly limited.
- a method of enriching the reduced coenzyme Q category can be employed. in this case If necessary, a common reducing agent such as sodium borohydride, sodium sodium dithionite, or sodium iodosulfite) is added to the above-mentioned coenzyme Q, and the above-mentioned enzymatic capture enzyme is produced by a conventional method.
- a common reducing agent such as sodium borohydride, sodium sodium dithionite, or sodium iodosulfite
- the oxidized enzymatic enzyme Q contained in Q may be reduced to the reduced enzymatic enzyme Q before concentration by chromatography. Further, it can also be obtained by a method in which the above-mentioned reducing agent is allowed to act on existing high-purity coenzyme Q.
- the reduced-type capture enzyme Q used in the present invention has an ability to use one having a side chain repeating unit (n in the formula) of 1 to 12. Among them, those having 10 side-chain repeating units, that is, reduced capture enzymes. Can be particularly preferably used.
- the cyclodextrin is not particularly limited, but, for example, a-cyclodextrin, -cyclodextrin, y-cyclodextrin and the like can be used.
- a-cyclodextrin, -cyclodextrin, y-cyclodextrin and the like can be used.
- one selected from ⁇ -cyclodextrin and ⁇ -cyclodextrin is used. Still more preferably, it is ⁇ -cyclodextrin.
- the ratio of cyclodextrin to be contained is 0.1 to 100 monoreca, preferably 0.2 to 20 monoreca S, per mol of the reduced capture enzyme Q, and more preferably 0.2 to 20 monoreca S.
- the polar solvent refers to water or alcohols.
- the polar solvent contained is not particularly limited, but examples of the polar solvent include water and alcohols such as ethanol. These may be used alone or as a mixture. Among them, a mixed solution of water and ethanol is preferably used, and water is more preferable.
- the ratio of reduced coenzyme Q to the polar solvent is in the range of 0.001 to 500% by weight based on the solvent. .
- the solubilized composition of reduced capture enzyme Q according to the present invention can contain an antioxidant.
- an antioxidant any compound having an antioxidant activity may be used. Examples thereof include citrate, citrate derivatives, vitamin C (ascorbic acid), vitamin C derivatives, vitamin E, vitamin E derivatives, and glutathione. , Reduced daltathione, sodium thiosulfate, L-cysteine, L-calcin, lycopene, riboflavin, curcuminide, superoxide dismutase (SOD), PQQ (pyro-mouth quinoline quinone) Alternatively, a mixture of two or more types is preferable. Furthermore, citric acid, a citrate derivative, vitamin C (ascorbic acid), a vitamin C derivative, a vitamin E, a vitamin E derivative, T JP2004 / 016079
- the contained antioxidant is preferably from 0.01 mol to 1000 mol, more preferably from 0.1 mol to 100 mol, per mol of reduced coenzyme Q.
- solubilization method examples include a method in which reduced capture enzyme Q and cyclodextrin are contacted or mixed in a suitable polar solvent. By contacting or mixing, it can be obtained as an inclusion compound. When contacting or mixing, it is preferable to vigorously stir the raw materials from the viewpoint of shortening the time required to obtain the clathrate compound. This is to ensure sufficient contact between the reduced-type capture enzyme Q and cyclodextrin.
- An example of the conditions of strong stirring here is a treatment at room temperature (about 20 ° C.) with a homomixer (Polytro PT2100) at 20000 rpm for 10 minutes.
- the same polar solvent as the above-mentioned composition for example, water, ethanol And the like, and these may be used as a mixture.
- a mixture of water and ethanol is preferred, and water is more preferred.
- the reduced capture enzyme Q may be used as it is, or may be used as dissolved in a non-polar solvent or fat or oil.
- non-polar solvent for example, hexane, ether, fat and oil
- oils and fats oily oil, perilla oil, rapeseed oil, rice bran oil, soybean oil, fish oil and the like are preferable because they can be used for food. These may be used as a mixture.
- the cyclodextrin may be used as dissolved in a polar solvent, or may be used as it is.
- the order of mixing reduced coenzyme Q, cyclodextrin, and the polar solvent is not particularly limited, but the cyclodextrin is dissolved in the polar solvent, and then the reduced capture enzyme Q is added to the lysate, and contacted. It is more preferable to dissolve the cyclodextrin in a polar solvent whose mixing order is preferred, and at the same time, add and contact and mix the reduced-type capture enzyme Q. By these procedures, the reduced-type capture enzyme Q is included by the cyclodextrin, and an inclusion compound is generated. Thereby, a solubilized composition of reduced capture enzyme Q that is soluble in water or uniformly dispersed in water is obtained.
