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    公开号:AU2005324603A1
    申请号:U2005324603
    申请日:2005-12-22
    公开日:2006-07-20
    发明作者:Shiro Kitamura；Tadao Ono；Takahiro Ueda；Yasuyoshi Ueda
    申请人:Kaneka Corp；
    IPC主号:A61K31-122
    专利说明:
    VERIFICATION OF TRANSLATION I, Fumio Akiyama of MT-2 BLDG. .5-36, Miyahara 3-chome. Yodogawa-ku, Osaka-shiOSAKA 532-0003 JAPAN, hereby declare that I am conversant with the Japanese and English languages and that I am the translator of the documents attached and certify that to the best of my knowledge and belief the following is a true and correct English translation of the PCT patent application No. PCT/JP2005/023623 in the name of KANEKA CORPORATION Dated this 3/ f day of / 2007 Fumio Akiyama 1 DESCRIPTION SOLID PREPARATION COMPRISING REDUCED COENZYME Qio AND PROCESS FOR PRODUCTION OF THE SPME 5 TECHNICAL FIELD This invention relates to a solid preparation containing reduced coenzyme Qio, a method for producing the same, a method for stabilizing a solid preparation containing reduced coenzyme 10 Qio, and a method of handling the same. BACKGROUND ART Reduced coenzyme Qlo shows higher oral absorbability as compared with oxidized coenzyme Qjo and is a favorable compound 15 suited for use in foods, functional nutritive foods, specific health foods, nutritional supplements, nutrients, animal drugs, drinks, feeds, cosmetics, medicines, remedies, preventive drugs, etc. Several methods have been disclosed in the prior art 20 literature for preparing reduced coenzyme Qio (Wo03/006408, WO03/006409, W003/006410, W003/006411, W003/006412, W003/008363 and W003/032967) . However, reduced coenzyme Qio is readily oxidized to oxidized coenzyme Qio by molecular oxygen, and it is still an important problem to stabilize reduced 25 coenzyme Qio in processing the same in foods, functional nutritive foods, specific health foods, nutritional supplements, nutrients, animal drugs, drinks, feeds, cosmetics, medicines, remedies, preventive drugs, etc., or raw materials or compositions for the production thereof, and/or to stabilize 30 the same in handling such products, raw materials or compositions after irLcorporation of the same. On the occasion of such handling, it is very difficult to completely eliminate or shut out oxygen and, in particular in the step of warming for processing or during long-period 35 preservation of such products, the remaining or contaminant 2 oxygen exerts a great adverse influence and is directly concerned with such quality problems as the formation of oxidized coenzyme Qio as a byproduct. Thus, it is averyinportantproblem to stabilize (protect 5 against oxidation) reduced coenzyme Q-o. To this time, however, few studies have been made on the method and composition for stabilizing coenzyme Qio. There are only two examples; one describes a composition comprising a coexisting reducing agent and a method for producing the same (WO01/052822) and, in the 10 other, reduced coenzyme Qio is stabilized in an oil or fat (WO03/062182) In WO01/052822, there are disclosed 1) a composition comprising an amount, effective in preventing reduced coenzyme Qio from being oxidized to oxidized coenzyme Qio, of a reducing 15 agent and an amount, effective in dissolving the reduced coenzyme Q-o and reducing agent, of a surfactant or a vegetable oil or a mixture of these, if necessary together with a solvent, 2) a composition for oral administration in the form of gelatin capsule or tablets as prepared from the above composition and, 20 further, 3) a method for preparing the above composition containing reduced coenzyme Qio in situ by using oxidized coenzyme Qio and a reducing agent. In Wo01/052822, however, there is no detailed description of the quality of the reduced coenzyme Qio contained in the 25 above-mentioned compositions or the stabilizing effect, for example. The above-mentioned compositions and the method for preparing the same are very complicated and troublesome so that the compositions may play a plurality of roles (namely the role as a reaction field for the reduction of oxidized coenzyme Qi.o 30 to reduced coenzyme Qio and the role in maintaining reduced coenzyme Q1o in a stable condition) . Further, it is known that when an ascorbic acid (reducing agent) is enclosed in gelatin capsules, the disintegrability of the gelatin capsules generally deteriorates, whereby the absorbability in the living 35 body is adversely affected.
    3 Furthermore, it is noteworthy that the safety of the above compositions and/or the method for preparing the same cannot be always be assured since the reaction mixture is used as such. More specifically, the use of an ascorbic acid as a reducing 5 agent in reducing oxidized coenzyme Qio to reduced coenzyme Qio results in the oxidation of the ascorbic acid, leading to the formation of a considerable amount of the corresponding dehydroascorbic acid, which contaminates the above-mentioned compositions. Unlike ascorbic acids, dehydroascorbic acids 10 and the decomposition product oxalic acid are highly harmful. For example, they reportedly cause increases in lipid peroxide level and decreases in arLtioxidant level in the liver and kidney and increases in oxalic acid level in the kidney, and there is a fear of their producing some adverse effects, for example the 15 effects of decreasing the resistance to oxidative stress and readily causing ureterolithiasis. In W003/062182, on the other hand, a method for stabilizing reduced coenzyme Qi which is characterized in that reduced coenzyme Qio is incorporated in a composition whose main 20 component is a fat or oil (except for olive oil) and/or a polyol and which will not substantially interfere with the stabilization of reduced coenzyme Qio is disclosed as a method for protecting reduced coenzyme Qio against oxidation. However, the above stabilization method may not enough to increase the 25 stability of reduced coenzyme Qio to a satisfactory extent in some instances. Like in the case of WO01/052822, the above method uses a fat or oil and/or a surfactant and, therefore, the range of application thereof is limited. 30 SUMMARY OF THE INVENTION In view of the above-mentioned state of the art, it is an object of the present invention to provide a solid preparation containing highly stabilized reduced coenzyme Qio and a method for producing the same as well as a method for 35 stabilizing such a solid preparation containing reduced 4 coenzyme Qio and a method for handling the same to be used or practiced in the fields of foods, functional nutritive foods, specific health foods, nutritional supplements, nutrients, animal drugs, drinks, feeds, cosmetics, medicines, remedies, 5 preventive drugs, etc. The present inventors made intensive investigations in an attempt to accomplish the above object and, as a result, found that a solid preparation containing reduced coenzyme Qio coated with at least one coating medium selected from among oil-soluble 10 coating media and water-soluble coating media can be protected in a surprisingly favorable manner against the oxidation, by molecular oxygen, of reduced coenzyme Qio in the solid preparation. Based on such finding, they have now completed the present invention. 15 Thus, the invention provides the following: (1) A solid preparation containing reduced coenzyme Qio which comprises a solid composition containing reduced coenzyme QIo coated with at least one coating medium selected from among oil-soluble coating media and water-soluble coating 20 media. (2) The solid preparation according to (1), wherein the solid composition containing reduced coenzyme Qio is coated with a water-soluble coating medium and then further with an oil-soluble coating medium. 25 (3) The solid preparation according to (1), wherein the coating medium is that accepted for use in foods. (4) The solid preparation according to (1), wherein the coating medium used is a water-soluble 30 coating medium. (5) The solid preparation according to (1), wherein the oil-soluble coating medium used is at least one species selected from among shellac and zein. (6) The solid preparation according to (1), 35 wherein the water-soluble coating medium used is at least 5 one species selected from the group consisting of gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast cell wall fractions. (7) The solid preparation according to (1), 5 wherein the total coating weight of the coating medium or media is not less than 5% by weight but not more than 99.9% by weight relative to the weight of the solid preparation. (8) The solid preparation according to (1), which shows a percent retention of reduced coenzyme Qio 10 of not lower than 50% by weight after 30 days of preservation in the air at 40*C in a condition protected from light. (9) A method for producing a solid preparation containing reduced coenzyme Qio, wherein a solid composition containing reduced coenzyme 15 Qio is coated with at least one coating medium selected from among oil-soluble coating media and water-soluble coating media. (10) The production method according to (9), wherein the solid composition containing reduced 20 coenzyme Qio is coated with a water-soluble coating medium and then further with an oil-soluble coating medium. (11) The production method according to (9), wherein the coating medium is that accepted for use in foods. 25 (12) The production method according to (9), wherein the coating medium used is a water-soluble coating medium. (13) The production method according to (9), wherein the oil-soluble coating medium used is at least 30 one species selected from among shellac and zein. (14) The production method according to (9), wherein the water-soluble coating medium used is at least one species selected from the group consisting of gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast 35 cell wall fractions.
    6 (15) The production method according to (9), wherein the coating is carried out at a temperature of not lower than 0 0 C but not higher than 120 0 C. (16) A method for stabilizing a solid preparation 5 containing reduced coenzyme Qio, wherein a solid composition containing reduced coenzyme Q1o is coated with at least one coating medium selected from among oil-soluble coating media and water-soluble coating media to thereby stabilize the resulting solid preparation containing 10 reduced coenzyme Qio. (17) The stabilization method according to (16), wherein the solid composition containing reduced coenzyme Qio is coated with a water-soluble coating medium and then further with an oil-soluble coating medium. 15 (18) The stabilization method according to (16), wherein the coating medium is that accepted for use in foods. (19) The stabilization method according to (16), wherein the coating medium used is a water-soluble 20 coating medium. (20) The stabilization method according to (16), wherein the oil-soluble coating medium used is at least one species selected from among shellac and zein. (21) The stabilization method according to (16), 25 wherein the water-soluble coating medium used is at least one species selected from the group consisting of gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast cell wall fractions. (22) The stabilization method according to (16), 30 wherein the percent retention of reduced coenzyme Qio is not lower than 50% by weight after 30 days of preservation in the air at 40'C in a condition protected from light. (23) A method for handling a solid preparation containing reduced coenzyme Qio, 35 wherein the solid preparation containing reduced 7 coenzyme Qio according to (1) is placed in an environment adjusted to a relative humidity of not higher than 75%. (24) The handling method according to (23), wherein the percent retention of reduced coenzyme Qio is 5 not lower than 80% by weight after 30 days of preservation in the air at 40'C in a condition protected from light. DETAILED DESCRIPTION OF THE INVENTION In the following, the present invention is described in 10 detail. The term "coenzyme Qio" used herein means both of reduced one and oxidized one, and, in the case where there are both of them, the above term means the mixture as a whole. First, the solid preparation of the invention and the 15 method for producing the same are described. The solid preparation of the invention which contains reduced coenzyme Qio comprises a solid composition containing reduced coenzyme Qio as coated with at least one coating medium selected from among oil-soluble coating media and water-soluble 20 coating media. The method of the invention for producing solid preparations containing reduced coenzyme Qio is characterized in that a solid composition containing reduced coenzyme Qio is coated with at least one coating medium selected from among 25 oil-soluble coating media and water-soluble coating media. Reduced coenzyme Qio, which is contained in the solid preparation of the invention is represented by the formula (1) OH 30 H 3
    H
    3 C
    CH
    2
    CHC(CH
    3 )CH2). H OH 35 ( 1) 8 (in which n = 10). The solid preparation of the invention which contains 5 reduced coenzyme Qio may contain reduced coenzyme Qio alone or may further contain oxidized coenzyme Qio. When the solid preparation contains both reduced coenzyme Qio and oxidized coenzyme Qio, the proportion of reduced coenzyme Qio relative to the whole amount of coenzyme Qo (namely the sum 10 of reduced coenzyme Q1o and oxidized coenzyme Qio) is not particularly restricted but, from the viewpoint of performing the function of reduced coenzyme Qio markedly, it is, for example not lower than about 20% by weight, generally not lower than about 40% by weight, preferably not lower than about 60% by 15 weight, more preferably not lower than about 80% by weight, still more preferably nct lower than about 90% by weight, most preferably not lower than about 96% by weight. The upper limit is, but is not limited to, 100% by weight and generally is not higher than about 99.9% by weight. 20 The weights of reduced coenzyme Qio and oxidized coenzyme Qio can be measured, for example, by the method described in the below-mentioned Examples. As is described in Japanese Kokai Publication Hei-10-109933, reduced coenzyme Q 1 can be produced, for example, 25 by preparing a mixture of oxidized coenzyme Qio and reduced coenzyme Q7o by such a known method as synthesis, fermentation or extraction from a natural product and subjecting the mixture to chromatography for the concentration of the reduced coenzyme Qio fraction in the eluate. On that occasion, the oxidized 30 coenzyme Qio contained together with the reduced coenzyme Qio may be reduced with an ordinary reducing agent such as sodium borohydride or sodium dithionite, followed by concentration by chromatography. Reduced coenzyme Qio can also be obtained by reacting an existing high purity grade of coenzyme Qio with such 35 a reducing agent as mentioned above. Preferably, reduced 9 coenzyme Qio is obtained by reducing oxidized coenzyme Qio such as an existing high purity grade of coenzyme Qio, or a mixture of oxidized coenzyme Qio and reduced coenzyme Qio with an ordinary reducing agent such as sodium dithionite, sodium borohydride 5 or ascorbic acids. More preferably, reduced coenzyme Qio is obtained by reducing oxidized coenzyme QiO such as an existing high purity grade of coenzyme Qio, or a mixture of oxidized coenzyme Qio and reduced coenzyme Qjo with ascorbic acids. In the practice of the invention, the solid composition 10 prior to coating with at least one coating medium selected from among oil-soluble coating media and water-soluble coating media is not particularly restricted provided that it contains reduced coenzyme Q-0. As disclosed herein, it is also possible to prepare the 15 solid composition using reduced coenzyme QIo alone. In that case, reduced coenzyme Qio as such in the form of a powder or granules may be used as the solid composition for coating with a coating medium. It is also possible to make the solid composition into 20 dosage forms suited for oral administration, for example powders, fine granules, granules, pills, tablets, hard capsules and soft capsules, according to the known methods for producing pharmaceutical preparations (e.g. the methods described in the Japanese Pharmacopoeia, 14th edition, General rules for 25 preparations) using one or more additives accepted for use in foods, cosmetics and drugs. Chewable tablets may be mentioned as a preferred tablet form. The solid composition may also be prepared by admixing the above-mentioned additive(s) with a reduced coenzyme 30 Qio-containing granular powder prepared by any of the generally employed methods of granulation (e.g. wet granulation methods such as spray granula-ion method, tumbling granulation method, extrusion granulation method and fluidized bed granulation method using a solution or dispersion containing water and/or 35 an organic solvent; dry granulation methods such as fluidized 10 bed granulation and tumbling granulation method using a powder binder) and compression molding the resulting mixture. The additives mentioned above are not particularly restricted but include those accepted for use in foods, 5 cosmetics and drugs. Those accepted for use in foods are particularly preferred. The additives include excipients, disintegrating agents, lubricants, binders, coloring agents, agglomeration inhibitors, absorption promoters, dissolution aids, stabilizers, oils and fats, surfactants, and the like. 10 It is of course possible to incorporate one or more active components other than reduced coenzyme Qio in the solid composition. These additives may be used singly or two or more of them may be used in combination. The excipients are not particularly restricted but 15 include, for example, sucrose (purified sucrose, white soft sugar), lactose, glucose, starch, cornstarch, mannitol, crystalline cellulose, calcium phosphate, calcium sulfate and the like. The disintegrating agents are not particularly 20 restricted but include, for example, starch, agar, calcium citrate, calcium carbonate, sodium hydrogen carbonate, dextrin, crystalline cellulose, carboxymethylcellulose, tragacanth, alginic acid and the like. The lubricants are not particularly restricted but 25 include, for example, talc, magnesium stearate, polyethylene glycol, silica, hydrogenated oils and the like. The binders are not particularly restricted but include, for example, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, 30 tragacanth, shellac, gelatin, pullulan, gum arabic, polyvinylpyrrolidone, polyvinylalcohol, polyacrylic acid, polymethacrylic acid, sorbitol and the like. The coloring agents are not particularly restricted but include, for example, titanium oxide, food colors, bengal 35 colors, safflower colors, caramel colors, gardenia colors, tar 11 colors, chlorophyll and the like. The agglomeration inhibitors are not particularly restricted but include, for example, stearic acid, talc, light anhydrous silicic acid, hydrous silicon dioxide and the like. 5 The absorption promoters are not particularly restricted but include, for example, higher alcohols, higher fatty acids and the like. The dissolution aids are not particularly restricted but include, for example, organic acids such as fumaric acid, 10 succinic acid, malic acid and the like. The stabilizers are not particularly restricted but include, for example, benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, beeswax and the like. The oils and fats are not particularly restricted but may 15 be, for example, natural oils and fats derived from animals or plants, synthetic oils and fats, or modified oils and fats. More preferred are those accepted for use in foods, cosmetics or drugs. As the vegetable oils and fats, there may be mentioned., for example, coconut oil, palm oil, palm kernel oil, linseed 20 oil, camellia oil, brown rice germ oil, rapeseed oil, rice oil, peanut oil, corn oil, wheat germ oil, soybean oil, perillan oil, cotton seed oil, sunflower seed oil, kapok oil, evening primrose oil, shea butter, sal fat, cacao butter, sesame oil, safflower oil, olive oil and the like. As the animal-derived oils and 25 fats, there may be mentioned, for example, lard, milk fat, fish oils, beef tallow and the like. Moreover, there may also be mentioned modified oils and fats obtainable by the fractionation, hydrogenation, transesterificaiton, etc. of these natural oils and fats (e.g. hydrogenated oils). It is 30 of course possible to use medium chain fatty acid triglycerides (MCTs) . Mixtures of these may also be used. As the medium chain fatty acid triglycerides, there may be mentioned, for example, triglycerides whose fatty acid-derived moieties each contain 6 to 12 carbon atoms, 35 preferably 8 to 12 carbon atoms.
    12 Among the oils and fats enumerated above, vegetable oils and fats, synthetic oils and fats, and modified oils and fats, for example, are preferred from the easy handing and odor viewpoint. As examples, there may be mentioned coconut oil, 5 palm oil, palm kernel oil, rapeseed oil, rice oil, soybean oil, cotton seed oil, safflower oil, olive oil, MCTs and the like. As the surfactants, there may be mentioned, for example, fatty acid partial glycerides, propylene glycol fatty acid esters, phospholipids, sucrose fatty acid esters, sorbitan 10 fatty acid esters, polyoxyethylenesorbitan fatty acid esters, polyglycerol fatty acid esters and the like. As the fatty acid partial glycerides, there may be mentioned, for example, monoglycerides and diglycerides derived from fatty acids each containing 6 to 18 carbon atoms, 15 preferably 6 to 12 carbon atoms. As the propylene glycol fatty acid esters, there may be mentioned, for example, monoesters and diesters derived from fatty acids each containing 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms. 20 As the phospholipids, there may be mentioned, for example, egg yolk lecithin, purified soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, dicetyl phosphate, stearylamine, phosphatidylglycerol, phosphatidic acid, 25 phosphatidylinositolamine, cardiolipin, ceramide phosphorylethanolamine, ceramide phosphorylglycerol, and mixtures of these, and the like. As the sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylenesorbitan fatty acid esters and 30 polyglycerol fatty acid esters, there may be mentioned, for example, ones derived from fatty acids each containing 6 or more carbon atoms, preferably 8 or more carbon atoms. The other active components are not particularly restricted provided that they are accepted for use in foods, 35 cosmetics or drugs. Thus, there may be mentioned, amino acids, 13 vitamins, minerals, polyphenols, organic acids, sugars, peptides, proteins and the like. Among these, the ones having an antioxidant activity, for example, glutathione, L-cysteine, N-acetylcysteine, reduced a-lipoic acid, tocotrienol, vitamin 5 E (a-tocopherol) and ester derivatives thereof, vitamin C (ascorbic acid) and ester derivatives and salts thereof, erythorbic acid and ester derivatives and salts thereof, vitamin A and ester derivatives thereof, carotenoids, rutin, zeaxanthin, astaxanthin, lycopene, flavonoids, L-carnitine 10 and pharmacologically acceptable salts thereof (e.g. tartrate, fumarate), acetyl-L-carnitine, propionyl-L-carnitine, magnesium, zinc, selenium, manganese, riboflavin, niacinamide, curcuminoids, proanthocyanidine extracted from the grape seed or pine tree bark, NADH (reduced nicotinamide adenine 15 dinucleotide), NADPH (reduced nicotinamide adenine dinucleotide phosphate), resveratrol, a bilberry extract, a milk thistle extract, highly unsaturated fatty acids obtained by concentration of fish oils or the like, and the like are particularly preferred. 20 Preferred are glutathione, L-cysteine, tocotrienol, vitamin E (a-tocopherol) and ester derivatives thereof, vitamin C (ascorbic acid) and ester derivatives and salts thereof, erythorbic acid and ester derivatives and salts thereof, vitamin A and ester derivatives thereof, carotenoids, rutin, 25 astaxanthin, lycopene, flavonoids, L-carnitine and the like. Preferred among these from the viewpoint of stabilization of reduced coenzyme Qio are carotenoids, astaxanthin, vitamin E and ester derivatives thereof, vitamin C and ester derivatives and salts thereof, and like antioxidants. It is of course 30 possible to use two or more of the active components mentioned above in admixture. In accordance with the invention, the above-mentioned solid composition is coated using at least one coating medium selected from among oil-soluble coating media and water-soluble 35 coating media so that reduced coenzyme Qio occurring in the solid 14 composition may be inhibited from being oxidized into oxidized coenzyme Q1o by molecular oxygen. The coating is preferably other than an enteric coating, considering that the coating should be dissolved in the stomach 5 or the like and coenzyme Q should be absorbed rapidly. As the enteric coating so referred to herein, there may be mentioned compositions containing hypromellose phthalate, diethyl phthalate, polyethylene glycol or a like pharmacologically acceptable enteric coating component. 10 The oil-soluble coating media in the present invention are not particularly restricted provided that they are soluble in organic solvents other than water, for example the below-mentioned alcohols, ketones, halogenated hydrocarbons, hydrocarbons and the like. The oil-soluble coating media are 15 the ones having solubility (the weight of a solute (% by weight) relative to the weight of a saturated solution) in organic solvents of usually not less than 0.1% by weight, preferably not less than 0.5% by weight, more preferably not less than 1% by weight. 20 As the oil-soluble coating media, there may be mentioned, for example, higher fatty acid sugar esters, shellac, cellulose derivatives, fatty acids and ester derivatives thereof, and oils and fats, zein and the like. From the viewpoint of stabilization of reduced coenzyme Qio, shellac, cellulose 25 derivatives and zein are preferred, and shellac and zein are more preferred. As the higher fatty acid sugar esters, there may be mentioned, for example, sucrose palmitate and the like, which have solubility in organic solvents of within the 30 above-mentioned ranges. As the cellulose derivatives, there may be mentioned, for example, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and sodium salts (sodium 35 carboxymethylcellose, etc.) and calcium salts (calcium 15 carboxymethylcellose, etc,.) thereof, and the like, which have solubility in organic solvents of within the above-mentioned ranges. As the fatty acids and ester derivatives thereof, there 5 may be mentioned, for example, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid, and esters thereof (for example, methylesters, ethylesters thereof), and the like. As the oils and fats, there may be mentioned, for example, 10 the above-mentioned oils and fats. From the viewpoint of maintaining the quality of the solid preparation, preferred are the oils and fats which are in solid state at ordinary temperature. The water-soluble coating media in the present invention 15 are not particularly restricted provided that they are soluble in water. The water-soluble coating media are the ones having solubility (the weight of a solute (% by weight) relative to the weight of a saturated solution) in water of usually not less than 0.1% by weight, preferably not less than 0.5% by weight, 20 more preferably not less than 1% by weight. As the water-soluble coating media, there may be mentioned, for example, gelatin, sugars, gum arabic, higher fatty acid sugar esters, tragacanth, pectin, pullulan, alginic acid, dried egg white, milk, curdlan, cellulose derivatives, 25 casein, casein compounds, starch, yeast cell wall fractions and the like. From the viewpoint of stabilization of reduced coenzyme Qio, gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast cell wall fractions are preferred, gelatin, sugars, cellulose derivatives and yeast cell wall 30 fractions are more preferred, gelatin, cellulose derivatives and yeast cell wall fractions are still more preferred, and yeast cell wall fractions are particularly preferred. As the sugars, there may be mentioned monosaccharides and disaccharides such as sucrose (purified sucrose, white soft 35 sugar), fructose, glucose, lactose and trehalose, sugar 16 alcohols such as erythritol, mannitol, sorbitol, xylitol, maltitol, powdered reduced maltose syrup and reduced lactose, polysaccharides such as dextrin and maltodextrin, and the like. As the higher fatty acid sugar esters, there may be 5 mentioned, for example, sucrose palmitate and the like, which have solubility in water of within the above-mentioned ranges. As the cellulose derivatives, there may be mentioned, for example, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, 10 carboxymethylcellulose, and sodium salts (sodium carboxymethylcellose, etc.) and calcium salts (calcium carboxymethylcellose, etc.) thereof, and the like, which have solubility in water of within the above-mentioned ranges. The solubility of the higher fatty acid sugar esters and 15 the cellulose derivatives can be adjusted according to the species of esters, degree of polymerization and the like. Among the coating media mentioned above, oil-soluble coating media and water-soluble coating media accepted for use in foods are preferred. The term "coating media accepted for 20 use in foods" as used herein means arbitrary nontoxic coating media currently in use in the food industry. Such coating media are not particularly restricted but include gelatin, sugars, gum arabic, pullulan, alginic acid, cellulose derivatives, yeast cell wall fractions, shellac, zein and the like. 25 Among the coating media mentioned above, water-soluble coating media are preferred from the in vivo disintegration and absorption viewpoint. Of course, these coating media may be used singly or in the form of a mixture of two or more of them. Two or more 30 coatings can also be made separately. For increasing the moisture resistance and water resistance of the solid composition, there may be mentioned, for example, the process comprising coating the solid composition first with an oil-soluble coating medium and then 35 further with a water-soluble coating medium. More 17 specifically, the solid composition is preferably coated with shellac or ethylcellulose, for example, and then further coated with a sugar, gelatin, a yeast cell wall fraction, a cellulose derivative or the like. More preferably, the solid composition 5 is coated with shellac and then further coated with a sugar. For increasing the moisture resistance and water resistance of the solid composition coated with a water-soluble coating medium, there may be mentioned, for example, the process comprising coating the solid composition first with a 10 water-soluble coating medium and then further with an oil-soluble coating medium. More specifically, the solid composition is preferably coated with gelatin, a yeast cell wall fraction or a cellulose derivative, for example, and then further coated with shellac, zein or the like. More preferably, 15 the solid composition is coated with a yeast cell wall fraction and then further coated with shellac. While the solid composition containing reduced coenzyme Qio can be coated with at least one coating medium selected from among such oil-soluble coating media and water-soluble coating 20 media as mentioned above, it is of course possible to coat reduced coenzyme Qio alone directly or coat a solid composition prepared by any of the methods known in the art, as mentioned above, to give a solid preparation containing reduced coenzyme Qio. 25 On the occasion of coating the above-mentioned solid composition with such a coating medium or media as mentioned above, an auxiliary agent: may be used, where necessary, for the purpose of forming suitable coatings, and the like. The auxiliary agent is not particularly restricted 30 provided that it is accepted for use in foods, cosmetics or drugs. One accepted for use in foods, for example a surfactant, plasticizer or coloring agent, is preferred, however. The above-mentioned surfactants are not particularly restricted but include, for example, glycerol fatty acid esters, 35 sucrose fatty acid esters, polysorbates and the like.
    18 The above-mentioned plasticizers are not particularly restricted but include, for example, polyethylene glycol, glycerol, triethyl citrate, propylene glycol, vegetable oils and fats, fish oils, animal oils and fats and the like. 5 The above-mentioned coloring agents are not particularly restricted but include, for example, titanium oxide, food colors, bengal colors, safflower colors, caramel colors, gardenia colors, tar colors, chlorophyll and the like. In particular, titanium oxide and caramel are preferred. 10 The process of coating with such a coating medium as mentioned above can be carried out in a per se known manner, for example in the manner of pan coating, dry coating, oscillating coating, fluidized bed coating or the like. The coating medium may also contain water and/or an 15 organic solvent which can dissolve the coating medium. The above-mentioned organic solvents are not particularly restricted in kind but include, for example, alcohols such as methanol, ethanol and 2-propanol; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons 20 such as chloroform and methylene chloride; hydrocarbons such as hexane, heptane and toluene; and the like. Alcohols are particularly preferred, however. Mixtures composed of two or more organic solvents, mixtures of water and an alcohol(s), mixtures of water and a ketone (s), and the like can of course 25 be suitably used as well. Further, the temperature at which the above coating process is carried out is not particularly restricted but, from the viewpoint of stabilization of reduced coenzyme Qio and cost, the coating can be carried out generally at a temperature not 30 higher than about 120 0 C, preferablynothigher than about 100'C, more preferably not higher than about 80'C, still more preferably not higher than about 60'C, most preferably not higher than about 40*C. In this case, the lower temperature limit is generally not lower than about 0 0 C, preferably not 35 lower than about 10'C, more preferably not lower than about 15'C, 19 still more preferably not lower than about 200C, most preferably not lower than about 250C. The solid preparation containing reduced coenzyme Qio, of the invention, as obtained in the above manner, in particular 5 when it occurs as a powder, fine granules or granules, for example, may be suitably used without any further processing or may be modified, by compression molding, into tablets, pills or the like or, further, may be used for filling hard or soft capsules or like shells, made of gelatin or the like, therewith. 10 For maximizing the effects of the invention and from the viewpoint of stability of reduced coenzyme Qio, the whole or a part of the production process is preferably carried out in a deoxidized atmosphere. For example, the whole production process is preferably carried out in a deoxidized atmosphere 15 such as nitrogen gas, argon gas, helium gas or carbon dioxide. The production method of the invention can be carried out at ordinary pressure, under increased pressure or under reduced pressure. The weight proportion (%) of the at least one coatingmedia 20 selected from among oil-soluble coating media and water-soluble coating media relative to the weight (100% by weight) of the solid preparation containing reduced coenzyme Qic in the solid preparation obtained in the above manner is not particularly restricted but, from the cost viewpoint and the viewpoint of 25 performing the function of the formed coatings, the upper limit value is generally not higher than about 99.9% by weight, preferably not higher than about 90% by weight, still more preferably not higher than about 80% by weight, still further preferably not higher than about 70% by weight. The lower limit 30 value is generally not lower than about 5% by weight, preferably not lower than about 10% by weight, more preferably not lower than about 15% by weight, still more preferably not lower than about 20% by weight, most preferably not lower than about 25% by weight. The above-mentioned weight of the coating media is 35 that determined after formulation.
    20 The content of reduced coenzyme Qio in the solid preparation is not particularly restricted but, from the effectiveness, and the like, of reduced coenzyme Qio and easiness of formulation viewpoint, it is preferably 0.1 to 95% 5 by weight, more preferably 1 to 90% by weight. The solid preparation of the invention, when preserved in the air at 40 0 C in a condition shielded from light for 30 days, shows a reduced coenzyme Q-o retention percentage (percentage of the weight of reduced coenzyme Qio after 10 preservation to the initial weight of reduced coenzyme Qio) of not lower than about 50% by weight, preferably not lower than about 60% by weight, still more preferably not lower than about 70% by weight, still further preferably not lower than about 80% by weight, most preferably not lower than about 90% by 15 weight. From the viewpoint of stabilization of reduced coenzyme Qio, the upper limit to the temperature at which the solid preparation of the invention is to be preserved is generally not higher than about 10OC 0 C, preferably not higher than about 20 80'C, still more preferably not higher than about 60'C, still further preferably not higher than about 40'C, most preferably not higher than about 20C. The lower limit to that temperature is generally not lower than about -100'C, preferably not lower than about -80 0 C, still more preferably not lower than about 25 -60*C, still further preferably not lower than about -40 0 C, most preferably not lower than about -20'C. The humidity of the atmosphere in which the preparation is to be preserved is not particularly restricted but, from the viewpoint of stabilization of reduced coenzyme Qio, it is 30 generally not higher than about 90%, preferably not higher than about 80%, more preferably not higher than about 75%, still more preferably not higher than about 60%, still further preferably not higher than about 40%, and the lower limit thereof is not lower than 0%, as expressed in terms of relative humidity. 35 Now, the method for stabilizing and the method for 21 handling a solid preparation containing reduced coenzyme Qio according to the invention are described. The method for stabilizing a solid preparation containing reduced coenzyme Qio according to the invention is characterized 5 in that a solid composition containing reduced coenzyme Qio is coated with at least one coating medium selected from among oil-soluble coating media and water-soluble coating media to thereby stabilize the resulting solid preparation containing reduced coenzyme Qio. 10 The method for handling a solid preparation containing reduced coenzyme Qio according to the invention is characterized in that the solid preparation containing reduced coenzyme Qio is placed in an environment adjusted to a relative humidity of not higher than 75%. 