MX2009001218A - Drug formulation containing fibrate medicament and process for producing the same. - Google Patents

Abstract

Drug formulations (pharmaceutical compositions) for lowering of the blood concentration of free fatty acids and/or fibrinogen, comprising a statin medicament composed at least of a statin compound having benzopyridine skeleton (pitavastatin, etc.) and a fibrate medicament (phenofibrate, etc.). These drug formulations are useful as a preventive or therapeutic agent for hyper-free fatty acidemia, metabolic syndrome, type II diabetes, etc.

Description

PREPARATION CONTAINING A FIBRATE AGENT AND A PROCESS TO PRODUCE THE SAME Field of the Invention The present invention describes a preparation which contains a statin agent and a fibrate agent, and which is useful for a preventive (or prophylactic) or treatment (or therapeutic) agent for a metabolic syndrome, type II diabetes (diabetes mellitus not dependent on insulin), complication of type II diabetes or other diseases, and a process to produce the preparation. Background of the Invention Statin agents (or statin drugs) have an action to suppress cholesterol synthesis, by inhibiting hydroxymethylglutaryl-CoA reductase (HMG-CoA), which is a rate-limiting enzyme on the way of cholesterol biosynthesis, and has been widely used as a preventive (or prophylactic) or treatment (or therapeutic) agent for hyperlipidemias, pravastatin, simvastatin, fluvastatin, atorvastatin, lovastatin, cerivastatin, rosuvastatin and others have been known as agents representative of statin These statin agents are relatively highly effective in lowering the concentrations of total cholesterol and low density lipoprotein (LDL) - by binding cholesterol in the blood.

However, these statin agents are not too efficient in lowering a triglyceride concentration in the blood, decreasing a free fatty acid concentration in the bleed and increasing a high density lipoprotein (HDL) - binding cholesterol. Consequently, a preparation (or agent) that can reduce the total cholesterol concentration, the LDL-cholesterol concentration, the triglyceride concentration and the fat-free acid concentration, and the increase in the cholesterol-H DL concentration has been required . In particular, a preparation (pharmaceutical composition) which shows the pharmacological activities mentioned above at a lower dose has been desired. Fibrate agents (or fibrate drugs) not only have an action to reduce an LDL cholesterol and a triglyceride by inhibiting the synthesis or secretion of triglyceride in the liver, but also by increasing an HDL cholesterol and which has been known as an agent to prevent or treat hyperlipidemias. However, the fibrate agent does not have an activity high in lowering total cholesterol in the blood. Incidentally, the following have been known: each of the statin agent and the fibrate agent is not only used alone, but also in combination with various agents. For example, the following combinations have been known: (1) a pharmaceutical composition containing a combination of fenofibrate and bezafibrate with metformin known as a remedy for diabetes, to reduce hyperglycemia due to non-insulin dependent diabetes (eg, see Patent Document 1), ( 2) a therapeutic agent for hyperlipidemias, atherosclerosis or hypercholesterolemia, which comprises fenofibrate, bezafibrate or clinofibrate, in combination with a cholesteryl ester that transfers protein that inhibits the compound (eg, see Pantente Document 2), (3) a therapeutic agent for hyperlipidemias, atherosclerosis or hypercholesterolemia, which comprises fenofibrate, bezafibrate or clinofibrate in combination with an ileal bilo acid that transports the inhibiting compound (e.g., see Patent Document 3), (4) an agent for prophylaxis or a treatment of atherosclerosis, hypercholesterolemia and hyperlipoproteinaemia, which includes lovastatin or cerivastatin , n combination with a β-blocker (for example, see Patent Document 4), (5) a TNF-a inhibitor useful as an agent for the prophylaxis or treatment of inflammatory diseases, which comprises pravastatin or cervastatin, in combination with pioglitazone known as an insulin sensitizer (eg, see Patent Document 5), (6) a therapeutic agent for angina, atherosclerosis or combined hyperlipidemia and hypertension, which comprises pravastatin or simvastatin, in combination with amlodipine as a therapeutic agent for hypertension (e.g., see Patent Document 6), (7) an action to reduce a triglyceride level in the blood by a combination of cerivastatin and fenofibrate (e.g., see Patent Document. 7), and (8) an action to reduce the level of triglyceride in the blood by a combination of atorvastatin and fenobibrate (eg, see Document without patent 1). Additionally, WO02 / 67901 (Patent Document 8) describes administering a dosage form of a pharmaceutical composition containing a combination of a statin and a micronized fenofibrate which is stabilized by an active substance of a phospholipid surface to substantially increase the bioavailability of the fibrate, and substantially reduce the difference between the amount of active species of the drug absorbed in a patient in the fast state, and the amount of active species of the drug absorbed in the patient in the feeding stage. WO03 / 26573 (Patent Document 9) describes a method for appropriately selecting a statin agent or a statin-free agent to co-administer to a patient in need of said co-administered agent treatment. WO2005 / 034908 (Patent Document 10) describes a particular material comprising as active substances fibrate (s) and statin (s) or a pharmaceutically active salt thereof, wherein at least 80% w / w of the total amount of the active substances is dissolved in the vehicle selected from the group consisting of a hydrophobic vehicle, a hydrophilic vehicle and a water-miscible vehicle, and mentions that the material can improve the bioavailability of the fibrate and / or statin. In "Medical Consultation &New Remedies" vol. 40, No. 9 (September, 2003), pp. 779 to 785 (Document without patent 2), there is a description that the observation of the presence of drug interactions when comparing them in a pharmacokinetic parameter of pitavastatin in a dose of 4 mg administered every day for 6 days, with pitavastatin administered in combination with fenofibrate in a dose of 160 mg administered twice a day for 7 days, reveals a low degree of drug interactions due to a low possibility of an excessive increase in the concentration of unchanged pivastatin in the blood, even in the case of use of combination of those drugs.

However, these documents do not specifically describe the preparation (e.g., a pharmaceutical preparation) comprising a statin compound having a benzopyridine backbone (e.g., pivastatin) as an HMG-CoA reductase inhibitor in combination with a fibrate agent. Additionally, in association with obesity or diabetes, the metabolic syndrome caused by the accumulation of visceral fat (obesity of visceral fat) has attracted attention in recent years Metabolic syndrome means a group of diseases that concurrently have a plurality of factors (atherosclerosis risk factors) such as obesity, abnormal glucose tolerance, hypertension and abnormal lipid metabolism. There were many unknown points about the mechanisms of expression of these factors. However, it is known that obesity, particularly obesity of visceral fat is very related to a development of the metabolic syndrome. For example, in "Theraoeutics", vol. 39, No. 6 (2005), pp. 59 to 62 (Document without patent 3) and "Adiposciene", vol. 3, No. 1 (2006), pp. 64 to 70 (Document without patent 4), a relationship between the metabolic syndrome and the increase of free fatty acid in the blood is reported. According to reports, an excessive increase in a free fatty acid, which is fed visceral fat, induces an abnormal lipid metabolism. Specifically, a free fatty acid fed in a sustained (or continuous) form of visceral fat or a free fatty acid retained in the blood causes hyper-free fatty academia (a disease which raises a hyper concentration of a free fatty acid in the blood) . Said free fatty acid flows into a non-adipose tissue such as liver, muscle, pancreatic-β-cell, and is excessively taken from there, where several dysfunctional cell disorders such as an inhibition of an insulin action (an inhibition of Insulin-dependent glucose absorption (lipotoxicity)) are generator. Accidentally, in type II diabetes, a free fatty acid is secreted even when diabetes is not accompanied by obesity, where a disturbance of an insulin action is triggered. In addition to the obesity of visceral fat, which is a cause of an excessive free fatty acid, it is a major risk factor of metabolic syndrome, and the free fatty acid particularly induces an abnormal glycolipid metabolism as lipotoxicity. On the other hand, WO2006 / 011495 (Patent Document 11) describes a preparation comprising pitavastatin and fenofibrate in combination as an agent for treating hypercholesterolemia and / or hypertriglyceridemia. However, this document does not refer to a proportion of the mixture of pitavastatin and fenofibrate. In addition, in the Examples a combination effect of these active components are not sufficient, and the document fails to describe or suggest an action to decrease a free fatty acid and fibrinogen, which is an independent risk factor of cholesterol or cholesterol lowering. of triglyceride. Additionally, the Patent Document does not refer to the manifestation of a metabolic syndrome or a disease derived therefrom, particularly a relationship between said disease and a free fatty acid, in all. Additionally, the metabolic syndrome caused by said fat obesity Visceral is a risk factor for arteriosclerosis, and it also has a close relationship to thrombus formation. [Patent Document 1] W099 / 40904 [Patent Document 2] WO00 / 38724 [Patent Document 3] WO00 / 38727 [Patent Document 4] WO01 / 74394 [Patent Document 5] US2003 / 60488 [Patent Document 6] ] WO03 / 26573 [Patent Document 7] US6511985 [Patent Document 8] WO02 / 67901 (claim 1) [Patent Document 9] WO03 / 26573 (claim 1) [Patent Document 10] WO2005 / 034908 (claim 1) [Patent Document 11] WO2006 / 011495 (claim 1, paragraph number [0026], Example 1) [Document without patent 1] "Diabetes Care" (Diabetes Care) ), vol. 25 (2002), pp. 1198 to 1202) [Unexplained Document 2] "Medical Consultation &New Remedies" (Medical Consultation &New Remedies), vol. 40, No. 9 (September 2003), pp. 779 to 785 [Non-Patent Document 3] "Therapeutics", vol. 39, No. 6 (2005), pp. 59 to 62. [Non-Patent Document 4] "Adiposcience" (Adipose Science), vol. 3, No. 1 (2006), pp. 64 to 70.

Brief Description of the Invention Problems to be Resolved by the Present Invention It is, therefore, an object of the present invention to provide a preparation that can drastically reduce a concentration of a free fatty acid in the blood. Another object of the present invention is to provide a preparation that can markedly reduce a concentration of fibrinogen in the blood, inhibit thrombus formation and is useful in preventing or treating a disease associated with diabetes, such as type II diabetes or metabolic. It is yet another object of the present invention to provide a preparation that is capable of effectively increasing a concentration of HDL cholesterol in the blood, and a process for producing the preparation. It is a further process of the present invention to provide a preparation having the activity even in a small dose indeed, and a process for producing the preparation. It is still a further object of the present invention to provide a combined pharmaceutical preparation having a high safety and a process for producing the preparation. Means for Solving Problems The creators of the present invention have made studies to achieve the objects mentioned above, and finally have found that a combined administration of at least one statin compound has a benzopyridine skeleton (e.g., pitavastatin) such as a statin agent and a fibrate agent can, (i) reduce a concentration of a free fatty acid and / or fibrinogen in the blood effectively or (ii) reduce a concentration of a free fatty acid and / or fibrinogen in the blood effectively and increase a concentration of HDL cholesterol in the blood effectively. The present invention was achieved based on the aforementioned discoveries. That is, the preparation (or pharmaceutical composition) of the present invention is a preparation that reduces a concentration of a free fatty acid and / or fibrinogen in the blood. The preparation contains a statin agent comprising the minor a statin compound having a benzopyridine backbone and a fibrate agent. The preparation can be a preparation to prevent or treat a hyper-free fatty acid academy, metabolic syndrome, type II diabetes, complication of type II diabetes, lipotoxicity, abnormal lipid metabolism, glucose intolerance, odd insulin secretion, fatty liver, lipoprotein of hypo-high density, or thrombosis, particularly may be a preparation for preventing or treating a disease caused by visceral fat, or an excessive free fatty acid in the blood. The fibrate agent may comprise at least one element selected from the group consisting of bezafibrate, clinofibrate, clofibrate, clofibratealuminium, fenofibrate, simifibrate, fenofibric acid, gemfibrozole and a salt thereof. The benzopyridine skeleton of the statin compound may have at least one substituent selected from the group consisting of a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 6-10 aryl group and a C 6-10 aryl halo group. Said statin compound may comprise a benzopyridylethyl- or benzopyridylvinyl-substituted, 3,5-dihydroxypentanoic acid or a derivative thereof, wherein the benzopyridine backbone may have the above mentioned as a substituent. The derivative may include a salt or lactone of 3,5-dihydroxypentanoic acid (for example 3-hydroxy-6-valerolactone). In the preparation, the statin agent can comprise at least pivastatin. In the statin agent, the content of the statin compound has the benzopyridine backbone (e.g., pivastatin) may be approximately 10 to 100% by weight. The proportion of the weight of the fibrate agent (eg, fenofibrate) relative to one part by weight of the statin agent (eg, pivastatin) can be, for example, about 1 to 500 parts by weight (e.g. approximately 3 to 300 parts by weight). Accidentally, the preparation can be a liquid preparation. The preparation is normally a solid preparation containing a physiological transporter acceptable. Additionally, the present invention includes an agent (or a pharmaceutical agent) that reduces a degree acid in the blood or an agent (or a pharmaceutical agent) that reduces fibrinogen in the blood. The agent (or a pharmaceutical agent) comprising a combination of statin agent comprises at least one statin compound having a benzopyridine backbone and a fibrate agent as effective (or active) ingredients, and the proportion of the fibrate agent is from 1 to 500 parts by weight (preferably, from 3 to 300 parts by weight) relative to one part by weight of the statin agent. The present invention can effectively reduce a free fatty acid content in the blood. Hyper-free fatty acidemia is a disease that a sustained free fatty acid (or continuously) feeds on visceral fat or a free fatty acid retained in the blood, which causes it to increase. Hyper-free fatty acidemia causes influx and excessive recovery of a free fatty acid in a non-adipose tissue (eg, liver, muscle, and pancreatic-β-cell), thereby inducing a disease such as a metabolic syndrome, type II diabetes, complication of type II diabetes, lipotoxicity, abnormal lipid metabolism, glucose intolerance, odd insulin secretion, fatty liver or high-density lipoprotein hypo.

Accidentally, through this specification, the meaning of the term "pharmaceutical" (or "pharmaceutical preparation") includes a drug, an almost drug and its like. In addition, the preparation concept in the present invention includes a pharmaceutical composition. EFFECTS OF THE PRESENT INVENTION In accordance with the present invention, a combination of a specific statin agent and a fibrate agent can markedly reduce a concentration of a free fatty acid and / or fibrinogen in the blood. In particular, said combination can reduce an excessive free fatty acid reduction in the blood and is useful for preventing or treating a disease or disorder (e.g., hyper-free fatty acidemia, metabolic syndrome, type II diabetes, diabetes type complication). II, lipotoxicity, abnormal lipid metabolism, glucose intolerance, odd insulin secretion and fatty liver) caused by (or accompanied by) an excessive increase of free fatty acid in the blood. In addition, since the preparation of the present invention can reduce a concentration of fibrinogen in the blood, and has a high antithrombogenicity, the preparation is useful for preventing or treating thrombosis caused by abnormalities of thrombocyte, fibrinolytic system coagulation, or the like. In particular, the preparation of the present invention can reduce the concentration of fibrinogen in the blood, inhibit a thrombus formation and is useful for preventing or treating a disease or disorder associated with diabetes (eg, type II diabetes, complication of type II diabetes and metabolic syndrome), which easily induces thrombosis. Furthermore, according to the present invention, the concentration of fatty acid and / or fibrinogen in the blood can be reduced and a concentration of HDL cholesterol in the blood can be raised effectively. In particular, the present invention is effective as an agent for reducing free fatty acid in the blood, for example, it is useful for preventing or treating a disease caused by (or accompanied by) visceral fat or an excessive free fatty acid in the blood or metabolic syndrome, whose risk factor is an abnormal lipid metabolism caused by (or accompanied by) an excessive free fatty acid in the blood. Additionally, the preparation of the present invention can effectively inhibit activities, even in a small dose. Additionally, the preparation has great security. Detailed Description of the Invention The preparation (or pharmaceutical composition) of the present invention comprises a combination of a statin agent and a fibrate agent. The statin agent is not particularly limited to a specific one, as long as the agent is a component or an agent which inhibits HMG-CoA reductase, and it has a lipid-lowering action (or lipid-lowering action), particularly, it reduces blood cholesterol. In particular, in the present invention, the aforementioned statin agent comprises at least one statin compound having a benzopyridine backbone (hereinafter, sometimes simply referred to as a "statin compound"). The statin compound may have a substituent on the benzopyridine backbone. Accidentally, the meaning of the term "benzopyridine skeleton" includes a quinoline skeleton and an isoquinoline skeleton. The statin compound may include a 3,5-dihydroxypentanoic acid having a group such as a benzopyridylC ^ -Cealkyl group (such as a quinoliethyl group) or a C2-C6alkenyl benzopyridyl group (such as a quinolylvinyl group) such as a benzopyridine, or an acid derivative. Incidentally, the derivative may include a Cn-ealkyl ester (e.g., methyl ester) of the aforementioned 3,5-dihydroxypentanoic acid, a 3,5-dihydroxypentanoic acid amide mentioned above with a Ci-6alkylamine (e.g. ., methylamine), a 3,5-dihydroxypentanoic acid salt or lactone mentioned above (specifically a closed-ring form of 3,5-dihydroxypentanoic acid lactone, for example, 3-hydroxy-o-valerolactone), and others. Among these derivatives, salt [by example, a salt with an inorganic base such as an alkali metal (eg, sodium and potassium), an alkaline earth metal (eg, calcium and magnesium) or aluminum] or the lactone is preferred. The substituent on the benzopyridine backbone of the statin compound may include, for example, a 6-alkyl group such as a methyl group; a C3-6cycloalkyl group such as a cyclopropyl group or a cyclobutyl group; a C6-10aryl group such as a phenyl group; and a halogenated C 6 -aryl group such as a fluorophenyl, chlorophenyl or bromophenyl group. The statin compound may have one of these substityents or a plurality of the same or different substituents. It is particularly preferable that the statin compound has at least one C3-5-cycloalkyl group and / or a fluoroC6-ioaryl group. Among these statin compounds, the preferred one includes a benzopyridiethyl- or benzopyridylvinyl-substituted with a 3,5-dihydroxypentanoic acid wherein the benzopyridine backbone can have the aforementioned substituent (ie, 7-benzopyridyl-3,5-dihydroxyheptanic acid) or 7-benzopyridyl-3,5-dihydroxy-6-heptaoic acid), particularly a quinoliethyl- or quinolylvinyl-substituted with a 3,5-dihydroxypentanoic acid (that is, 7-quinolyl-3,5-dihydroxyheptanoic acid or 7-benzopyridyl-3,5-dihydroxy-6-heptaoic acid). -quinolyl-3,5-dihydroxy-6-heptanoic acid), or a derivative thereof (eg, a salt of the same with an inorganic base and a lactone body thereof). It is particularly preferable that the statin compound has the substituent (eg, cyclopropyl group and / or fluorophenyl group (such as a 4-fluorophenyl group)) in the benzopyridine backbone. Concrete examples of the statin compound include a 5- acid. { 2- [2-cyclopropyl-4- (p-fluorophenyl) -3-quinolyl] vinyl} -3,5-dihydroxopentane such as (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5-dihydroxy-6-heptanoic acid, a salt thereof (eg, an alkali metal salt, an alkaline earth metal salt [a calcium salt such as pitavastatin (or pitavastatin calcium))] or a lactone body thereof, and others. In the present invention, the statin compound, particularly the statin agent preferably comprises at least pitavastatin. In the present invention, the statin agent is not particularly limited to a specific one, as long as the statin agent comprises at least the specific statin compound mentioned above. The statin agent may contain other statin compounds (active components of statin), for example, pravastatin, simvastatin, fluvastatin, atorvastatia, lovastatin, cerivastatin, rosuvastatin or salts thereof (eg, pravastatin sodium, fluvastatin sodium and hydrate). of atorvastatin calcium). These other compounds can be used individually or in combination. The proportion (content) of the statin compound having a benzopyridine backbone (eg, pitavastatin) in the statin agent can be from about 10 to 100% by weight (eg, about 20 to 90% by weight) , preferably from 25 to 100% by weight (eg, approximately 30 to 90% by weight), and more preferably approximately from 50 to 100% by weight (eg, approximately 60 to 80% by weight). The fibrate agent (or active fibrate component) is not particularly limited to a specific one, so long as the statin agent is a component or agent having a lipid lowering action, particularly, a component or agent to reduce a level of triglyceride in the blood and / or a level of cholesterol in the blood. For example, the agent can be a compound that exhibits a lipid lowering action upon triglyceride synthesis or secretion in the liver, activating lipoprotein lipase and others. Examples of the fibrate agent may include bezafibrate, clinofibrate, clofibrate, clofibrate aluminum, fenofibrate, simifibrate, fenofibric acid, gemfibrosyl or salts thereof. These fibrate agents can be used individually or in combination. The preferred fibrate agent (or active fibrate component) includes fenofibrate, bezafibrate and salts thereof (by example, a physiologically or pharmaceutically acceptable salt), particularly fenofibrate. The aforementioned salt of the fibrate agent and the salt of the statin agent (eg, a physiologically or pharmaceutically acceptable salt) are not limited to the salts mentioned above and may include, for example, a salt with an inorganic or organic base , a salt with an inorganic or organic acid and a salt with a neutral, basic or acidic amino acid. The inorganic base may include, for example, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, aluminum and ammonium. The organic base may include, for example, an alkylamine such as trimethylamine or triethylamine; a heterocyclic amino such as pyridine or picoline; an alkanolamine such as ethanolamine, diethanolamine or triethanolamine; a cycloalkylamine such as dicyclohexylamine; and an alkylenediamine derivative such as N, N-dibenzylethylenediamine. The inorganic acid may include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. The organic acid may include, for example, a monocarboxylic acid such as formic acid, acetic acid or trifluoroacetic acid; a polycarboxylic acid such as fumaric acid, malic acid; and a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. The neutral amino acid may include, for example, glycine, valine and leucine; he amino acid basic can include, for example, arginine, Usin and ornithine; the amino acid acidic can include, for example, aspartic acid and glutamic acid. Incidentally, the aforementioned statin agent and the fibrate agent also include derivatives of the respective active compounds (e.g., an ester, a salt hydrate and a hydrate) or prodrugs thereof. The statin agent or fibrate agent can be an optically active body or a racemic body. The weight ratio of the specific statin agent mentioned above (for example, pitavastatin) relative to the fibrate agent (for example fenofibrate) [the previous / the subsequent] in the preparation can be selected from the range of about 0.01 / 99.99 to 99. / 11 (for example, approximately 0.1 / 99.9 to 90/10). The ratio of the two agents [the previous / the following] can be from about 0.2 / 99.8 to 50/50, preferably from about 0.3 / 99.7 to 30/70, and more preferably from about 0.5 / 99.5 to 10/90. Additionally, with respect to the statin agent (or the statin compound (e.g., pitavastatin)) in a preparation containing the statin agent and the fibrate agent (e.g., fenofibrate) in a preparation containing the fibrate agent, the proportion of the fibrate agent relative to a part of the weight of the statin agent (or Statin compound (eg., pitavastatin)) can normally be selected from the range of about 1 to 500 parts by weight, for example, about 3 to 300 parts by weight, preferably about 5 to 250 parts therefor (for example. example, approximately 10 to 250 parts by weight) and more preferably from 15 to 200 parts by weight (eg, approximately 20 to 150 parts by weight) or may be from approximately 3 to 120 parts by weight, preferably about 5 100 parts by weight, and more preferably about 7 to 80 parts by weight, with the assumption that, in the case of a combination of pitavastatin and fenofibrate, the proportion of one part by weight of fenofibrate relative to one Part by weight of pitavastatin is normally excluded. The preparation of the present invention may contain other agents for hyperlipidemias (e.g., nicotinic acid and a derivative thereof (such as nicomol or niceritrol), an ion exchange agent, and probucol), an antianginal agent, a β-blockade , a Ca antagonist, an antirrhythmic agent, a diuretic agent, a depressant (a sympathetic blocking agent such as a α central agonist, a peripheral sympathetic blocking agent, an autonomic ganglionic blocking agent, a -blocker or the blocker ß; a vasodilator, the antagonist Ca mentioned above, an ACE inhibitor and an antagonist receptor angiotensin II), a vasopressor, an agent for diabetes, an antiphlogistic agent, a vitamin compound (eg, vitamin A, vitamin B, vitamin C, vitamin D and vitamin E), an amino acid (eg., cysteine ) and others. The preparation form of the present invention is not particularly limited to a specific one and can be a solid preparation (for example powder preparations, particles, spherical or spheroidal pills, pills, tablets, capsules and suppositories), a semi-solid preparation (for example example, creams, ointments and gels), a liquid preparation (for example, solutions, suspensions, emulsions, gum drop preparations, syrup, elixir, lotions and injected solutions (or injections)), and others. Accidentally, the capsules can be a capsule having a liquid filled therein or a capsule having a solid preparation (such as granules) filled therein. In addition, the preparation can be a lyophilized preparation. Additionally, an agent contained in the preparation of the present invention can be released in a controlled rate, that is, the preparation of the present invention can be a sustained release preparation or a rapid release preparation. Additionally, the preparation may be a preparation for oral administration or a preparation for administration by the parents. In addition, the preparation it may be a preparation for topical administration or administration (e.g., solutions, suspensions and cataplasms). The preparation of the present invention is practically a solid preparation (particularly for oral administration). The preparation normally contains an acceptable physiological transporter. The transporter can be selected, depending on the dosage form, route of administration, application and others, for example, of components listed in the Japanese Pharmacopoeia and "Encyclopedia of Pharmaceutical Excipients 2000 (lyakuhin Tenkabutsu Jiten 2000)" ( Yakuji Nippo Ltd., the second edition, presented on March 25, 2002), ("Encyclopedia of Pharmaceutical Excipients 2000"). For example, at least one conveyor selected from the group consisting of an excipient, a linker and a disintegrator is practically used as a conveyor for the solid preparation. An additive such as a lipid can also be used. The excipient may include a saccharide or a sugar alcohol such as lactose, white soft sugar or refined sugar, glucose, sucrose, mannitol or sorbitol; a starch such as a corn starch; a polysaccharide such as a crystalline cellulose (including a microcrystalline cellulose); silicon dioxide or silicate such as a light silicic anhydride or a synthetic aluminum silicate; and others. The linker may include a starch that can be diluted in water such as a starch pregelatinized or a partially pre-gelatinized starch; a polysaccharide such as agar, acacia gum (or gum arabic), dextrin, sodium alginate, a tragacanth gum, a xanthan gum, a hyaluronic acid or a sodium chondroitin sulfate; a synthetic polymer such as polyvinylpyrrolidone, a polyvinyl alcohol, a carboxyvinyl polymer, a polyacrylic polymer, a polylactic acid or a polyethylene glycol; a cellulose ether such as a methyl cellulose, an ethyl cellulose, a carboxymethyl cellulose, a carboxymethyl cellulose sodium, a hydroxyethyl cellulose, a hydroxypropyl cellulose or a hydroxypropylmethyl cellulose; and others. The binder may include calcium carbonate, a carboxymethyl cellulose or a salt thereof (e.g., a carmellose, a carmellose sodium and a carmellose calcium), a polyvinylpyrrolidone (e.g., a polyvinylpyrrolidine and a transverse polyvinylpyrrolidone ( transverse povidone)), a low-substituted hydroxypropyl cellulose and others. These conveyors can be used individually or together. Examples of the oil-based carrier for the liquid preparation may include an oil derived from plants or animals (eg, an oil derived from vegetables such as jojoba oil, olive oil, palm oil or cottonseed oil). and an oil derived from animals such as scalene), or mineral oil (for example., a liquid petrolatum and a silicone oil), and others. An aqueous carrier may include water (eg, a purified water or a sterile water, a water distilled for injection), a physiological salt, a Ringer's solution, a glucose solution, a water-soluble organic solvent [e.g., a minor aliphatic alcohol such as ethanol or isopropanol; a (poly) alkylene glycol (for example, ethylene glycol, diethylene glycol and polyethylene glycol); and glycerin] dimethyl isosorbide, dimethylacetamide and others. In addition, the conveyor for the semi-solid preparation can be selected from the conveyor for the solid preparation and / or for the liquid preparation. Additionally, the carrier for the semisolid preparation may also contain a lipid. The lipid may include a wax (eg, a beeswax, a carnauba wax, a lanolin, a paraffin and a petrolatum), a higher fatty acid ester (or long chain) [eg, an alkyl ester of a saturated or unsaturated fatty acid and an ester of a fatty acid with polyhydric (polyvalent) alcohol (such as a polyC2-4alkylene glycol, glycerin or a polyglycerol) (eg, a glyceride)], a hardened oil (or hydrogenated), a higher alcohol (e.g., a saturated aliphatic alcohol such as a stearyl alcohol and an unsaturated aliphatic alcohol such as oleyl alcohol), a higher fatty acid (e.g., stearic acid and oleic acid), a soap metallic (for example., a metal salt of an acid fatty, such as a sodium salt of fatty acid palm oil or calcium stearate), and others. The additive may include, for example, a lubricant (eg, a talc, magnesium stearate and a polyethylene glycol 6000), a disintegrating aid, an antioxidation agent or an antioxidant, an emulsifier (eg, a variety of surfactants such as a nonionic surfactant), a dispersing agent, a suspending agent, a dissolution aid, a thickener (eg, a water soluble polymer such as a carboxyvinyl polymer, a polyvinyl alcohol, a carragene , or a gelatin, and a cellulose ether such as a carboxymethyl cellulose), a pH adjusting agent or a buffer (eg, a citric acid sodium citrate buffer), an antiseptic agent or a condom ( for example, a paraben such as a methyl paraben or butyl paraben), a fungicide or antibacterial agent (eg, a benzoic acid compound such as sodium benzoate), an antistatic agent, a curing agent or an agent of r coating (e.g., a sweetening agent) a coloring agent (e.g., an ink and a pigment such as colcotating), a deodorant or a perfume (e.g., an aromatic substance), an allgestant, an antifoaming agent , an isotonizing agent and a softening agent. These additives can be used individually or together.

The preparation of the present invention comprises a combination of a specific statin agent, and a fibrate agent can synergistically reduce a concentration of a free fatty acid in the blood, compared to the use of the specific statin agent alone, and the use of the fibrate agent alone. Additionally, the preparation can reduce a concentration of fibrinogen in the blood, thereby inhibiting thrombus formation followed by coagulation and / or thrombocyte cohesion. In particular, a disease associated with diabetes (eg, type II diabetes, complication of type II diabetes and metabolic syndrome) facilitates thrombocyte adhesion or cohesion, due to abnormal thrombocyte, fibrinolytic coagulation of abnormal system and others, where the thrombus It is easily formed. However, even when in the state where the thrombus is easily formed, the combination mentioned above ensures the reduction of a concentration of fibrinogen in the blood and performs a high antithrombogenicity. Therefore, the combination is effective in preventing or treating a disease associated with diabetes. In addition, the combination mentioned above can effectively increase a concentration of HDL cholesterol in the blood. In addition, the preparation (or pharmaceutical composition) of the present invention has high security. For example, the incidence of an adverse event in the use of an agent of Statins other than the specific statin agent in a clinical trial is approximately 9%, while the specific statin compound (eg, pitavastatin) and the fibrate agent (eg, fenofibrate) have a high safety, and the The incidence of an adverse event in a clinical trial can be reduced to approximately 5 to 6%. The proportions of the statin agent and the fibrate agent in the preparation can be selected depending on the subject to which it will be applied or administered, the age and body weight, the condition, the number of administrations, the method (or route) of administration, and others. The content of the specific statin compound (or statin agent) and the fibrate agent, mainly depend on a dose. For example, the total content of the specific statin compound and the fibrate agent in the preparation may be, for example, from about 0.01 to 99% by weight, preferably from about 0.1 to 95% by weight, and more preferably about from 1 to 80% by weight (eg, approximately 5 to 50% by weight) in terms of a solid content. The total content of the specific statin compound (or statin agent) and the fibrate agent in the preparation is usually from 5 to 70% by weight, and preferably from 10 to 50% by weight. Accidentally, the present invention also includes a team comprising a preparation containing a statin agent and a preparation containing a fibrate agent in combination. The preparation of the present invention can be produced by a conventional production process using the statin agent, the fibrate agent and the carrier (eg, a physiologically acceptable carrier). For example, the solid preparation can be, for example, produced when a carrier is used together with effective ingredients (the specific statin compound (or statin agent) such as pitavastatin and the fibrate agent). For example, the granules can be prepared by granulating the effective ingredient and the carrier component through extrusion granulation, spray granulation, or other means, and if necessary, regulate the size of the resulting granule. The tablets can be produced by mixing granular material and the carrier and / or additive if necessary, and compressing-molding the resultant. In addition, if necessary, the granules or tablets may per se be covered by known methods for masking the taste or imparting a gastro-soluble property, an enteric property or durability thereof. The capsules can be prepared by filling the granules or liquid preparation in a capsule. The liquid preparation can be prepared by mixing (eg, dissolving, suspending and emulsifying) the effective ingredients and the liquid carrier (eg., A aqueous carrier such as a purified water and an oil-based carrier), and if necessary, the carrier for the solid or semi-solid preparation, the additive (eg, an emulsifier, a dispersing agent, a suspending agent, a isotonizing agent, a dissolving aid, a preservative, a concealer and a pH adjusting agent or a buffer), and if necessary, the liquid preparation is sterilized. The semi-solid preparation can be prepared by mixing or kneading the effective ingredients and the carrier for the semisolid preparation (and if necessary, the additive), if necessary under heat. The amount to be administered (or dose) of the preparation of the present invention and the administration schedule, the extent of the patient's (or subject's) illness, and the age, sex and body weight of the patient (or subject), and normally the pharmacological activity of the preparation can be effectively exhibited even in a small dose. For example, the dose of the statin compound (or statin agent) such as pitavastatin may be from 0.1 to mg, preferably 0.5 to 7 mg, and more preferably 1 to 5 mg to an adult human per day. Accidentally, the form of administration of the equipment is not particularly limited to a specific one. For example, a preparation containing the compound of statin and a preparation containing the fibrate agent can be administered at the same time (simultaneously) separately. In separate administration, these preparations can be administered separately to a subject who leaves a period of time in between. While a pre-administered preparation maintains the effects of the active component contained therein, the other preparation is normally administered. When a preparation containing the statin compound and a preparation containing the fibrate agent are administered separately, it is preferable that both preparations be administered simultaneously or that one preparation be administered immediately after the administration of the other preparation. In addition, a preparation containing the statin compound and a preparation containing the fibrate agent can be administered in the form of a mixture, by mixing these preparations (and a diluent or its like, if necessary) before (e.g. immediately before) of the administration. Industrial Application The preparation of the present invention can reduce a level of free fatty acid in the blood, and is useful for a preventive (prophylactic) or treatment (therapeutic) agent for a disease or disorder caused by (or accompanied by) an increase excessive in the level of free fatty acid in the blood, for example, hyper-free fatty acid academy, metabolic syndrome, type II diabetes, complication of type II diabetes, lipotoxicity, abnormal lipid metabolism, glucose intolerance, odd insulin secretion, or fatty liver. In addition, since the preparation of the present invention can reduce a concentration of fibrinogen in the blood, the preparation inhibits the formation of thrombus, and is useful for an antithrombotic agent. Additionally, the preparation reduces a concentration of a free fatty acid in the blood and is useful for a preventive (prophylactic) or a (therapeutic) treatment agent for hypo-high density lipoproteinemia. EXAMPLES The following examples are intended to describe the present invention in greater detail, and should not be interpreted by any means as defining the scope of the present invention. Example 1 (Test Example) Pitavastatin (PIT) was adhered to a food and was provided to normal rabbits (rabbits with normal blood lipid levels) in a dose of 0.5mg / kg / day for weeks (PIT administration group) ). Fenofibrate (FEN) was adhered to a food, and was given to normal rabbits at a dose of 30 mg / kg / day for 4 weeks (FEN administration group). They were PIT and FEN were attached to a food, and was given to normal rabbits for 4 weeks (combination administration group). Accidentally, in the combination administration group, the dose of PIT was 0.5 mg / kg / day and that of FEN was 30 mg / kg / day. After the final administration of the agents, these rabbits were advanced for one day, and each blood was collected from the atrial vein, and treated with ethylenediamine tetraacetic acid (EDTA) to prepare a plasma. Total oleterol (TC) and triglyceride concentration (TG) were measured according to the enzymatic method by using an assay kit for enzymatic method (manufactured by Wako Puré Chemical Industries, Ltd.). Additionally, part of the plasma was ultracentrifuged to be separated into the following lipoprotein fractions: low density lipoprotein (LDL), very low density lipoprotein (VLDL) and a medium density lipoprotein (IDL). Cholesterol and Tg at home lipoprotein were measured. After the blood collection, each rabbit was sacrificed. The liver was extracted and homogenized to measure the cholesterol content in the liver, according to the enzymatic method. The result revealed that the combination administration group, where both the PIT and the FEN have been administered, showed a marked reduction in TC and TG levels, purchased with the PIT administration group, where the PIT has been administered individually, where the FEN has been administered individually. In addition, the combination administration group exhibits additional values lower than TC and TG, compared to the decrease in predicted TC and TG levels based on the PIT administration group and the FEN administration group. Example 2 (Test Example) Pitavastatin (PIT) was administered orally to guinea pigs (guinea pigs with normal blood lipid levels) in a dose of 1 mg / kg / day for 2 weeks (PIT administration group) ). Fenofibrate (FEN) was administered orally to guinea pigs in a dose of 30 mg / kg / day for 2 weeks (FEN administration group). PIT and FEN were administered orally to guinea pigs in India for 2 weeks (combination administration group). Accidentally, in the combination administration group, the dose of PIT was 1 mg / kg / day and that of the FEN was 30 mg / kg / day. After the final administration of the agent, the guinea pigs were advanced one day, and each blood was collected from the abdominal aorta. Using the same manner as in Example 1, a plasma was prepared, the TC and TG values were measured and the cholesterol content in the liver was measured. The results revealed that the combination administration group, where both the PIT and the FEN have been administered, showed an outstanding reduction in the TC and TG levels, compared in the PIT administration group, where the PIT has been administered individually, where the FEN has been administered individually. Additionally, the combination administration group additionally exhibited lower TC and TG values, compared to the decrease in predicted TC and TG values based on the PIT administration group and the FEN administration group. Example 3 (Test Example) The examination of the decrease of lipid and others in the blood by the combined use of fenofibrate (FEN) and pitavastatin (PIT) in a dog. (1) Subject Dogs [female and male beagles (BEAGLE YAKUKEN) (11 male bucks and 2 female dogs, 27 to 30 months old)] were used for the examination. Accidentally, each of the dogs was accommodated in a separate cage in a nursery under the following conditions: an ambient temperature of 23 +/- 3 ° C, a humidity of 50 + (-10%, a period of light from 8:00 a.m. to 8:00 p.m. and a period without light from 8:00 p.m. to 8:00 p.m. In addition, the dog was given 300g of CD-5M (manufactured by CLEA Japan, Corp.) as a meal once a day. Accidentally, the dog was freely allowed to have water. (2) Substance test and control substance Fenofibrate (FEN) (20 mg / kg) and pitavastatin (PIT) (2 mg / kg) were used as test substances. (3) Test Four hours (Day 4-4) and 24 hours (Day0-24hr) after feeding on the day before the day of administration, blood was collected from the antebrachial radial veins and serum and plasma containing Sodium citrate (an aqueous citric sodium solution having a concentration of 3.8% by weight) were obtained. Then using the same serum, total cholesterol (TC), triglyceride (TG), phospholide (PL) and free fatty acid (NEFA) were quantitatively determined by a Toshiba automatic analyzer (manufactured by Toshiba Medical Systems Corporation, TBA- 120FR). In addition, using the plasma containing sodium citrate, the amount of fibrinogen was quantitatively determined according to the trombone time method. Based on the quantification of the results, 12 dogs that showed a stable relative value of serum lipid on both Day4-4hr and Day0-24hr were selected, and each 4 dogs formed a group based on the TC value as a index (that is, three groups were formed). Then, FEN was administered individually at a dose of 20 mg / kg to a first group of dogs once a day for 7 days in a row (FEN group); PIT was administered individually at a dose of 2 mg / kg to a second group of dogs once a day for 7 days in a row (PIT group); and FEN was administered orally in a dose of 20 mg / kg and PIT was administered in a dose of oral form in a dose of 2 mg / kg to a third group of dogs once a day for 7 days in a row (group of combination). Incidentally, the feeding was carried out immediately after each administration. Blood was collected after 4 hours of the seventh administration (Day 7-4hr). Using the same method as in the case of Day 4-4, serum and plasma containing sodium citrate were obtained and each of the examinations were carried out. Table 1 shows the list of each group. [Table 1] Table 1 Number of Group Group name Dogs treatment FEN group Oral administration of FEN 20 mg / kg 1 4 for 7 days PIT group Oral administration of PIT 2 mg / kg for 4 2 7 days Oral administration of Fen 20 mg / kg and 4 3 combination PIT 2 mg / kg for 7 days (4) Statistical treatment of the quantification results The quantification results were shown as "an average value + - a standard error". The statistical analysis was carried out in the following way: each difference between the quantitative value on Day 4-4 and each difference in blood time collected after administration was calculated with respect to each dog, and a difference between the average quantitative value and a difference between the average quantitative value of the FEN group or the PIT group, and that of the combination group was tested using the Student's test (unilateral test) at the time which was identified there in half homoscedasticity by an F test, or when using the Wilcoxon Rank Sum test (unilateral test) at the time it was not identified there in the middle homoscendasticity by an F test. Accidentally, the value obtained from each test It was taken as a significant difference when the difference value was less than 5%. (5) Results The results on Day7-4hr are shown in Table 2. More in addition, Table 2 shows a relative index of a concentration of each component in the blood, calculated with respect to each of the individual administration groups and the combination group, and a product of the relative index of the FEN group and a product of the PIT group. Accidentally, the relative index of each component was calculated based on the formula (the average value of the concentration in the blood after administration) / (the value of average concentration in the blood before administration). [Table 2] As was apparent in Table 2, compared to the FEN group, the combination group showed significant lower values in the ATC, ANEFA and Afibrinogen. Accidentally, the significant difference between ATC and ANEFA was P < 0.05 and P < 0.05, respectively. More in addition, compared to the PIT group, the combination group showed significant lower values in ATC and ATG. The significant difference of ATC and that of ATG was P < 0.05 and P < 0.01, respectively, purchased with the PIT group. The decrease in the level of lipid in the combination group was probably caused by an additive effect of FEN and PIT, whereas ANEFA and Afibrinogen was probably induced by a synergistic effect of FEN and PIT. Incidentally, it is known that the decrease of the TG level in the blood raises the level of HDL cholesterol regardless of the species of animals (Progreso en Medicina, Vol, 17, No. 2, 1997. 2, pp. 291 to 296, and Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 15, No. 11, November 1995, pp. 1819 to 1828). That is, the significant decrease of the TG level in the Test Examples mentioned above, induces a significant increase in the concentration of HDL cholesterol in the blood. Additionally, when the product of the relative index of the FEN group and the relative index of the PIT group was calculated and compared with the relative index of the combination group based on the Bulge formula (TAKAGI Keijiro et al .: Pharmacology, 1987, Nanzando Co., Ltd.), the product of the relative indices of the individual administration groups were greater than the relative index of the combination group with respect to all the components (that is, TC, TG, PL and NEFA), as it was apparent from Table 2. It is clear that the combination administration had a synergistic effect. Incidentally, as described in Specification Examples WO2006 / 011495, when pitavastatin in a dose of 10 mg / kg and / or fenofibrate in a dose of 10 mg / kg are used, the product of the relative indexes of the individual management groups is 0.650, while the relative index of the combination group is 0.627, with respect to TG. The difference between them is small. In contrast, from the results shown in Table 2, the relative index of the combination group is 0.185, and the product of the relative indices of the individual administration groups is 0244, with respect to TG. From the comparison, it is clear that reducing the amount of the specific statin agent is remarkably effective in lowering the concentration of TG in the blood.

Claims (12)

1. CLAIMS 1. A preparation for reducing a concentration of free fatty acid and / or fibrinogen in the blood, the preparation comprising: a statin agent comprising at least one statin compound having a benzopyridine backbone and. a fibrate agent.
2. 2. A preparation, as described in claim 1, which is a preparation for preventing or treating hyper-free fatty acid academy, metabolic syndrome, type II diabetes, complication of type II diabetes, lipotoxicity, abnormal lipid metabolism, glucose intolerance, unequal insulin secretion, fatty liver, hypo-high density lipoproteinemia, or thrombosis.
3. 3. A preparation, as described in claim 1, which is a preparation for preventing or treating a disease caused by visceral fat or an excessive free fatty acid in the blood.
4. 4. A preparation, as described in the claim, wherein the fibrate agent comprises at least one element selected from the group consisting of bezafibrate, clinofibrate, clofibrate, clofibrate aluminum, fenofibrate, simfibrate, fenofibric acid, gemfibrozil and a come out of it
5. 5. A preparation, as set forth in claim 1, wherein the statin compound comprises a benzopyridylethyl- or benzopyridylvinyl-substituted 3,5-dihydroxypentanoic acid or a derivative thereof, wherein a benzopyridine backbone of the benzopyridylethyl or benzopyridyl-vanyenyl group may having a substituent selected from the group consisting of a Ci-6alkyl group, a C3-6cycloalkyl group, a C6-ioaryl group and a halogenated C6-ioaryl group, and the derivative is a 3,5-dihydroxypentanoic acid salt or lactone.
6. 6. A preparation, as described in claim 1, wherein the statin agent comprises at least pivastatin, and the proportion of the fibrate agent is from 1 to 500 parts by weight relative to 1 part by weight of the statin agent .
7. 7. A preparation, as described in claim 1, wherein the proportion of the fibrate agent is from 3 to 300 parts by weight relative to 1 part by weight of the statin agent.
8. 8. A preparation, as described in claim 1, which is a solid preparation containing an acceptable physiological transporter.
9. 9. An agent for reducing a free fatty acid in the blood, comprises a combination of a statin agent comprising the minor a statin compound having a benzopyridine backbone and a fibrate agent as effective ingredients, wherein the proportion of the fibrate agent is from 3 to 300 parts by weight relative to 1 part by weight of the statin agent.
10. 10. An agent for reducing fibrinogen in the blood, comprising a combination of, a statin agent comprising the minor a statin compound having a benzopyridine skeleton and a fibrate agent as effective ingredients, wherein the proportion of the fibrate agent it is from 3 to 300 parts by weight relative to 1 part by weight of the statin agent.
11. 11. A method to prevent or treat hyper-free fatty academia, metabolic syndrome, type II diabetes, complication of type II diabetes, lipotoxicity, abnormal lipid metabolism, glucose intolerance, odd insulin secretion, fatty liver, hypo-lipoproteinmia -High density, or thrombosis when using a preparation mentioned in claim 1.
12. 12. Use of a preparation mentioned in claim 1 for preparing a preparation capable of preventing or treating hyper-free fatty acid academia, metabolic syndrome, type II diabetes, complication of type II diabetes, lipotoxicity, abnormal lipid metabolism, glucose intolerance, secretion of unequal insulin, fatty liver, hypo-high density lipoproteinemia or thrombosis.