JP4896531B2 - Pharmaceutical composition for increasing blood CoQ10 level - Google Patents

Description

  The present invention relates to a pharmaceutical composition containing 3 or more selected from the group consisting of tocopherols, ascorbic acids, riboflavins and CoQ10 (particularly, a pharmaceutical composition for increasing the amount of CoQ10).

CoQ10 is a substance indispensable for ATP production in mitochondria, that is, energy production, and is also present in cells and blood other than mitochondria, and functions as an antioxidant. Since CoQ10 is an important and indispensable component for the living body, the living body is synthesized by itself, but shows a peak in the twenties, and the level of CoQ10 decreases with aging. (See Non-Patent Document 1 above)
Known diseases other than aging that show CoQ10 deficiency include diabetes, renal failure, liver diseases such as cirrhosis and liver cancer, hyperthyroidism, Parkinson's disease, phenylketonuria, and mitochondrial abnormalities. . In addition to such diseases, it is known that the blood CoQ10 concentration decreases in patients taking statins, those with hypotension, and those who exercise vigorously. (Non-Patent Document 2)
The significance of administering CoQ10 in the above cases has been suggested. Besides these, the purpose of reducing body fat by activating fat burning, improvement of congestive heart failure symptoms, palpitation, shortness of breath, swelling・ Improvement of coldness, anti-cancer auxiliary purpose that stimulated immune system, auxiliary purpose of periodontal disease treatment, treatment of male infertility, skin care, etc. are being implemented or proposed. (Non-Patent Document 3)
In Japan, 30 mg / day of CoQ10 has been observed for mild and moderate congestive heart failure symptoms during basic therapy (Non-patent Document 4).
On the other hand, there are reports that administration of 390 mg per day is effective for stimulating the immune system for the purpose of recommending 50-300 mg per day and treating cancer in cases of congestive heart failure (Non-patent Document 3). Furthermore, in the treatment of Parkinson's disease, 44% suppression of progression of the disease state was observed in the 1200 mg daily administration group, and a statistically significant effect was obtained (Non-patent Document 5). The number of case reports effective at such high doses is expected to increase further in the future.

So far, the following reports have suggested the possibility of a pharmaceutical composition containing three or more selected from the group consisting of tocopherols, ascorbic acids, riboflavins and CoQ10, or such a pharmaceutical composition.
1) Supplements containing 10 types of CoQ10, catechin, L-carnitine, collagen, hyaluronic acid, DHA, EPA, vitamin E, vitamin B1, and vitamin B2 are commercially available (see Non-Patent Document 6).
2) A combination of CoQ10, tocopherol, nicotinamide, and riboflavin that is effective in alleviating palpitations, shortness of breath and swelling that occurs when the physical activity of daily life is slightly exceeded due to mild heart disease is commercially available. (Refer nonpatent literature 7).
3) Development of CoQ10-containing products in which vitamin Q and other vitamins such as vitamin E, amino acids, DHA, EPA, or other materials such as polyphenol are blended with CoQ10 has been suggested (see Non-Patent Document 8).
4) Blood lipid improving agents containing vitamin B2, vitamin C, and vitamin E as active ingredients are known (see Patent Document 1).
5) Respiration comprising one or more antioxidant vitamins together with one or more of eugenol, flavonoids, phytoestrogens, proanthocyanidins, selenium, ubiquinone (CoQ10), catotenoids or plant phenolic compounds Nutritional supplements for assisting in the prevention or treatment of organ diseases are known (see Patent Document 2)
However, until now, there has been no report that a pharmaceutical composition containing three or more selected from the group consisting of tocopherols, ascorbic acids, riboflavins and CoQ10 significantly increased the amount of CoQ10 in the blood, Nor is it suggested.
JP 60-41611 A Special table 2004-530407 gazette “Animus”, Volume 36, 2004, p. 37-40 “CoQ10”, “online”, Mitsubishi Chemical BLC, [searched on January 11, 2006], Internet <http://www.mbcl.co.jp/topics/topic02.html> “Coenzyme Q10”, “online”, Marumaya Japanese and Chinese Medicine Research Institute, [Search January 6, 2006], Internet <URL: http://www.naoru.com/CoQ10.htm> “Medical Medicine Japan Pharmaceutical Collection”, 28th edition, Jiho, 2005, p. 2378 “Special Feature 1 Women-friendly Medicine”, “online”, Preventive Medicine Promotion Committee, [Searched on January 11, 2006], Internet <http://yobou.com/contents/tokushu/report/t35_03.html > "Health Industry Distribution Newspaper" December 9, 2004 issue “Popular Medicine Dictionary”, 9th edition, Jiho, 2004-2005, p. 118 “New Food Industry”, Vol. 45, No. 7, 2003, p. 23-28

As described above, CoQ10 is an indispensable substance for the living body, and in particular, supplementation of CoQ10 in the diseases as described above is meaningful. However, CoQ10 is difficult to obtain in large quantities compared to other vitamins, and the price is also expensive, so especially when it is taken for a long time or when a high dose is required. However, there was a problem that the financial burden on the patient became very heavy, and that sufficient treatment could not be performed, leading to a situation in which the patient had to give up.
Therefore, the present inventor
1) Search for a safe concomitant substance capable of realizing a CoQ10 level in blood comparable to that of a high dose CoQ10 with less CoQ10 administration, and 2) An effect of increasing the level of CoQ10 in blood other than CoQ10 Research has been conducted with the aim of searching for certain substances.
As a result, when CoQ10 is used in combination with two or more selected from the group consisting of tocopherols, ascorbic acids and riboflavins, a significant increase in the amount of CoQ10 in the blood, which cannot be predicted with CoQ10 alone, is manifested. I found.
Furthermore, when tocopherols, ascorbic acids and riboflavins are used in combination, it has been found that an excellent effect of increasing the amount of CoQ10 in blood is expressed, and the present invention has been completed.

The present invention is (1) a pharmaceutical composition for increasing the amount of CoQ10 in blood, comprising three or more selected from tocopherols, ascorbic acids, riboflavins and CoQ10,
(2) A pharmaceutical composition for increasing blood CoQ10, comprising tocopherols, ascorbic acids and riboflavins,
(3) A pharmaceutical composition for increasing the amount of CoQ10 in blood, comprising tocopherols, ascorbic acids, riboflavins and CoQ10;
(4) Tocopherols are selected from the group consisting of d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate and dl-α-tocopherol acetate. The pharmaceutical composition according to any one of (1) to (3), which is one type or two or more types,
(5) The pharmaceutical composition according to any one of (1) to (3), wherein the tocopherols are d-α-tocopherol acetate,
(6) The pharmaceutical composition according to any one of (1) to (5), wherein the ascorbic acid is one or more selected from the group consisting of ascorbic acid, calcium ascorbate and sodium ascorbate. ,
(7) The pharmaceutical composition according to any one of (1) to (5), wherein the ascorbic acid is ascorbic acid,
(8) Any of (1) to (7), wherein the riboflavin is one or more selected from the group consisting of riboflavin, sodium riboflavin phosphate, riboflavin butyrate, flavin adenine dinucleotide and flavin adenine dinucleotide sodium (9) The pharmaceutical composition according to any one of (1) to (7), wherein the pharmaceutical composition according to (1) and (9) riboflavin is riboflavin butyrate.
The present invention also provides:
(10) A pharmaceutical composition containing three or more selected from tocopherols, ascorbic acids, riboflavins and CoQ10 for treating or preventing deficiency of CoQ10,
(11) A pharmaceutical composition containing three or more selected from tocopherols, ascorbic acids, riboflavins and CoQ10 for reducing the amount of CoQ10 used in the treatment or prevention of CoQ10 deficiency,
(12) A pharmaceutical composition containing three or more selected from tocopherols, ascorbic acids, riboflavins, and CoQ10 for treating or preventing a disease or the like that requires administration of a large amount of CoQ10,
(13) A medicine containing three or more selected from tocopherols, ascorbic acids, riboflavins and CoQ10 for reducing the amount of CoQ10 used in the treatment or prevention of diseases or the like that require administration of CoQ10 in large quantities Composition,
(14) The pharmaceutical composition according to (1) and (15) the tocopherols, ascorbine, which is a compounding agent containing three or more selected from tocopherols, ascorbic acids, riboflavins and CoQ10 in the same pharmaceutical composition The pharmaceutical composition according to (1), wherein three or more kinds selected from acids, riboflavins and CoQ10 are kits.

Furthermore, the present invention provides
(16) A method of administering three or more selected from tocopherols, ascorbic acids, riboflavins and CoQ10 simultaneously, sequentially or separately,
(17) A method for treating or preventing CoQ10 deficiency, comprising administering an effective amount of the pharmaceutical composition according to any one of (1) to (9) to a mammal, and (18) ) To (9), a method for increasing the amount of CoQ10 in blood is provided by administering an effective amount of the pharmaceutical composition described in any one of (9) to (9).

Since the pharmaceutical composition of the present invention achieves a significant increase in the amount of CoQ10 in the blood at a low cost, it may cause diseases such as diabetes, renal failure, liver cirrhosis, and liver cancer. Useful for diseases, hyperthyroidism, Parkinson's disease, phenylketonuria, mitochondrial abnormalities, statins, low blood pressure, strenuously exercising, and heavy workers.

  In addition, the purpose of body fat reduction, improvement of congestive heart failure symptoms, improvement of palpitations, shortness of breath, swelling, and coldness, anticancer support that stimulated the immune system, support of periodontal disease treatment, treatment of male infertility, skin care Also useful. Furthermore, it is also useful in cases that require administration of high doses, such as congestive heart failure, immune system stimulation, Parkinson's disease and the like.

(Definition)
In the present invention, “CoQ10” is a fat-soluble vitamin-like substance called ubidecalenone, coenzyme (Coenzyme) Q10, ubiquinone, vitamin Q, coenzyme Q (50), ubiquinone 50, etc., and is also synthesized in the body. A function as a coenzyme in a circuit related to ATP production in mitochondria is known. The number “10” in Coenzyme Q10 represents the number of repeating units having a chemical structure called isoprene in the structure. Further, “ubi” of ubiquinone is “where” derived from Latin, and therefore “ubiquinone” is a quinone present everywhere. In fact, as its name suggests, ubiquinone is distributed in every tissue in the body.

  In the present invention, the “tocopherols” are one selected from the group consisting of d-α-tocopherol, dl-α-tocopherol and pharmacologically acceptable salts thereof, and preferably d-α succinate. -Tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate or dl-α-tocopherol acetate, more preferably d-α-tocopherol acetate.

  In the present invention, “ascorbic acid” is one selected from the group consisting of ascorbic acid and pharmacologically acceptable salts thereof, preferably ascorbic acid, calcium ascorbate, sodium ascorbate, Preferably, it is ascorbic acid.

  In the present invention, the “riboflavin” is one selected from the group consisting of riboflavin and pharmacologically acceptable salts thereof, and preferably riboflavin, sodium riboflavin phosphate, riboflavin butyrate, flavin adenine dinucleotide or Flavin adenine dinucleotide sodium, more preferably riboflavin butyrate.

  In the present invention, the “pharmacologically acceptable salt” refers to a basic salt or acidic salt by reacting with a base or acid when the active ingredient of the present invention has an acidic group or basic group. As it can, its salt is shown.

  The “basic salt” is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; N-methylmorpholine salt, triethylamine salt, Organic base salts such as tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid Amino acid salts such as salt and aspartate.

  As the “acid salt”, preferably, hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt and the like; and glycine salt, lysine salt , Amino acid salts such as arginine salt, ornithine salt, glutamate, aspartate.

  The active ingredient of the present invention may absorb moisture by adhering to the atmosphere or recrystallize, and may adsorb water or become hydrate. Are also used in the present invention.

  In the present invention, “treat” means to cure or ameliorate a disease or symptom or to suppress a symptom.

  In the present invention, “increasing the amount of CoQ10” means increasing the amount of CoQ10 in the blood to a certain degree of clinical significance.

  In the present invention, “treating or preventing CoQ10 deficiency” means suppressing a decrease in the blood coenzyme Q10 level caused by a disease or the like, or increasing the blood CoQ10 level to a normal value. To do.

  In the present invention, “a disease or the like that requires administration of a large amount of CoQ10” means that, when CoQ10 is administered at a current normal dose (30 mg / day) or more, a better result can be expected. Examples include, but are not limited to, diabetes, renal failure, liver diseases such as cirrhosis and liver cancer, hyperthyroidism, Parkinson's disease, phenylketonuria, mitochondrial abnormalities, congestive heart failure, palpitation, shortness of breath, swelling, coldness In addition to diseases such as obesity, cancer, periodontal disease, and male infertility, statins, low blood pressure people, intense exercise people, heavy workers, and UV-exposed people can be cited.

  The active ingredients of the present invention can be administered simultaneously, sequentially or separately, but generally it is convenient to administer at the same time clinically, and therefore, it is preferable to administer them as a combination drug. In addition, when it is not preferable for the preparation technique to physically mix the two compounds, each single agent can be administered simultaneously, sequentially or separately.

  In the present invention, “simultaneously” administration includes administration at exactly the same time as pharmacologically acceptable as well as administration at the same time. The dosage form is not particularly limited as long as it can be administered at approximately the same time, but it is preferably a single composition.

  “Sequential or separate” administration in the present invention is not particularly limited as long as it is a dosage form that can be administered separately at different times. For example, one component is administered, and then, after a predetermined time, There are ways to administer other ingredients.

(Acquisition method and content of active ingredients)
dl-α-tocopherol, dl-α-tocopherol acetate, ascorbic acid, riboflavin, riboflavin butyrate, sodium flavin adenine dinucleotide and ubidecarenone (CoQ10) are listed in the 14th revised Japanese Pharmacopoeia.
Components other than the above are also commercially available and can be easily obtained.

When the pharmaceutical composition of the present invention is a solid preparation, the amount of each active ingredient contained in a daily dose (6 tablets) is as follows.
The content of tocopherols is 0.5 mg to 2000 mg, preferably 5 mg to 600 mg.
The content of ascorbic acids is 1 mg to 6000 mg, preferably 20 mg to 3000 mg.
The content of riboflavin is 0.1 mg to 200 mg, preferably 1 mg to 60 mg.
The content of CoQ10 is 0.1 mg to 200 mg, preferably 1 mg to 70 mg.

When the pharmaceutical composition of the present invention is a liquid, the content of each active ingredient is as follows.
The content of tocopherols is 0.05 mg / mL to 200 mg / mL, preferably 0.5 mg / mL to 60 mg / mL.
The content of ascorbic acids is 0.1 mg / mL to 600 mg / mL, preferably 2 mg / mL to 300 mg / mL.
The content of riboflavins is 0.01 mg / mL to 20 mg / mL, preferably 0.1 mg / mL to 10 mg / mL.
The content of CoQ10 is 0.01 mg / mL to 20 mg / mL, preferably 0.1 mg / mL to 7 mg / mL.
In the pharmaceutical composition of the present invention, the dose of each active ingredient varies depending on the type and dosage form of the active ingredient, but is usually as follows.
The dosage of tocopherols is 0.01 mg / kg / day to 40 mg / kg / day, preferably 0.1 mg / kg / day to 12 mg / kg / day.
The dose of ascorbic acid is 0.02 mg / kg / day to 120 mg / kg / day, preferably 0.4 mg / kg / day to 60 mg / kg / day.
The dose of riboflavin is 0.002 mg / kg / day to 4 mg / kg / day, preferably 0.02 mg / kg / day to 1.2 mg / kg / day.
The dosage of CoQ10 is 0.002 mg / kg / day to 4 mg / kg / day, and preferably 0.02 mg / kg / day to 1.4 mg / kg / day.

  The pharmaceutical composition of the present invention may contain additives for formulation as desired, and may further contain other components within a range that does not adversely affect the combined action.

  Specific dosage forms of the pharmaceutical composition of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups) and the like, and are suitable for each dosage form. An additive and a base material can be used as appropriate, and can be produced according to the usual method described in the Japanese Pharmacopoeia.

  In the above dosage forms, various commonly used additives can be used depending on the dosage form.

For example, in the case of tablets, lactose, crystalline cellulose or the like as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, hydroxypropyl cellulose or the like as a coating agent, magnesium stearate or the like as a lubricant Can be used,
In the case of fine granules and capsules, lactose or purified sucrose is used as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, corn starch or the like as an adsorbent, hydroxypropylcellulose or the like as a binder As can be used.

  In each of the above dosage forms, a disintegrant such as crospovidone; a surfactant such as polysorbate; an adsorbent such as calcium silicate; a colorant such as iron sesquioxide and caramel; a stabilizer such as sodium benzoate; A pH adjuster; a fragrance, etc. can also be added.

  Hereinafter, the present invention will be described in more detail with reference to examples and the like, but the scope of the present invention is not limited thereto.

(Example 1) Chewable tablet (1) Constituents in daily dose (Table 1) Weight in 6 tablets (mg)
Component (1a) (1b) (1c)
――――――――――――――――――――――――――――――――――――
D-α-Tocopherol succinate 300 300 250
Ascorbic acid 1000 1000 800
Riboflavin butyrate 12 12 −
CoQ10-10 30
Sucrose fatty acid ester 180 180 180
Calcium silicate 300 300 300
Methylcellulose 75 75 75
Hydroxypropyl cellulose 270 250 300
Ethyl cellulose 12 12 12
Crystalline cellulose 25 25 25
Sucrose 2000 2000 2000
Lactose 1226 1216 1428
――――――――――――――――――――――――――――――――――――

(2) Production method Take the above ingredients and the amount, and produce tablets according to the section of the general formulation “Tablet” (Example 2) Fine granules (1) Constituents in daily dose (Table 2) Weight in 3 packets (mg)
Component (2a) (2b) (2c)
――――――――――――――――――――――――――――――――――――
D-α-Tocopherol acetate 300 300 250
Ascorbic acid 1000 1000 800
Riboflavin butyrate 12 12 −
CoQ10-10 30
Corn starch 600 600 850
Crystalline cellulose 24 25 30
Purified white sugar 3000 2500 2500
Polysorbate 80 8 10 15
Hydroxypropyl cellulose 17 17 30
Dextrin 89 89 89
Fragrance (orange oil) 6 6 6
Lactose 944 1431 1400
――――――――――――――――――――――――――――――――――――

(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section “Granule” of the General Rules for Preparations.

(Example 3) Capsule (1) Components in daily dose (Table 3) Weight in 6 capsules (mg)
Component (3a) (3b) (3c)
――――――――――――――――――――――――――――――――――――
D-α-Tocopherol acetate 300 300 250
Ascorbic acid 1000 1000 800
Riboflavin butyrate 12 12 −
CoQ10-10 30
Magnesium oxide 150 150 130
Corn starch 200 200 350
Polysorbate 80 60 60 60
Magnesium stearate 15 15 15
Lactose 263 253 365
――――――――――――――――――――――――――――――――――――

(2) Manufacturing method Take the above components and quantities, and make a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”, then fill the capsule and make a hard capsule.

(Example 4) Solution (1) Constituents in Daily Dose (Table 4) Weight in 60 mL (mg)
Component (4a) (4b) (4c)
――――――――――――――――――――――――――――――――――――
D-α-Tocopherol acetate 50 50 35
Ascorbic acid 100 100 −
Riboflavin butyrate 10 10 10
CoQ10-10 30
Sodium benzoate 180 180 180
Citric acid 20 20 60
Sucrose 1500 1500 1500
Concentrated glycerin 90 130 210
Polyvinyl alcohol 80 100 130
Ethanol (95%) 50 160 220
Purified water Remaining Remaining Remaining Remaining ――――――――――――――――――――――――――――――――――――

(2) Manufacturing method Take the above components and quantities, and make a liquid according to the section of the Japanese Pharmacopoeia General Rules “Syrup”, then fill it into a brown glass bottle to make the liquid.

(Test example)
(1) Test substance: d-α-tocopherol acetate was manufactured by Riken Vitamin Co., Ltd., ascorbic acid was manufactured by Nippon Roche Co., Ltd., and riboflavin butyrate was manufactured by Mitsubishi Pharma Co., Ltd. (CoQ10) manufactured by Nisshin Pharma Co., Ltd. was used.

(2) Animals As test animals, Covance Research Products Inc. Beagle dogs were purchased at 5 months of age and used after approximately one month of quarantine and acclimatization.

(3) Dosage Form, Preparation Method and Preservation Method The required amount of the test substance calculated based on the body weight of each test animal was filled into a gelatin capsule (1/2 ounce) manufactured by TORPAC. After filling, the capsules were placed in cases separated by animal and stored refrigerated until administration.

(4) Administration route and administration period Capsules filled with the test substance were orally administered by gavage to test animals once a day between 9:00 and 12:30. The test animals were fasted for 2 to 3 hours before administration.

  The administration period was 11 days.

(5) Preparation of test sample About 10 mL of blood was collected from the cephalic vein on the 14th and 7th days before capsule administration (2nd week and 1st week before administration start), and on the 4th, 8th and 12th days after administration. The test animals were fasted for about 18 hours before blood collection.

  The obtained blood was placed in a test tube, allowed to stand at room temperature for 30 minutes to 1 hour, and then serum obtained by centrifugation (about 1600 × g, 10 minutes) was used.

(6) Test method The total amount of serum CoQ10 was determined using the HPLC-ECD method.

(7) Test results The total blood CoQ10 amount in the administration was determined by converting the average of the total blood CoQ10 amount 2 weeks before and 1 week before administration to 100.

  The results obtained are shown in Table 5. Each value is an average value of 5 animals per group.

(Table 5)
Test substance Fluctuation rate of serum total CoQ10 (%)
(Mg / Kg) 4 days after administration 8 days after administration 12 days after administration ――――――――――――――――――――――――――――――――― ―――
Example 2a (500) 106.6 115.8 117.7 *
CoQ10 (10) 145.0 * 173.6 * 138.5
Example 2a (500) 170.6 * 194.0 # 189.9 #
+ CoQ10 (10)
――――――――――――――――――――――――――――――――――――
*: P <0.05 #: p <0.01
Here, Example 2a refers to the fine granule of Example 2-2a (Table 2), and the amount of the active ingredient of Example 2a (500 mg / Kg) is d-α-tocopherol acetate (25 mg / Kg). Corresponds to + ascorbic acid (83 mg / Kg) + riboflavin butyrate (1 mg / Kg).
Moreover, p shows the significant difference test result with the value before administration by paired-t-test.

From Table 5, it can be seen that the pharmaceutical composition containing tocopherols, ascorbic acids and riboflavins exhibits an excellent effect of increasing the total amount of CoQ10 in blood.
Furthermore, it can be seen that a pharmaceutical composition containing tocopherols, ascorbic acids, riboflavins and CoQ10 exhibits an effect of increasing the total amount of CoQ10 in blood, which is even better than can be predicted from a single CoQ10 agent.

Claims (2)

A pharmaceutical composition for increasing blood CoQ10, comprising tocopherols, ascorbic acids and riboflavins. A pharmaceutical composition for increasing the amount of CoQ10 in blood, comprising tocopherols, ascorbic acids, riboflavins and CoQ10.