Title of Invention

MEDICINAL COMPOSITION COMPRISING OXIDIZED AND REDUCED FORM OF COENZYME Q10.

Abstract

TITLE: MEDICINAL COMPOSITION COMPRISING OXIDIZED AND REDUCED FORM OF COENZYME Q10. THE PRESENT INVENTION HAS FOR ITS OBJECT TO PROVIDE A MEDICINAL COMPOSITION COMPRISING COENZYME Q10 AS AN ACTIVE INGREDIENT, WHICH COMPOSITION FEATURES AN ENHANCED ABSORPTION AFTER ORAL ADMINISTRATION. THE PRESENT INVENTION IS DIRECTED TO A MEDICINAL COMPOSITION COMPRISING COENZYME Q10 AS AN ACTIVE INGREDIENT WITH THE REDUCED FORM OF COENZYME Q10 ACCOUNTING FOR MORE THAN 20 WEIGHT % OF SAID COENZYME Q10.

Full Text

TECHNICAL FIELD The present invention relates to a medicinal composition with improved absorption after oral administration which comprises a coenzyme Q10 of the following general formula (1- A) as an active ingredient. BACKGROUND ART Coenzyme Q10 is a class of physiological substances occurring as component factors of the mitochondrial electron transfer system within the biological cell. Coenzyme Q10 acts directly as an electron carrier in the oxidative phosphorylation reactions, through metabolic pathways, particularly aerobic pathways, to produce ATP and hence energy. It seems that the demand for coenzyme Q10 is increased in normal subjects in the state of severe physical fatigue and patients with cardiovascular disease, chronic debilitating disease, or on prolonged pharmacotherapy. It has been shown that a deficiency of coenzyme Q10 occurs particularly in ischemic heart diseases, senile myocardial sclerosis, and hypertensive heart diseases. Therefore, it is a sound therapeutic choice to administer coenzyme Q10 to those patients. Moreover, coenzyme Q10 has boon used for non-therapeutic purposes as a nutrient or nutritional supplement just like vitamins. In order that coenzyme Q10 may express its therapeutic efficacy or nutritional effect, it is most important to increase the coenzyme Ql0 level within the patient"s tissue cells. Coenzyme Q10 is a lipid-soluble. and practically water- insoluble substance and, therefore, it is only sparingly soluble in gastric juice. Consequently, oral dosage forms containing coenzyme Q10 in solid state, such as tablets, granules, capsules, and suspensions for extemporaneous preparation, are not well absorbed after oral administration. This means that a considerably greater amount of coenzyme Q10 than actually needed must be administered to the patient but such a practice tends to cause adverse gastrointestinal reactions such as epigastric discomfort, anorexia, nausea, and diarrheas. Much research has heretofore been undertaken for overcoming those disadvantages. Japanese Kokai Publications Sho-55-81813 and Sho-6l-221131, among others, disclose coenzyme Q10 formulations of the solution type or the emulsion/dispersion type. However, such pharmaceutical devices are not sufficient to improve the absorption of coenzyme Q10 in a satisfactory measure. Japanese Kokai Publication Sho-56-18914 discloses a technology for accelerating the lymphatic absorption of coenzyme Q10. This technology has been demonstrated to increase the absorption of coenzyme Q10 in a certain measure but has not proved practically useful as yet. Japanese Kokai Publication Sho-60-89442 discloses a cyclodextrin-clathrated coenzyme Q10 formulation. Japanese Kokai Publication Sho-60-1124 discloses a coenzyme Q10- containing ribosomal formulation. Elowever, those coenzyme Q10 preparations require a complicated pharmaceutical procedure for production and are not practically fully satisfactory. Italian Patent 1190442 Specification discloses a technology which, instead of using coenzyme Q10 as such, comprises converting a reduced form of coenzyme Q10 to a derivative such as an acyl ester, a sulfuric acid ester, or a phosphoric acid ester and administering this coenzyme Q10 derivative for enhanced absorption. However, the effect of the technology has not been supported by experimental data. SUMMARY OF THE INVENTION The present invention has for its object to provide a medicinal composition comprising coenzymc Q10 as an active ingredient, which composition features an enhanced absorption after oral administration. In the course of their intensive research for overcoming the above-mentioned disadvantages of the prior art, the inventors of the present invention discovered that when a medicinal composition containing a reduced form of coenzyme Q10 was prepared and administered to patients by the oral route, a considerably higher bioavai.lability was surprisingly obtained as compared with the conventional medicinal composition containing only the oxidized coenzyme Q10. The present invention has been developed on the basis of the above finding. The present invention, therefore, is directed to a medicinal composition comprising coenzyme Q10 as an active ingredient with the reduced form of coenzyme Q10 accounting for more than 20 weight % of said coenzyme Q10. ACCOMPANYING BRIEF DESCRIPTION OF THE/DRAWINGS Fig. 1 is a graphical representation of the relationship of plasma total coenzyme Q10 concentration with the time after administration; The ordinate represents the plasma total coenzyme Q10 concentration and the abscissa represents the time after administration. Each plot represents moan ? standard deviation (n=4). Fig. 2 is a graphical representation of the relationship of the total plasma coenzyme Q10 concentration at 3 hours after administration with the weight ratio of oxidized coenzyme Q10 to reduced coenzyme Q10 in each sample. The ordinate represents the plasma total coenzyme Q10 concentration and the abscissa represents the oxidized coenzyme Q10-reduced coenzyme Q10 ratio by weight. Each bar represents mean + standard deviation (n=4). DETAILED DESCRIPTION OF THE INVENTION The present invention is now described in detail. It is known that a fairly high proportion, usually about 40 to 90%, of coenzyme Q10 occurs in reduced form in the body. In vivo, the reduced form of coenzyme Q10 is readily transformed to the oxidized form, while the oxidized form of coenzyme Q10 is readily transformed into the reduced form. Therefore, coenzyme Q10 in vivo can be qenerally expressed by the following formula (1). Referring to the above formula (1), the general formula (1-A) represents the oxidized form of coenzyme Q10 and the general formula (1-B) represents the reduced form of coenzyme Q10 In the conventional medicinal composition containing a coenzyme Q10 as an active ingredient, the sole active ingredient is the oxidized coenzyme Q10 of the above chemical formula (1-A). In contrast, the medicinal composition of the present invention comprises a reduced coenzyme Q10 of the above chemical formula (1-B) as an active ingredient coenzyme Q10. Consequently, as compared with the conventional medicinal composition containing only the oxidized form of coenzyme Q10 as an active ingredient, the medicinal composition of the present invention is improved in absorption after oral administration and insures a higher bioavailability. There is no particular limitation on the technology for providing said reduced form of coenzyme Q10 A typical method, which is by no means exclusive, comprises harvesting a coenzyine Q10 from a synthetic reaction mixture, a fermentation broth, or a natural source by procedures known in the art and subjecting it to chromatography to separate and concentrate the reduced form of coenzyme Q10 fraction. Where necessary, there can be followed the procedure of adding a conventional reducing agent such as sodium borohydride or sodium dithionite (sodium hydrosulfite) to the above coenzyme Q10 to reduce the oxidized coenzyme Q10 fraction of said coenzyme Q10 and, then, concentrate the reduced Q10 by chromatography. As a further alternative, the objective reduced coenzyme Q10 can be obtained by permitting said reducing agent to act on the available high-purity coenzyme There is no particular limitation on the technology for manufacturing the medicinal composit ion of the invention. A typical but by no means exclusive method comprises dissolving the reduced coenzyme Ql0 thus obtained and a commercial oxidized coenzyme Q10 in a suitable common solvent such as isopropyl alcohol acelone or ether to provide a medicinal composition containing said reduced coenzyme Q10 in a desired proportion. As an alternative, the above-mentioned reduced and oxidized forms of coenzyme Q10 can be simply admixed in solid stage. It is also possible to directly use the mixture of oxidized and reduced forms of coenzyme Q10 obtained in the course of the above-mentioned production process for coenzyme Q10. Furthermore, the active ingredient for the medicinal composition of the invention can be directly obtained by controlling the time of reduction reaction of the high-purity coenzyme Ql0 already available and the type or amount of reducing agent to be used. In the medicinal composition of the present invention, the reduced coenzyme Q10 accounts for more than 20 weight % of the total amount of coenzyme Q10. If its proportion is smaller than 20 weight. %, the bioavailability of the resulting medicinal composition will not be as high as expected. The preferred proportion is not smaller than 40 weight % and the most preferred proportion is not smaller than 60 weight %. Conversely if the proportion of the reduced form of coenzyme Q10 is too large, the production process will be complicated and the cost of production increased. Therefore, it is not necessary to increase the coenuyiue Q10 content too much. The medicinal composition of the present invention can be used as, for example, a cardiotonic effective against symptoms in ischemic heart disease, senile myocardial sclerosis, hypertensive heart disease, etc. It can also be used as a nutrient, a nutritional supplement, or a veterinary medicine. There is no particular limitation on the dosage form for the medicinal composition of the present invention. It may for