WO2004014427A1

WO2004014427A1 - Medicinal composition for lowering blood lipid level

Info

Publication number: WO2004014427A1
Application number: PCT/JP2003/010028
Authority: WO
Inventors: Tatsuhito Kondo; Ikuo Takagi; Masato Nakayama; Yasuhiro Torizumi
Original assignee: Sankyo Company, Limited
Priority date: 2002-08-08
Filing date: 2003-08-06
Publication date: 2004-02-19
Also published as: AU2003257814A1; CN1688341A; CA2494916A1; TW200404533A

Abstract

[Problem] To provide an excellent medicinal composition for lowering blood lipid level. [Means for Resolution] A medicinal composition containing an HMG-CoA reductase inhibitor and bile acids.

Description

Description '' Pharmaceutical compositions for lowering blood lipids [Technical field] ''

The present invention relates to a pharmaceutical composition for lowering blood lipids, comprising a HMG-CoA reductase inhibitor and bile acids.

[Background technology]

A sutin drug is a drug that specifically and competitively inhibits HMG-CoA reductase in a living body, and is a drug that lowers the blood cholesterol level.

In addition, bile acid components are known to have a bile stasis ameliorating effect, a cholesterol gallstone dissolving effect, a cholesterol intestinal absorption inhibitory effect, and the like (for example, see Japan Pharmaceutical Collection 2002, Japan Pharmaceutical Information Center, Jiho).

On the other hand, the use of statins and bile acid components in combination is almost entirely related to the lytic treatment of cholesterol gallstones.In addition, the bile properties caused by impaired bile outflow to the duodenum for some reason There are scattered literature on treatment of liver damage, biliary cirrhosis, stasis jaundice, and secondary hypercholesterolemia.

Examples of the combination use of the statin agent and the bile acid component are listed below for each application.

1) Dissolution therapy of cholesterol gallstones using a combination of pravastatin and ursodeoxycholic acid (for example, see New Drugs and Clinical Practice, Vol. 43, No. 1, 1994, p. 10, pp. 105).

2) Dissolution therapy of cholesterol gallstones using a combination of simpastatin and ursodeoxycholic acid (see, for example, Clinical Practice and New Drugs, Vol.33 No.10 1996, p.1477-1488).

3) The combined use of oral pastatin and ursodeoxycholic acid further reduces the biliary cholesterol saturation index (see Gastroenterology, Vol. 98 1990, pp.1572-1576).

4) Treatment of cerebrotendinous xanthomatosis and Achilles tendon thickening with a combination of brapastatin and chenodeoxycholic acid (for example, see Japanese Society of Clinical Metabolism, Vol. 29 1992 ρ · 184-185).

5) Combination of simpastatin and ursodeoxycholic acid for treatment of cholestatic liver disease (Gut, Vol.44 No.3 1999 p.552-556).

'6) Treatment of hyperlipidemia using a combination of pravasutin and ursodeoxycholic acid (see Arterial Hardening, Vol. 20, 1992, p. 857). There is consensus that the use of bile acids in combination with a sutin solution further reduces bile cholesterol levels and is useful in gallstone dissolution therapy, and there is no conflicting opinion.

On the other hand, the situation is different in publicly known reports that report the effects of combined use of statins and bile acids on blood lipids. For example, it is reported that it is not effective if there is a disease in the bile duct system such as gallstones. 1488), and reports that it is effective (J. Gastroenterology Vol. 29 1994 p47-55 Lancet Vol. 336 1990 pll96 and the Journal of the Japanese Society of Gastroenterology Vol. 90 1993 p. 539). Not.

In addition, it is reported that it is not effective in non-familial hypercholesterolemia patients without gallstones and in healthy subjects (Gastroenterology, Vol. 981990 p.1572-1576, Japanese Society of Clinical Metabolism, Vol. 29 1992 p. 184-185 and Gut, Vol.44 No.3 1999 p.552-556) and reports that it is effective (arteriosclerosis, Vol.201992 p.857). It can not be said.

That is, it can be said that it is difficult to estimate the effect on blood lipids by the combined use of a statin and bile acids from known literature.

[Disclosure of the Invention]

In view of this situation, the present inventors have concluded that the combined effect of a sutin solution and a bile acid component can be achieved only by an animal test in which species differences, age, diet, and living environment are completely controlled. , Diligent research.

As a result, they have found that a statin drug has a significant blood lipid lowering effect when used in combination with a bile acid component, and have completed the present invention.

HMG—COA reductase inhibitors are long-lasting, It would be desirable if blood lipid lowering effects could be obtained at lower doses. Furthermore, it would be ideal for a hyperlipidemic patient or animal with cholestasis or cholelithiasis to be able to provide an efficient treatment at one time. The present invention

(1) a pharmaceutical composition for lowering blood lipids containing an HMG-COA reductase inhibitor and bile acids,

(2) In (1), the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simpastatin, flupastatin, rivastatin, atorpastatin, pitapastatin, and rospastatin. One or more selected compositions,

(3) The composition according to (1), wherein the HMG-CoA reductase inhibitor is simpastatin and / or atorpastatin.

(4) In item (1), the bile acids are selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, cholic acid, bile powder, bile extract, bear bile, and beef yellow A composition of two or more,

(5) The composition according to (1), wherein the bile acids are ursodeoxycholic acid,

(6) The composition according to (1) for use in prevention or treatment of hyperlipidemia or arteriosclerosis. Further, the present invention provides

(7) An HMG-CoA reductase inhibitor and bile for lowering blood lipids by simultaneously or separately administering the HMG-CoA reductase inhibitor and bile acids. Combinations with acids, and

(8) Combination of bile acids and HMG-CoA reductase inhibitor to improve blood lipids

I will provide a. Further, the present invention provides

(9) A method for lowering blood lipids by administering an HMG-CoA reductase inhibitor and bile acids simultaneously or separately at an interval.

I will provide a.

Of the above (9), the preferred method is

(10) The method according to (9) for preventing or treating a disease caused by high blood lipid concentration, and

(11) The method according to (9) for preventing or treating hyperlipidemia or arteriosclerosis.

It is. "HMG_CoA reductase inhibitor", which is one of the components of the composition according to the present invention, is specific to HMG (3-hydroxy-13-methylidalaryl) -C0A reductase, which is a rate-limiting enzyme in the cholesterol biosynthesis system. It is a drug that inhibits both competitively and competitively and lowers blood cholesterol, so it is originally used as a therapeutic agent for hyperlipidemia. Such HMG-CoA reductase inhibitors include all natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all synthetic compounds. For example, Japanese Patent Publication No. 57-2240 ( (+) — (3R, 5R)-1,5-dihydroxy-1 7— [((IS, 2S, 6S, 8S, 8aR) —6-hydroxy-1) described in USP4346227) 2-Methyl-8-[(S) _2-Methylbutyryloxy] — 1,2,6,7,8,8a-Hexahydro-1-naphthyl] heptanoic acid ), (+)-(1S, 3R, 7S, 8S, 8aR) —1,2,3,7 described in JP-A-57-163374 (USP 423 1938). , 8,8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-l- 2-ethyl] ethyl] -l-naphthyl (S) 12-methyl butyrate (+) — (1 S, 3 R, 7 S, 8 S, 8 a R)-1, described in JP-A-56-122375 (US Pat. No. 4,444,784). 2, 3, 7, 8, 8 a-Hexahydro-3,7-dimethyl-1- 8-[2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-1H-pyran-1-yl] ethyl] I: I-naphthyl 2,2-dimethylbutyrate (simpastatin (Sat.) (3 R *, 5 S *, 6 E)-7-[3-(4 -fluorophene) described in Tokushou 60-5000 15 (USP473907 3) Nyl) 1 1 _ (1-methylethyl) — 1 H-indole — 2-yl] —3,5-dihydroxy-6-heptenoic acid (hereinafter abbreviated as “fullpass”), JP-A 1-216974 (3R, 5S, 6E) -7- [4- (4-fluorophenyl) —2,6-di (1-methylethyl) —5-methoxymethylpyridine described in (US P 5006530) 3-yl] -3,5-dihydroxy-6-heptenoic acid (hereinafter abbreviated as ripastatin), (3R, 5S) -7 described in JP-A-3-58967 (USP 5273995). -[2--(4-Fluorophenyl)-5-(1-methylethyl) 1-3-phenyl 4- 1-phenylamino 1 H-pyrrol-1 -yl] 1, 3, 5-dihydroxyheptane Acid (hereinafter abbreviated as atorpastatin), described in JP-A-11-279866 (US Pat. No. 5,854,259 and US Pat. No. 5,583,3636), containing (E) -3,5-dihydroxy-17- [4 ′-(4 "—Fluorophenyl) -2, —cyclopropyl-quinoline-13,1-yl] -16-heptenoic acid (hereinafter abbreviated as pitapastatin) or described in JP-A-5-178841 (US Pat. No. 5,260,440). (+)-(3R, 5S) —7— [4- (4-Fluorophenyl) -16-isopropyl-12- (N-methyl-1-N-methanesulfonylamino) pyrimidine-15-yl ] — 3,5-dihydroxy_6 (E) monoheptenic acid (hereinafter abbreviated as rospastatin) The HMG-CoA reductase inhibitor, which is a component of the composition of the present invention, may be any of the other HMG-CoA reductase inhibitors disclosed in the publications describing the HMG-CoA reductase inhibitor. — Also contains CoA reductase inhibitors.

The planar structural formula of a typical HMG-CoA reductase inhibitor is shown below.

Plastic bath evening chin

Simbus Evening Chin Full Bath Evening Chin

Rivas Evening Chin 7 Torpastatin

Pi Yu Bus Evening Chin Ross Bus Even Chin The bile acids include, for example, animal bile such as bear bile obtained from bile such as ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, cholic acid, bile powder, or bile extract. Animal gallstones such as cow yellow can be mentioned, and preferably, ursodeoxycholic acid can be mentioned.

In the present invention, each component to be contained may be contained as a pharmacologically acceptable salt.

When the component has a basic functional group, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfuric acid Inorganic salts such as salts and phosphates; lower organic sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfonate and P-toluenesulfonate; Such as aryl sulfonates; amino acid salts such as ortinate and daltamate; and carboxylate salts such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid and maleic acid. Can,

When the component has an acidic functional group, alkali metal salts such as sodium salt, potassium salt, lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt, zinc salt, copper Metal salts such as salts, nickel salts, cobalt salts and the like; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldaricin alkyl ester salts, ethylenediamine salts, N— Methyldalcamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'—dibenzylethylenediamine salt, clomouth pro-force salt, pro-force salt, diethanolamine salt, N— Benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, Squirrel (hydroxymethyl Shimechiru) Aminometan organic amine salts such as salts can be exemplified as salts, for example, in the case of 7 Torubasu evening Chin, preferably a § Torr pasta Chin calcium hydrate. In the present invention, of the components contained, those that form a hydrate or a solvate may be contained as a hydrate or a solvate.

It should be noted that “reducing” the composition for lowering blood lipid of the present invention means lowering blood lipid to a clinically significant level. Examples include lowering of celide, lowering of blood LDL or lowering of total blood cholesterol. Therefore, the composition of the present invention is effective for treating diseases caused by high blood lipid levels (eg, diseases such as hyperlipidemia and arteriosclerosis).

[Embodiment of the invention]

The HMG-CoA reductase inhibitor contained in the composition of the present invention, for example, plapastin, oral pastatin, simpastatin, flupastatin, ripastatin, atorpastatin, pipabastin or rospastatin is JP-A-57-2240 (USP4346227), JP-A-57-163374 (USP4231 938), JP-A-56-122375 (US-P4444784), JP-T-60-500015

(USP473 9073), JP-A-1-216974 (USP5006530), JP-A-3-58967 (USP5273995), JP-A-1-279866 (USP5854259 and USP5856336) or JP It can be easily produced according to the method described in 5-178841 (USP 5260440).

Of the bile acids, for example, ursodeoxycholic acid is listed in the Japanese Pharmacopoeia 14th Edition and is readily available, and other bile acids are also commercially available. The pharmaceutical composition of the present invention contains an HMG-C◦A reductase inhibitor and bile acids as essential components, and may optionally contain additives for formulation. o Other components may be contained as long as the combined use of the A reductase inhibitor and bile acids is not adversely affected. Preferably, << [1 ^ 0—. A pharmaceutical composition containing only an inhibitor and bile acids as active ingredients, and further containing additives for formulation.

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. It can be produced according to a usual method described in the Japanese Pharmacopoeia or the like, using additives and base materials as appropriate. In each of the above dosage forms, various commonly used additives may be used depending on the dosage form.

For example, in the case of tablets, lactose, crystalline cellulose, etc. are used as excipients, magnesium metasilicate or magnesium oxide is used as a stabilizer, hydroxypropyl cellulose is used as a coating agent, and magnesium stearate is used, etc. Can be used as an agent,

In the case of fine granules and capsules, lactose or purified sucrose is used as an excipient, metasilicate, magnesium aluminate or magnesium oxide is used as a stabilizer, corn starch is used as an adsorbent, and hydroxypropyl cellulose is used as a binder As can be used. _r

In each of the above dosage forms, if necessary, a disintegrating agent such as crospovidone; a surfactant such as polysorbate; an adsorbent such as calcium silicate; a coloring agent such as iron sesquioxide and caramel; Stabilizers; PH regulators; fragrances; and the like can also be added. In the present invention, the term “combination” refers to a method of administering two or more active ingredients to a human body simultaneously or separately at an interval.

When the composition of the present invention is administered, each component of the composition can be administered simultaneously or separately at intervals.

The “simultaneous” administration described above includes administration at exactly the same time as well as administration at about the same time as pharmacologically permitted. The administration form is not particularly limited as long as it can be administered at substantially the same time, but is preferably a single composition. In addition, the above-mentioned “separately administered at different times” is not particularly limited as long as it can be administered separately at different times, but for example, one component is administered, and then After a period of time, other components may be administered.

When there are three or more components of the composition to be administered, `` administering simultaneously or separately at intervals '' refers to the method of administering all of them at the same time. To administer two or more drugs at the same time and the rest of the drug, or to administer two or more drugs at a time and administer the remaining drugs at the same time. including. Subjects to which the pharmaceutical composition of the present invention is administered include mammals, and include, for example, humans, dogs, cats, egrets, puppies, pomas, sheep, and pigs, preferably humans or pigs. Dogs, and more preferably humans. Since the pharmaceutical composition of the present invention has a blood lipid lowering action, it is useful as a medicament for preventing or treating diseases (eg, hyperlipidemia or arteriosclerosis) caused by a high blood lipid concentration. . In the present invention, the dose of the HMG-Co A reductase inhibitor varies depending on the type, dosage form, etc. of the HMG-Co A reductase inhibitor, but is usually 1 mg to 20 Omg per day, preferably 5 mg to 16 Omg per day.

In the present invention, the dose of bile acids is usually 1 Omg to 500 Omg per day, preferably 10 Omg to 200 Omg per day. In the case where the pharmaceutical composition of the present invention is a solid preparation, the content by weight is, for example, usually 0.005 to 3% in the case of simpastatin, and preferably 0.03 to 2%, Also, in the case of atorpastatin, it is usually 0.01 to 5%, preferably 0.05 to 3%, and in the case of ursodeoxycholic acid, it is usually 0.3. To 90%, preferably 3 to 50%.

The content contained in the case where the blood lipid-lowering agent composition of the present invention is a liquid is, for example, the content of simpastatin is usually 0.005 to 5 mg / mL, preferably 0.03 to 5 mg / mL. 3 mg / mL, and the content of atorvastatin is usually 0.01 to 1 Omg / mL, preferably 0.05 to 5 mg / mL, and the content of ursodeoxycholic acid The amount is usually between 1 and 100 mg / mL, preferably between 10 and 50 mg / mL.

[Best Mode for Carrying Out the Invention]

(Example) 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 Tablet

(1) Ingredient

Arthur Λ'statin calcium 20 10

Syn; Statin 10 5

Ullite'oxycholate 300 300 300

Oxidized Mac's Nem. 400 400 400

Mac-aluminum metasilicate silicate 140 140 140

Crystal cellulose 120 120 120

Constar-140 140 140

Hydroxy ropircell mouth 60 60 60

Cross force Loose sodium 15 15 15

Mac stearate 25 25 25

Triacetin 6 6 6

Lactose appropriate amount

Total 1200. 1200 1200

(2) Manufacturing method

Take the above ingredients and amounts, and prepare a disintegrant in accordance with the "Tablets" section of the Japanese Pharmaceutical General Regulations, Example 2 Fine Granules

(1) Ingredient (Rag) in 3 packets (mg) in 3 packets (rag) in 3 packets Ong) Attleha'statin calcium 20 10

Sinha'statin 10 5

Ur! ; T-ethoxycholic acid 300 300 300

Mac oxide magnesium 400 400 400

Nucasilicate Aluminate Mac Nesium 140 140 140

Refined sucrose 1400 1400 1400

Stevia extract product 15 15 15

Corn τ. 1200 1200 1100

Go to the lilyl '-80 80 80 80

Mac stearate 25 25 25

Lactose

Total 4300 4300 4300

(2) Manufacturing method

Take the above components and amounts, and prepare a fine granule according to the section of the Japanese Pharmacopoeia General Regulations “Granules”, Example 3 Capsules

(1) Ingredient

6 cuffs. 6 cuffs in cell (mg). 6 cuffs in cell (mg). In cell (mg) Rat Λ'statin calcium 20 10

Shin), 'statin 10 5

Ulli τ-oxycholate 300 300 300

Mac oxide magnesium 400 400 400

Corn τ. 600 400 500

E. To Lily'-g 80 50 50 50

Mac stearate 25 25 25

Lactose

Cuff. Cell 480 480 480

2300 2300 2300 (2) Manufacturing method

Take the above components and amounts, prepare fine granules in accordance with the “Granules” of the Pharmaceuticals for Pharmaceuticals, and then fill them into capsules to produce hard capsules. Example 4 Syrup

(1) Ingredient

In 60mL (mg) In 60mL (mg) In 60mL (mg)

Attleha's Statin Calcium 20 10

Sinha'statin 10 5

Ullite's Xicholic acid 300 300 300

Sodium benzoate 240 240 240

Cuic acid 60 60 60

White sugar 1500 1500 1500

Dark Klycerin 1800 1800 1800

E. Revinyl alcohol 120 120 120

Ethanol (95%) 500 9000 4500 Sodium hydroxide

purified water

(2) Manufacturing method

Take the above components and amounts, prepare a syrup according to the Pharmaceuticals for Pharmaceuticals, “Syrup”, and fill in a brown glass bottle to produce a syrup.

(Test example)

Test Example 1 Evaluation test for lipid content in blood

(1) Test substance

Simpastatin and atorpastatin calcium used were manufactured by Chemtech Lab Co., Ltd., and ursodeoxycholic acid used was manufactured by Mitsubishi Pharma Corporation.

(2) Animals As test animals, beagle dogs and males were purchased from Covance Research Products Inc. at the age of 5 months and used after quarantine and acclimatized breeding for about 1 month.

(3) Dosage form, formulation preparation method and formulation storage method

The required amount of the test substance calculated based on the body weight of each test animal was filled into a T0RPAC gelatin capsule (1 Z 2 oz.). After filling, the capsules were placed in cases classified for each animal and kept refrigerated until administration.

(4) Administration route and administration period

The capsules filled with the test substance were administered by gavage to the test animals once a day between 9: 0 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

Approximately 1 O mL of blood was collected from the cephalic vein on the 14th and 17th days before the capsule administration (the 2nd and 1st weeks before the administration) and on the 4th, 8th and 12th days after the 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 centrifuged (about 1.600 X g, 10 minutes) to use the serum obtained.

(6) Test method

As for the test results, total cholesterol was measured by an enzymatic method, and LDL was measured by a chemically modified enzyme method. An automatic clinical chemistry analyzer (TBA-120FR, manufactured by Toshiba) was used for the measurement.

(Test results)

Ursodeoxycholic acid and simbasitin and atorbasitin calcium The amount of lipids in various blood samples in single and combination doses at each dose was determined using various blood samples 2 weeks and 1 week before administration. The average amount of lipid in the sample was calculated as 100.

Tables 1 and 2 show the obtained results. Each value is the average of 5 animals per district. , Fluctuation rate of total blood cholesterol% Test substance (mg / Kg)

-1 ο ρ d -9-1¾ 丄 Ursodeoxycholic acid (100) 100.3 99.4 95.4 Simbas quintin (1) 94.8 94.1 92.4 Syn), 'statin (1) + Ursoteric oxycholate (100) 9 1. 6 82.4 81.5 Atropastatin Ca (2) 90. 2 94. 1 91. 7 Attle Λ'statin Ca (2) + Ursote ' Oxycholic acid (100) 9 1. 0 82. 8 82. 1

Fluctuation rate of blood LDL%

Test substance (mg / Kg)

4 days after administration 8 days after administration 12 days after administration Ursodeoxycholic acid (100) 94. 8 95.0 0 94.0 Simvastin (1) 83. 9 90. 4 81.3 Simha'statin (1 ) + Urlite'oxycholate (100) 73.0 62.9 66.5 Atorpastatin Ca (2) 82.4 82.1 83.6 Attle Λ'statin Ca (2) + Urlite'oxychol Acid (100) 69. 9 68. 159.1 The combination of ursodeoxycholic acid with simpastatin or atorpastatin produced a significant blood lipid lowering effect.

[Possibility of industrial use]

Since the pharmaceutical composition containing the HMG-CoA reductase inhibitor and bile acids of the present invention has an effect of lowering blood lipids, diseases caused by high blood lipid levels (eg, hyperlipidemia) It is useful as a medicament for preventing or treating disease or arteriosclerosis. Hereinafter, the present invention will be described in more detail with reference to Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.

Claims

The scope of the claims

1. HMG—A pharmaceutical composition for lowering blood lipids containing a CoA reductase inhibitor and bile acids.

2. In claim 1, wherein the HMG-C 0 A reductase inhibitor is brapastatin, oral pastatin, simpastatin, fluvastin, rivasutin, pilapassin, pivasbastin and A composition comprising one or more selected from the group consisting of rospastatin.

3. A composition according to claim 1, wherein the HMG-CoA reductase inhibitor is simpastatin and Z or atorpastatin.

4. In claim 1, the bile acids are one selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, cholic acid, bile powder, bile extract, and bear yellow and cow yellow Or a composition comprising two or more.

5. The composition according to claim 1, wherein the bile acids are ursodeoxycholic acid.

6. The composition according to claim 1, which is used for preventing or treating hyperlipidemia or arteriosclerosis.

7. A combination of an HMG-CoA reductase inhibitor and a bile acid for lowering blood lipids by simultaneously or separately administering the HMG-C0A reductase inhibitor and a bile acid.

8. HMG—COA reductase inhibitor and bile acids to improve blood lipids Used with

9. HMG—A method of lowering blood lipids by administering a CoA reductase inhibitor and bile acids simultaneously or separately at an interval.

10. A method according to claim 9 for preventing or treating diseases caused by high blood lipid levels. ,

1 1. The method according to claim 9 for preventing or treating hyperlipidemia or arteriosclerosis.