- the order of mixing reduced coenzyme Q with cyclodextrin, polar solvent, and antioxidant is not particularly limited.
- reduced coenzyme Q may be added, contacted and mixed, or cyclodextrin may be added to the polar solvent.
- the reduced coenzyme Q may be eaten and mixed, and then an antioxidant may be added.
- the antioxidant may be used as it is, or may be used as dissolved in the polar solvent.
- composition comprising cyclodextrin, a polar solvent, and reduced enzymatic Q, characterized by mixing cyclodextrin, a polar solvent, and reduced enzymatic Q represented by the above (1).
- a method for producing a composition in which reduced enzyme Q is solubilized in the composition will be described.
- the conditions such as the ratio of reduced coenzyme Q to oxidized enzyme Q, the raw materials used, the order of charging the raw materials, and the ratio of reduced coenzyme Q to cyclodextrin are determined by the above-mentioned solubilization method. Is the same as
- the composition according to the present invention can be obtained as a powdery composition by subjecting it to spray drying, freeze drying and the like. It is more preferable to obtain a powdery composition which is practically easy to handle and has a low power of industrial use. As a result, the composition is excellent in solubility or dispersibility in water and can be suitably obtained as a composition that can be stored at room temperature or refrigerated for a long period of time.
- the composition to be prepared may further contain other pharmaceutically acceptable pharmaceutical ingredients.
- the formulation material that can be contained include a colorant, an emulsifier, a tonicity agent, a buffer, a solubilizing agent, a preservative, a flavoring agent, a stabilizer, and an excipient.
- other active ingredients such as a drug, a nutritional supplement and the like may be contained according to the intended use.
- These preparation materials are appropriately adjusted by a conventional method.
- the composition according to the present invention can be subjected to granulation such as extrusion granulation and fluidized bed granulation.
- the present composition may contain various components considered to be useful for maintaining the health of animals such as humans, pets, livestock, etc., such as pharmaceutical components, functional food components, supplement components, and the like. These components can be appropriately added by a conventional method.
- the dosage form of the composition obtained by the present invention is not particularly limited and can be appropriately selected depending on the intended use.Since it is excellent in solubility or dispersibility in water, it should be used for oral administration. Is preferred.
- composition containing reduced enzyme Q according to the present invention can be used as foods, functional foods, pharmaceuticals or quasi-drugs for humans or animals.
- Functionality here Food means foods such as health foods, dietary supplements, supplements, and nutritional foods that are consumed for the purpose of maintaining health or supplementing nutrition in place of food. Specific forms include, but are not limited to, drinks, tuples, tablets, capsules, tablets, injections, infusions, eye drops, feeds, and the like.
- the solubilized composition obtained by the solubilization method of the present invention can stably maintain reduced coenzyme Q against oxidation.
- the term ⁇ can be stably maintained '' as used herein means that the solubilized composition is stored at room temperature (about 20 ° C) in a light-tight atmosphere for 4 weeks at room temperature (approximately 20 ° C). In this case, the evaluation was made based on the fact that the residual ratio of reduced capture enzyme Q was 80 ° / 0 or more of the concentration at the start of storage. ⁇
- the present invention relates to a method for preventing oxidation of reduced coenzyme Q, comprising mixing cyclodextrin, a polar solvent, and reduced capture enzyme Q represented by the formula (1).
- the method when reduced coenzyme Q is stored at room temperature (about 20 ° C) in an air atmosphere for 4 weeks under light shielding, the residual ratio of reduced coenzyme Q is 80% or more of the amount at the start of storage. Then, it was determined that reduced coenzyme Q was prevented from being oxidized.
- the conditions such as the ratio of reduced enzyme Q to oxidized enzyme Q, the raw materials used, and the ratio of reduced coenzyme Q to cyclodextrin are the same as in the above composition.
- FIG. 5 is a graph showing stability against autoxidation at 23 ° C.
- the vertical axis represents the total coenzyme C ⁇ contained in the composition (test sample).
- Reduced enzyme in. And the horizontal axis represents the number of storage days. Four weeks after the start of storage, the reduced enzyme was used.
- the reduced coenzyme Q ratio is reduced to 41% in the bulk powder, the reduced composition Q ratio is 80% or more in each of the powdery compositions I to IV.