15 The stabilization, so referred to herein, indicates the inhibition of the oxidation of reduced coenzyme Q O to oxidized coenzyme Qio. The handling, so referred to herein, is the exertion of an external action on something to cause the same to maintain 20 or perform some or other function thereof. Examples of the handling are not particularly restricted but may include discharging from the coating machine, packaging, packing, preservation, storage, transfer and the like. A preferred handling consists in preservation. 25 From the viewpoint of stability of reduced coenzyme Qio, the upper limit to the temperature at which the solid preparation containing reduced coenzyme Qio, of the invention, is to be preserved or handled in according to the method for stabilizing and the method for handling that preparation is 30 generally not higher than about 100*C, preferably not higher than about 80'C, still more preferably not higher than about 60'C, still further preferably not higher than about 40'C, most preferably not higher than about 20'C. In this case, the lower limit to that temperature is generally not lower than about 35 -100'C, preferably not. lower than about -80'C, still more 22 preferably not lower than about -60'C, still further preferably not lower than about -40C, most preferably not lower than about -20"C. The solid preparation of the invention, when preserved 5 in the air at 40'C in a condition shielded from light for 30 days, shows a reduced coenzyme Qio retention percentage of not lower than about 50% by weight, preferably not lower than about 60% by weight, still more preferably not lower than about 70% by weight, still further preferably not lower than about 80% 10 by weight, most preferably not lower than about 90% by weight. In practicing the method for stabilizing and the method for handling the solid preparation containing reduced coenzyme Qio according to the invention, the humidity in the preserving atmosphere is important and, by controlling that humidity, it 15 becomes possible to markedly improve the stability of the solid preparation containing reduced coenzyme QIo. The upper limit to the relative humidity is generally not higher than about 90%, preferably not higher than about 80%, more preferably not higher than about 75%, still more preferably not higher than about 60%, 20 still further preferably not higher than about 40%, and, in such a controlled environment, the solid preparation containing reduced coenzyme Qio can be handled in a more stable condition. The lower limit to the relative humidity is not lower than 0%. In a preferred mode of embodiment in which the humidity 25 in the preserving atmosphere is controlled in the above manner, the reduced coenzyme Qi) retention percentage after 30 days of preservation in the air at 40 0 C in a condition shielded from light is not lower than about 80% by weight, preferably not lower than about 85% by weight, more preferably not lower than about 30 90% by weight, still more preferably not lower than about 95% by weight, most preferably not lower than about 97% by weight. Such an environment with a controlled relative humidity can be given, for example, by dehumidification from the environment; introduction of a dehumidified gas (preferably a 35 dry inert gas, though air may also be employed) into the 23 environment; and the like. The method of dehumidification is not particularly restricted but the dehumidification may be accomplished by the freezing of moisture or the use of a dehumidifier or a desiccant (e.g. silica gel, calcium chloride, 5 synthetic zeolite), and the like. It goes without saying that if an environment having a controlled relative humidity is given, the method for creating the same does not matter in any way. For maximizing the effects of the invention and from the viewpoint of the stability of reduced enzyme Qio, the 10 preservation and/or handling of the solid preparation is preferably carried out irL a deoxidized atmosphere, as a matter of course. Thus, for example, the present invention is preferably practiced in a deoxidized atmosphere such as an inert gas, for example nitrogen gas, argon gas, helium gas, carbon 15 dioxide or the like. The solid preparation containing reduced coenzyme Qio as obtained according to the invention can be handled, for example packaged and packed, using a glass bottle, a plastic bottle, a plastic bag, an aluminum-laminated bag or the like. As the 20 materials to be used in the above-mentioned handling, for example packaging or packing, there may be mentioned glass, high-density polyethylene, medium-density polyethylene, low-density polyethylene, polyethylene terephthalate, polyvinyl alcohol, polypropylene, polyvinyl chloride, 25 polyvinylidene chloride and like materials. Metal (e.g. aluminum) film-basedmaterials manufactured by lamination with any of the above-mentioned grades of polyethylene or polyethylene terephthalate, for example, can also be suitably used. When a material relatively inferior in gas barrier 30 performance and moistureproofing performance, for example polyethylene, is used, it is desirable that at least double packaging or packing be done using an outer bag made of a material excellent in gas barrier performance and moistureproofing performance, for example an aluminum-laminate film. 35 It is also possible to carry out PTP packaging, three 24 side-sealed packaging, four side-sealed packaging, pillow packaging, strip packaging, aluminum shaped packaging, stick packaging or the like using the materials mentioned above. After packaging/packing, the packages/packs obtained can be 5 enclosed, if necessary, in a steel drum, resin drum, fiber drum, corrugated fiberboard box or like container for transportation and/or storage. It is of course possible to enclose a desiccant such as silica gel, calcium chloride or a synthetic zeolite in such a container. 10 (EFFECT OF THE INVENTION) In accordance with the present invention, reduced coenzyme Q-o which is unstable in the air can be maintained very stably. 15 BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the weight proportions (%) of reduced coenzyme Q1o after 15 clays and 30 days of preservation of the coated tablets produced in Example 1 in the following adjusted environments: shielded from light, in the air, 40'C, relative 20 humidity 10%, 40%, 6C% and 75%. Fig. 2 shows the weight proportions (%) of reduced coenzyme Qio after 15 days and 30 days of preservation of the coated tablets produced in Example 2 in the following adjusted environments: shielded from light, in the air, 40 0 C, relative 25 humidity 10%, 40%, 60% and 75%. BEST MODE FOR CARRYING OUT THE INVENTION The following examples illustrate the invention in further detail. They are, however, by no means limitative of 30 the scope of the invention. The purity of reduced coenzyme Qio and the weight proportion (%) of reduced coenzyme Qio were determined by the following HPLC analysis (weight proportion (%) = reduced coenzyme Qio/ (oxidized coenzyme Qio + reduced coenzyme Qio) x 35 100).
    25 (HPLC analysis conditions) Column: SYMMETRY C18 (product of Waters Corporation) , 250 mm (length), 4.6 mm (inside diameter); mobile phase: C 2
    H
    5
    OH/CH
    3 0H = 4/3 (v/v); detection wavelength: 210 nm; flow rate: 1.0 5 ml/min; retention time of reduced coenzyme Qio: 9.1 min; retention time of oxidized coenzyme QIo: 13.3 min. (Synthesis Example 1) Crystals of oxidized coenzyme Qio (100 g) and 60 g of 10 L-ascorbic acid were added to 1000 g of ethanol, and the reduction reaction was carried out with stirring at 78 0 C. After the lapse of 30 hours, the mixture was cooled to 50'C and, while maintaining that temperature, 400 g of ethanol and 100 g of water were added. The resulting ethanol solution was cooled to 2 0 C 15 at a rate of 10 0 C/hour with stirring. The precipitate was washed in sequence with cold ethanol and cold water, and the wet crystals obtained were dried under reduced pressure to give 95 g of dry white crystals (yield after isolation: 95 mole %). All the procedural steps except for vacuum drying were carried 20 out in a nitrogen atmosphere. The purity of the crystals obtained was 99.1%, and the weight proportion (%) of reduced coenzyme Qio was 99.0%. (Synthesis Example 2) 25 The reduced coenzyme Qio crystals obtained in Synthesis Example 1, crystalline cellulose (AVICEL(R)), cornstarch and lactose were mixed up according to the formulation given below and, further, magnesium stearate (1 part by weight) was admixed with the mixture obtained, to give a mixed powder. The particle 30 size of the mixed powder obtained was adjusted by sifting, and the sieved powder was tableted on a rotary tablet machine tc give uncoated tablets each having a total weight of 150 mg and containing 30 mg of reduced coenzyme Qio. Reduced coenzyme Qio crystal 20 weight parts 35 Crystalline cellulose (AVICEL(R)) 20 weight parts 26 Cornstarch 20 weight parts Lactose 39 weight parts (Example 1) 5 The uncoated tablets containing reduced coenzyme Qio as obtained in Synthesis Example 2 were sprayed with a solution composed of 500 g of an aqueous solution of a yeast cell wall fraction (product of KIRIN BREWERY CO., LTD., YeastWrap (R)) and 4 gof glycerol, followedby drying. Thus was produced a reduced 10 coenzyme Q 1 o-containing solid preparation (coated tablets) coated with about 50 mg, per tablet, of the yeast cell wall fraction. (Example 2) 15 The uncoated tablets containing reduced coenzyme Qio as obtained in Synthesis Example 2 were sprayed with a solution composed of 450 g of purified water and 50 g of gelatin (product of Nitta Gelatin Inc., APH-100), followed by drying. Thus was produced a reduced coenzyme Qio-containing solid preparation 20 (coated tablets) coated with about 50 mg, per tablet, of gelatin. (Example 3) The uncoated tablets containing reduced coenzyme Qio as 25 obtained in Synthesis Example 2 were sprayed with a solution composed of 450 g of purified water and 50 g of hydroxypropylmethylcellulose (product of Shin-Etsu Chemical Co., Ltd., Metolose 90SH-04)), followed by drying. Thus was produced a reduced coenzyme Qio-containing solid preparation 30 (coated tablets) coated with about 50 mg, per tablet, of hydroxypropylmethylcellulose. (Example 4) The uncoated tablets containing reduced coenzyme Qio as 35 obtained in Synthesis Example 2 were sprayed with an ethanol 27 solution of shellac (product of GIFU SHELLAC), followed by drying. Thus was produced a reduced coenzyme Qio-containing solid preparation (coated tablets) coated with about 30 mg, per tablet, of shellac. 5 (Example 5) The uncoated tablets containing reduced coenzyme Qio as obtained in Synthesis Example 2 were sprayed with an ethanol solution of shellac (product of GIFU SHELLAC), followed by 10 drying. The tablets thus provided with a moistureproofing coating were further sprayed with an aqueous solution composed of 44 g of purified water, 44 g of purified sucrose and 12 g of gumarabic (product of Ina Food IndustryCo., Ltd., GumArabic A), followed by drying. Thus was produced a reduced coenzyme 15 Q 1 0 -containing solid preparation (sugar-coated tablets) coated with about 80 mg, per tablet, of purified sucrose and gum arabic. (Example 6) The uncoated tablets containing reduced coenzyme Qio as 20 obtained in Synthesis Example 2 were sprayed with a solution composed of 500 g of an aqueous solution of a yeast cell wall fraction (product of KIRIN BREWERY CO., LTD., YeastWrap (R) ) and 4 gof glycerol, followedby drying. Thus was produced a reduced coenzyme Qio-containing solid preparation (coated tablets) 25 coated with about 50 mg, per tablet, of the yeast cell wall fraction. Further, this solid preparation was sprayed with an ethanol solution of shellac (product of GIFU SHELLAC), followed by drying. Thus was produced a reduced coenzyme Qio-containing solid preparation (coated tablets) coated with about 2 mg, per 30 tablet, of shellac. (Example 7) Reduced coenzyme Qio-containing granules were prepared by mixing the reduced coenzyme Qio crystals obtained in 35 Synthesis Example 1, hydroxypropylcellulose, lactose and 28 ethanol together according to the formulation shown below, stirring and drying the mixture. Those granules were sprayed with a solution composed of 500 g of an aqueous solution of a yeast cell wall fraction (product of KIRIN BREWERY CO., LTD., 5 YeastWrap(R)) and 4 g of glycerol, followed by drying. Thus was produced a reduced coenzyme Qio-containing solid preparation (granules) coated with about 30 g of the yeast cell wall fraction per 70 g of the granules. Magnesium stearate (1 part by weight per 100 parts by weight of the granules) was 10 admixed with this solid preparation (granules) and the resulting mixed powder was tableted on a rotary tablet machine to give reduced coenzyme Qio-containing tablets each having a total weight of 200 mg and containing 30 mg of reduced coenzyme Qio. 15 Reduced coenzyme Qio crystal 20 weight parts Hydroxypropylcellulose 6 weight parts Lactose 73 weight parts Ethanol 50 weight parts 20 (Example 8) The reduced coenzyme Qio crystals obtained in Synthesis Example 1, crystalline cellulose (AVICEL(R)), cornstarch and purified sucrose were mixed up according to the formulation given below and, further, magnesium stearate (1 part by weight) 25 was admixed with the mixture obtained, to give a mixed powder. The particle size of the mixed powder obtained was adjusted by sifting, and the sieved powder was tableted on a rotary tablet machine to give chewable tablets each having a total weight of 500 mg and containing 100 mg of reduced coenzyme Qio. Those 30 chewable tablets were sprayed with a solution composed of 500 g of an aqueous solution of a yeast cell wall fraction (product of KIRIN BREWERY CO., LTD., YeastWrap (R) ) and 4 g of glycerol, followed by drying. Thus was produced a reduced coenzyme
    Q
    1 0 -containing solid preparation (chewable tablets) coated with 35 about 170 mg, per tablet, of the yeast cell wall fraction. The 29 solid preparation was further sprayed with an ethanol solution of shellac (product of GIFU SHELLAC), followed by drying. Thus was produced a reduced coenzyme Q-o-containing solid preparation (coated tablets) coated with about 40 mg, per tablet, 5 of shellac. Reduced coenzyme Qio crystal 20 weight parts Crystalline cellulose (AVICEL(R)) 10 weight parts Cornstarch 5 weight parts Purified sucrose 64 weight parts 10 (Example 9) The coated tablets produced in Examples 1 to 4 and 6 to 8 were preserved in the following adjusted environment: shielded from light, in the air, 40'C and relative humidity 60%. 15 After 15 days and 30 days, the weight proportions (%) of reduced coenzyme Qio were determined by the above-mentioned HPLC analysis. The results are shown in Table 1. For comparison, the results obtained with the uncoated tables produced in Synthesis Example 2 as a control are also shown. In evaluating 20 the results, reduced coenzyme Qio retention percentages of not lower than about 80% by weight after 30 days of preservation in the adjusted environment (shielded from light, in the air, 40*C, relative humidity 60%) were regarded as indicative of successful stabilization. 25 30 35 30 Table 1 Weight proportion (%) of Coating medium reduced coenzyme Q10 5 After 15 days After 30 days Example 1 Yeast cell wall 100% 100% Example 2 Gelatin 100% 100% Example 3 Hydroxypropylmethylcellulose 94% 90% Example 4 Shellac 97% 94% 10 Example 6 Yeast cell wall+Shellac 100% 100% Example 7 Yeast cell wall 100% 100% Example 8 Yeast cell wall+Shellac 100% 100% Control Uncoated tablets 67% 45% 1.5 (Example 10) The coated tablets produced in Example 1 were preserved in the following adjusted environments: shielded from light, in the air, 40*C, relative humidity10%, 40%, 60% and75%. After 15 days and 30 days, the weight proportions (%) of reduced 20 coenzyme Qio were determined by the above-mentioned HPLC analysis. The results are shown in Fig. 1. In evaluating the results, reduced coenzyme Qio retention percentages of not lower than about 80% by weight after 30 days of preservation in the adjusted environment (shielded from light, in the air, 40*C, 25 each of relative humidity) were regarded as indicative of successful stabilization. (Example 11) The coated tablets produced in Example 2 were preserved 30 in the following adjusted environments: shielded from light, intheair, 40 0 C, relative humidity10%, 40%, 60% and75%. After 15 days and 30 days, the weight proportions (%) of reduced coenzyme Qio were determined by the above-mentioned HPLC analysis. The results are shown in Fig. 2. In evaluating the 35 results, reduced coenzyme Qio retention percentages of not lower 31 than about 80% by weight after 30 days of preservation in the adjusted environment (shielded from light, in the air, 401C, each of relative humidity) were regarded as indicative of successful stabilization. INDUSTRIAL APPLICABILITY In accordance with the present invention, reduced coenzyme Qio which is unstable in the air can be maintained very stably. 10 15 20 25 30 35
    权利要求:
    Claims (24)
    [1] 1. A solid preparation containing reduced coenzyme Qio which comprises a solid composition containing reduced 5 coenzyme Qio coated with at least one coating medium selected from among oil-soluble coating media and water-soluble coating media.
    [2] 2. The solid preparation according to Claim 1, 10 wherein the solid composition containing reduced coenzyme Qio is coated with a water-soluble coating medium and then further with an oil-soluble coating medium.
    [3] 3. The solid preparation according to Claim 1, 15 wherein the coating medium is that accepted for use in foods.
    [4] 4. The solid preparation according to Claim 1, wherein the coating medium used is a water-soluble 20 coating medium.
    [5] 5. The solid preparation according to Claim 1, wherein the oil-soluble coating medium used is at least one species selected from among shellac and zein. 25
    [6] 6. The solid preparation according to Claim 1, wherein the water-soluble coating medium used is at least one species selected from the group consisting of gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast. 30 cell wall fractions.
    [7] 7. The solid preparation according to Claim 1, wherein the total coating weight of the coating medium or media is not less than 5% by weight but not more than 99.9% 35 by weight relative to the weight of the solid preparation. 33
    [8] 8. The solid preparation according to Claim 1, which shows a percent retention of reduced coenzyme Qio of not lower than 50% by weight after 30 days of preservation S in the air at 40'C in a condition protected from light.
    [9] 9. A method for producing a solid preparation containing reduced coenzyme Q-c, wherein a solid composition containing reduced coenzyme 10 Qio is coated with at least one coating medium selected from among oil-soluble coating media and water-soluble coating media.
    [10] 10. The production method according to Claim 9, 15 wherein the solid composition containing reduced coenzyme Qio is coated with a water-soluble coating medium and then further with an oil-soluble coating medium.
    [11] 11. The production method according to Claim 9, 20 wherein the coating medium is that accepted for use in foods.
    [12] 12. The production method according to Claim 9, wherein the coating medium used is a water-soluble 25 coating medium.
    [13] 13. The production method according to Claim 9, wherein the oil-soluble coating medium used is at least one species selected from among shellac and zein. 30
    [14] 14. The production method according to Claim 9, wherein the water-soluble coating medium used is at least one species selected from the group consisting of gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast 35 cell wall fractions. 34
    [15] 15. The production method according to Claim 9, wherein the coating is carried out at a temperature of not lower than 00C but not higher than 120'C.
    [16] 16. A method for stabilizing a solid preparation containing reduced coenzyme QLo, wherein a solid composition containing reduced coenzyme Qio is coated with at least one coating medium selected from 10 among oil-soluble coating media and water-soluble coating media to thereby stabilize the resulting solid preparation containing reduced coenzyme Q o.
    [17] 17. The stabilization method according to Claim 16, 15 wherein the solid composition containing reduced coenzyme QIO is coated with a water-soluble coating medium and then further with an oil-soluble coating medium.
    [18] 18. The stabilization method according to Claim 16, 20 wherein the coating medium is that accepted for use in foods.
    [19] 19. The stabilization method according to Claim 16, wherein the coating medium used is a water-soluble 25 coating medium.
    [20] 20. The stabilization method according to Claim 16, wherein the oil-soluble coating medium used is at least one species selected from among shellac and zein. 30
    [21] 21. The stabilization method according to Claim 16, wherein the water-soluble coating medium used is at least one species selected from the group consisting of gelatin, sugars, gum arabic, pullulan, cellulose derivatives and yeast 35 cell wall fractions. 35
    [22] 22. The stabilization method according to Claim 16, wherein the percent retention of reduced coenzyme Qio is not lower than 50% by weight after 30 days of preservation in 5 the air at 40 0 C in a condition protected from light.
    [23] 23. A method for handling a solid preparation containing reduced coenzyme Qio, wherein the solid preparation containing reduced 10 coenzyme Qio according to Claim 1 is placed in an environment adjusted to a relative humidity of not higher than 75%.
    [24] 24. The handling method according to Claim 23, wherein the percent retention of reduced coenzyme Qio is 15 not lower than 80% by wei-ght after 30 days of preservation in the air at 40'C in a condition protected from light. 20 25 .30 35
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    JP5021319B2|2012-09-05|
    TW200635605A|2006-10-16|
    KR20070091680A|2007-09-11|
    DK1829538T3|2016-05-02|
    EP1829538B1|2016-01-20|
    CA2588925A1|2006-07-20|
    EP1829538A4|2012-06-27|
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    法律状态:
    2011-07-21| MK4| Application lapsed section 142(2)(d) - no continuation fee paid for the application|
    优先权:
    申请号 | 申请日 | 专利标题
    JP2004373553||2004-12-24||
    JP2004-373553||2004-12-24||
    PCT/JP2005/023623|WO2006075502A1|2004-12-24|2005-12-22|Solid preparation comprising reduced coenzyme q10 and process for production of the same|
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