TW200409635A - A pharmaceutical composition containing a HMG-CoA reductase - Google Patents

Abstract

The present invention provides a pharmaceutical composition for promoving the synthesis of endothelial nitrogen oxide and/or mentaining or improving the concentration of the blood endothelial nitrogen oxide or a pharmaceutical composition for improving blood lipid. A pharmaceutical composition comprising a HMG-CoA reductase and γ-oryzanol and/or thiamine is disclosed.

Description

200409635 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a pharmaceutical composition (especially vascular endothelial nitric oxide) containing Η MG-C ο reductase inhibitor and r rice furfuryl alcohol / or thiamine A pharmaceutical composition that promotes synthesis and / or maintenance or increase of blood vessel endothelial nitric oxide concentration, or a pharmaceutical composition that improves blood lipids). [Prior art] Since ancient times, "humans have been aging with blood vessels". This is related to the decrease in the production of nitric oxide (NO), which is an endothelial NO synthetase (eNOS) activity, due to the vascular endothelium caused by dysentery or various diseases. The decline is deeply related recently. Vascular endothelial dysfunction is closely related to the onset and progression of arteriosclerosis, and the decrease in NO produced from eNOS is a major cause. The origin of the vascular wall is vascular relaxation, inhibition of platelet aggregation, inhibition of neutrophil adhesion to endothelial cells, migration and inhibition of proliferation of vascular smooth muscle cells, and inhibition of LDL oxidation (see, for example, vasculature) Learn Vo 1.3 8 Νο · 4 1 9 9 8 ρ · 2 1 5-2 1 6). In animal experiments, inhibition of NO synthesis has worsened arteriosclerosis, and it is also known that arteriosclerosis is directly involved in the onset and progression of arteriosclerosis (see, for example, Vascular Medicine Vo 1.2 No. 2 200 1 p. 1 89). The production of NO in human vascular endothelium also plays a multi-faceted role for vascular protection. For the treatment of cardiovascular diseases, a therapeutic strategy that preserves and improves vascular endothelial function is very important. Agents that increase eN 0 S activity are known as statins, L-arginine, ACE inhibitors, angiotensin 11 type 1 receptor antagonists, hormones, some Ca antagonists, and prevent the loss of N 0 Antioxidants such as vitamin C, vitamin E, and probucol, which indirectly promote the effect of No, are also effective (see, for example, Pharmacology and Therapy V〇1.29 No. 1 0 2 0 0 1 p. 176). -6- 200409635 It is also known that vitamin C also increases eNOS activity (see, for example, Vitamins Vol. 75 No. 2 200 1 ρ · 5 1 1). In the composition of traditional Chinese medicine, ginseng, scutellaria baicalensis, and scutellaria baicalensis have been found to have a stimulating effect on blood vessel Ν Ο (see, for example, and Chinese Medicine Journal v. 1 1 1994 p. 102) ° NO synthetic enzymes (NOS) in blood vessels It also exists outside the endothelium and plays an important role in regulating systemic circulation. Diseases with reduced NO production include hypertension, hyperlipidemia, arteriosclerosis, deficient heart disease, heart failure, thrombosis and other circulatory diseases; asthma, chronic obstructive pulmonary disease, pulmonary hypertension, A RD S (adults Respiratory insufficiency syndrome) and other respiratory diseases; liver disorders, liver cirrhosis, gastrointestinal mucosal disorders, hypertrophic pyloric stenosis, pancreatitis and other digestive diseases; cerebral deficiency blood, cerebral infarction, cerebral circulation failure, senile dementia and other cerebral blood vessels Disorders; Kidney and urinary diseases such as kidney disorders and impotence; Obstetrics and gynecology diseases such as pregnancy poisoning; Infectious diseases, immune diseases, diabetes, heat injury, or other medicines with reduced NO production 3 3 8 6 3 7). Statin is a drug that specifically reduces HMG-CoA reductase in vivo and antagonizes the inhibition to reduce the amount of cholesterol in the blood. It is also known that the eNOS activity increases as described above. However, for T-furfuryl alcohol and thiamine, there is no report of eN 0 S activity enhancement effect, and the use of statin and r-furfuryl alcohol and / or thiamine is not known, which can multiply vascular endothelial oxidation Nitrogen synthesis promotes and / or vascular endothelial nitric oxide maintains and increases blood levels. It is also unknown that the use of r-furfuryl alcohol and / or thiamine can multiply reduce blood lipids. [Summary of the Invention] As a result of repeated researches on the pharmacological effects of MG-C ο A reductase inhibitors and τ rice furfuryl alcohol and / or thiamine, the inventors have found that the use of 倂 200409635 to promote vascular endothelium The present invention completes the synthesis of sexual nitric oxide, maintains or increases the blood endothelial nitric oxide blood concentration, and improves blood lipids. The present invention relates to: (1) a pharmaceutical composition containing a HMG-CoA reductase inhibitor and τ rice furfuryl alcohol and / or thiamine. In the above, the pharmaceutical composition is: (2) the HMG-Co A reductase inhibitor is selected from pravastatin, Lovastatin, simvastatin, fluvastatin, fluvastatin, One or two or more of the components described in (1) of Rivastatin, Atorvastatin, Pitavastatin, and Rosvastati η, (3 ) Η MG-C ο A reductase inhibitor is selected from the group consisting of 1 or 2 or more of Simbastatin or Adolbastatin, (4) 5 clawsin is selected from the group consisting of Thiamine (τ ^ 丨 am 丨 ne), Dicethiamine, octotiamine, Cytotiamine, bisib ii thiamine), B isbentiamine, fursu 11 iamine, Pro suit i amine, Benfoti amine, and Benfoti amine / Or one or more of its salts (1) ~ (3) The composition described in any one of (1) ~ (3), (5) Thiamine is benzyl thiamine, a composition selected from any of (1) ~ (3),. (6) The synthesis of vascular endothelial nitric oxide promotes and / or maintains or increases the concentration of vascular endothelial nitric oxide in blood, a composition selected from any one of () to (5), -8- 200409635 (7) improving blood The lipid is selected from the composition described in any one of (1) to (5), (8) the HMG-CoA reductase inhibitor is the composition described in (7) of Simbastatin, and (9) the prevention or treatment is caused by Diseases in which the activity of vascular endothelial nitric oxide synthase is reduced and / or the concentration of nitric oxide in blood derived from vascular endothelial cells is selected from the composition of any one of (1) to (5), (10) preventing or treating vascular endothelial nitric oxide Diseases caused by a decrease in the activity of synthetic enzymes and / or a decrease in the concentration of nitrogen oxides in blood from vascular endothelium are selected from the composition of any one of (1) to (5), (1 1) prevention or treatment of circulatory diseases and cerebrovascular disorders , Kidney / urinary disease, diabetes, or a condition caused by a decrease in the production of a drug NO is selected from (1) to (5) The composition according to any one of (12) a composition selected from (1) to (5) for preventing or treating a disease caused by high blood lipid concentration, (13) being inhibited by HMG-CoA reductase The agent and r rice furfuryl alcohol are the components described in (1 2) contained in the essential ingredients, and (1 4) are selected from (1) to (5) in the prevention or treatment of hyperlipidemia or arteriosclerosis. Thing. The present invention further provides: (15) HMG-CoA reductase inhibitors and r rice furfuryl alcohol and / or thiamine are administered simultaneously or at intervals from the synthesis of vascular endothelial nitric oxide to promote and / or maintain or improve blood vessels The concentration of endothelial nitric oxide in blood Η MG-C ο A reductase inhibitor combined with 7m furfuryl alcohol and / or thiamine, (16) HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or sulfur The amines are the same as -9-200409635, which is administered at intervals or at intervals to improve blood lipids. The combination of hmg-c0a tube accompaniment inhibitor and 7 m furfuryl alcohol and / or thiamine, (1 7) the synthesis of vascular endothelial nitric oxide to promote and / or maintain or increase the concentration of vascular endothelial nitric oxide in blood by HMG-CoA reductase inhibitors and γ # furfuryl alcohol and / or thiamine, 18) Improve the use of r-furfuryl alcohol and / or thiamine in lipids in blood. The invention further provides: (19) HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine are administered simultaneously or at intervals from the synthesis of vascular endothelial nitrogen oxide to promote and maintain or increase vascular endothelial oxidation A method of nitrogen concentration in blood, and a method of (20) HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine are administered simultaneously or at intervals to improve lipids in blood. In the above (19), the suitable method is: (2 1) the method according to (19) for preventing or treating a disease caused by a decrease in the activity of vascular endothelial nitric oxide synthase {and a decrease in the concentration of nitrogen oxide in blood from vascular endothelial origin (22) The method of (19) for preventing or treating diseases in which the activity of vascular endothelial nitric oxide synthase is decreased and / or the concentration of nitrogen oxides in blood derived from vascular endothelial cells is reduced, (2 3) preventing or treating circulatory disease, cerebrovascular disease Disorders, kidney / urinary diseases, diabetes, or the state caused by a decrease in the production of NO by the agent, the method according to (19). In the above (20), a suitable method is: (24) the method of (20) for preventing or treating a disease caused by high blood lipid concentration, and -10- 200409635 (25) preventing or treating hyperlipidemia or arteries Method of hardening (20). The present invention further provides: (26) the production of vascular endothelial nitric oxide containing HMG-CoA reductase inhibitor and 7 m furfuryl alcohol and / or thiamine to promote and / or maintain or improve vascular endothelial nitric oxide Use of HMG-Co A reductase inhibitors and r rice furfuryl alcohol and / or thiamine in a medium-concentration pharmaceutical composition, and (2 7) manufacture of HMG-CoA reductase inhibitors and τ rice bran alcohol and / or The use of thiamine as a pharmaceutical composition for improving lipids in blood MG-C ο A reductase inhibitor and the use of T-furfuryl alcohol and / or thiamine. "Η MG-C ο A reductase inhibitor", which is one of the ingredients of the pharmaceutical composition of the present invention, refers to MG (MG 3 -Hydroxy-3 -methylglutaryl), which is a rhizolytic enzyme that produces cholesterol. CoA reductase is an agent that specifically and antagonistically inhibits. Because it can lower blood cholesterol, it was originally used as a therapeutic agent for hyperlipidemia. The Η MG-C ο A reductase inhibitor includes natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all fully synthetic compounds, such as described in JP 57-2240 (USP4346227) (+) -(3R55R) -3, 5-dihydroxy-7-[(lS, 2S56S, 8S, 8aR) -6-hydroxy-2-methyl-8-[(S) -2 · methylbutoxy]- l, 2,6,7,8,8a-hexaki-1-naphthyl] heptanoic acid (hereinafter referred to as prabastatin), Japanese Patent Application Laid-Open No. 5 7-1 6 3 3 74 (! ^? 42 3 1 93 8) (+)-(13,311,73,8358 & 11) -1,2,3,7,8,82-hexahydro-3,7-dimethyl_8- [2- (211, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl (s) -2-methylbutanoate (hereinafter referred to as robastatin), JP-A Sho 56- 1 2 2 3 7 5 (USP4444784) describes (+)-(lS53R57S, 8S, 8aR) -l52,3,758,8a-hexahydro-3,7-dimethyl-8- [ 2- (2R54R) -tetrahydro-4-hydroxy-6_oxy_2H ^ pyran 200409635-2-yl] ethyl] -1-naphthyl 2,2-dimethylbutyrate (hereinafter referred to as simba (Statin), Special Table No. 6 0-5 0 0 0 1 5 (USP 4 7 3 9 0 7 3) (±) (3R *, 5S *, 6E) -7- [3- (4- Fluorobenzene Group) -1- (1-methylethyl) -1Η-ordinole-2 -yl] -3,5-dihydroxy-6-heptenoic acid (hereinafter referred to as flubutastine), Tokai Hei 1 -2 No. 1 of 6974 (1 ^? 5 0 0 6 5 3 0) already stated in (311553,6) -7- [4- (4-fluorophenyl) -2,6-di- (bumethylethyl ) -5-methoxymethylpyridin-3-yl] -3, 5-dihydroxy-6-heptenoic acid (hereinafter referred to as Libasstatin), Japanese Unexamined Patent Publication No. 3-5 8 9 6 7 (USP5273995) Of (3R, 5S) -7- [2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-phenylaminecarbonyl-1H-pyrrole-butyl] -3,5-Dihydroxyheptanoic acid (hereinafter referred to as Adoropastatin), JP-A No. 1-2 7 9 8 6 6 (USP 5 8 5 42 5 9 and USP 5 8 5 6 3 3 6) (E)-3,5-dihydroxy-7-[4,-(4 ”-fluorophenyl) -2'-cyclopropyl-quinolin-3-yl] -6-heptenoic acid (hereinafter referred to as (Bustatistatin) or Japanese Unexamined Patent Publication No. 5-1 7 8 8 4 (USP 5 2 604 4 0) (+)-(3R, 5S) -7- [4- (4-fluorophenyl)- 6-isopropyl- 2- (N -methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3, 5-dihydroxy-6 (E) -heptenoic acid (hereinafter referred to as Rosebastatin Waiting for Star Ting compounds. The ΗMG-CοA reductase inhibitor of the component of the pharmaceutical composition of the present invention also contains other HMG-CoA reductase inhibitors disclosed in the publication of the above-mentioned ΗMG-CοA reductase inhibitor. The planar structural formula of a representative of HMG-CoA reductase inhibitory qi is as follows.