- FIG. 4 is a graph showing the stability of acetonitrile against autoxidation at 40 ° C.
- FIG. Reduced coenzyme in the total coenzyme Q 10 and the vertical axis contained in the composition (test sample). , And the horizontal axis represents the number of storage days. 4 weeks after the start of storage, reduced enzyme was used. Although the reduced coenzyme Q ratio was reduced to 11 ° / 0 for the bulk powder, the reduced coenzyme Q ratio was 65 ° / 0 or more for powdered compositions I to IV in all cases. .
- BEST MODE FOR CARRYING OUT THE INVENTION The effects of the present invention are clarified by the following examples. The present invention is not limited to these examples.
- Spray drying was carried out using an Okawara Plant L-12 spray drying apparatus at an inlet temperature of 170 ° C, an outlet temperature of 80 ° C, and a spray rate of 100 mlZmin.
- Example 13-: L6, Comparative Example 3 A coenzyme containing 98% of reduced capture enzyme Q1Q .
- Bulk powder (Q-OH bulk powder) and Example :! The solubility test of each of the powdery compositions obtained in to 4 was performed as follows. That is, each reddish product (test sample) lg was weighed in 100 ml of water, stirred with a mixer at 5000 rpm for 30 seconds, and then allowed to stand. The state of the aqueous solution one hour after standing was observed, and the solubility in water was confirmed. Table 2 shows the results. Table 2
- the reduced enzymatic enzyme Q which is highly useful as an antioxidant or a nutritional supplement, can be supplied as a composition that is soluble in water and has excellent storage stability.
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Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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DK04793187.8T DK1681053T3 (en) | 2003-10-31 | 2004-10-22 | COMPOSITION CONTAINING REDUCED COENZYM Q AS CLATHRAT |
CN200480031013XA CN1870982B (zh) | 2003-10-31 | 2004-10-22 | 含还原型辅酶q的组合物 |
US10/577,211 US20070243180A1 (en) | 2003-10-31 | 2004-10-22 | Composition Containing Reduced Coenzyme Q |
EP04793187.8A EP1681053B1 (en) | 2003-10-31 | 2004-10-22 | Composition containing clathrated reduced coenzyme Q |
JP2005515160A JP4732898B2 (ja) | 2003-10-31 | 2004-10-22 | 還元型補酵素q含有組成物 |
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JP2003371793 | 2003-10-31 | ||
JP2003-371793 | 2003-10-31 |
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US (1) | US20070243180A1 (ja) |
EP (1) | EP1681053B1 (ja) |
JP (1) | JP4732898B2 (ja) |
KR (1) | KR20060100402A (ja) |
CN (1) | CN1870982B (ja) |
DK (1) | DK1681053T3 (ja) |
WO (1) | WO2005041945A1 (ja) |
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-
2004
- 2004-10-22 DK DK04793187.8T patent/DK1681053T3/en active
- 2004-10-22 CN CN200480031013XA patent/CN1870982B/zh active Active
- 2004-10-22 JP JP2005515160A patent/JP4732898B2/ja active Active
- 2004-10-22 KR KR1020067008249A patent/KR20060100402A/ko not_active Application Discontinuation
- 2004-10-22 WO PCT/JP2004/016079 patent/WO2005041945A1/ja active Application Filing
- 2004-10-22 EP EP04793187.8A patent/EP1681053B1/en active Active
- 2004-10-22 US US10/577,211 patent/US20070243180A1/en not_active Abandoned
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JP2016520037A (ja) * | 2013-04-25 | 2016-07-11 | ジャージャン メディスン カンパニー リミテッド シンチョン ファーマシューティカル ファクトリー | 還元型コエンザイムq10粉末、その組成物及び製造方法 |
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US11911350B2 (en) | 2018-02-28 | 2024-02-27 | Petroeuroasia Co., Ltd. | Reduced coenzyme Q10-containing composition and method for producing same |
Also Published As
Publication number | Publication date |
---|---|
EP1681053B1 (en) | 2014-10-08 |
DK1681053T3 (en) | 2014-11-17 |
EP1681053A1 (en) | 2006-07-19 |
US20070243180A1 (en) | 2007-10-18 |
CN1870982A (zh) | 2006-11-29 |
CN1870982B (zh) | 2010-05-26 |
JP4732898B2 (ja) | 2011-07-27 |
EP1681053A4 (en) | 2010-09-15 |
JPWO2005041945A1 (ja) | 2007-04-26 |
KR20060100402A (ko) | 2006-09-20 |
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