TWI302457B - A pharmaceutical composition for improving blood lipid or reducing blood homocysteine - Google Patents

Description

1302457 发明Invention Description: [Technical Field] The present invention relates to a pharmaceutical composition containing an HMG-CoA reductase inhibitor and a pyridoxine (especially a pharmaceutical composition for improving blood lipids or high blood cysteine) . [Prior Art] Since ancient times, "human aging with blood vessels" has become an independent risk factor for arteriosclerosis in recent years, and the increase in the amount of homocysteine in the blood has been attracting attention and is widely known. Although homocysteine is an amino acid produced by the metabolic process of methionine, one of the essential amino acids, it is known that due to genetic factors, the lack of vitamin cofactors (folic acid, vitamin B6, vitamin B12), plus Age, sex, decreased renal function, diabetes, other diseases, drugs, smoking, etc., and the amount of hypercysteine in the blood rises (Progress in Medicine, Vol, 19 N0.8, 1999 ρ·49-52), this symptom is called Hyperhomocysteinemia. Now for the treatment of hyperhomocysteinemia, in order to make the metabolism of homocysteine smooth, the folic acid is administered to the first stage of treatment, and the second stage is the administration of vitamin B 6 and vitamin B 1 2 (Progress in Medicine, V ο 1. 1 9 Ν ο . 8 ? 1999, ρ. 52-53). On the one hand, the Statin agent is a drug that specifically inhibits HMG-CoA reductase in vivo to reduce the amount of cholesterol in the blood, but has an effect on the amount of homocysteine in the blood: 1) For 16 patients with hypercholesterolemia Reporting the results of 8 weeks of Prabastastatin to reduce the amount of hypercysteine in the blood (Nikkei Medicine January 01, 2011 p73), 2) Casting Robustin for 1 year 2 In 0705 cases, the average amount of homocysteine-6-1302457 in the blood decreased by 3.7% (a decrease of 1.9% in the pseudo-drug group) (Circulation, ^

Vol.15, 2002, pl 7 7 8 ), 3) In 7 patients with cardiovascular disease, 3 patients were given Adoruba Shistatin, and the remaining 4' patients were treated with Simbastatin for 6 weeks. The amount of cystine in the Adoluba Statin dose group increased, in the 31st Hemophilia Symposium Hamburg 2000, p258), may not be clear. In order to prevent or reduce the risk of progression of atherosclerosis, there is a revelation of statin and folic acid therapy (WO 9 7, 3 8 6 94). φ At present, the use of statin and pyridoxine in W Ο 9 7 / 3 8 6 9 4 page 7 in addition to the statin and folic acid, including Η MG - C ο A synthetase inhibition Agent, squalene epoxidase inhibitor, squalene synthetase inhibitor, ACAT inhibitor, probucol, nicotinic acid, fiber ester, cholesterol absorption inhibitor, bile acid adsorbent, LDL receptor inducer, vitamin B6 , vitamin B12, aspirin, cold amputation, vitamin C, vitamin E and /3 carotene. However, in WO 97,38694, there is no description about the use of the HMG-CoA synthetase inhibitor of the present invention and the two doses of pyridoxine, and the effect of the present invention, that is, the significant improvement of the lipid in the blood of the present invention. There was no record or suggestion for the significant reduction in the amount of homocysteine in the blood. Also in WO 02/43 65 9 as a nutritional supplement for reducing the risk of cardiovascular disease, Η MG - C ο A reductase inhibitor (statin) and 7 adjuvants (ω-3 fatty acids, vitamin E) , vitamin c, vitamin Β 6, vitamin Β 1, 2, folic acid, calcium) combined with the composition. However, this is a known effect of -7-1302457, based on Statin and ω-3 fatty acids to improve blood stasis lipids. 'Vitamin and C have antioxidant effects, and the combination of folic acid and vitamins β 6 and Β 1 2 The composition of the speculative test for reducing the concentration of homocysteine in the blood and reducing the blood pressure by calcium, which is useful for the health of the cardiovascular system, does not disclose specific test data, etc., so the effect of the present invention is also made in WO 02/43 65 9 That is, there is no description or suggestion regarding the significant reduction effect of the present invention on the significant improvement of blood lipids and the high level of cysteine in blood. [Description of the Invention] The present invention is to find a safe agent for improving blood lipids and a safe agent for lowering the amount of homocysteine in the blood, and strives to find out that HMG-Co A reductase inhibitor and pyridoxine are found. The present invention has finally been completed by significantly reducing the action of lipids in the blood and the reduction of the amount of homocysteine in the blood. The present invention relates to: (1) A pharmaceutical composition comprising an HMG-CoA reductase inhibitor and a pyridoxine. The pharmaceutical composition is: (2) a composition for improving the amount of high cysteine in blood lipids or high blood (1), (3) the HMG-CoA reductase inhibitor is selected from Pravastatil®. , Lovatatin, Simvastatin, Fluvastatin, Rivasatin, Atorvastatin, Pitavastatin, and Rothbastatin (R)组成 svastati η) one or more of the compositions described in (1) or (2), (4) the HMG-CoA reductase inhibitor is selected from the group consisting of Prabastatin, Simba Shi-8-1302457 reductase The use of an inhibitor and a pyridoxine. The "HMG-CoA reductase inhibitor" which is one of the components of the pharmaceutical composition of the present invention and the HMG (3-hydroxy-3-methyl) which is a rhythmic enzyme which synthesizes cholesterol. An agent that specifically and antagonically inhibits glutarinyl-C〇A reductase. It is used as a therapeutic agent for hyperlipidemia because it lowers blood cholesterol. This MG MG - C ο A reductase inhibitor includes a natural substance derived from microorganisms, thereby Derived semi-synthetic materials, and all fully synthetic compounds, such as (+)-(3R,5R)-3,5-dihydroxy-7-[(18,), as disclosed in JP-A-5-7-2240 (USP 4,346,227). 23,68,88,8&6-hydroxy-2-methyl-8-[(8)-2-methylbutoxy]-l,2,6,7,8,8a-hexahydro -1-naphthyl]heptanoic acid (hereinafter referred to as Praba statin), (+)-(1 S, 3R, 73, 83) (Japanese Patent Publication No. 5-7 - 1 6 3 3 74 (USP 423 1 93 8 ) ,8&11)-1,2,3,7,8,8&-hexahydro-3,7-dimethyl-8-[2-(211,411)-tetrahydro-4-hydroxy-6- Oxygen-2H-pyran-2-yl]ethyl]-1.naphthyl(S)-2-methylbutyrate (hereinafter referred to as Robustast), JP-A-5-6 - 1 2 2 3 7 5 (+)-(lS,3R,7S,8S,8aR)-l,25357,8,8a-hexahydro-3,7-dimethyl-8-[2-(2R54R) as described in US Pat. No. 4,444,784. -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthyl 2,2-dimethylbutyrate (hereinafter referred to as Simbastatin), special opening (±)-(3R,5S,6£)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-111-吲 described in US Pat. No. 60-500015 (USP4739073) Indole-2-yl]3,5-dihydroxy-6-heptenoic acid (hereinafter referred to as fluorobarba) (Datin), JP-A-i-1, 6974 (118?5006530) (311,58,6 £)-7-[4-(4-fluorophenyl)-2,6-di-(1) -Methylethyl)-5-methoxymethylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid (hereinafter referred to as Libastastatin), JP-A-3-58967 (USP5273995) (3R,5S)-7-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-1302457 phenylaminecarbonyl-1 Η-pyrrole -Buji]-3,5-dihydroxyheptenoic acid (hereinafter referred to as "Adoluba statin"), JP-A-1-2 7 9 8 6 6 (USP 5 8 5 42 5 9 and USP 5856336) Ε)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2,-cyclopropyl-quinolin-3-yl]-6-heptenoic acid (hereinafter referred to as the bus (+)-(3R,5S)-7-[4. (4-Fluorophenyl)-6-isopropyl as described in US Pat. No. 5 - 1 7 8 8 4 1 (USP 5 260440) - 2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl;] -3,5-dihydroxy-6(E)-heptenoic acid (hereinafter referred to as Rosbergastatin) and other statin compounds . Further, the HMG-CoA reductase inhibitor of the component of the pharmaceutical composition of the present invention also contains other HMG-CoA reductase inhibitors disclosed in the above-mentioned HMG-CoA reductase inhibitor. The planar structural formula of a representative of the HMG-CoA reductase inhibitor is as follows.

Simba Statin Finbastatin 1302457

Lipa Statin

Adorba Statin

One of the components of the composition of the traditional Chinese medicine composition of the present invention is pyridoxine, 1:1, furfural, pyridoxamine or a salt thereof, preferably pyridoxine hydrochloride or pyridoxine phosphate. Aldehyde or pyridoxamine phosphate. More preferred is pyridoxine hydrochloride. The above-mentioned respective components contained in the present invention may be contained in a pharmacologically acceptable salt. If the component has a basic functional group, it may be, for example, a hydrofluoric acid salt, a hydrochloride salt, a hydrobromide salt, a hydroiodide salt or the like. Hydrohalide; inorganic acid salt such as nitrate, perchlorate, sulfate, phosphate; lower organic sulfonate such as methanesulfonate, triflate, ethanesulfonate; An aryl sulfonate such as p-toluenesulfonate; an amine acid salt such as alanate or glutamate; and a carboxylic acid such as fumaric acid, butyl 1302457 monoacid, citric acid, tartaric acid, oxalic acid, maleic acid salt. When the component has an acidic functional group, it may be an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a 15 salt or a magnesium salt, an aluminum salt, an iron salt, a zinc salt, a copper salt or a nickel salt. a metal salt such as a cobalt salt; an inorganic salt such as an ammonium salt; a third octylamine salt; a bis; an amine salt, a morpholine salt, a glucosamine salt, an alkyl phenylglycine salt, an ethylenediamine salt, and an N-methyl gluco Glycosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, _: benzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt An amine salt such as an organic salt such as N-benzyl-phenethylamine salt, a piperazine salt, a tetramethylammonium salt or a hydroxymethylaminomethane salt, such as Prabastatin, preferably Prapastatin sodium, Such as Adorba Badin's when 'Yaduolu Bastaratin calcium hydrate. When the respective components contained form a hydrate or a solvate, a pharmaceutical composition containing these hydrates or gluten-based compositions is also included in the present invention. In the present invention, "improving blood lipids" means lowering blood lipids to a clinically significant extent, lowering blood triglycerides, lowering blood LDL or lowering total blood cholesterol. In the present invention, "improving the amount of homocysteine in high blood" means suppressing an increase in the amount of homocysteine in high blood and reducing the amount of homocysteine in high blood. The increase in the amount of hypercysteine in high blood is, for example, ageing, smoking, dystrophic disorders associated with homocysteine metabolism, pharmacy, decreased renal function, chronic renal failure, diabetes, insulin resistance, malignancy Tumor, hypothyroidism, and pernicious anemia. In the present invention, "a disease caused by a high amount of homocysteine in a high blood" is not particularly specific as long as the amount of hypercysteine in the blood is too high, for example, 1302457 pharmaceutical composition is reduced by HMG-CoA. The enzyme inhibitor and pyridoxine are essential components, and may contain additives which are formulated as desired, and may further contain other components which have no adverse effect on the action of HMG-CoA reductase to inhibit the use of pyridoxine and pyridoxine. . It is preferable to use only the HMG-CoA reductase inhibitor and pyridoxine as active ingredient contents, and further contain a pharmaceutical composition of the formulated additive. The specific dosage form of the pharmaceutical composition of the present invention may be, for example, a tablet, a fine granule (including a powder), a capsule, a liquid (containing a syrup), and the like, and an additive and a substrate suitable for each agent are suitably used, and may be used in Japan. It is manufactured by the usual method described in the Pharmacy Bureau. Various additives which are generally used can also be used in the form of the above-mentioned respective dosage forms. For example, in the case of a tablet, lactose, crystalline cellulose or the like is used as an excipient, magnesium or magnesium sulphate or magnesium oxide is used as a stabilizer, and hydroxypropylcellulose or the like is used as a coating agent to magnesium stearate. Wait for a slip agent. In the case of fine granules and capsules, excipients such as lactose or refined white sugar, stabilizers such as magnesium citrate or magnesium oxide, and adsorbents such as corn starch, hydroxypropyl cellulose, etc. The binder is used. In the above-mentioned respective dosage forms, a disintegrating agent such as polyvinylpolypyrrolidone or a surfactant such as polysorbate; an adsorbent such as calcium citrate; a coloring agent such as ferric oxide or caramel; and benzene may be added as necessary. Stabilizers such as sodium formate; p Η conditioner; spices, etc. In the present invention, "application" means a method of administering two or more active ingredients to a human body at the same time or at intervals. In the case of administering the pharmaceutical composition in the present invention, the components may be administered separately or separately. The above-mentioned "simultaneous" administration also includes the pharmacological capacity of 1302457 2 0% in addition to the simultaneous simultaneous administration. When the pharmaceutical composition of the present invention is a liquid preparation, the amount of the component may be, for example, the content of adolubastatin and pramastatin is usually 0.01 to 10 mg/mL·, and it is 〇.05 to 5 mg/mL. Further, the content of simbastatin is usually 0.005 to 5 mg/mL, preferably 0.03 to 3 mg/mL, and the content of pyridoxine is usually 0.1 to 20 mg/mL, preferably 1 to 10 mg/mL. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to examples and the like, and the scope of the invention is not limited thereto. [Examples] [Example 1] Lozenges 6 (mg) 6 in the mirror (mg) 6 ingots (mg) Prabastatin sodium 20 - • Simbastatin - 10 Indobarta Statin fishing - - 2 0 pyridoxine 100 100 _ pyridoxal phosphate - - 60 magnesium oxide 400 400 400 magnesium metasilicate magnesium silicate 140 140 140 crystalline cellulose 120 120 120 corn starch 140 140 140 hydroxypropyl cellulose 60 60 60 carboxymethyl Ether Cellulose Sodium 15 15 1 5 Magnesium Stearate 25 25 25 Triacetin 6 6 6 Lactose Appropriate amount of appropriate amount δ 卞 1200 1200 1200 -18- 1302457 (2) Method of preparation of the above ingredients and components according to the Japanese General Regulations The lozenge manufactures tablets. [Example 2] Fine granules (1) Ingredients 3 packs (mg) 3 packs (mg) 3 packs (mg) Prabastatin sodium 20 • Simbastatin-10 - Adoluba Shistatin calcium - - 20 pyridoxine 100 100 - pyridoxal phosphate - - 60 magnesium oxide 400 400 400 magnesium metasilicate magnesium silicate 140 140 140 refined white sugar 1400 1400 1400 stevia extract 15 15 1 5 corn starch 1200 1200 1200 poly sorbic acid Ester 8 0 80 80 80 Magnesium stearate 25 25 25 Lactose Appropriate amount Appropriate amount 4 3 00 4 3 0 0 4 3 00

(2) Preparation method The above-mentioned components and components are manufactured into fine granules according to the general term "granules" of the preparations for the Japanese government. 1302457 [Example 3] Capsule (1) Ingredient 6 Capsules (mg) 6 Capsules (mg) 6 Capsules (mg) Praba Shistatin Sodium 20 - • Simbastatin - 10 - Adorba Basatin Calcium - 2 0 pyridoxine 100 100 pyridoxal phosphate - 60 magnesium oxide 400 400 400 corn starch 600 600 600 polysorbate 8 0 50 50 50 magnesium stearate 25 25 25 lactose right amount appropriate amount of capsule 480 480 480 Total 2 3 00 23 00 2 3 00 (2), the method of making the above ingredients and components in accordance with the general provisions of the "Nuclear" of the preparation of the daily preparation of fine particles, and then filling the capsule into a hard capsule. [Example 4] syrup -20-1302457 (1) Ingredient 6 mL Medium (mg) 6 mL Medium (mg) 6 mL Medium (mg) Praba statin sodium 20 - Zinbabadin - 10 Adorba statin calcium - - 20 Pyridoxine 100 100 • Pyridoxal phosphate - 60 Sodium benzoate 240 240 240 Citric acid 60 60 60 White sugar 1500 1500 1500 Concentrated glycerol 1800 1800 1800 Polyvinyl alcohol 120 120 120 Ethanol (9 5 % ) 500 500 500 Hydrochloric acid Appropriate amount of moderate amount of sodium hydroxide, moderate amount, appropriate amount of refined water, appropriate amount of appropriate amount (2)

The syrup is prepared by adding the above ingredients and components to the "syrup" of the general formulation of the Japanese medicine, and then filling the syrup in a brown glass bottle. [Example 5] Lozenge 1302457 (1) Ingredient 6 sharp medium (mg) Adodalustatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Magnesium metasilicate magnesium silicate 140 Crystalline cellulose 120 Corn starch 140 Hydroxypropyl Cellulose 60 Carboxymethyl Cellulose Sodium 15 Magnesium Stearate 25 Triacetin 6 Lactose Appropriate Total 1200 (2) Method of Preparation The above ingredients and the ingredients are used to make tablets in accordance with the general provisions of the "Nipples". [Example 6] Fine granule-22-1302457 (1) Ingredient 3 packs (mg) Adolavir statin calcium 20 Guanosin hydrochloride 100 Magnesium oxide 400 Magnesium metasilicate magnesium silicate 140 Refined white sugar 1400 Stevia extract Item 15 Corn Starch 1200 Polysorbate 80 80 Magnesium Stearate 25 Lactose Appropriate Total 43 00 (2) Method The above ingredients and the components are used to prepare fine granules according to the general term "granules" of the Japanese preparations. [Example 7] Capsule-23-1302457 (1) Ingredient 6 Capsules (mg) Adoluba Shistatin Calcium 20 Pyridoxine Hydrochloride 1 00 Magnesium Oxide 400 Corn Starch 600 Polysorbate 8 0 50 Stearic Acid Magnesium 25 Lactose suitable capsule 480 Total 2 3 00 (2) Preparation method The above ingredients and the components are prepared according to the general provisions of the "granules" of the Japanese preparations, and then the capsules are filled with hard capsules. [Example 8] syrup (1) Ingredients 6 mL Medium (mg) Adloba Bastatin Calcium 20 Pyridoxine Hydrochloride 1 00 Sodium Benzoate 240 Citric Acid 60 White Sugar 1500 Concentrated Glycerin 1800 Polyvinyl Alcohol 120 Ethanol (9 5 % ) 500 hydrochloric acid, an appropriate amount of sodium hydroxide, an appropriate amount of refined water -24-1302457 (2) Method of preparation The syrup is prepared by adding the above ingredients and components to the "syrup" of the general preparation of the Japanese medicine, and then filling the syrup in a brown glass bottle. [Test agent] [Test Example 1] Evaluation test of lipid quality in blood (1) Test substance Prabastastatin sodium was manufactured by Sankyo Co., Ltd., Simba Statin and Adorabastatin calcium were manufactured by Chemtechlab AG. Pyridoxine hydrochloride is manufactured by Japan Roche Co., Ltd. (2) Animals Test animals were purchased from Covance Research Products Inc. for 5 months old male wax dogs, which were used after quarantine and domestication for about 1 month. (3) Formulation method of administration, preparation method of preparation, and preservation method of preparation The test substance which was calculated according to the body weight of the test animal was filled in a capsule of TO RPAC (1/2 ounce). After filling, the capsules are placed in a box divided by animals and stored in cold storage until they are administered. (4) During the period of administration and administration, the capsules filled with the substance to be tested are forcibly administered orally to the test animals between 9:00 and 1 2:30. The test animals were hunger strike for 2 to 3 hours before administration. The period of investment is 1 1曰. (5) The test capsules of the test materials were administered before the first 14 and 7 days (the second week and the first week before the start of the investment). Blood was collected from the lateral cutaneous vein on the 4th, 8th, and 12th after the administration. About 〇mL. The animals were hunger strike for about 18 hours before blood collection. -25- 1302457 The obtained blood was transferred to a test tube, and after standing at room temperature for 30 minutes to 1 hour, it was centrifuged (about 16 〇〇 x g, 1 〇), and the resulting blood was used. (6) Test method Inspection results 'Total cholesterol is determined by enzyme measurement method, HDL homogenization method, LDL using deuterated modified enzyme method, and triglyceride using whole enzyme method. Further, a clinical chemical automatic analyzer (TBA-120FR, manufactured by Toshiba Corporation) was used for the measurement. (7) Test results ft Π 素 素 、, with Praba statin sodium, simbastatin and Adorabastatin calcium in each dose of a single dose The average of the lipid masses in the blood before and one week ago was calculated as 1 〇〇. The results obtained are shown in Tables 1 to 6. Each of them is the average of 5 groups of 5 groups. Table 1 Test substance (mg/Kg) Total cholesterol change rate in blood % After administration, 4 曰 after administration, 8 曰 after administration, simbastatin (1) 94.8 94.1 92.4 Pyridoxine hydrochloride (5 0 ) 98.0 93.3 90.5 Simbastatin (1) + 88.5 83.6 80.0 Pyridoxine hydrochloride (5 0 ) -26- 1302457

Table 2 Test substance (mg/Kg) % change rate of LDL in blood After administration, 4 days after administration, 8 曰 after administration, 12 曰 Simabastatin (1) 83.9 90.4 8 1.3 Pyridoxine hydrochloride (50) 10 1.7 95.0 9 1.4 Simbastatin (1) + 83.0 70.4 70.4 Pyridoxine hydrochloride (50) Table 3 Test substance (mg/Kg) Change rate of triglyceride in blood % After administration 4 days after administration曰 与 后 1 1 曰 曰 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 Substance (mg/Kg) % change rate of LDL in blood. After administration of 4 曰, 8 曰 after administration, 12 曰 Prabastatin sodium (2) 92.6 91.6 90.4 Pyridoxine hydrochloride (50) 10 1.7 95.0 9 1.4 Prabastatin sodium (2) + 50.1 54.4 65.1 Pyridoxine hydrochloride (5 0 ) -27- 1302457 Table 5 Test substance (mg/Kg) The rate of change of LDL in blood is 4% after administration on the 4th day after administration. After the administration of 1 2 曰 Adorba Shidatin fishing (2) 82.4 82.1 83.6 Pyridoxine Hydrochloride (5 0) 101.7 95.0 9 1.4 Adorubastatin calcium (2) + pyridoxine hydrochloride (5 0 ) 7 6.1 73.8 66.2 Table 6 Test substance (mg/Kg) The rate of change of triglyceride in blood is % after administration of 4 曰 after administration of 8 曰 after administration of 2 2 曰 Adalba statin calcium (2) 77.2 86.3 86.4 Pyridoxine hydrochloride (5 0 ) 83.8 86.7 8 1.2 Adorenbastatin calcium (2) + pyridoxine hydrochloride (50) 59.1 68.7 65.4 Due to Simbastatin, Prabastatin or Adoruba Shistatin and pyridinium The combination of coughs presents a significant improvement in lipids in the blood. [§ Test Example 2] Evaluation test for the amount of homocysteine in blood (1) Test substance Adoluba Shistatin calcium was manufactured by Chemtechlab AG, and salt acid B was made by Japan Roche Co., Ltd. (2) Animals Type 5 Animals purchased from Covance Research Products Inc. for 5 months old males! Dogs, used after quarantine and domestication for about 1 month. (3) S and dosage form, preparation method of preparation and preparation method of preparation -28- 1302457 · The necessary amount of the substance to be tested according to the body weight of the test animal is filled in the capsule of - TO RPAC company (1/2 plate ). After filling, the capsules are placed in a box divided by animals and stored in cold storage until they are administered. (4) During the period of administration and administration, the capsules filled with the substance to be tested are forcibly administered by the test animals between 9:00 and 12:30 once a day. The test animals were hunger strike for 2 to 3 hours before administration. The period of investment is 1 1曰. (5) The capsules to be tested are administered on the first 14 and 7 days (the second week and the first week before the start of the application), and the sacral veins are removed from the sacral skin on the 4th and 8th Blood collection is about 1 〇 mL. The animals were hunger strike for about 18 hours before blood collection. The obtained blood was transferred to a test tube, and after standing at room temperature for 30 minutes to 1 hour, it was centrifuged (about 1 600 ng, 10 minutes), and the resulting blood was used. (6) Test method The amount of homocysteine in the blood is determined by the HPLC method commonly used in clinical examinations. (Test results) The lipid quality of adolubastatin calcium and pyridoxine hydrochloride in each dose and the β-complexing agent, in order to affect the lipid quality of various blood before 2 weeks and 1 week ago. The average is determined by the conversion of 1 0 0. The results obtained are shown in Table 7. Each of them is the average of 5 groups of 5 groups. -29·

Claims (1)

1302457 corpse 曰修iL for the weeping page f No. 9 2 1 1 8 8 0 5 "Used to improve lipids in the blood or reduce the plasma composition of homocysteine in blood" (August 20, 2008 amendment) Patent application scope: 1. A pharmaceutical composition for improving lipids in blood, which comprises 0.01 to 5% of Pravastatin Sodium, 0.005 to 3% of Simvastatin, or 0.01 to 5 % of Atorvastatin Calcium, one or more HMG-CoA reductase inhibitors, and 0.01 to 30% of pyridoxine hydrochloride, HMG-CoA reductase The ratio of the inhibitor to the pyridoxine hydrochloride is 1 to 2:50. 2 - A pharmaceutical composition for improving the amount of homocysteine in high blood, which comprises 1 to 5 % of Prabastastatin sodium, 0.005 to 3% of Simbastatin, or 0.01 ~5% of Adorba Statin Calcium! The ratio of the HMG-CoA reductase inhibitor of the species or the two types of HMG-CoA reductase inhibitors, and the 1% to 3% by weight of the pyridoxine hydrochloride 'HMG-CoA reductase inhibitor to the pyridoxine hydrochloride is 1 to 2:50. 3 · The composition of claim 1 or 2 of the patent scope, wherein the Η M G - C ο A reductase inhibitor is 〇 0 1 to 5 % of Prabastastatin sodium. 4. If you apply for a patent scope! Or a composition of 2, wherein the HMG_CoA Reducing & Inhibitor is 〇. 0 1~5 % of Adorba Statin.