Prabastatin Robastatin -12- 200409635

Simba statin

Rebastatin

Adorubastatin

Η3σ ", so2ch3

C〇〇H

Rosbastatin than busstatin. Among these M G-C ο A reductase inhibitors, should be Simbastatin and Adoropastatin, especially Simbastatin. "T rice branol" refers to a compound in which sterol or triterpene alcohol extracted from rice bran oil or rice germ oil is combined with ferulic acid, or a mixture of these. "Thiamines" can be thiamine, thiamine, octylthiamine, fine thiamine, ezetamine thiazide, benzylthiamine, thiazine 200409635 Thiamine or benzyl thiamine or its salt; preferably benzyl thiamine. The above-mentioned components contained in the present invention may also be contained in a pharmacologically acceptable salt. If the component has a basic functional group, it may be, for example, hydrofluoride, hydrochloride, hydrobromide, hydroiodate, etc. Hydrohalides; Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower organic sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; benzenesulfonate Aromatic expansion salts such as p-toluenesulfonate; amine salts such as ornithine and glutamate; and carboxylates such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid . ft When the component has an acidic functional group, it can be an alkali metal salt such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, and other alkaline earth metal salts, aluminum salts, iron salts, zinc salts, copper salts, and nickel salts. Metal salts such as cobalt and cobalt salts; inorganic salts such as ammonium salts, third octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine esters, ethylenediamine salts, N-methyl Glucosamine salt, guanidinium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, -dibenzylethylenediamine salt, chloroprocaine salt, 'said' Vicaine salt , Amine salts such as organic female salt, N-caryl-phenylethylamine salt, piperazine salt, tetramethylammonium salt, ginsyl (hydroxymethyl) aminomethane salt, etc., for example, Praprastatin ' It should be Praprastatin sodium, such as Adoropastatin calcium adduct. When the contained components form a hydrate or a solvate, a pharmaceutical composition containing these hydrates or a solvate is also included in the present invention. In the present invention, "various diseases" refers to diseases caused by a decrease in the activity of vascular endothelial nitric oxide synthase and / or a decrease in the concentration of nitric oxide in blood from the vascular endothelium, such as hypertension, hyperlipidemia, arteriosclerosis, and hypoxic heart disease. -14- 200409635, circulatory diseases such as heart failure, thrombosis, pulmonary hypertension, restenosis, or peripheral circulation disorders; etc .; cerebrovascular disorders such as pulmonary hypertension, cerebral asthenia, cerebral infarction, cerebral circulation failure, senile dementia, etc. ; Kidney and urinary diseases such as kidney disorders and impotence; diabetes or other drugs and the state caused by the decline in NO production. In the early stages of the above "various diseases", there are no obvious subjective symptoms. Although it is difficult to judge by yourself, the subjective symptoms of the "various diseases" in the present invention may be, for example, headache, dizziness, numbness or paralysis, cold feeling in the limbs, shoulder condensation, Atrophy of skin and muscles, etc. Therefore, the pharmaceutical composition of the present invention is used for subjective symptoms to treat the above-mentioned diseases at an early stage. In the present invention, "improving blood lipids" means reducing blood lipids to a clinically significant level, and even if blood triglyceride is lowered, blood L D L or blood cholesterol is lowered. [Embodiment] The HMG-CoA reductase inhibitor contained in the composition of the present invention, for example, prabastatin, robostatin, simabastatin, flubastatin, rebastatin, adolopastatin, pidastatin and Rosbastatin can be published in Japanese Patent Publication No. 5 7-2 2 4 0 (USP 4 3 4 6 2 2 7), Japanese Patent Publication No. 57-163374 (USP4231938), and Japanese Patent Publication No. 56-122375 (USP4444784). ), Japanese Patent Publication No. 60-500015 (USP4739073), Japanese Patent Publication No. 1-216974 (USP5006530), Japanese Patent Publication No. 3-58967 (USP5273995), Japanese Patent Publication No. 1-279866 (USP5854259 and USP5856336), or The method described in Kaiping 5-178841 (USP5260440) is easy to manufacture. In addition, the r rice furfuryl alcohol of the present invention may be commercially available (for example, manufactured by Ribo Vitamin Co., Ltd. 200409635) or a known method. Thiamines are included in, for example, the 14th revision of the Japanese Pharmacopoeia and the Japanese Pharmacopoeia's pharmaceutical specifications, and they are easily available. The "pharmaceutical composition containing Η MG-C ο A reductase inhibitor and r rice furfuryl alcohol and / or thiamine" in the present invention uses HMG-CoA reductase inhibitor and T rice furfuryl alcohol or thiamine as Essential ingredients are included, and if necessary, formulated additives may also be included, and other ingredients will be included in a range that will not adversely affect the application of HMG-CoA reductase inhibitors and r rice furfuryl alcohol or thiamine. It is better to use only HMG-CoA reductase inhibitors and 7m furfuryl alcohol and / or thiamine as active ingredients, and moreover, pharmaceutical compositions containing formulated additives. The specific dosage form of the pharmaceutical composition of the present invention may be, for example, lozenges, fine granules (containing powder), capsules, liquids (containing syrup), etc., and additives and substrates suitable for each combination are suitable. Manufactured by the usual method described by the pharmacy. Various additives commonly used in the above-mentioned dosage forms can also be used depending on the dosage form. For example, in the case of tablets, lactose, crystalline cellulose, etc. are used as excipients, magnesium aluminosilicate or magnesium oxide, etc. are used as stabilizers, hydroxypropyl cellulose, etc. are used as coating agents, and magnesium stearate is used. Etc. for lubricants. For fine granules and capsules, excipients such as lactose or refined sugar, stabilizers such as magnesium aluminosilicate or magnesium oxide, stabilizers such as corn flour, and hydroxypropyl cellulose, etc. For binding agents. Disintegrating agents such as polyvinyl polypyrrolidone; surfactants such as polysorbate; adsorbents such as calcium silicate; luxury coloring agents such as trioxide, caramel, etc. Stabilizers such as sodium formate; ρ Η regulators; spices and so on. -16- 200409635 In the present invention, "use" refers to a method of administering two or more active ingredients to the human body simultaneously or at intervals. When the pharmaceutical composition is administered in the present invention, each component may be administered simultaneously or at intervals. The above-mentioned "simultaneous" administration, in addition to the complete simultaneous administration, also includes the administration of pharmacological tolerances at intervals. The form of administration is not specific as long as the forms of administration can be administered at substantially the same time, but a single composition is preferred. The above-mentioned "individual administration at separate intervals" is not specific as long as the administration forms are administered separately at different times, for example, a method of administering one component and then other components after a predetermined time. When there are three or more components of the composition to be administered, "simultaneous or intermittent administration" includes all of these simultaneous administration methods, each interval of individual administration methods, and two or more simultaneous administrations. The method of administration of the remaining medicines at intervals, or two or more methods of administration at separate times, and the methods of simultaneous administration of the remaining medicines. The medicinal composition containing Η MG-C ο A reductase inhibitor and r rice furfuryl alcohol and / or thiamine has the effect of promoting the synthesis of vascular endothelial nitric oxide and maintaining or improving vascular endothelial nitric oxide. The effect of medium concentration and the improvement of blood lipids can be considered as diseases caused by decreased activity of vascular endothelial nitric oxide synthetase and / or blood vessel endothelial nitrogen oxide concentration, decreased vascular endothelial nitric oxide synthase activity, and / Or vascular endothelial diseases caused by a decrease in the concentration of nitrogen oxides in blood, or medicines for the prevention or treatment of diseases caused by high lipid concentrations in blood, such as hypertension 'hyperlipidemia, arteriosclerosis, hypoxic heart disease, Circulatory diseases such as heart failure, thrombosis, pulmonary high-17-200409635 blood pressure, restenosis or peripheral circulation disorder, pulmonary hypertension, cerebral insufficiency blood, cerebral infarction, cerebral circulation failure or senile dementia, cerebrovascular disorders, kidney Disorders or impotence, such as renal urinary diseases, diabetes, or other medicines to reduce the N 0 production caused by the state of prevention or treatment of medicine. In the present invention, the dosage of ΗMG-C ο A reductase inhibitor depends on the type and dosage form of ΗMG-Co Α reductase inhibitor, usually 丨 daily ～ mg ～ 200 mg, preferably 1 5 mg to 160 mg per day. In the present invention, the dosage of 7 m furfuryl alcohol is usually 10 mg to 1000 mg per day, preferably 100 mg to 600 mg per day. In the present invention, the dosage of thiamine is according to sulfur. The types and dosage forms of amines vary, usually 0.5mg ~ 500mg per day, preferably 5mg ~ 200mg per day. The weight percentage of the HMG-CoA reductase inhibitor contained in the pharmaceutical composition of the present invention when it is a solid preparation is usually 0.00 5 to 3%, preferably 0.03 to 2%. For example, in the case of simbastatin, it is usually 0.005. 5% ~ 3%, preferably 〇3〜2%, in the case of Adoropastatin, it is usually 〇1 ～ 5%, preferably 〇 · 〇5 ～ 3%. When it contains 7 meters of furfuryl alcohol, it is usually 0.5 to 90%, preferably 3 to 60%. When containing thiamine, it is usually 0.2 ~ 40%, preferably 1 ~. When the medicinal composition of the present invention is a liquid, the content of the HMG_CoA reductase inhibitor is usually 0.05 to 5 mg / mL, preferably 0.03 to 3 mg / mL. For example, the content of simbastatin is usually 0. .0 0 5 ~ 5ms / m] L, preferably 0.03 ~ 3mg / mL, the content of Adolbastatin is usually 0.01 ~ 10mg / mL, preferably 0.05 ~ 5 mg / m L. 〇 contains r When rice branol is contained, its content is usually 2 to 200 mg / m L 'and 10 to 100 mg / m L 〇200409635 When thiamine is contained, its content is usually 1 to 100 mg / mL, preferably 5 to 50 mg / m L 〇 [Best Mode for Carrying Out the Invention] (Examples) The present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto. Example 1 Lozenges (1) Ingredients 6 tablets (mg) 6 tablets (mg) 6 tablets (mg) Adoropastatin 20 Simbastatin 10 10 r rice furfuryl alcohol 300 benzyl thiamine 1 00 100 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 Carboxymethyl cellulose sodium 15 15 15 Magnesium stearate 25 25 25 Three Glyceryl acetate 6 6 6 Proper amount of lactose Appropriate amount Proper amount Total 1200 1200 1200 (2) The manufacturing method uses the above ingredients and components to imitate according to the general rule of the Japanese Formulation "Lozenges". -19- 200409635 Example 2 Fine granules (1) Ingredients in 3 packs (mg) 3 packs (mg) 3 packs (mg) Adorubastatin 20 Simbastatin 10 10 r rice furfuryl alcohol 3 00 benzyl Thiamine 1 00 1 00 Magnesium oxide 400 400 400 Magnesium aluminosilicate 140 140 140 m White sugar 1400 1400 1400 Stevia extract 15 15 15 Corn starch 1200 1000 1100 Polysorbate 8 0 80 8 0 80 Hard Magnesium stearate 25 25 25 The right amount of lactose The right amount of the total amount 4 3 0 0 4 3 00 4 3 0 0 (2) Production method The above-mentioned ingredients and components are made into fine granules in accordance with the general rule of granules of Japanese preparations. Example 3 Capsule Lu 200409635 (1) Ingredients 6 capsules (mg) 6 capsules (mg) 6 capsules (mg) Adoropastatin 20 Simbastatin 10 10 T rice furfuryl alcohol 3 00 ephedrine 1 00 100 Magnesium oxide 400 400 400 Corn starch 600 600 500 Polysorbate 8 0 50 50 50 Magnesium stearate 25 25 25 Suitable lactose amount Moderate amount capsules 480 480 480 Total 2 3 0 0 2 3 0 0 2 3 0 0 (2) Manufacturing method After the above ingredients and components are made into fine granules in accordance with the general rules of "Japanese granules", the capsules are filled to obtain hard capsules. Example 4 Syrup 200409635 (1) Ingredient 60mL Medium (mg) 60mL Medium (mg) 60mL Medium (mg) Adorubastatin Calcium 20 Simbastatin 10 10 T Furfuryl alcohol 3 00 Benzofuramine 1 00 100 Sodium benzoate 240 240 240 Citric acid 60 60 60 White sugar 15 00 1500 1500 Concentrated glycerin 1800 1800 1800 Polyvinyl alcohol 120 120 120 Ethanol (95%) 5 00 9 0 0 0 4 5 00 Moderate amount of hydrochloric acid Moderate amount of sodium hydroxide Moderate amount Proper amount of purified water Proper amount of water Proper amount of water (2) Production method After the above ingredients and components are made into the syrup of the general Japanese formulations, the syrup is filled in a brown glass bottle to obtain a syrup. (Test example) Test example 1 Evaluation test of the amount of nitrogen oxides in blood and the quality of blood lipids (1) Test substance Simbastatin and Adoropastatin Manufactured by Chem Tech Lab for calcium, R vitamins for rice branol The manufacturer of the stock company, the manufacturer of Sankyo Co., Ltd. for benzyl thiamine. > 22- 200409635 (2) Animals δ-type test animals were purchased from Cov a n c e R e s e a r c h p r d du c t s I n c. The males were purchased at 5 months of age and used after quarantine and domestication for about 丨 months. (3) The dosage form, preparation method of preparation and storage method of preparation are filled in capsules (1/2 ounces) of the test substance required by the test animal based on the weight of the test substance. After filling, the capsules are put into boxes separated by animals and stored refrigerated until administration. (4) Administration route and period of administration The capsules filled with the test substance shall be administered between 9: 00 and 12: 30 once a day. The test animals shall be administered orally. The test animals were fasted for 2 to 3 hours before administration. The administration period is 11 days. (5) -14 and -7 days before the administration of the test capsules (the second week and the first week before the start of the administration), and the blood was collected from the contralateral cutaneous vein on the 4th, 8th, and 12th days after the administration. About 丨 0ml. The test animals were fasted for about 18 hours before blood collection. The obtained blood was transferred into a test tube and left at room temperature for 30 minutes to 1 hour, and then separated by centrifugation (approximately 16 00 X g, 10 minutes), and the obtained blood was used to scoop. (6) Test method The NO generated from nitric oxide synthase (NOS) is rapidly transformed into nitrate ions (NO 3_) and nitrite ions (NO). The total concentration of nitrogen oxides in blood (NOx) is used Calculated by HPLC > ^ 〇3_ and Ν02 ·. Calculated. Enzyme method for total cholesterol, homogenization method for HDL, chemically modified enzyme method for LDL, and Bessey-Lowry method for PAL. Also used for clinical chemistry. Automatic analysis device (TBA-120FR, manufactured by Toshiba Corporation). -23- 200409635 (test result) A single dose of Simbastatin and Adorubastatin calcium and 7 meters of furfuryl alcohol or benzyl thiamine. The total concentration of nitrogen oxides (NOx) in the blood of the compounding agent is calculated by converting the average value of NOx in various blood 2 weeks before and 1 week before the administration. The simbastatin and r rice furfuryl alcohol are respectively calculated. The various blood lipid masses of the single dose and the compounding agent of each administration amount were calculated by converting the average blood lipid masses of 2 weeks and 1 week before the administration to 100. The results are shown in Tables 1 to 5. Each tadpole is the average tadpole in the 丨 group. Table 1 Test substance (mg / Kg)-N OX in blood After the 4th administration, after the 8th administration, after the 12th administration, r rice furfuryl alcohol (100) 105.3 111.7 102.4 simbastatin (1) 10 1.6 85.8 12 1.9 simbastatin (1) + r rice furfuryl alcohol (100) 135.2 13 1.9 1 1—a 14 1.4 Table 2 Test substance (mg / Kg) N OX Xing Ping ij yu in blood. / N 4 days after administration and 8 days after administration. (50) 96.4 9 1.6 107.1 Simba statin (1) 101.6 85.5 12 1.9 Simba statin (1) + 107.7 136.1 126.6 benzyl thiamine (50) adodol statin calcium (2) 117.7 --- -1 14.4 117.9 Adoropastatin Calcium (2) + 10 1.2 118.0 162.3 Benzylthiamine (50) ---------24- 200409635

Table 3 Tested substances (mg / Kg)% change in total cholesterol in blood 4% after administration, 8% after administration, 12% r rice furfuryl alcohol (100) 98.8 98.5 10 1.9 Simbastatin (1 ) 94.8 94. 1 92.4 Simba statin (1) + 94.3 87.1 86.8 r rice furfuryl alcohol (100) Table 4 Test substance (mg / Kg)% change rate of blood LDL 4% after administration 8 After the administration, 12 meters, 7 meters of furfuryl alcohol (100) 100.4 98.5 98.3 simbastatin (1) 93.9 90.4 8 1.3 simbastatin (1) + 84.7 69.2 69.0 T rice furfuryl alcohol (100) Table 5 Tested Substance (mg / Kg) Change rate of arteriosclerosis index (LDL / HDL)% r 4% after administration and 8th after administration r rice furfuryl alcohol (100) 10 1.4 99.5 95.9 Simbastatin ( 1) 8 6.6 93.8 86.3 Simbastatin (1) + 87.4 76.1 75.8 Tau rice furfuryl alcohol (100%)

-25- 200409635 It is known from Tables 1 and 2 that the combination of simbastatin or adolubastatin with r rice furfuryl alcohol or benzyl thiamine shows a promotion of significant vascular endothelial nitric oxide synthesis and / or The effect of maintaining or increasing the concentration of vascular endothelial nitric oxide in blood. It is known from Tables 3 to 5 that the combination of simbastatin and r rice furfuryl alcohol showed a significant blood lipid lowering effect. [Possibility of industrial use] The pharmaceutical composition containing the HMG-CoA reductase inhibitor and 7 m furfuryl alcohol and / or thiamine in the present invention has the effect of promoting the synthesis of endothelial nitric oxide, maintaining or improving blood vessels The role of endothelial nitric oxide in blood concentration and the improvement of blood lipids can be considered as diseases caused by decreased endothelial nitric oxide synthase activity and / or endothelial nitric oxide decreased blood vessel endothelial nitric oxide Medicines for the prevention or treatment of diseases caused by a decrease in synthetic enzyme activity and / or a decrease in the concentration of nitrogen oxides in blood from endothelial blood vessels, or diseases caused by high blood lipid concentrations, such as hypertension, hyperlipidemia, arteriosclerosis, Circulatory diseases such as congestive heart disease, heart failure, thrombosis, pulmonary hypertension, restenosis, or peripheral circulation disorders, pulmonary hypertension, cerebral asthenia, cerebral infarction, cerebral circulation failure, or cerebrovascular disorders such as senile dementia, A medicine for the prevention or treatment of a state caused by a decrease in N0 production of renal urinary diseases such as renal disorders or impotence, diabetes, or other agents. [Schematic description] None -26-

Claims (1)

200409635 The scope of patent application: 1. A pharmaceutical composition containing ΗMG-CοA reductase inhibitor and 7 meters of furfuryl alcohol and / or thiamine. 2. The pharmaceutical composition according to item 1 of the patent application scope, wherein the HMG-Co A reductase inhibitor is selected from Pravastatin, Lovastati, Simvastatin, Fluba One or more of Fluvastatin, Rivastatin, Atorvastatin, Pitavastatin, and Rosvastatin. Xin 3 · The pharmaceutical composition according to item 1 of the scope of patent application, wherein it is one or two or more selected from the group consisting of simbastatin or adolopastatin. 4. The pharmaceutical composition according to any one of claims 1 to 3 in the scope of the patent application, wherein the thiamine is selected from the group consisting of Thiamine, Dicethi amine, and Octylthiamine ( Octoti amine), Cycotiamine, Bisibuthiamine, B isbentiamine, Fursu 11 iamine, Propane One or two or more kinds of Prosultiamine, Benfotiamine, and / or salts thereof. 5. The pharmaceutical composition according to any one of the claims 1 to 3, wherein the thiamine is benzyl thiamine. 6. The pharmaceutical composition according to any one of claims 1 to 5 of the scope of patent application, which is used to promote the synthesis of vascular endothelial nitrogen oxide and / or to maintain or increase the concentration of vascular endothelial nitrogen oxide in blood. 7. The pharmaceutical composition according to any one of claims 1 to 5 of the scope of application for a patent, which is -27-200409635 for improving blood lipids. 8. The pharmaceutical composition according to item 7 of the patent application scope, wherein the η M G-C ο A reductase inhibitor is simbastatin. 9 · The pharmaceutical composition according to any one of claims 1 to 5 in the scope of patent application, which is used to prevent or treat the decrease in nitric oxide synthase activity caused by vascular endothelium and / or decrease in the concentration of nitrogen oxide in blood from vascular endothelium. disease. 10. The pharmaceutical composition according to any one of items 1 to 5 of the scope of patent application, which is used to prevent or treat a decrease in the activity of vascular endothelial nitric oxide synthase and / or a decrease in the concentration of nitric oxide in blood from the vascular endothelium. disease. 1 1 · The pharmaceutical composition according to any one of claims 1 to 5 in the scope of patent application, which is used to prevent or treat circulatory diseases, cerebrovascular disorders, kidney and urinary diseases, diabetes, or reduction of N 0 production caused by drugs Of the state. 12. The pharmaceutical composition according to any one of claims 1 to 5 of the scope of patent application, which is used to prevent or treat diseases caused by high blood lipid concentrations. 1 3 · The pharmaceutical composition according to item 12 of the scope of patent application, which contains Η M G-C ο A reductase inhibitor and r rice furfuryl alcohol as essential components. 1 4 · The pharmaceutical composition according to any one of claims 1 to 3, which is used to prevent or treat hyperlipidemia or arteriosclerosis. 1 5. A combination of a HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine, which is a combination of Η MG-C ο A reductase inhibitor and r rice furfuryl alcohol and / or thiamine Simultaneously or at intervals, the synthesis of vascular endothelial nitric oxide promotes and / or maintains or increases the blood endothelial nitric oxide blood concentration. 1 6. A combination of a HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine, which is a combination of Η MG-C ο A reductase inhibitor and r rice furfuryl alcohol and /-28- 200409635 or Thiamines are administered simultaneously or at intervals to improve blood lipids. 1 7. —The effect of a HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine, which is used to promote the synthesis of vascular endothelial nitric oxide and / or maintain or improve vascular endothelial nitric oxide Medium concentration. 18.-A combination of a HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine, which is used to improve blood lipids. 19. A method for promoting the synthesis of vascular endothelial nitric oxide and / or maintaining or increasing the blood concentration of vascular endothelial nitric oxide, which comprises: Η MG-C ο reductase inhibitor and r rice furfuryl alcohol and / or Thiamines are administered simultaneously or separately. 2 0. A method for improving blood lipids, which comprises administering an HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine at the same time or separately. 2 1. The method according to item 19 of the scope of patent application, which is used to prevent or treat a decrease in the activity of vascular endothelial nitric oxide synthase and / or a decrease in the concentration of nitric oxide in blood derived from vascular endothelium. 2 2 · The method according to item 19 of the scope of patent application, which is used to prevent or treat diseases caused by a decrease in the activity of vascular endothelial nitric oxide synthase and / or a decrease in the concentration of nitric oxide in blood from vascular endothelium. 23 · The method according to item 19 of the scope of patent application, which is used to prevent or treat circulatory disease, cerebrovascular disorder, kidney-urinary disease, diabetes, or a state in which the production of N 0 is reduced by a medicament. 24. The method of claim 20 in the scope of patent application, which is used to prevent or treat diseases caused by high blood lipid concentrations. 2 5. The method according to item 20 of the scope of patent application, which is used to prevent or treat hyper-29-200409635 dyslipidemia or arteriosclerosis ° 2 6 ·-Η MG-C ο A reductase inhibitor and r Use of rice furfuryl alcohol and / or thiamine, which is used to manufacture a pharmaceutical composition containing Η MG-C ο A reductase inhibitor and 7 rice furfuryl alcohol and / or thiamine, to reduce HMG-Co A The enzyme inhibitor and r rice furfuryl alcohol and / or thiamine are administered simultaneously or at intervals to maintain or increase the vascular endothelial nitric oxide synthesis promotion and / or vascular endothelial nitric oxide blood concentration. 27. The use of a HMG-CoA reductase inhibitor and r rice furfuryl alcohol and / or thiamine, which is used to manufacture a medicine containing a HMG-CoA reductase inhibitor and rice furfuryl alcohol and / or thiamine A composition, wherein HMG-Co A reductase inhibitor and 7 m furfuryl alcohol and / or thiamine are administered simultaneously or at intervals to improve lipids in blood. -30- 200409635 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the element representative symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: