TW200404533A - Blood lipid ameliorant compositions - Google Patents

Abstract

The present invention provides a superior pharmaceutical composition for decreasing lipid in blood. The present invention relates a pharmaceutical composition comprising the HMG-CoA reducase inhibitor and bile acids.

Description

200404533 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a pharmaceutical composition containing a HMG-CoA reductase inhibitor and a bile acid which reduce blood lipids. [Prior art] A statin is a drug that specifically and agonistically inhibits HMG-CoA reductase in a living body and lowers the sterols in the blood. In addition, bile acid components are known to have an effect of improving bile stagnation, cholesterol-type gallstone dissolution, and cholesterol intestinal absorption inhibition (for example, refer to Japanese Pharmaceutical Products 2002, Japan Medical Information Center, Times). On the one hand, the use of statins and bile acids is generally about the treatment of cholesterol gallstones. On the other hand, it is scattered in the bile properties that cause the bile to be inhibited from flowing to the duodenum. Hepatic impairment, biliary cirrhosis, depressive jaundice, and secondary hypercholesterolemia are documented in the literature. The previous examples of statin and bile acid ingredients are listed below. 1) Pravastatin and ursodeoxycholic acid are used to dissolve cholesterol gallstones (for example, refer to New Drugs and Clinical Medicine, Vo 1.43 Νο · 1 1994 p.101-105 ). 2) Simvastatin and ursodeoxycholic acid are used to dissolve cholesterol gallstones (for example, refer to diagnosis and treatment, Vo 1.3 3 N 0.1 1 1996 1996 ρ · 1477-1488) ° 3 ) Lovastatin and ursodeoxycholic acid are used to reduce the bile saturation index of bile 200404533 juice (see Gastroenterology, Vol. 9 8 1 99 0 P.1572-1 576) ° 4) Pravastatin Chewing with cheno-deoxycholicacid is used to treat van Bogaert or Achilles tendon hypertrophy (for example, refer to the records of the Japanese Society of Clinical Metabolism, Vo 1.2 9 1 992 ρ · 1 84 -1 85) ° 5) Simvastatin and ursodeoxycholic acid, but it is suggested to be used for the treatment of bile stagnation liver disease (see Gut, Vol. 4 4 No .3 1 999 ρ · 5 52-55 6). 6) 治疗 Treatment of hyperlipidemia with pravastatin and ursodeoxycholic acid (see Arteriosclerosis, Vol. 20 1 992 ρ · 85 7). The combination of bile acids and statins is consistent with the evaluation of gallstone dissolution therapy for reducing the concentration of bile in the bile, but data such as opposing opinions do not exist. On the one hand, the status in the well-known literature on the effects of statin and bile acid dysprosium on lipids in blood is not consistent. For example, when there are bile duct diseases such as gallstones, there are reports of ineffectiveness (new drugs and clinical , Vo 1.43 No. 1 1 994 p. 101-105, and Diagnosis and New Drugs, Vol. 33 No. 10 1996 p. 1477-1488), and a report on its effectiveness (J. Gastroenterology Vo 1.29 1994 ρ47-55 ; Lancet Vo 1.336 1990 ρ.1196 and the Journal of the Japanese Society of Digestive Diseases Vol. 90 1 993 ρ · 539), their views may not be consistent. In addition, there are reports of ineffectiveness in patients with nonfamilial hypercholesterolemia or healthy people without gallstones (Gastroenterology, Vol. 9 8 1 990 p. 1572-1576; recorded by the Japanese Society of Clinical Metabolism, Vo 1.29 1992p .184-185 and Gut, Vol · 44 No · 3 1 99 9 ρ · 5 5 2-5 5 6), and report of effectiveness 200404533 (arteriosclerosis, Vo 1.2 0 1 9 9 2 p. 8 5 7) , Its views are not necessarily consistent. That is, the effect of the statin and bile acid on blood lipids is estimated to be difficult from known literature. [Summary of the invention] In view of these circumstances, the present inventors have reached a situation where it is possible to judge the effects of statins and bile acid components on animal tests that comprehensively manage species, age, feed content, and living environment. , And repeatedly focus on research. _ As a result, the use of statins and bile acid components can significantly reduce blood lipids, and thus completed the present invention. HMG-CoA reductase inhibitor, because it can be taken for a long period of time, it is desirable to take a small amount to obtain a blood lipid lowering effect. Furthermore, for patients with hyperlipidemia with bile stagnation or cholelithiasis For animals, it is desirable to be able to treat them efficiently at one time. The present invention provides (1) a pharmaceutical composition capable of reducing blood lipids, which comprises a HMG-CoA reductase inhibitor and a bile acid. (2) The pharmaceutical composition according to (1), wherein the HMG-CoA reductase inhibitor is pravastatin, rovastatin, simvastatin, favastatin (f 1 uvastati η), and cerivastati (cerivastati) η), one or more selected from the group consisting of atorvastatin, pitavastatin, and rosuvastatin. 