CN1681499A - Medicinal composition for mitigating blood lipid or lowering blood homocysteine - Google Patents

Abstract

A safe drug for mitigating blood lipid and for reducing the amount of blood homocystein. It is a medicinal composition containing an HMG-CoA redactase inhibitor and a pyridoxine compound.

Description

The pharmaceutical composition that is used for improving the blood lipid or reduces homocysteine in the blood

Technical field

The present invention relates to contain the pharmaceutical composition (especially for the pharmaceutical composition that improves homocysteine in lipid in the blood or the blood) of HMG-CoA reductase inhibitor and Benadon class (pyridoxine).

Background technology

The saying that " people with blood vessel old and feeble " just arranged from ancient times, in recent years, as arteriosclerosis risk factor independently, the increase of homocysteine amount is noticeable, and widely understood gradually in the blood.

Homocysteine is the aminoacid that generates in the metabolic process as the methionine of one of essential amino acids, the shortage of known because inherited genetic factors, vitamin cofactor (folic acid, vitamin B6, vitamin B12), aging, property, renal function reduction, diabetes, other disease, medicine, smoking etc., cause homocysteine amount rising (Progress in Medicine in the blood, Vol.19 No.8,1999 p.49-52), this symptom is called as high homocysteine mass formed by blood stasis.At present, as treatment, to be treated as the phase I with the folic acid that is used to homocysteine metabolism is carried out smoothly to high homocysteine mass formed by blood stasis, as second stage, give and vitamin B6 or vitamin B12 (1999 p.52-53 for Progress in Medicine, Vol.19 No.8).

On the other hand, statins (statins) is special in vivo and antagonism ground suppresses the HMG-CoA reductase, reduces the medicine of cholesterol amount in the blood, and the influence about to homocysteine amount in the blood has following report:

(1) 16 routine high homocysteine mass formed by blood stasis patients are given and 8 weeks of Pravastatin (pravastatin), the result make the report that the homocysteine amount reduces in the blood (NikkeiMedical, November calendar year 2001 number, p73);

(2) give with 20705 examples in 1 year of lovastatin (lovastatin) in, the report of homocysteine amount decreased average 3.7% in the blood (the placebo group reduces 1.9%) (2002, p 1778 for Circulation, Vol.105 No.15);

(3) in 7 routine cardiovascular patients, 3 examples are given and 6 weeks of atorvastatin (atorvastatin), all the other 4 examples are given and 6 weeks of simvastatin, the result, homocysteine amount in the blood, in atorvastatin administration group, increase, the report that in the simvastatin group, reduces (31st Hemophilia Symposium Hamburg) 2000, p258);

We can say that present situation is to access clear and definite conclusion.

In addition, in order to prevent or alleviate the progress danger of arteriosclerosis, the therapy (WO 97/38694) of statins and folic acid and usefulness is disclosed.

In addition, at present, document about statins and Benadon class and usefulness, 17 pages of WO97/38694, put down in writing except statins and folic acid, also contained the material that is selected from HMG-CoA synthetase inhibitors, squalene epoxidase inhibitor, inhibitor for squalene synthetic enzyme, ACAT inhibitor, probacol, nicotinic acid, fibrate, cholesterol absorption inhibitor, bile acid adsorbent, ldl receptor derivant, vitamin B6, vitamin B12, aspirin, beta-Blocking agent, vitamin C, vitamin E and beta-carotene.

But, WO 97/38694 does not relate to the record of HMG-CoA synthetase inhibitors of the present invention and two kinds of drug combinations of Benadon class, in addition, both not record did not hint that effect of the present invention, i.e. the present invention significantly improved the effect of lipid in the blood or significantly reduce the discovery of the effect of homocysteine amount in the blood yet.

In addition, WO discloses for No. 02/43659 as the dietary supplement that is used to reduce cardiovascular disease danger, cooperates the compositions of HMG-CoA reductase inhibitor (statins) and 7 kinds of additives (omega-fatty acid, vitamin E, vitamin C, vitamin B6, vitamin B12, folic acid, calcium).But, this is based on the known drug effect of each composition, be that statins and omega-fatty acid improve serum lipids, vitamin E and vitamin C have antioxidation, the combination of folic acid and vitamin B6 and B12 reduces homocysteine levels in the blood, calcium brings high blood pressure down, thereby be the compositions that this useful supposition and considering obtains for the health of cardiovascular system, concrete test data etc. is not disclosed, therefore, No. 02/43659, WO both not record do not hint that effect of the present invention, i.e. the present invention significantly improve the effect of lipid in the blood and significantly reduce the discovery of the effect of homocysteine amount in the blood yet.

Summary of the invention

The inventor is in order to find the safe drugs of improving lipid in the blood and the safe drugs that reduces homocysteine amount in the blood, carried out concentrated research, found that HMG-CoA reductase inhibitor and Benadon class and usefulness, can show the reduction effect of homocysteine amount in lipid improvement effect in the significant blood and the blood, thereby finish the present invention.

The present invention relates to:

(1) a kind of pharmaceutical composition, it contains HMG-CoA reductase inhibitor and Benadon class.

Wherein, pharmaceutical composition is

(2) compositions described in (1), it is used for improving blood lipid or high blood homocysteine levels;

(3) above-mentioned (1) or (2) described compositions, wherein the HMG-CoA reductase inhibitor is to be selected from Pravastatin, lovastatin, simvastatin, fluvastatin (fluvastatin), upright one or more of his spit of fland (rivastatin), atorvastatin, Pitavastatin (pitavastatin) and rosuvastatin (rosuvastatin) of cutting down.

(4) above-mentioned (1) or (2) described compositions, wherein the HMG-CoA reductase inhibitor is to be selected from one or more of Pravastatin, simvastatin or atorvastatin.

(5) above-mentioned (1) or (2) described compositions, wherein the HMG-CoA reductase inhibitor is an atorvastatin.

(6) any described compositions in above-mentioned (1) to (5), wherein the Benadon class is to be selected from Benadon, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine or their salt one or more.

(7) any described compositions in (1) to (5), wherein the Benadon class is Benadon or its salt.

(8) (2) described compositions, HMG-CoA reductase inhibitor are atorvastatin or its salt, and wherein the Benadon class is Benadon or its salt.

(9) any described compositions in (1) to (8), it is used for improving the lipid of blood.

(10) any described compositions in (1) to (8), it is used to improve high blood homocysteine levels.

(11) any described compositions in (1) to (8), the disease that it is used for the treatment of or prevents high blood homocysteine levels to cause.

(12) any described compositions of (1) to (8), it is used for prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or parkinson disease; And

(13) (8) described compositions, it is used for prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or parkinson disease.

And, the invention provides

(14) combination of HMG-CoA reductase inhibitor and Benadon class, it is used for by simultaneously or separate the time and give respectively and HMG-CoA reductase inhibitor and Benadon class, thereby improves lipid or high blood homocysteine levels in the blood; And

(15) coupling of HMG-CoA reductase inhibitor and Benadon class, it is used for improving blood lipid or high blood homocysteine levels.

And, the invention provides

(16) improve the method for lipid in the blood or high blood homocysteine levels, this method comprises simultaneously or separates the time gives respectively and HMG-CoA reductase inhibitor and Benadon class.

In above-mentioned (16), preferable methods is

(17) (16) described method, it is used for improving the blood lipid.

(18) (16) described method, it is used to improve high blood homocysteine levels.

(19) (16) described method, the disease that it is used for the treatment of or prevents high blood homocysteine levels to cause.

(20) (16) described method, it is used for prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or parkinson disease.

(21) any described method in (16) to (20), it comprise to the pharmaceutical composition that contains HMG-CoA reductase inhibitor and Benadon class.And

(22) (20) described method, it comprise to the pharmaceutical composition that contains HMG-CoA reductase inhibitor and Benadon class.

And, the invention provides

(23) HMG-CoA reductase inhibitor and the purposes of Benadon class in preparation of pharmaceutical compositions, said composition contain HMG-CoA reductase inhibitor and Benadon class, are used for improving the homocysteine levels in blood lipid or the reduction blood.

As " the HMG-CoA reductase inhibitor " of one of pharmaceutical composition composition of the present invention, be the medicine that specificity and antagonism ground suppress cholesterol biosynthesis system rate-limiting enzyme (ratelimitingenzyme) HMG (3-hydroxy-3-methyl glutaryl)-CoA reductase.Cholesterol reduces in the blood owing to make, thereby originally is used as the therapeutic agent use of hyperlipidemia.This HMG-CoA reductase inhibitor comprises the natural materials that derives from microorganism; by its deutero-semi-synthetic material and complete synthesis chemical compound; for example can be (+)-(3R that the spy opens clear 57-2240 communique (USP4346227) record; 5R)-3; 5-dihydroxy-7-((1S; 2S; 6S; 8S; 8aR)-6-hydroxy-2-methyl-8-((S)-and 2-methylbutyryl oxygen base)-1; 2; 6; 7; 8; 8a-six hydrogen-1-naphthyl) enanthic acid (being designated hereinafter simply as Pravastatin); the spy opens (+)-(1S of clear 57-163374 communique (USP4231938) record; 3R; 7S; 8S; 8aR)-1; 2; 3; 7; 8; 8a-six hydrogen-3; 7-dimethyl-8-(2-((2R; 4R)-and tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl (S)-2-Methyl Butyric Acid ester (being designated hereinafter simply as lovastatin); the spy opens (+)-(1S of clear 56-122375 communique (USP4444784) record; 3R; 7S; 8S; 8aR)-1; 2; 3; 7; 8; 8a-six hydrogen-3; 7-dimethyl-8-(2-((2R; 4R)-and tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl 2; 2-dimethyl butyrate acid esters (being designated hereinafter simply as simvastatin); (±) (3R* of the special clear 60-500015 communique of table (USP4739073) record; 5S*; 6E)-7-(3-(4-fluorophenyl)-1-(1-Methylethyl)-1H-indole-2-yl)-3; 5-dihydroxy-6-heptenoic acid (being designated hereinafter simply as fluvastatin); (the 3R of Te Kaiping 1-216974 communique (USP5006530) record; 5S; 6E)-7-(4-(4-fluorophenyl)-2; 6-two-(1-Methylethyl)-5-methoxy pyridin-3-yl)-3; 5-dihydroxy-6-heptenoic acid (be designated hereinafter simply as upright cut down him spit of fland); (the 3R of Te Kaiping 3-58967 communique (USP5273995) record; 5S)-7-(2-(4-fluorophenyl)-5-(1-Methylethyl)-3-phenyl-4-phenyl amino carbonyl-1H-pyrroles-1-yl)-3; 5-dihydroxy enanthic acid (being designated hereinafter simply as atorvastatin); (E)-3 of Te Kaiping 1-279866 communique (USP 5854259 and USP5856336) record; 5-dihydroxy-7-(4 '-(4 "-fluorophenyl)-2 '-cyclopropyl-quinoline-3 '-yl)-6-heptenoic acid (being designated hereinafter simply as Pitavastatin); perhaps the spy opens (+) of flat 5-178841 communique (USP5260440) record-(3R; 5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesyl amino) pyrimidine-5-yl)-3,5-dihydroxy-6 (E)-heptenoic acid statins such as (being designated hereinafter simply as rosuvastatin).In addition, the composition HMG-CoA reductase inhibitor of pharmaceutical composition of the present invention also comprises disclosed other HMG-CoA reductase inhibitor in the communique of having put down in writing above-mentioned HMG-CoA reductase inhibitor.

It below is the planar structure formula of the representative substances of HMG-CoA reductase inhibitor.

The Pravastatin lovastatin

The simvastatin fluvastatin

Upright his the spit of fland atorvastatin that cuts down

Pitavastatin

Rosuvastatin

The Benadon class of one of pharmaceutical composition composition of the present invention is Benadon, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine or their salt, preferred pyridoxine hydrochloride, pyridoxal 5-phosphate or phosphopyridoxamine, more preferably pyridoxine hydrochloride.

In the present invention, contained above-mentioned various compositions can be made officinal salt and contain, as this salt,

Composition has the occasion of basic functionality, comprises for example hydrogen halides hydrochlorates such as hydrofluoride, hydrochlorate, hydrobromate, hydriodate; Inorganic acid salts such as nitrate, perchlorate, sulfate or phosphate; Rudimentary organic sulfonates such as mesylate, fluoroform sulphonate, esilate; Arylsulphonate such as benzene sulfonate or tosilate; Amino acid salts such as ornithine salt, glutamate, Glu; And carboxylates such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid;

Composition has the occasion of acidic functionality, comprises for example alkali metal salts such as sodium salt, potassium salt, lithium salts, alkali salts such as calcium salt, magnesium salt, slaines such as aluminum salt, iron salt, zinc salt, mantoquita, nickel salt, cobalt salt; Inorganic salts such as ammonium salt, t-octanylamine salt, .alpha.-aminodiphenylmethane. salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, the phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, the diethyl amine salt, triethylamine salt, hexanamine salt, N, N '-benzhydryl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl phenethylamine salt, piperazine salt, tetramethyl ammonium, amine salt such as organic salt such as three (methylol) aminomethane salt, for example, when being Pravastatin, preferred sodium Pravastatin, for example when the time for atorvastatin, preferred atorvastatin hydrate of calcium.

When contained various compositions formed hydrate or solvate, the pharmaceutical composition that contains these hydrates or solvate was also contained among the present invention.

In the present invention, " improving lipid in the blood " is to instigate that lipid is reduced to significant clinically degree in the blood, promptly is meant to reduce triglyceride in the blood, reduce in the blood LDL or reduce T-CHOL in the blood.

In the present invention, " improving high blood homocysteine levels " is meant the rising that suppresses high blood homocysteine levels and reduces high blood homocysteine levels.In addition, as the reason that causes that high blood homocysteine levels rises, comprise for example old, smoking, the malnutrition relevant, medicine, decreased renal function, chronic renal failure, diabetes, insulin resistance, malignant tumor, thyroid function decline, pernicious anemia etc. with homocysteine metabolism.

In the present invention, " disease that high blood homocysteine levels causes ", so long as the rising of homocysteine amount causes that the disease of morbidity gets final product in the blood, be not particularly limited, blood circulation diseasess such as arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease for example, cerebrovascular disorders such as cerebral infarction, cerebral circulation disease, alzheimer disease, nervous system disease such as Alzheimer's disease, parkinson disease etc.

In addition, there is not tangible subjective symptoms at the above-mentioned disease initial stage, it is very difficult that the oneself judges, as with " disease that high blood homocysteine levels causes " of the present invention relevant subjective symptoms, for example headache, migraine, dizzy, numb, feeling of numbness, cold limbs sense, shoulder are ached etc.Therefore, by these subjective symptomss are used pharmaceutical composition of the present invention, the stage is treated above-mentioned disease in the early stage.

The specific embodiment

The HMG-CoA reductase inhibitor that pharmaceutical composition of the present invention is contained, Pravastatin for example, lovastatin, simvastatin, fluvastatin, upright his spit of fland of cutting down, atorvastatin, Pitavastatin or rosuvastatin can be opened clear 57-2240 communique (USP4346227) according to the spy, the spy opens clear 57-163374 communique (USP4231938), the spy opens clear 56-122375 communique (USP4444784), special table clear 60-500015 communique (USP4739073), Te Kaiping 1-216974 communique (USP5006530), Te Kaiping 3-58967 communique (USP5273995), the method that Te Kaiping 1-279866 communique (USP5854259 and USP5856336) or spy open flat 5-178841 communique (USP5260440) record easily prepares.

In addition, contained Benadon class can be used commercially available material or use the material for preparing by known method in the pharmaceutical composition of the present invention, and for example, pyridoxine hydrochloride is collected in the 14th edition revision Japanese Pharmacopoeia, can easily obtain.

" pharmaceutical composition that contains HMG-CoA reductase inhibitor and Benadon class " of the present invention contains HMG-CoA reductase inhibitor and the necessary composition of Benadon class conduct, according to circumstances, can contain the additive that is useful on preparation, and, can there be dysgenic scope to contain other composition in coupling effect to HMG-CoA reductase inhibitor and Benadon class yet.Preferably only contain HMG-CoA reductase inhibitor and Benadon class as effective ingredient, also contain the pharmaceutical composition of the additive that is useful on preparation.

Concrete dosage form as pharmaceutical composition of the present invention, comprise for example tablet, granule (comprising powder), capsule, liquid preparation (comprising syrup) etc., can suitably use the additive or the base material that are suitable for various dosage forms, be prepared according to the conventional method of records such as Japanese Pharmacopoeia.

In above-mentioned various dosage forms,, also can use normally used various additive according to this dosage form.

For example, the occasion of tablet can use lactose, crystalline cellulose etc. as excipient, uses metasilicic acid magnesium aluminate or magnesium oxide etc. as stabilizing agent, uses hydroxypropyl cellulose etc. as coating materials, uses magnesium stearate etc. as lubricant,

The occasion of granule or capsule can use lactose or refined sucrose etc. as excipient, uses metasilicic acid magnesium aluminate or magnesium oxide etc. as stabilizing agent, and use corn starch etc. are as adsorbent, and use hydroxypropyl cellulose etc. are as binding agent.

In above-mentioned each dosage form, as required, also can add disintegrating agents such as crospovidone; Surfactants such as polysorbate; Adsorbents such as calcium silicates; Coloring agent such as iron sesquioxide, caramel; Stabilizing agents such as sodium benzoate; The pH regulator agent; Spice etc.

In the present invention, " coupling " be simultaneously or separate the time and in human body, give method with two or more effective ingredient respectively.

When giving, can simultaneously or separate the time to give respectively and each composition with pharmaceutical composition of the present invention.

Above-mentioned " simultaneously " give with, remove give fully simultaneously with, also comprise the pharmacology go up tolerance level ground time of front and back to.This administration state so long as can much at one time give with the administration form get final product, be not particularly limited, but be preferably single compositions.

In addition, above-mentioned " separate time respectively " given and finger, so long as can the different time give respectively with the administration form get final product, be not particularly limited, for example give and a kind of composition, then behind official hour to the method for another kind of composition.

In addition, give with the composition of compositions add up to occasion more than 3 kinds or 3 kinds, " simultaneously or separate time respectively " give with comprise with they all give simultaneously with method, respectively separate the time give respectively with method, with give simultaneously more than 2 kinds or 2 kinds with, separating the time then gives with the method for residual drug or separates the time and give with more than 2 kinds or 2 kinds, gives with the method for residual drug then simultaneously etc.

Pharmaceutical composition of the present invention has the significant effect that improves the effect of lipid in the blood and reduce homocysteine amount in the blood, therefore, can be with acting on the medicine that improves homocysteine in lipid in the blood or the blood, for example, can be as prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or Parkinsonian medicine.

In the present invention, the dosage of HMG-CoA reductase inhibitor is different because of the kind of HMG-CoA reductase inhibitor, dosage form etc., but is generally 1mg to 200mg every day, preferred every day 5mg to 160mg.

In the present invention, the dosage of Benadon class is different because of the kind of Benadon class, dosage form etc., but is generally 0.1mg to 1200mg every day, preferred every day 1mg to 800mg.

The weight % of ingredient when being solid preparation for pharmaceutical composition of the present invention, for example, the occasion of atorvastatin and Pravastatin is generally 0.01 to 5%, preferred 0.05 to 3%, in addition, the occasion of simvastatin is generally 0.005 to 3%, preferred 0.03 to 2%, in addition, the weight % of Benadon class is generally 0.01 to 30%, and preferred 0.1 to 20%.

The amount of ingredient when being liquid preparation for pharmaceutical composition of the present invention, for example, the content of atorvastatin and Pravastatin is generally 0.01 to 10mg/mL, preferred 0.05 to 5mg/mL, and in addition, the content of simvastatin is generally 0.005 to 5mg/mL, preferred 0.03 to 3mg/mL, in addition, the content of Benadon class is generally 0.1 to 20mg/mL, and preferred 1 to 10mg/mL.

Below, by embodiment the present invention is described in further detail, but scope of the present invention is not limited to these embodiment.

[embodiment]

[embodiment 1] tablet

(1) composition

	6 (mg)	6 (mg)	6 (mg)
				Sodium Pravastatin	????20	????-	????-
Simvastatin	????-	????10	????-
				Atorvastatin calcium	????-	????-	????20
Pyridoxine hydrochloride	????100	????100	????-
				Pyridoxal 5-phosphate	????-	????-	????60
Magnesium oxide	????400	????400	????400
				The metasilicic acid magnesium aluminate	????140	????140	????140
Crystalline cellulose	????120	????120	????120
				Corn starch	????140	????140	????140
Hydroxypropyl cellulose	????60	????60	????60
				Cross-linked carboxymethyl cellulose sodium (Croscarmellose sodium)	????15	????15	????15
Magnesium stearate	????25	????25	????25
				Triacetin	????6	????6	????6
Lactose	In right amount	In right amount	In right amount
				Add up to	????1,200	????1,200	????1,200

(2) preparation method

Get mentioned component and weigh, prepare tablet according to the content of Japanese Pharmacopoeia preparation general provisions " tablet ".

[embodiment 2] granule

(1) composition

	3 bags (mg)	3 bags (mg)	3 bags (mg)
				Sodium Pravastatin	????20	????-	????-
Simvastatin	????-	????10	????-
				Atorvastatin calcium	????-	????-	????20
Pyridoxine hydrochloride	????100	????100	????-
				Pyridoxal 5-phosphate	????-	????-	????60
Magnesium oxide	????400	????400	????400
				The metasilicic acid magnesium aluminate	????140	????140	????140
Refined sucrose	????1400	????1400	????1400
				Flos Chrysanthemi (stevia) is extracted product	????15	????15	????15
Corn starch	????1200	????1000	????1100
				Tween 80	????80	????80	????80
Magnesium stearate	????25	????25	????25
				Lactose	In right amount	In right amount	In right amount
Add up to	????4,300	????4,300	????4,300

(2) preparation method

Get mentioned component and weigh, prepare granule according to the content of Japanese Pharmacopoeia preparation general provisions " granule ".

[embodiment 3] capsule

(1) composition

	6 capsules (mg)	6 capsules (mg)	6 capsules (mg)
				Sodium Pravastatin	????20	????-	????-
Simvastatin	????-	????10	????-
				Atorvastatin calcium	????-	????-	????20
Pyridoxine hydrochloride	????100	????100	????-
				Pyridoxal 5-phosphate	????-	????-	????60
Magnesium oxide	????400	????400	????400
				Corn starch	????600	????400	????500
Tween 80	????50	????50	????50
				Magnesium stearate	????25	????25	????25
Lactose	In right amount	In right amount	In right amount
				Capsule	????480	????480	????480
Add up to	????2,300	????2,300	????2,300

(2) preparation method

Get mentioned component and weigh, prepare granule according to the content of Japanese Pharmacopoeia preparation general provisions " granule " after, be filled in the capsule preparation hard capsule.

[embodiment 4] syrup

(1) composition

	Among the 60mL (mg)	Among the 60mL (mg)	Among the 60mL (mg)
				Sodium Pravastatin	????20	????-	????-
Simvastatin	????-	????10	????-
				Atorvastatin calcium	????-	????-	????20
Pyridoxine hydrochloride	????100	????100	????-
				Pyridoxal 5-phosphate	????-	????-	????60
Sodium benzoate	????240	????240	????240
				Citric acid	????60	????60	????60
Sucrose	????1,500	????1,500	????1,500
				Concentrated glycerin	????1,800	????1,800	????1,800
Polyvinyl alcohol	????120	????120	????120
				Ethanol (95%)	????500	????9,000	????4,500
Hydrochloric acid	In right amount	In right amount	In right amount
				Sodium hydroxide	In right amount	In right amount	In right amount
Purified Water	In right amount	In right amount	In right amount

(2) preparation method

Get mentioned component and weigh, prepare syrup according to the content of Japanese Pharmacopoeia preparation general provisions " syrup " after, in the amber glass bottle of packing into, the preparation syrup.

[embodiment 5] tablet

(1) composition

	6 (mg)
		Atorvastatin calcium	????20
Pyridoxine hydrochloride	????100
		Magnesium oxide	????400
The metasilicic acid magnesium aluminate	????140
		Crystalline cellulose	????120
Corn starch	????140
		Hydroxypropyl cellulose	????60
Cross-linked carboxymethyl cellulose sodium	????15
		Magnesium stearate	????25
Triacetin	????6
		Lactose	In right amount
Add up to	????1,200

(2) preparation method

Get mentioned component and weigh, prepare tablet according to the content of Japanese Pharmacopoeia preparation general provisions " tablet ".

[embodiment 6] granule

(1) composition

	3 bags (mg)
		Atorvastatin calcium	????20
Pyridoxine hydrochloride	????100
		Magnesium oxide	????400
The metasilicic acid magnesium aluminate	????140
		Refined sucrose	????1400
Flos Chrysanthemi is extracted product	????15
		Corn starch	????1200
Tween 80	????80
		Magnesium stearate	????25
Lactose	In right amount
		Add up to	????4,300

(2) preparation method

Get mentioned component and weigh, prepare granule according to the content of Japanese Pharmacopoeia preparation general provisions " granule ".

[embodiment 7] capsule

(1) composition

	6 capsules (mg)
		Atorvastatin calcium	????20
Pyridoxine hydrochloride	????100
		Magnesium oxide	????400
Corn starch	????600
		Tween 80	????50
Magnesium stearate	????25
		Lactose	In right amount
Capsule	????480
		Add up to	????2,300

(2) preparation method

Get mentioned component and weigh, prepare granule according to the content of Japanese Pharmacopoeia preparation general provisions " granule " after, be filled in the capsule preparation hard capsule.

[embodiment 8] syrup

(1) composition

	????60mL(mg)
		Atorvastatin calcium	????20
Pyridoxine hydrochloride	????100
		Sodium benzoate	????240
Citric acid	????60
		Sucrose	????1,500
Concentrated glycerin	????1,800
		Polyvinyl alcohol	????120
Ethanol (95%)	????500
		Hydrochloric acid	In right amount
Sodium hydroxide	In right amount
		Purified Water	In right amount

(2) preparation method

Get mentioned component and weigh, prepare syrup according to the content of Japanese Pharmacopoeia preparation general provisions " syrup " after, in the amber glass bottle of packing into, the preparation syrup.

[test example]

The evaluation test of lipid amount in [test example 1] blood

(1) measured matter

Sodium Pravastatin uses Sankyo Co., Ltd to make, and simvastatin and Atorvastatin calcium use Chemtech Labo., and Inc. makes, and pyridoxine hydrochloride uses Nippon RocheK.K. to make.

(2) animal

As experimental animal,, raise the back use in about 1 month quarantine and domestication from the male Beagle dog that Covance Research Products Inc. buys 5 monthly ages.

(3) store method of the preparation method of form of administration, preparation and preparation

The measured matter that will be the necessary amount that goes out of basic calculation with the body weight of each experimental animal is filled in the gelatine capsule (1/2 ounce) of TORPAC company.After the filling, capsule is put into the box of dividing to every animal, and stored refrigerated is during to administration.

(4) during route of administration and the administration

Every day forced oral giving and experimental animal 1 time by the capsule of filling measured matter between 9:00～12:30.In addition, experimental animal fasting 2 to 3 hours before administration.

Be 11 days during the administration.

(5) preparation of tested sample

Give with capsule before-14 and-7 days (administration begins preceding the 2nd week and the 1st week), administration after 4 days, 8 days, 12 days, get the about 10mL of blood by cephalic vein.In addition, got the blood precontract 18 hours, make the experimental animal fasting.

The blood that obtains is taken in the test tube, at room temperature place 30 minutes to 1 hour after, the serum obtain is used in centrifugalize (about 1600 * g, 10 minutes).

(6) test method

For check result, T-CHOL uses enzyme assay, and HDL uses the homogenate method, and LDL uses chemical modification enzymatic method, and triglyceride uses full-enzyme method.In addition, measure use clinical chemistry automatic analysing apparatus (TBA-120FR, Toshiba's system).

(7) result of the test

With before administration 2 week and before 1 week in the various blood meansigma methods of lipid amount be 100, convert and obtain pyridoxine hydrochloride and sodium Pravastatin, simvastatin and Atorvastatin calcium lipid amount in the various blood of single agent of dosage and compounding ingredient separately.

The result who obtains as table 1 to shown in the table 6.In addition, each value is 1 group 5 a meansigma methods.

Table 1

Measured matter (mg/Kg)	The rate of change % of T-CHOL in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Simvastatin (1)	????94.8	????94.1				????92.4
Pyridoxine hydrochloride (50)				????98.0	????93.3	????90.5
	Simvastatin (1)+pyridoxine hydrochloride (50)	????88.5	????83.6				????80.0

Table 2

Measured matter (mg/Kg)	The rate of change % of LDL in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Simvastatin (1)	????83.9	????90.4				????81.3
Pyridoxine hydrochloride (50)				????101.7	????95.0	????91.4
	Simvastatin (1)+pyridoxine hydrochloride (50)	????83.0	????70.4				????70.4

Table 3

Measured matter (mg/Kg)	The rate of change % of triglyceride in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Simvastatin (1)	????66.4	????85.3				????82.0
Pyridoxine hydrochloride (50)				????83.8	????86.7	????81.2
	Simvastatin (1)+pyridoxine hydrochloride (50)	????50.1	????54.4				????65.1

Table 4

Measured matter (mg/Kg)	The rate of change % of LDL in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Sodium Pravastatin (2)	????92.6	????91.6				????90.4
Pyridoxine hydrochloride (50)				????101.7	????95.0	????91.4
	Pravastatin Na (2)+pyridoxine hydrochloride (50)	????50.1	????54.4				????65.1

Table 5

Measured matter (mg/Kg)	The rate of change % of LDL in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Atorvastatin calcium (2)	????82.4	????82.1				????83.6
Pyridoxine hydrochloride (50)				????101.7	????95.0	????91.4
	Atorvastatin Ca (2)+pyridoxine hydrochloride (50)	????76.1	????73.8				????66.2

Table 6

Measured matter (mg/Kg)	The rate of change % of triglyceride in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Atorvastatin calcium (2)	????77.2	????86.3				????86.4
Pyridoxine hydrochloride (50)				????83.8	????86.7	????81.2
	Atorvastatin Ca (2)+pyridoxine hydrochloride (50)	????59.1	????68.7				????65.4

By combination simvastatin, Pravastatin or atorvastatin and pyridoxine hydrochloride, show the effect of improving of lipid in the significant blood.

The evaluation test of homocysteine amount in [embodiment 2] blood

(1) measured matter

Atorvastatin calcium uses Chemtech Labo., and Inc. makes, and pyridoxine hydrochloride uses Nippon Roche K.K. to make.

(2) animal

As experimental animal,, raise the back use in about 1 month quarantine and domestication from the male Beagle dog that Covance Research Products Inc. buys 5 monthly ages.

(3) store method of the preparation method of form of administration, preparation and preparation

The measured matter that will be the necessary amount that goes out of basic calculation with the body weight of each experimental animal is filled in the gelatine capsule (1/2 ounce) of TORPAC company.After the filling, capsule is put into the box of dividing to every animal, and stored refrigerated is during to administration.

(4) during route of administration and the administration

Every day forced oral giving and experimental animal 1 time by the capsule of filling measured matter between 9:00～12:30.In addition, experimental animal fasting 2 to 3 hours before administration.

Be 11 days during the administration.

(5) preparation of tested sample

Give with capsule before-14 and-7 days (administration begins preceding the 2nd week and the 1st week), administration after 4 days, 8 days, 12 days, get the about 10mL of blood by cephalic vein.In addition, got the blood precontract 18 hours, make the experimental animal fasting.

The blood that obtains is taken in the test tube, at room temperature place 30 minutes to 1 hour after, the serum obtain is used in centrifugalize (about 1600 * g, 10 minutes).

(6) test method

The homocysteine amount uses HPLC method commonly used in the present clinical examination to obtain in the blood.

(7) result of the test

With before administration 2 week and before 1 week in the blood meansigma methods of homocysteine amount be 100, convert and obtain pyridoxine hydrochloride and Atorvastatin calcium homocysteine amount in the blood of single agent of dosage and compounding ingredient separately.

The result who obtains is as shown in table 7.In addition, each value is 1 group 5 a meansigma methods.

Table 7

Measured matter (mg/Kg)	The rate of change of homocysteine amount (%) in the blood
				After the administration 4 days	After the administration 8 days	After the administration 12 days
	Atorvastatin calcium (2)+pyridoxine hydrochloride (5)	????97.4	????101.2				????93.0
Atorvastatin calcium (2)+pyridoxine hydrochloride (50)				????90.8	????89.0	????85.7
	Comparative example
Atorvastatin calcium (2)				????107.6	????106.3	????106.9
	Pyridoxine hydrochloride (5)	????100.0	????116.0				????109.8
Pyridoxine hydrochloride (50)				????101.4	????111.5	????103.0

By combination Atorvastatin calcium and pyridoxine hydrochloride, the significant effect that reduces homocysteine amount in the blood of performance.

Industrial applicibility

The pharmaceutical composition that the present invention contains HMG-CoA reductase inhibitor and Benadon class has in the good blood homocysteine reducing effect in the lipid improvement effect and blood, therefore, for causing circulatory diseases such as hyperlipidemia, artery sclerosis, ischemic heart disease, miocardial infarction, thrombus, peripheral vascular obstacle, Burger are sick, Raynaud is sick, the cerebrovascular disorders such as cerebral infarction, brain circulatory diseases, senile dementia, the prevention of the nervous system diseases such as degenerative brain disorder, Parkinson's etc. or treatment etc. are useful. In addition, to since in the blood of the performances such as old, smoking, the dystrophia relevant with homocysteine metabolism, medicament, decreased renal function, chronic renal failure, diabetes, insulin resistance, malignant tumour, thyroid function decline, pernicious anaemia prevention or the treatment of the rising of homocysteine amount be useful.

Claims (23)

1. pharmaceutical composition, it contains HMG-CoA reductase inhibitor and Benadon class.

2. compositions as claimed in claim 1 is used for improving blood lipid or high blood homocysteine levels.

3. compositions as claimed in claim 1 or 2, HMG-CoA reductase inhibitor are to be selected from Pravastatin, lovastatin, simvastatin, fluvastatin, uprightly to cut down in his spit of fland, atorvastatin, Pitavastatin and the rosuvastatin one or more.

4. compositions as claimed in claim 1 or 2, HMG-CoA reductase inhibitor are to be selected from Pravastatin, simvastatin or the atorvastatin one or more.

5. compositions as claimed in claim 1 or 2, the HMG-CoA reductase inhibitor is an atorvastatin.

6. as any described compositions in the claim 1 to 5, the Benadon class is to be selected from Benadon, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine or their salt one or more.

7. as any described compositions in the claim 1 to 5, the Benadon class is Benadon or its salt.

8. compositions as claimed in claim 2, HMG-CoA reductase inhibitor are atorvastatin or its salt, and the Benadon class is Benadon or its salt.

9. as any described compositions in the claim 1 to 8, it is used for improving the blood lipid.

10. as any described compositions in the claim 1 to 8, it is used to improve high blood homocysteine levels.

11. as any described compositions in the claim 1 to 8, the disease that it is used for the treatment of or prevents high blood homocysteine levels to cause.

12. as any described compositions in the claim 1 to 8, it is used for prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or parkinson disease.

13. compositions as claimed in claim 8, it is used for prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or parkinson disease.

14.HMG-CoA the combination of reductase inhibitor and Benadon class, it is used for improving lipid or high blood homocysteine levels in the blood by simultaneously or separate the time and give respectively and HMG-CoA reductase inhibitor and Benadon class.

15.HMG-CoA the coupling of reductase inhibitor and Benadon class, it is used for improving blood lipid or high blood homocysteine levels.

16. improve the method for lipid in the blood or high blood homocysteine levels, this method comprises simultaneously or separates the time gives respectively and HMG-CoA reductase inhibitor and Benadon class.

17. method as claimed in claim 16, it is used for improving the blood lipid.

18. method as claimed in claim 16, it is used to improve high blood homocysteine levels.

19. method as claimed in claim 16, the disease that it is used for the treatment of or prevents high blood homocysteine levels to cause.

20. method as claimed in claim 16, it is used for prevention or treatment hyperlipemia, arteriosclerosis, ischemic heart desease, myocardial infarction, thrombosis, peripheral blood vessel obstacle, Burger disease, Raynaud disease, cerebral infarction, cerebral circulation disease, alzheimer disease, Alzheimer's disease or parkinson disease.

21. as any described method in the claim 16 to 20, it comprise to the pharmaceutical composition that contains HMG-CoA reductase inhibitor and Benadon class.

22. method as claimed in claim 20, it comprise to the pharmaceutical composition that contains HMG-CoA reductase inhibitor and Benadon class.

23.HMG-CoA reductase inhibitor and the purposes of Benadon class in preparation of pharmaceutical compositions, said composition contain HMG-CoA reductase inhibitor and Benadon class, are used for improving the blood lipid or reduce homocysteine levels in the blood.