example be powders, granules containing a binder component, or compression-molded tablets. Such powders or granules may be filled in capsule shells to provide capsules. They may also be processed into soft capsules by adding a natural oil, an oily higher fatty acid, a higher fatty acid monoglyceride, or a mixture thereof and wrapping the medicated oil in soft capsule sheet materials. In this application, the capsule shell may be one predominantly composed of gelatin or any other water-soluble macromolocular substance. The capsule includes microcapsules. The medicinal composition of the present: invention may contain, in addition to said reduced coenzyme Ql0, a variety of pharmaceutically acceptable formulating substances as added in suitable amounts in the routine manner. There is no particular limitation on the kinds of such substances. Thus, an excipient, a disintegrator, a lubricant, a binder, an antioxidant, a coloring agent, an antiflocculant, an absorption promoter, a solubilizer for the active ingredient, a stabilizer, etc. can be added as necessary. The above-mentioned excipient includes but is not limited to sucrose, lactose, glucose, corn starch, mannitol, crystalline cellulose, calcium phosphate, and calcium sulfate. The disintegrator includes but is not limited to starch, agar, calcium citrate, calcium carbonat.fi, sodium hydrogen carbonate, dextrin, crystalline cellulose, carboxymethyl- cellulose, and gum tragacanth. The lubricant includes but is not limited to talc, magnesium stearate, polyethylene glycol, silica, and hydrogenated vegetable oil . The binder includes but is not limited to ethylcellulose, methylccllulose, hydroxypropylmethylcellulose, gum tragacanth, shellac, gelatin, gum arable, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polymethaorylic acid, and sorbitol. The antioxidant includes but is not limited to ascorbic acid, tocophcrol, vitamin A, b -carotene, sodium hydrosulfite, sodium thiosulfate, sodium pyrolsulfite, and citric acid. There is no particular limitation on the coloring agent that can be used. For example, a variety of pharmaceutically acceptable colors can be mentioned. The antiflocculant includes but is not limited to stearic acid, talc, light silicic anhydride, and hydrous silicon dioxide. The absorption promoter includes but is not limited to higher alcohols, higher fatty acids, and glycerin fatty acid esters and other surfactants. The above-mentioned solubilizer for the active ingredient includes but is not limited to organic acids such as furnaric acid, succinic acid, and malic acid. The stabilizer includes but is not limited to benzoic acid, sodium benzoate, and ethyl p-hydroxybenzoate. The dosage for the medicinal composition of the present invention should be selected according to whether the composition is used as a drug, a veterinary medicine, or a nutrient. For oral administration to domestic animals or fowls, the composition can be used as admixed into the feed or administered by a conventional forced manner. Because of the above constitution, the medicinal composition of the present invention is well absorbable after oral administration and shows a high level of bioavailability. BEST MODE FOR CARRYING OUT THE INVENTION The following examples and formulation examples are intended to illustrate the invention in further detail and should by no means be limitative of the scope of the invention. Example 1 (1) Preparation of samples Preparation of Samplc 1 A 5:95 (w/w) mixture {0.3 g) of oxidized coenzyme Q10 and reduced coenzyme Q10 was melted on a. water bath at 50°C and an olive oil was added to the melt to make 6.0 ml. This mixture was homogenized at 500c to provide an oily composition. Preparation of Comparative Sample 1 Oxidized coenzyme Q10 (0.3 g) was melted on a water bath at 50°C and an olive oil was added to the melt to make 6.0 ml. This mixture was homogenized at 50cC to provide an oily composition. (2) Oral absorption test Sample 1 and Comparative Sample 1 were used as tact samples. The tost was porfonnod using male Cij:CD (SD) rats (body weights 260 to 300 g). under well-fed conditions. As to dosage, each test sample was administered orally at the rate of 100 mg of total coenzyme Q10 per kg body weight. In the test, the total plasma coenzyme Q10 concentration was determined before administration (not administered) and serially after administration. Four rats were used per test sample for each time-point. The total coenzyme Q10 moans the sum of the mixture comprising the oxidized and reduced forms of coenzyme Q10. The total plasma coenzyme Q10 concentration was assayed as the concentration of oxidized coenzyme Q10 in the following manner. To 1.0 ml of the obtained plasma sample, 2.0 ml of water, 4.0 ml of ethanol, and 10.0 ml of n-hexane were added in the order mentioned. The mixture was shaken vigorously for about. 5 minutes and then centrifuged to separate into two layers. The organic layer was taken and the aqueous layer was further extracted with 10.0 ml of n- hexane twice in the same manner. The resulting organic layers and the organic layer previously taken were combined and evaporated to dryness. To the residuo was added 250 m 1 of ethanol:lN-hydrochloric acid (99:1, v/v) for use as an assay sample. The assay of coenzyme Q10 was carried out by high- performance liquid chromatography under the following conditions. Column: 250 mm long x 4.6 mm in diameter SYMMETRY C18 (Waters) Mobile phase: 0.5 M NaC1O, /C2H50H:CH ,OH:CH,CN:70%HC1O, (400:300:300:1, v:v) Detection wavelength: 27 5 nm Flow rate: 1 ml/min. The test results are presented in Fig. 1. In Fig. 1, the ordinate represents total plasma coenzyme Q10 concentration and the abscissa represents the time after administration. Each plot is mean ± standard deviation. It is apparent from Fig. 1 that whereas the plasma concentration peak appeared at. 3 hr after administration in the case of the composition containing only the oxidized form of coenzyme Q10, the peak appeared 1 hour earlier, i.e. at 2 hours after administration, in the case of the composition comprising the reduced form of coenzyme Q10. Furthermore, the concentration level is also 2.1 times as high for the composition comprising the reduced form of coenzyme Q10. It is, thus, clear that compared with the composition containing only the oxidized form of coenzyme Q10, the medicinal composition of the present invention is absorbed faster and in a larger amount. Example 2 (1) Preparation of samples Preparation of Sample 2 Using a 20:80 (w/w) mixture of oxidized coenzyme Q10 and reduced coenzyme Q10, Test Sample 2 was prepared in the same manner as the preparation of Sample 1 in Example 1. Preparation of Sample 3 Using a 40:60 (w/w) mixture of oxidized coenzyme Q10 and reduced coenzyme Q10, Test Sample 3 was prepared in the same manner as the preparation of Sample 1 in Example 1. Preparation of Sample 4 Using a 60:40 (w/w) mixture of oxidized coenzyme Q10 and reduced coenzyme Q10, , Test Sample 4 was prepared in the same manner as the preparation of Sample 1 in Example 1. Preparation of Comparative Sample 2 Using a 80:20 (w/w) mixture of oxidized coenzyme Q10, and reduced coenzyme Q10, Comparative Sample 2 was prepared in the same mariner as the preparation of Sample 1 in Example 1. (2) Oral absorption test Sample 1, Sample 2, Sample 3, Sample 4, Comparative Sample 1, and Comparative Sample 2 were Used as test samples. The test was performed in the same mariner as described in Example 1 except that the determination of total plasma coenzyme Q10 concentration was carried out at 3 hours after administration. The test results are presented in Fig. 2. In Fig. 2, the ordinate represents the total plasma coenzyme Q10 concentration at 3 hours after administration and the abscissa represents the weight ratio of oxidized coenzyme Q10 to reduced coenzyme Q10 in the test sample. Rach bar represents mean = standard deviation. It is apparent from Fig. 2 that compared with the composition containing only the oxidized form of coenzyme Q10 and the composition in which the reduced form of coenzyme Q10 accounts for 20 weight % of total coenzyme Q10 administration of the compositions in which reduced coenzyme Q10 accounts for 40 weight % or more of total coenzyme Ql0 resulted in higher plasma coenzyme Q10 concentrations. Moreover, with a weight ratio of contained reduced coenxyine Q10 increasing, the plasma coenzyme Q10 concentration was further increased. Those results indicate that because it contains 40 weight % or more of the reduced form of coenzyme Q10, the medicinal composition of the present invention is absorbed in a definitely larger amount than the composition containing only the oxidized form of coenzyme Q10 and the composition in which the reduced form of coenzyme Ql0 accounts for 20 weight % or,less of the total coenzyme Q10 content. Then, using a 15:85 (w/w) mixture of oxidized coenzyme Q10 and reduced coenzyme Q10 (hereinafter rpfprrpd to as main medicine) as an active ingredient, several, dosage forms were prepared by the conventional pharmaceutical procedures. Formulation Example 1 (powders) The main medicine was dissolved in acetone and the solution was adsorbed on microcrystalline cellulose, followed by drying. The product was mixed with corn starch to provide formulation Example 3 (capsules) The following components were granulated by the routine procedure and filled in hard gelatin capsule shells to provide capsules each containing 20 mg of the main medicine. Formulation Example 2 (tablets) The main medicine was dissolved in acetone and the solution was adsorbed on microcrystalline cellulose, followed by drying. The product was mixed with corn starch, lactose, carboxymethylcellulose, and magnesium stearate and the mixture was granulated in the routine manner by adding an aqueous solution of poiyvinylpyrrolidone as a binder. To the granules thus obtained was added talc as a lubricant followed by mixing and the resulting composition was compressed into tablets each containing 20 mg of the main medicine. Formulation Example 4 (soft: capsules) Soybean oil was warmed to 600C and the main medicine melted at 60°C was added and dissolved. Then, vitamin E was added gradually to prepare a homogeneous mixture, which was then processed into soft capsules each containing 20 mg of the main medicine. Main medicine 20 Parts by weight Vitamin E 15 Parts by weight Soybean oil 350 Parts by weight We claim : 1. A medicinal composition with improved bioavailability comprising oxidized and reduced form of coenxyme Q10, such as herein described, wherein the reduced form is more than 20 weight % of the total weight of the two forms of coenzyme Q10. 2. The medicinal composition, as claimed in claim 1, wherein said reduced coenxyme Ql0 accounts for 40 weight % or more of the total coenxyme Q10 content. [Name] Shinya Furutani [Indication of Fee] [Number of Deposit Ledger] 033891 [The Amount of Payment] ¥21,000 [List of Attached Documents] [Document Name] Specification 1 [Document Name] Drawing 1 [Document Name] Abstract 1 [Power of Attorney] 9503244 [Document Name] SPECIFICATION [Title of the Invention] Medicinal Composition [Scope of the Claim for Patent] [Claim 1] A medicinal composition comprising coenzyme Q10 as an active ingredient, wherin said coenzyme Q10 comprises reduced coenzyme Q10. [Claim 2] The medicinal composition according to Claim 1 wherein said reduced coenzyme Q10 accounts for 20 weight % or more of the total coenzyme Q10 content. [Detailed Description of the Invention] [0001] [Field of the Invention] The present invention relates to a medicinal composition with improved absorption after oral administration which comprises a coenzyme Q10 of the following general formula (1- A) as an active ingredient. Coenzyme Q10 is a class of physiological substances occurring as component factors of the mitochondrial electron transfer system within the biological cell. Coenzyme Q10 acts directly as an electron carrier in the oxidative phosphorylation reactions, through metabolic pathways, particularly aerobic pathways, to produce ATP and hence energy. It seems that the demand for coenzyme Q10 is increased in normal subjects in the state of severe physical fatigue and patients with cardiovascular disease, chronic debilitating disease, or on prolonged pharmacotherapy. It has been shown that a deficiency of coenzyme Q10 occurs particularly in ischemic heart diseases, senile myocardial sclerosis, and hypertensive heart diseases. Therefore, it is a sound therapeutic choice to administer coenzyme Q10 to those patients. Moreover, coenzyme Q10 has been used for non-therapeutic purposes as a nutrient or nutritional supplement just like vitamins. In order that coenzyme Q10 may express its therapeutic efficacy or nutritional effect, it is most important to increase the coenzyme Q10 level within the patient"s tissue cells. Coenzyme Q10 is a lipid-soluble and practically water- insoluble substance and, therefore, it is only sparingly soluble in gastric juice. Consequently, oral dosage forms containing coenzyme Q10 in solid state, such as tablets, granules, capsules, and suspensions for extemporaneous preparation, are not well absorbed after oral administration. This means that a considerably greater amount of coenzyme Q10 than actually needed must be administered to the patient but such a practice tends to cause adverse gastrointestinal reactions such as epigastric discomfort, anorexia, nausea, and diarrheas. Much research has heretofore been undertaken for overcoming those disadvantages. Japanese Kokai Publications Sho-55-81813 and Sho-61-221131, among others, disclose coenzyme Q10 formulations of the solution type or the emulsion/dispersion type. However, such pharmaceutical devices are not sufficient to improve the absorption of coenzyme Q10 in a satisfactory measure. [0007] Japanese Kokai Publication Sho-56-18914 discloses a technology for accelerating the lymphatic absorption of coenzyme Q10. This technology has been demonstrated to increase the absorption of coenzyme Q10 in a certain measure but has not proved practically useful as yet. [0008] Japanese Kokai Publication Sho-60-89442 discloses a cyclodextrin-clathrated coenzyme Q10 formulation. Japanese Kokai Publication Sho-60-1124 discloses a coenzyme Q10- containing ribosomal formulation. However, those coenzyme Q10 preparations require a complicated pharmaceutical procedure for production and are not practically fully satisfactory. [0009] Italian Patent 1190442 Specification discloses a technology which, instead of using coenzyme Q10 as such, comprises converting a reduced form of coenzyme Q10 to a derivative such as an acyl ester, a sulfuric acid ester, or a phosphoric acid ester and administering this coenzyme Q10 derivative for enhanced absorption. However, the effect of the technology has not been supported by experimental data. [Problems which the Invention is to Solve] The present invention has for its object to provide a medicinal composition comprising coenzyme Q10 as an active ingredient, which composition features an enhanced absorption after oral administration. [Means for Solving the Problems] In the course of their intensive research for overcoming the above-mentioned disadvantages of the prior art, the inventors of the present invention discovered that when a medicinal composition containing a reduced form of coenzyme Q10 was prepared and administered to patients by the oral route, a considerably higher bioavailability was surprisingly obtained as compared with the conventional medicinal composition containing only the oxidized coenzyme Q10. The present invention has been developed on the basis of the above finding. The present invention, therefore, is directed to a medicinal composition comprising coenzyme Q10 as an active ingredient with said coenzyme Q10 comprising the reduced form of coenzyme Q10. The present invention is now described in detail. It is known that a fairly high proportion, usually about 40 to 90%, of coenzyme Q10 occurs in reduced form in the body. In vivo, the reduced form of coenzyme Q10 is readily transformed to the oxidized form, while the oxidized form of coenzyme Q10 is readily transformed into the reduced form. Therefore, coenzyme Q10 in vivo can be generally expressed by the following formula (1). Referring to the above formula (1), the general formula (1-A) represents the oxidized form of coenzyme Q10 and the general formula (1-B) represents the reduced form of coenzyme Q10. In the conventional medicinal composition containing a coenzyme Q10 as an active ingredient, the sole active ingredient is the oxidized coenzyme Q10 of the above chemical formula (1-A). In contrast, the medicinal composition of the present invention comprises a reduced coenzyme Q10 of the above chemical formula (1-B) as an active ingredient coenzyme Q10. Consequently, as compared with the conventional medicinal composition containing only the oxidized form of coenzyme Q10 as an active ingredient, the medicinal composition of the present invention is improved in absorption after oral administration and insures a higher bioavailability. There is no particular limitation on the technology for providing said reduced form of coenzyme Q10. A typical method, which is by no means exclusive, comprises harvesting a coenzyme Q10 from a synthetic reaction mixture, a fermentation broth, or a natural source by procedures known in the art and subjecting it to chromatography to separate and concentrate the reduced form of coenzyme Q10 fraction. Where necessary, there can be followed the procedure of adding a conventional reducing agent such as sodium borohydride or sodium dithionite (sodium hydrosulfite) to the above coenzyme Q10 to reduce the oxidized coenzyme Q10 fraction of said coenzyme Q10 and, then, concentrate the reduced Q10 by chromatography. As a further alternative, the objective reduced coenzyme Q10 can be obtained by permitting said reducing agent to act on the available high-purity coenzyme Q10. There is no particular limitation on the technology for manufacturing the medicinal composition of the invention. A typical but by no means exclusive method comprises dissolving the reduced coenzyme Q10 thus obtained and a commercial oxidized coenzyme Q10 in a suitable common solvent such as isopropyl alcohol, acetone, or ether to provide a medicinal composition containing said reduced coenzyme Q10 in a desired proportion. As an alternative, the above-mentioned reduced and oxidized forms of coenzyme Q10 can be simply admixed in solid stage. It is also possible to directly use the mixture of oxidized and reduced forms of coenzyme Q10 obtained in the course of the above-mentioned production process for coenzyme Q10. Furthermore, the active ingredient for the medicinal composition of the invention can be directly obtained by controlling the time of reduction reaction of the high-purity coenzyme Q10 already available and the type or amount of reducing agent to be used. In the medicinal composition of the present invention, the reduced coenzyme Q10 preferably accounts for more than 20 weight % of the total amount of coenzyme Q10. If its proportion is smaller than 20 weight %, the bioavailability of the resulting medicinal composition will not be insufficient. The more preferred proportion is not smaller than 40 weight % and the most preferred proportion is not smaller than 60 weight %. Conversely if the proportion of the reduced form of coenzyme Q10 is too large, the production process will be complicated and the cost of production increased. Therefore, it is not necessary to increase the coenzyme Q10 content too much. The medicinal composition of the present invention can be used as, for example, a cardiotonic effective against symptoms in ischemic heart disease, senile myocardial sclerosis, hypertensive heart disease, etc. It can also be used as a nutrient, a nutritional supplement, or a veterinary medicine. There is no particular limitation on the dosage form for the medicinal composition of the present invention. It may for example be powders, granules containing a binder component, or compression-molded tablets. Such powders or granules may be filled in capsule shells to provide capsules. They may also be processed into soft capsules by adding a natural oil, an oily higher fatty acid, a higher fatty acid monoglyceride, or a mixture thereof and wrapping the medicated oil in soft capsule sheet materials. In this application, the capsule shell may be one predominantly composed of gelatin or any other water-soluble macromolecular substance. The capsule includes microcapsules. [0020] The medicinal composition of the present invention may contain, in addition to said reduced coenzyme Q10, a variety of pharmaceutically acceptable formulating substances as added in suitable amounts in the routine manner. There is no particular limitation on the kinds of such substances. Thus, an excipient, a disintegrator, a lubricant, a binder, an antioxidant, a coloring agent, an antiflocculant, an absorption promoter, a solubilizer for the active ingredient, a stabilizer, etc. can be added as necessary. The above-mentioned excipient includes but is not limited to sucrose, lactose, glucose, corn starch, mannitol, crystalline cellulose, calcium phosphate, and calcium sulfate. The disintegrator includes but is not limited to starch, agar, calcium citrate, calcium carbonate, sodium hydrogen carbonate, dextrin, crystalline cellulose, carboxymethyl- cellulose, and gum tragacanth. The lubricant includes but is not limited to talc, magnesium stearate, polyethylene glycol, silica, and hydrogenated vegetable oil. The binder includes but is not limited to ethylcellulose, methylcellulose, hydroxypropylmethyIcellulose, gum tragacanth, shellac, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, and sorbitol. The antioxidant includes but is not limited to ascorbic acid, tocopherol, potassium hydrogenphosphate, vitamin A, b -carotene, sodium hydrosulfite, sodium thiosulfate, sodium pyrolsulfite, sodium D-sorbitolbenzoate, citric acid, sodium citrate, magnesium silicate, sodium hydrogencarbonate and propylene glycol. There is no particular limitation on the coloring agent that can be used. For example, a variety of pharmaceutically acceptable colors can be mentioned. The antiflocculant includes but is not limited to stearic acid, talc, light silicic anhydride, and hydrous silicon dioxide. The absorption promoter includes but is not limited to higher alcohols, higher fatty acids, and glycerin fatty acid esters and other surfactants. The above-mentioned solubilizer for the active ingredient includes but is not limited to organic acids such as fumaric acid, succinic acid, and malic acid. The stabilizer includes but is not limited to benzoic acid, sodium benzoate, and ethyl p-hydroxybenzoate. The dosage for the medicinal composition of the present invention should be selected according to whether the composition is used as a drug, a veterinary medicine, or a nutrient. For oral administration to domestic animals or fowls, the composition can be used as admixed into the feed or administered by a conventional forced manner. [Example] The following examples and formulation examples are intended to illustrate the invention in further detail and should by no means be limitative of the scope of the invention. Example 1 (1) Preparation of samples Preparation of Sample 1 A 5:95 (w/w) mixture (0.3 g) of oxidized coenzyme Q10 and reduced coenzyme Q10 was melted on a water bath at 500C and an olive oil was added to the melt to make 6.0 ml. This mixture was homogenized at 50°C to provide an oily composition. Preparation of Comparative Sample 1 Oxidized coenzyme Q10 (0.3 g) was melted on a water bath at 50°C and an olive oil was added to the melt to make 6.0 ml. This mixture was homogenized at 50°C to provide an oily composition. (2) Oral absorption test Sample 1 and Comparative Sample 1 were used as test samples. The test was performed using male Crj:CD (SD) rats (body weights 260 to 300 g) under well-fed conditions. As to dosage, each test sample was administered orally at the rate of 100 mg of total coenzyme Q10 per kg body weight. In the test, the total plasma coenzyme Q10 concentration was determined before administration (not administered) and serially after administration. Four rats were used per test sample for each time-point. The total coenzyme Q10 means the sum of the mixture comprising the oxidized and reduced forms of coenzyme Q10. The total plasma coenzyme Q10 concentration was assayed as the concentration of oxidized coenzyme Q10 in the following manner. To 1.0 ml of the obtained plasma sample, 2.0 ml of water, 4.0 ml of ethanol, and 10.0 ml of n-hexane were added in the order mentioned. The mixture was shaken vigorously for about 5 minutes and then centrifuged to separate into two layers. The organic layer was taken and the aqueous layer was further extracted with 10.0 ml of n- hexane twice in the same manner. The resulting organic layers and the organic layer previously taken were combined and evaporated to dryness. To the residue was added 250 m 1 of ethanol:lN-hydrochloric acid (99:1, v/v) for use as an assay sample. The assay of coenzyme Q10 was carried out by high- performance liquid chromatography under the following conditions. The test results are presented in Fig. 1. in Fig. 1, the ordinate represents total plasma coenzyme Q10 concentration and the abscissa represents the time after administration. It is apparent from Fig. 1 that whereas the plasma concentration peak appeared at 3 hr after administration in the case of the composition containing only the oxidized form of coenzyme Q10, the peak appeared 1 hour earlier, i.e. at 2 hours after administration, in the case of the composition comprising the reduced form of coenzyme Q10. Furthermore, the concentration level is also 2.1 times as high for the composition comprising the reduced form of coenzyme Q10. It is, thus, clear that compared with the composition containing only the oxidized form of coenzyme Q10, the medicinal composition of the present invention is absorbed faster and in a larger amount. Then, using a 15:85 (w/w) mixture of oxidized coenzyme Q10 and reduced coenzyme Q10 (hereinafter referred to as main medicine) as an active ingredient, several dosage forms were prepared by the conventional pharmaceutical procedures. Formulation Example 1 (powders) The main medicine was dissolved in acetone and the solution was adsorbed on microcrystalline cellulose, followed by drying. The product was mixed with corn starch to provide powders in the routine manner. Main medicine 10 Parts by weight Microcrystalline cellulose 40 Parts by weight Corn starch 55 Parts by weight [0033] Formulation Example 2 (tablets) The main medicine was dissolved in acetone and the solution was adsorbed on microcrystalline cellulose, followed by drying. The product was mixed with corn starch, lactose, carboxymethylcellulose, and magnesium stearate and the mixture was granulated in the routine manner by adding an aqueous solution of polyvinylpyrrolidone as a binder. To the granules thus obtained was added talc as a lubricant followed by mixing and the resulting composition was compressed into tablets each containing 20 mg of the main medicine. Main medicine 20 Parts by weight Corn starch 25 Parts by weight Lactose 15 Parts by weight Carboxymethylcellulose calcium 10 Parts by weight Microcrystalline cellulose 40 Parts by weight Polyvinylpyrrolidone 5 Parts by weight Magnesium stearate 3 Parts by weight Talc 10 Parts by weight [0034] Formulation Example 3 (capsules) The following components were granulated by the routine procedure and filled in hard gelatin capsule shells to provide capsules each containing 20 mg of the main medicine. Main medicine 20 Parts by weight Microcrystalline cellulose 40 Parts by weight Corn starch 20 Parts by weight Lactose 62 Parts by weight Magnesium stearate 2 Parts by weight Polyvinylpyrrolidone 3 Parts by weight [0035] Formulation Example 4 (soft capsules) Soybean oil was warmed to 60°C and the main medicine melted at 60°C was added and dissolved. Then, vitamin E was added gradually to prepare a homogeneous mixture, which was then processed into soft capsules each containing 20 mg of the main medicine. Main medicine 20 Parts by weight Vitamin E 15 Parts by weight Soybean oil 350 Parts by weight [0036] [Effect of the Invention] Because of the above constitution, the medicinal composition of the present invention is well absorbable after oral administration and shows a high level of bioavailability. [BRIEF DESCRIPTION OF THE DRAWINGS] [Fig. 1] Fig. 1 is a graphical representation of the relationship of plasma total coenzyme Q10 concentration with the time after administration. The ordinate represents the plasma total coenzyme Q10 concentration and the abscissa represents the time after administration. [Problem] The present invention provides a medicinal composition comprising coenzyme Q10 as an active ingredient, which composition features an enhanced absorption after oral administration. [Means for Solving] A medicinal composition comprising coenzyme Q10 as an active ingredient with the reduced form of coenzyme Q10 accounting for more than 20 weight % of said coenzyme Q10.

Documents:

01505-cal-1997-abstract.pdf

01505-cal-1997-claims.pdf

01505-cal-1997-correspondence.pdf

01505-cal-1997-description (complete).pdf

01505-cal-1997-drawings.pdf

01505-cal-1997-form 1.pdf

01505-cal-1997-form 18.pdf

01505-cal-1997-form 2.pdf

01505-cal-1997-form 3.pdf

01505-cal-1997-form 5.pdf

01505-cal-1997-letter patent.pdf

01505-cal-1997-pa.pdf

01505-cal-1997-priority document.pdf

01505-cal-1997-reply f.e.r.pdf

1505-CAL-1997-FORM-27.pdf