200404533 (3) The pharmaceutical composition of (1), wherein the HMG-CoA reductase inhibitor is simvastatin and / or atorvastatin. (4) The pharmaceutical composition of (1), wherein the bile acids are from ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, bile acid, bile powder, bile extract, bear bile and One or two or more components selected from a group consisting of bezoar. (5) The pharmaceutical composition of (1), wherein the bile acids are ursodeoxycholic acid. (6) The pharmaceutical composition according to (1), which is a composition for preventing or treating hyperlipidemia or arteriosclerosis. The present invention further provides (7) a combination of a HMG-CoA reductase inhibitor and a bile acid, which is administered at the same time or individually as a HMG-CoA reductase inhibitor and a bile acid in order to reduce blood lipids, and (8) in order to improve blood lipid HMG-CoA reductase inhibitors and bile acids. Furthermore, the present invention provides (9) a method for simultaneously or individually administering an HMG-CoA reductase inhibitor and a bile acid to reduce blood lipids. In the above (9), the preferred method is (10) The method described in (9) 'is used to prevent or treat diseases causing high blood lipid concentration' and (11) The method described in (9) is' It is used to prevent or treat hyperlipidemia or arteriosclerosis. 200404533 "HMG-CoA reductase inhibitor", which is one of the constituents of the present invention, is a specific and antagonistic regulating enzyme HMG (3-hydroxy-3-methylglutaryl) that inhibits cholesterol biosynthesis. -CoA reductase agent, because it can lower blood cholesterol, has been used as a therapeutic agent for hyperlipidemia. These HMG-CoA reductase inhibitors are natural substances derived from microorganisms, including semi-synthetic substances and fully synthetic substances derived from them, such as described in JP-A 57-2240 (USP4346227) (+)-(3R, 5R) -3,5-dihydroxy-7-[(18,23,63,83,8 & 10-6-hydroxy-2-methyl-8-[(3) -2-methylbutanyloxy [Hexyl] -1,2,6,7,8,8 ^ hexahydro-1-naphthyl] heptanoic acid (hereinafter abbreviated as pravastatin); Japanese Patent Laid-Open No. 5 7- 1 63 3 74 (USP423 1 93 8) described in (+)-(lS, 3R, 7S, 8S, 8aR) -1, 2, 3, 7, 8, 8 & -hexahydro-3,7-dimethyl-8- [2- [ (2, 4,10-tetrahydro-4-hydroxy-6-oxy-21piperan-2-yl] ethyl-bonaphthyl (S) -2-methylbutanoate (hereinafter abbreviated as lovastatin ); Disclosed in JP-A-56-122375 (USP4444784) (+)-(lS, 3R, 7S, 8S, 8aR)-1, 2, 3, 7, 8, 8a-hexahydro-3, 7-two Methyl-8- [2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxy-2H-piperan-2-yl] ethyl-1-naphthyl 2,2-dimethyl Butyrate (hereinafter abbreviated as Simvastatin); Special Table No. 6 0-5 0 0 0 1 5 (USP 4 7 3 9 0 7 3) (Earth)-(3R *, 5S *, 6E ) -7- [3- (4-fluorophenyl) -1- (Bu Ethyl) -1Η-indol-2-yl] -3,5-dihydroxy-6-heptenoic acid (hereinafter abbreviated as vastatin); Japanese Patent Laid-Open No. 1-2 1 6974 (USP5 0065 3 0 ) (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2,6-bis- (1-methylethyl) -5-methoxymethylpyridine-3- [] Yl] -3,5-dihydroxy-6-heptenoic acid (hereinafter abbreviated as rivastatin); (3R, 5S) fluorophenyl) described in Japanese Patent Application Laid-Open No. 3-58967 (USP5273995) -5- (1 -Methylethyl) -3-phenyl-4-phenylaminocarbonyl-200404533 1 hydrazone-pyrrole-1-yl] -3,5-dihydroxyheptanoic acid (hereinafter abbreviated as atorvastatin); Japanese Patent Application Laid-Open No. 1-279866 (USP5854259 and USP5856336) describes (E) -3,5-dihydroxy-7- [4 '-(4' '-fluorophenyl) -2, cyclopropyl-quinoline-3 '-Yl] -6-heptenoic acid (hereinafter abbreviated as pitavastatin); or described in JP-A-5-178841 (USP5260440) (+)-(3R, 5S) -7- [4- (4- Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptanoic acid (hereinafter The statin compound (called Russellstatin) is omitted. The HMG-CoA reductase inhibitor, which is a component of the present invention, includes other HMG-CoA reductase inhibitors described in the aforementioned publication. The following is the planar structure formula of the representative of HMG-CoA reductase inhibitor.

-10- 200404533

Atorvastatin

h3c ^ N'nso2ch3

F OH

COOH Russell statin-11-200404533 In addition, bile acids can be exemplified by ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, bile acid, end of bile or bile extract, etc. Animal bile such as bear bile or animal gallstone such as bezoar is preferably ursodeoxycholic acid. The ingredients contained in the present invention may generally contain pharmacologically acceptable salts. These salts are as follows. When the component has a basic functional group, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodate; nitrates, perchlorates, sulfates, and phosphoric acid Inorganic acid salts such as salts; lower organic sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; aromatic sulfonates such as benzene sulfonate and p-toluene sulfonate; birds Amino acid salts such as amine salts and glutamates; and carboxylic acid salts such as fumaric acid, succinic acid, citric acid, tartaric acid, nitric acid, maleic acid, etc .; when the component has an acidic functional group, Examples include alkali metal salts such as sodium, potassium, and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; metal salts such as aluminum, iron, zinc, copper, nickel, and cobalt salts; ammonium; Inorganic salts such as salt; t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycinate methyl salt, ethylene diamine salt, N-methyl glucosamine sugar salt, guanidinium salt , Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylene diamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, Amine salts such as organic salts such as N-benzyl-phenethylamine methane salt, piperidine salt, and tetramethylammonium salt. For example, in the case of atorvastatin, atorvastatin calcium hydrate is preferred. The present invention contains hydrates or solvates formed by each component, and may also contain hydrates or solvates.

-12- 200404533 Furthermore, the "reduction" in the blood lipid-lowering composition of the present invention refers to the reduction of blood lipids to a clinically significant level. 'For example, the reduction of triglyceride in blood, Decreased LDL in the blood or decreased total cholesterol in the blood. Therefore, the composition of the present invention can effectively treat diseases caused by local blood lipid concentration. Aspects of the Invention The composition of the present invention contains a HMG-CoA reductase inhibitor, such as pravastatin, rovavastatin, simvastatin, ivervastatin, rivastatin, atorvastatin, pitavastatin, or Russell Statins are available in JP-A-Sho 57-2240 (USP4346227), JP-A-Sho 57-163374 (USP4231938), JP-A-Sho 56-122375 (USP4444784), and TB-Sho 60-500015 (USP47 3 907 3) , Japanese Patent Application No. 1 -2 1 6974 (USP 5 0 0 6 5 3 0), Japanese Patent Application No. 3-58967 (USP5273995), Japanese Patent Application No. 1-279866 (USP5854259 and USP5856336) or Japanese Patent Application No. 5-178841 (USP5260440) ) And can be easily prepared. Among the bile acids, for example, ursodeoxycholic acid is contained in the i 4th correction Japanese Pharmacy and is easily obtained, and other bile acids are also easily obtained by those on the market. The pharmaceutical composition of the present invention contains HMG-CoA reductase inhibitors and bile acids as essential components, and the applicant may also contain formulated additives, and further It is also good to include other ingredients in the range where there is no adverse effect on application. The preferred pharmaceutical composition is an HMG-CoA reductase inhibitory 200404533 agent and a bile acid which are effective ingredients and further formulated additives. Specific dosage forms of the pharmaceutical composition of the present invention include, for example, lozenges, fine granules (including powders), capsules, liquids (including syrups), and the like, which can be appropriately used in accordance with the usual methods described in the Japanese Pharmacy and the like It is suitable for the manufacture of additives such as various dosage forms. In each of the above dosage forms, various additives commonly used are used depending on each dosage form. For example, in the case of tablets, excipients such as lactose and crystalline cellulose; stabilizers such as magnesium aluminosilicate or magnesium oxide; coating agents such as hydroxypropyl cellulose; lubricants such as magnesium stearate Agent. In the case of fine granules and capsules, excipients such as white sugar or refined white sugar; stabilizers such as magnesium aluminosilicate or magnesium oxide; adsorbents such as corn starch; and binding agents such as carboxypropyl cellulose. In the above various dosage forms, if necessary, disintegrating agents such as polyvinyl polypyrrolidone; surfactants such as polysorbate; adsorbents such as calcium silicate; coloring agents such as ferric oxide and caramel; benzoic acid Stabilizers such as sodium; pH 値 regulators; perfumes, etc. _ "Use" in the present invention refers to a method in which two or more active ingredients are administered to the human body simultaneously or separately over time. When the composition of the present invention is administered, it is achieved by simultaneously or separately administering the individual components of the composition. The above-mentioned "simultaneous" administration refers to all simultaneous administrations, and can also include other pharmacologically acceptable levels of time before and after. This form of administration is not particularly limited to reducible simultaneous administration. The form of administration is preferably a single composition of -14-200404533. The above-mentioned "separate by time" administration is not particularly limited to the form of individual administration at different times. For example, after one of the components is administered, the second is after the selected time. Method. In addition, when the composition of the administration composition is a combination of three or more types, the so-called "simultaneous or time-dependent administration" refers to the method of all simultaneous administrations and the individual administrations at different times. Method, a method of administering two or more kinds of residual medicaments at the same time, or a method of administering two or more kinds of medicaments at different times and simultaneously administering the residual medicaments. Examples of mammals to be administered to the pharmaceutical composition of the present invention include, for example, humans, dogs, cats, rabbits, cows, horses, sheep, or pigs, preferably humans or dogs, and more preferably humans. Since the pharmaceutical composition of the present invention has a function of lowering blood lipids, it can be used as medicine for preventing or treating diseases caused by high blood lipid concentrations, such as hyperlipidemia or arteriosclerosis. The dosage of the HMG-CoA reductase inhibitor in the present invention will vary depending on the type and dosage form of the HMG-CoA reductase inhibitor, but it is usually 1 mg to 200 mg per day, preferably 5 mg to 160 mg per day. The dosage of bile acids in the present invention is usually 10 mg to 5000 mg, preferably 10 100 mg to 2000 mg per day. The weight percentage of the pharmaceutical composition of the present invention when the solid preparation is used, for example, in the case of simvastatin 0.005 to 3%, preferably 0.03 to 2%. In the case of atorvastatin, it is usually 0.00 to 5%, preferably 0.05 to 3%. Furthermore, ursodeoxycholic acid The content is usually from 0.3 to 90%, preferably from 3 to 50% compared to 200404533. · Stomach-containing when the blood lipid-lowering agent of the present invention is liquid _ 5 cases 1 The content of simvastatin is usually 0.005 to 5 mg / ml, preferably 0.03 to 3 mg / ml, and atova The content of statin is usually 0.01 to 10 mg / ml, preferably 0.05 to 5 mg / ml. Furthermore, the content of ursodeoxycholic acid is usually 1 to 100 mg / ml, preferably 10 to 50 mg / ml. [Embodiment] The best mode for carrying out the invention (Example) φ The examples shown below are intended to further describe the present invention in detail, but not to limit the scope of the present invention. -16- 200404533 Example 1 Tablets (1) Ingredients 6 tablets (mg) 6 tablets (mg) 6 tablets (mg) Atorvastatin calcium 20 — 10 Simvastatin — 10 5 Ursodeoxycholic acid 300 300 300 Magnesium oxide 400 400 400 Magnesium aluminosilicate 140 140 140 Crystalline cellulose 120 120 120 Corn starch 140 140 140 Hydroxypropyl cellulose 60 60 60 Cross-linked carboxymethyl cellulose Sodium 15 15 15 (croscarmellose sodium) Magnesium stearate 25 25 25 Triacetin 6 6 6 Suitable amount of lactose Suitable amount of total amount 1200 1200 1200 (2) The ingredients and ratios mentioned above in the manufacturing method are in accordance with the general rules of the Japanese Bureau of Preparations " "Lozenges" to make lozenges. -17- 200404533 Example 2 Fine granules (1) Ingredients 3 packets (mg) 3 packets (mg) 3 packets (mg) Atorvastatin calcium 20 — 10 Simvastatin — 10 5 Bear fruit deoxygenation Cholic acid 300 300 300 Magnesium oxide 400 400 400 Magnesium aluminosilicate 140 140 140 Refined sugar 1400 1400 1400 Stevia extract 15 15 15 (stevia) extract corn starch 1200 1000 1100 polysorbate 80 80 80 80 Magnesium stearate 25 25 25 Moderate amount of lactose-Moderate amount of lactose total 4300 4300 4300 (2) Production method The above-mentioned ingredients and ratios are prepared according to the "granule" item in the General Rules of Japanese Bureau of Preparation. -18- 200404533 Example 3 Capsule (2) Ingredients 6 capsules (mg) 6 capsules (mg) 6 capsules (mg) Atorvastatin calcium 20 — 10 Simvastatin — 10 5 Bear fruit Deoxycholic acid 300 300 300 Magnesium oxide 400 400 400 Corn starch 600 400 500 Polysorbate 80 50 50 50 Magnesium stearate 25 25 25 Suitable amount of lactose Suitable amount of capsules 480 480 480 Total 2300 2300 2300 (2) The ingredients and ratios are made into fine granules according to the item "granule" in the general rules of Japanese preparations, and then filled into capsules to make hard capsules. -19- 200404533 Syrup Example 4 (0 Ingredients Atorvastatin Calcium Simvastatin Ursodeoxycholic Acid Sodium Benzoate Citric Acid White Sugar Glycerin Polyvinyl Alcohol (95%) Sodium Hydrochloride Pure Water _ (2 ) The method described above is used to make syrup 5 (Experimental Example) Blood of Test Example 1: (1) The white system is used for the test.) Pharmacy 5 300 240 60 1500 φ 1800 120 4500 An appropriate amount An appropriate amount 60ml Medium (mg) 60ml Medium (Mg) 60ml Medium (mg) 20 — 10-10 300 300 240 240 60 60 1500 1500 1800 1800 120 120 500 9000 Appropriate amount Appropriate amount Appropriate amount Proportion and ratio, according to the fij of "syrup" in the general rules of the Japanese Bureau of Preparations , Put in a brown glass bottle to make a syrup. Ye Zhongfa Quality Evaluation Test J Quality 1 Kamitikulapa Co., Ltd. (simvastatin and atorvastatin calcium manufactured by Sankyo Co., Ltd., and Mitsubishi Tokyo's ursodeoxycholic acid. -20- 200404533 (2) Animals will be purchased from Covance Research Products Inc., a 5-month-old male Beagle, which will be used as a test animal after quarantine and domestication for about 1 month. (3) Administration of dosage forms and preparations The adjustment method and the storage method of the preparation are based on the weight of each test animal to calculate the necessary amount of the test substance, filled in TO RPAC gelatin capsules (1/2 pan Division), after filling, placed according to each animal situation Capsules are frozen and stored until the time of administration. (4) Administration route and administration period φ Capsules filled with the test substance, once a day between 9. · 0 0 to 1 2: 3 0 'It is mandatory to administer the test animals orally, and the test animals are to be fasted 2 to 3 hours before the administration. The administration period is 11 days. (5) The preparation of the test materials is to be administered 14 to 7 days before the capsule administration ( 2nd week and 1st week before the start of administration), 4 days, 1 day, and 12 days after the administration Approximately 10 ml of blood was collected from the dermal vein, and the test animals were fasted for approximately 18 hours before the blood was collected. · The blood was collected in a test tube and left at room temperature for 30 minutes to 1 hour, then centrifuged (about 16 0 (0 x g, 10 minutes) blood (6) test method using total cholesterol enzyme assay, LD L chemically modified enzyme method, and the use of automatic clinical chemistry analyzer (TBA-120FR, manufactured by Toshiba) to measure the test results -21- 200404533 (experimental results) Individual administration of ursodeoxycholic acid, simvastatin, and atorvastatin calcium. The dosages of the single doses and mixtures relative to the quality of lipids in various blood. The average of the fat mass in various blood before and one week ago was converted to 100 to obtain 0. The results obtained are shown in Tables 1 and 2. In addition, each number 値 is the average 値 for each group. Table 1 _ _A test substance (mg / kg) __ ^ The rate of total cholesterol in blood (%) 4 days after administration and 12 days after administration. Ursodeoxycholic acid (100) 100.3 99.4 95.4 Simvastatin ( 1) 94.8 ---------- 94.1 92.4 Simvastatin (1) + Ursodeoxycholic acid (100) 91.6 ........................... 82.4 81.5 Atorvastatin Ca (2) 90.2 94.1 .............. 91.7 Atorvastatin Ca (2) + Ursodeoxycholic acid (100) 91.0… _________...... 82.8 82.1 -22- 200404533 Table 2 Test substances (mg / kg) in blood LDL Rate of change (%) 4th after the administration 8th after the administration 12th after the administration Ursodeoxycholic acid (100) 94.8 95.0 94.0 Simvastatin (1) 83.9 90.4 81.3 Simvastatin (1) + bear fruit 73.0 62.9 66.5 Deoxycholic acid (100) Atorvastatin Ca (2) 82.4 82.1 83.6 Atorvastatin Ca (2) + 69.9 68.1 59.1 Ursodeoxycholic acid (100) Found ursodeoxycholic acid The combination with simvastatin or atorvastatin has a significant effect on reducing blood lipids. [Possibility of industrial use] The pharmaceutical composition containing the HMG-CoA reductase inhibitor and bile acid of the present invention has the function of reducing blood lipids, and is used for diseases caused by high blood lipid concentrations (such as high lipids) Blood or arteriosclerosis). The examples listed in the examples, preparation examples, and test examples are more specific details of the present invention, but the present invention is not limited thereto. -twenty three-

Claims (1)

200404533 The scope of patent application: 1. A pharmaceutical composition for reducing blood lipids, which contains HMG-CoA reductase inhibitor and bile acids. 2. For example, the pharmaceutical composition of the first patent application scope, wherein the HMG-CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin ), Cerivastatin, atorvastatin, pitavastatin, and rosuvastatin. One or two or more selected components. 3. The pharmaceutical composition as claimed in item 1 of the application, wherein the HMG-CoA reducing enzyme inhibitor is a composition of simvastatin and / or atorvastatin. 4. For example, the pharmaceutical composition of the scope of patent application, wherein the bile acids are ursodeoxycholic acid, cheno-deoxycholic acid, deoxycholic acid, bile acid 1 or 2 or more compounds selected from the group consisting of, bile extract, bile extract, bear bile and bezoar. 5. The pharmaceutical composition according to item 1 of the patent application scope, wherein the bile acid is a composition of ursodeoxycholic acid. 6. The pharmaceutical composition according to item 1 of the scope of patent application, which is used for preventing or treating hyperlipidemia or arteriosclerosis. 7. A combination of a HMG-CoA reductase inhibitor and a bile acid for lowering blood lipids, which is a combination of the HMG-CoA reductase inhibitor and the bile acids being administered at the same time or individually at different times. -24- 200404533 8 · —A kind of HMG-CoA reductase inhibitor and bile · acid for improving blood lipid. 9. A method for reducing blood lipids, which comprises administering an HMG-CoA reductase inhibitor and a bile acid simultaneously or individually at different times. 10 · The method according to item 9 of the scope of patent application is for preventing or treating diseases caused by high blood lipid concentration. 1 1 · The method according to item 9 of the scope of patent application, which is used to prevent or treat hyperlipidemia or arteriosclerosis. -25- 200404533 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the element representative symbols of this representative figure: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention ...