CA2492781A1 - Medicinal composition for mitigating blood lipid or lowering blood homocystein - Google Patents
Medicinal composition for mitigating blood lipid or lowering blood homocystein Download PDFInfo
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- CA2492781A1 CA2492781A1 CA002492781A CA2492781A CA2492781A1 CA 2492781 A1 CA2492781 A1 CA 2492781A1 CA 002492781 A CA002492781 A CA 002492781A CA 2492781 A CA2492781 A CA 2492781A CA 2492781 A1 CA2492781 A1 CA 2492781A1
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- hmg
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- coa reductase
- pyridoxine
- reductase inhibitor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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
Specification Medicinal composition for mitigating blood lipid or lowering blood homocysteine [Technical Field of the Invention]
The present invention relates to a medicinal composition comprising an HMG-CoA reductaseinhibitor and a pyridoxine derivative as active ingredients (particularly a medicinal composition for mitigating blood lipid levels or lowering high blood homocysteine levels) .
[Background of the Invention]
An old proverb wisely says that a man is as old as his arteries .
Recently, it has been noted and become widely known that increased blood homocysteine levels are an independent risk factor for arteriosclerosis.
Homocysteine is an amino acid produced in the metabolism of methionine, which is one of the essential amino acids. It has been observed that blood homocysteine levels are increased by genetic factors, deficiencies in vitamin cofactors (folic acid, vitamin B6, and vitaminBl2) , aging, sex difference, renal hypofunction, diabetes mellitus and other diseases, some drugs, smoking, and the like (Progress in Medicine, vol. 19 No. 8, 1999, p. 49 - 52) . This symptom is called homocysteinemia. Treatment against homocysteinemia currently consists of folic acid to advance homocysteine metabolism as a first step, followed by treatment with vitamins B6 and B12 as second-step therapy (Progress in Medicine, vol. 19 No.B, 1999, p.
52 - 53 ) .
On the other hand statins, which reduce blood cholesterol levels by specifically and competitively inhibiting HMG-CoA reductase in vivo, have elicited the following effects on blood homocysteine levels:
1) Following administration of pravastatin for 8 successive weeks in 16 patients with hypercholesterolemia, blood homocysteine levels FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 were reduced (Nikkei Medical, November 2001, p. 73), 2) In 20,705 patients treated with lovastatin for one year, bloodhomocysteine levels decreased by 3 .7% on average (versus a 1.9%
decrease in the placebo control group) (Circulation, vol. 105, No.
15, 2002, p. 1778), 3) Three of 7 patients with cardiovascular diseases were treated with atorvastatin and the other 4 patients were treated with simvastatin for 6 successive weeks. Blood homocysteine levels in patients treated with atorvastatin were increased, while those in patients treated with simvastatin were decreased (31st Hemophilia Symposium Hamburg, 2000, p. 258).
Thus it would appear that the results are inconsistent and no clear conclusion has yet been reached.
Furthermore, combination therapy with statins plus folic acid has been disclosed to prevent or reduce the risk of developing arteriosclerosis (WO 97/38694).
Regarding combination therapy with a statin plus a pyridoxine derivative, it has also been described on page 17 of WO 97/38694 that some other agents selected from HMG-CoA synthetase inhibitors, squalene epoxidase inhibitors, squalene synthetase inhibitors, ACAT
inhibitors, probucol, niacin, fibrates, cholesterol-binding antagonists, bile acid sequestrants, LDL receptor inducers, vitamin B6, vitamin B12, aspirin, (3-blockers, vitamin C, vitamin E, and ~3-carotene may be contained in the combination therapy in addition to a statin and folic acid.
However, there is no description in WO 97/38694 of a combination therapy containing an HMG-CoA synthetase inhibitor and a pyridoxine derivative alone, which is the present invention. Furthermore, there are neither descriptions norsuggestions about remarkable mitigating effects on blood lipid levels or reducing blood homocysteine levels, which is the medical intention of the present invention.
On the other hand, a composition comprising an HMG-CoA reductase inhibitor (statin) and 7 supplements (omega-3 fatty acid, vitamin E, vitamin C, vitamin B6, vitamin B12, folic acid, and calcium) is disclosed in WO 02/43659 as a dietary supplement to reduce risk of FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 cardiovascular diseases. However, this composition was contrived from speculation based on the known efficacies of the various individual compositions, that is, statin and omega-3 fatty acid mitigate serum lipid levels, vitamin E and vitamin C exert anti-oxidant activities, a combination containing folic acid, vitamin B6, and vitamin B12 reduces blood homocysteine levels, and calcium is beneficial for the cardiovascular system due to decreases in blood pressure. No concrete data are disclosed in WO 02/43659.
Therefore the novel effects of the present invention, namely, the remarkable mitigating effects of the present invention on blood lipid levels and remarkable reducing effects on blood homocysteine levels are not described in WO 02/43659.
[Disclosure of the Invention]
In light of this background, the present inventors have diligently conducted research to discover new and safe drugs that mitigate blood lipid levels and reduce blood homocysteine levels, and found that a medicinal composition comprising an HMG-CoA
reductaseinhibitor and a pyridoxine derivative as activeingredients exerts good effects on mitigating blood lipids levels and reducing blood homocysteine levels, and thus completed the present invention.
The present invention relates to (1) a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative as active ingredients.
Of the said description, the present invention includes (2) a medicinal composition as stated in (1) for mitigating blood lipid levels or reducing high blood homocysteine levels, (3) a medicinal composition as stated in (1) or (2), comprising one or more HMG-CoA reductase inhibitors selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, and rosuvastatin as active ingredients, (4) a medicinal composition as stated in (1) or (2), comprising one or more HMG-CoA reductase inhibitors selected from the group FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 consisting of pravastatin, simvastatin, and atorvastatin as active ingredients, (5) a medicinal composition as stated in (1) or (2), comprising an HMG-CoA reductase inhibitor of atorvastatin, as an active ingredient, (6) a medicinal composition according to any one selected from (1) to (5) described above, comprising one or more pyridoxine derivatives selected from the group consisting of pyridoxine, pyridoxal, pyridoxamine, and pharmacologically acceptable salts thereof, (7) a medicinal composition according to any one selected from (1) to (5) described above, comprising a pyridoxine derivative selected from pyridoxine and a pharmacologically acceptable salt thereof, (8) a medicinal composition as stated in (2) where the HMG-CoA
reductase inhibitor is atorvastatin or a pharmacologically acceptable salt thereof, and the pyridoxamine derivative is pyridoxine or a pharmacologically acceptable salt thereof, (9) a medicinal composition according to any one selected from (1) to (8) for mitigating blood lipid levels, (10) a medicinal composition according to any one selected from (1) to (8) for reducing high blood homocysteine levels, (11) a medicinal composition according to any one selected from (1) to (8) for therapy or prevention of diseases caused by high blood homocysteine levels, (12) a medicinal composition according to any one selected from (1) to (8) for therapy or prevention of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular diseases, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease, and (13) a medicinal composition as stated in (8) for prevention or therapy of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular diseases, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 Parkinson disease.
In addition, the present invention provides (14) combination use of an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels by administration of an HMG-CoA
reductase inhibitor and a pyridoxine derivative at the same time or independently at certain time intervals, and (15) combination use of an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels.
Furthermore, the present invention provides (16) a method to mitigate blood lipid levels or to reduce high blood homocysteine levels by administration of an HMG-CoA reductase inhibitor and a pyridoxine derivative at the same time or independently at certain time intervals.
The preferable methods in said (16) are (17) a method as stated in (16) for mitigating blood lipid levels, (18) a method as stated in (16) for reducing a high blood homocysteine levels, (19) a method as stated in ( 16 ) for therapy or prevention of diseases caused by high blood homocysteine levels, (20) a method as stated in (16) for prevention or therapy of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular diseases, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease, (21) a method according to any one selected from (16) - (20), in which a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative is administered, and (22) a method as stated in (20) , in which a medicinal composition comprising an HMG-CoA reductaseinhibitor and a pyridoxine derivative FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 is administered.
Furthermore, the present invention provides (23) the use of an HMG-CoA reductase inhibitor and a pyridoxine derivative in the manufacture of a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels.
"HMG-CoA reductase inhibitor", one component of the medicinal composition of the present invention, refers to agents that competitively and specifically inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, which is a rate limiting enzyme in the biosynthesis of cholesterol. Since such inhibitors suppress blood cholesterol levels, the inhibitors are used as therapeutic agents for patients with hypercholesterolemia. As such HMG-CoA
reductase inhibitors, natural products derived from microorganisms and semi-synthesized compounds derived from the natural products described above, and totally synthesized chemical compounds are all included. For instance, such compounds are (+)-(3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methy lbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphtyl] heptanoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Sho 57-2240 (USP 4346227) (hereinafter called pravastatin), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[
(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphth yl(S)-2-methylbutyrate which is disclosed in Japanese Patent Publication (Kokai) Number Sho 57-163374 (USP 4231938) (hereinafter called lovastatin), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[
(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphth yl 2,2-dimethylbutyrate which is disclosed in Japanese Patent Publication (Kokai) Number Sho 56-122375 (USP 4444784) (hereinafter called simvastatin), (~) (3R*, 5S*, 6E) -7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 -2-yl]-3,5-dihydroxy-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kohyo) Number Sho 60-500015 (USP
4739073) (hereinafter called fluvastatin), (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-di(1-methylethyl)-5-methoxy methylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 1-216974 (USP 5006530) (hereinafter called rivastatin), (3R,5S)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-pheny laminocarbonyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 3-58967 (USP 5273995) (hereinafter called atorvastatin), and (E)-3,5-dihydroxy-7-(4'-(4" -fluorophenyl)-2'-cyclopropyl-quinol in-3'-yl]-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 1-279866 (USP 5854259 and USP 5856336) (hereinafter called pitavastatin), or (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-meth anesulfonylamino)pyridin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 5-178841 (USP 5260440) (hereinafter called rosuvastatin). In addition, an HMG-CoA reductase inhibitor, which is one component of the medicinal composition of the present invention, refers to other HMG-CoA reductase inhibitors described in the disclosed patents described above.
Planar chemical structures of representative HMG-CoA reductase inhibitors are shown below:
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 . 8 )H
O
H3C' Y 'O
H3 IC ~ ~CH3 Pravastatin Lovastatin F
H3C ~ CH3 O O COOH
H3C m ig Si ~mva~s%tat~i%n Fluvastatin F
Rivastatin Atorvastatin COOH
N
H3C~ ~SOzCH3 Pitavastatin Rosuvastatin "Pyridoxine derivative", which is an active ingredient of the FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 medicinal composition of the present invention includes pyridoxine, pyridoxal, pyridoxamine, or salts thereof, and is preferably pyridoxine hydrochloride, pyridoxal phosphate, or pyridoxamine phosphate, and is more preferably pyridoxine hydrochloride.
Each active ingredient of the present invention described above may be present as pharmacologically acceptable salts thereof, and in the case that the active ingredients present a basic functional group, such salts are, for example, a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, or the like; an inorganic acid salt such as a nitrate, a perchlorate, a sulfate, a phosphate, or the like; a lower organic sulfonate such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, or the like; an arylsulfonate such as benzenesulfonate p-toluenesulfonate, or the like; an amino acid salt such as ornithine salt, glutamate, or the like; carboxylic acid salt such as a fumarate, a succinate, a citrate, a tartrate, an oxalate, a maleate, or the like, in the case that the active ingredients present an acidic functional group, such salts are, for example, an alkaline metal salt such as sodium salt, potassium salt, lithium salt, or the like; an alkaline earth metal salt such as calcium salt, magnesium salt, or the like; a metal salt such as an aluminium salt, an iron salt, a zinc salt, a copper salt, a nickel salt, a cobalt salt, or the like;
an amine salt, for example, an inorganic salt such as ammonium salt, an organic acid salt such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris(hydroxymethyl)aminomethane salt, or the like. For instance, in the case of pravastatin, a preferable salt is pravastatin sodium, and for instance, in the case of atorvastatin, a preferable salt is atorvastatin calcium salt hydrate.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 In the case that each active ingredient involved forms a hydrate or solvate, such hydrates or solvates are included in the medicinal compositions of the present invention.
In the present invention, "mitigating blood lipid levels" means reducing bloodlipidlevelsto clinically significant values, namely, reducing blood triglyceride levels, reducing blood LDL levels, or reducing blood total cholesterol levels.
In the present invention, "reducing blood homocysteine levels"
means suppressing increases in high blood homocysteine levels, and reducing blood homocysteine levels. Factors that increase homocysteine levels in the blood are, for example, aging, smoking, nutritionimpairment related to homocysteine metabolism, some drugs, renal hypofunction, chronic renal dysfunction, diabetes mellitus, insulin resistance, malignant neoplasm, thyroidal hypofunction, pernicious anemia, and the like.
"Diseases caused by high blood homocysteine levels" described in the present invention have no limitation so long as the diseases derive from high blood homocysteine levels . They are, for example, cardiovascular diseases such as arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular disease, Burger's disease, Raynaud's disease, and cerebrovascular diseases such as cerebral infarction, cerebrovascular disorders, senile dementia, neurological diseases such as Alzheimer' s disease, Parkinson disease, and the like.
Since the early stages of the said diseases exhibit few subjective symptoms, it is difficult for patients themselves to become aware of having these diseases in the early stages . The subj ective symptoms of the "diseases caused by high blood homocysteine levels" in the present invention are, for example, headache, migraine, dizziness, numbness or feeling of numbness, cold sensation of the four limbs, shoulder stiffness, and the like. Therefore the said diseases may possibly be treated at their early stages by taking the medicinal composition of the present invention when such subjective symptoms first appear.
FP0330s.doc Sankyo/PB8879/PCT specification/ACF/29.12.04 [Mode for carrying out the Invention]
HMG-CoA reductase inhibitors used as an active ingredient in the medicinal composition of the present invention, for example, pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, or rosuvastatin, can be easily prepared according to the methods described hereinafter in Japanese Patent Publication (Kokai) Number Sho57-2240 (USP 4346227), Japanese Patent Publication (Kokai) Number Sho 57-16337 (USP 4231938), Japanese Patent Publication (Kokai) Number Sho 56-122375 (USP 4444784), Japanese Patent Publication (Kohyo) Number Sho 60-500015 (USP
4739073), Japanese Patent Publication (Kokai) Number Hei 1-216974 (USP5006530), Japanese Patent Publication (Kokai) Number Hei3-58967 (USP 5273995), Japanese Patent Publication (Kokai) Number Hei 1-279866 (USP 5854259 and USP 5856336), or Japanese Patent Publication (Kokai) Number Hei 5-178841 (USP 5260440).
In addition, pyridoxine derivatives used in the medicinal compositions of the present invention as an active ingredient can be easily obtained as commercially available products, or can be easily manufactured by previously known methods. For example, since pyridoxine hydrochloride is disclosedin"The Japanese Pharmacopoeia (JP) 14th Edition", the compound can be easily obtained.
The medicinal compositions of the present invention comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative as active ingredients contain both an HMG-CoA reductase inhibitor and a pyridoxine derivative as essential active ingredients. Additive agents may be contained in the formulation, when required. In addition, other inactive ingredients included in the medicinal compositions are not particularly restricted provided that they have no adverse effects when they are co-administered with the HMG-CoA reductase inhibitor and the pyridoxine derivative contained in the present medicinal composition. The preferable medicinal composition is restricted to an HMG-CoA reductase inhibitor and a pyridoxine derivative alone as active ingredients, and it may contain additive FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 agents for its formulation.
The concrete preparations of the medicinal composition of the present invention are, for example, tablets, granules (including powders), capsules, liquids and solutions (including syrups), and the like. These preparations are prepared by conventionally known methods disclosed in "The Japanese Pharmacopoeia (JP)" or the like using additive agents and bases that are suitable for each preparation, as necessary.
In each preparation, various conventionally used additive agents suitable for each preparation may also be used.
For example, in the case of tablets, diluents such as lactose, crystalline cellulose or the like, stabilizers such as magnesium aluminometasilicate, magnesium oxide orthelike, coating agentssuch as hydroxypropylcellulose or the like, and lubricants such as magnesium stearate or the like may be used.
In the case of granules and capsules, diluents such as lactose, purified sucrose, or the like, stabilizers such as magnesium aluminometasilicate, magnesium oxide, or the like, adsorbents such as corn starch, or the like, binders such as hydroxypropylcellulose, or the like may be used.
In each preparation described above, disintegrants such as crospovidone, or the like; surfactants such as polysorbate, or the like; adsorbents such as calcium silicate, or the like; colouring agents such as red ferric oxide, caramel, or the like; stabilizers such as sodium benzoate, or the like; pH modifiers; flavours; or the like, may be added as necessary.
In the present invention, "co-administration" means methods of administration of more than the 2 active ingredients to humans at the same time, or independent administration of more than the 2 active ingredients described above at a certain time interval.
When the 2 active ingredients of the present invention are administered, each active ingredient of the medicinal composition may be administered at the same time or independently at a certain time interval.
"Administration at the same time" described above includes FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 administration of each active ingredient at a pharmacologically acceptable time interval in addition to administration of all active ingredients at the same time . There is no restriction provided that their pharmaceutical preparations are to be taken at roughly the same time. Nevertheless, it is favourable to take the 2 active ingredients as a single pharmaceutical preparation.
"Independent administration of the more than 2 active ingredients described above at a certain time interval" described above hasno restriction provided thattheir available pharmaceutical preparations are to be taken independently at different times. For instance, it indicates that first one active ingredient is administered, and then after a defined time delay, the other active ingredient is administered.
Furthermore, in the case that the medicinal composition contains more than 3 active ingredients, "simultaneous administration or independent administration at certain time intervals" includes all cases wherein all active ingredients contained in the medicinal composition are taken at the same time, each composition is taken independently at certain time intervals, more than 2 active ingredients contained in the medicinal composition are simultaneously taken and the rest of them are independently taken at certain time intervals, or more than 2 active ingredients in the medicinal composition are simultaneously taken and the rest of them are simultaneously taken at a certain time interval.
Since the medicinal composition of the present invention exerts remarkable mitigating effects on blood lipid levels and reducing effects on high blood homocysteinelevels, the medicinalcompositions of the present invention are useful as pharmaceutical agents for mitigating blood lipid levels and reducing high blood homocysteine levels. Thus the medicinal compositions of the present invention are useful as preventive or therapeutic agents against diseases, for example, hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 disease, Burger' s disease, Raynaud' s disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease.
In the present invention, the dosage of HMG-CoA reductase inhibitors varies depending on the types of HMG-CoA reductase inhibitors used, the formulations, and the like. It is usual to administer 1 rng - 200 mg per day and preferably 5 mg - 160 mg per day.
In the present invention, the dosage of pyridoxine derivative varies depending on the type of pyridoxine derivative used, its formulation, and the like. It is usual to administer 0.1 mg - 1,200 mg per day and preferably 1 mg - 800 mg per day.
In the case that the dosage form of the medicinal composition of the present invention is a solid dosage form, the weight percentages of the active ingredients contained in the medicinal composition are, for example, usually 0.01 - 5% in the case of atorvastatin or pravastatin, and preferably 0.05 - 3%. In the case of simvastatin, the weight percentage is usually 0.005 - 3%, preferably 0.03 - 2%. Furthermore, weight percentage of pyridoxine derivative is usually 0.01 - 30%, and preferably it is 0.1 - 20%.
In the case that the dosage form of the medicinal composition of the present invention is a liquid or solution, the percentages of the active ingredients contained in the medicinal composition are, for example, usually 0 .O1 - 10 mg/mL for atorvastatin andpravastatin, and preferably 0.05 - 5 mg/mL. In the case of simvastatin, the percentage is usually 0.005 - 5 mg/mL, and preferably 0.03 - 3 mg/mL.
Furthermore, the percentage of pyridoxine derivative is usually 0.1 - 20 mg/mL, and preferably 0.1 - 10 mg/mL.
[Best Mode for carrying out the Invention]
The present invention will further be exemplified in more detail by the Examples . However, the scope of the present invention is not limited by these Examples.
[Examples]
(Example 1) Tablets FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (1) Compositions 6 Tablets 6 Tablets 6 Tablets (mg) (mg) (mg) Pravastatin sodium 20 - -Simvastatin - 10 -Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Magnesium oxide 400 400 400 Magnesium 140 140 140 aluminometasilicate Crystalline cellulose 120 120 120 Corn starch 140 140 140 Hydroxypropylcellulose 60 60 60 Croscarmellose sodium 15 15 15 Magnesium stearate 25 25 25 Glycerin triacetate 6 6 6 A suitable A suitable A suitable Lactose amount amount amount Total 1,200 1,200 1,200 (2) Manufacturing methods Each active ingredient described above is weighed and the tablets are manufactured according to methods described in General Rules for Preparation (tablets) of the Japanese Pharmacopoeia.
(Example 2) Granules (1) Compositions 3 Packages 3 Packages 3 Packages (mg) (mg) (mg) Pravastatin sodium 20 - -Simvastatin - 10 -Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Magnesium oxide 400 400 400 Magnesium aluminometasilicate 140 140 140 Purified sucrose 1400 1400 1400 Extracted products from 15 15 15 stevia Corn starch 1200 1000 1100 Polysorbate 80 80 80 80 Magnesium stearate 25 25 25 A suitable A suitable A suitable Lactose amount amount amount Total 4,300 4,300 4,300 FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (2) Manufacturing methods Each active ingredient described above is weighed and the granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia.
(Example 3) Capsules (1) Compositions 6 Capsules 6 Capsules 6 Capsules (mg) (mg) (mg) Pravastatin sodium 20 - -Simvastatin - 10 -Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Magnesium oxide 400 400 400 Corn starch 600 400 500 Polysorbate 80 50 50 50 Magnesium stearate 25 25 25 A suitable A suitable A suitable Lactose amount amount amount Capsule 480 480 480 Total 2,300 2,300 2,300 (2) Manufacturing methods Each active ingredient described above is weighed and granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia. The capsules are manufactured by filling the granules in hard capsules.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (Example 4) Syrups (1) Compositions 60 mL (mg) 60 mL (mg) 60 mL (mg) Pravastatin sodium 20 - -Simvastatin - 10 Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Sodium benzoate 240 240 240 Citric acid 60 60 60 Sucrose 1,500 1,500 1,500 Conc. Glycerin 1,800 1,800 1,800 Polyvinylalcohol 120 120 120 Ethanol (95%) 500 9,000 4,500 Hydrochloric acid A suitable A suitable A suitable amount amount amount Sodium hydroxide A suitable A suitable A suitable amount amount amount Purified water A suitable A suitable A suitable amount amount amount (2) Manufacturing methods Each active ingredient described above is weighed and the syrups are manufactured according to methods described in General Rules for Preparation (syrups) of the,lapanese Pharmacopoeia. The syrups are kept in brown glass bottles.
(Example 5) Tablets (1) Compositions 6 Tabl__ets (mg) Atorvastatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Magnesium aluminometasilicate 140 Crystalline cellulose 120 Corn starch 140 Hydroxypropylcellulose 60 Croscarmellose sodium 15 Magnesium stearate 25 Glycerin triacetate 6 Lactose A suitable amount Total 1,200 FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (2) Manufacturing methods Each active ingredient described above is weighed and the tablets are manufactured according to methods described in General Rules for Preparation (tablets) of the Japanese Pharmacopoeia.
(Example 6) Granules (1) Compositions 3 Packages (mg) Atorvastatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Magnesium aluminometasilicate 140 Purified sucrose 1400 Extracted products from stevia 15 Corn starch 1200 Polysorbate 80 80 Magnesium stearate 25 Lactose A suitable amount Total 4,300 (2) Manufacturing methods Each active ingredient described above is weighed and the granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia.
(Example 7) Capsules (1) Compositions 6 Capsules (mg) Atorvastatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Corn starch 600 Polysorbate 80 50 Magnesium stearate 25 Lactose A suitable amount Capsule 480 Total 2,300 (2) Manufacturing methods Each active ingredient described above is weighed and granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia. The capsules FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 are manufactured by filling the granules in hard capsules.
(Example 8) Syrups (1) Compositions _ 60 mL (mg) Atorvastatin calcium 20 ~
Pyridoxine hydrochloride 100 Sodium benzoate 240 Citric acid 60 Sucrose 1,500 Conc. Glycerin 1,800 Polyvinylalcohol 120 Ethanol (95%) 500 Hydrochloric acid A suitable amount Sodium hydroxide A suitable amount Purified water A suitable amount (2) Manufacturing methods Each active ingredient described above is weighed and the syrups are manufactured according to methods described in General Rules for Preparation (syrups) of the Japanese Pharmacopoeia. The syrups are kept in brown glass bottles.
[Test Examples]
[Test Example 1]
(1) Test Substance Pravastatin sodium manufactured at Sankyo Co., Ltd. was used.
Simvastatin and atorvastatinsynthesized at Chemtech Labo., Inc.were used. Pyridoxine hydrochloride manufactured at Nippon Roche K.K. was used.
(2) Animals Male Beagle dogs of 5 months of age were purchased from Covance Research Products Inc. as the test animals and were used after accommodation breeding for approximately 5 months.
(3) Dosage form, Preparation of the Formulation, and Storage The required amount of the test substance calculated based on the body weight of the test animals was weighed and put in gelatin capsules (TORPAC Inc., 1/2 oz) . After filling up, the capsules were placed in a box divided up for every animal and stored under freezing FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 until use.
(4) Route of Administration and Administration Period The capsules filled up with the test substance were orally administered to the test animals once daily via an oral gavage between 9:00 - 12:30. The test animals were fasted for 2-3 hrs prior to each administration. The administration period was 11 days.
(5) Preparation of the Test Samples Approximately 10 mL of blood was collected from the cephalic vein of each dog on -14 and -7 day (the 1st and the 2nd week prior to administration) as well as 4, 8, and 12 days after administration.
The animals were fasted for approximately 18 hrs before collection of the blood.
The collected blood was placed in a test tube and allowed to stand at room temperature for 30 min to 1 hour. Then the blood was centrifuged (approximately 1, 600 g, for 10 min) and the resultant serum obtained was used for assays.
(6) Test Procedure Total cholesterol content was assayed by enzymatic assay method, while HDL, LDL, and triglyceride were determined by homogeneous method, chemically modified method, and enzymatic techniques, respectively. Clinical Laboratory System (TBA-120FR, Toshiba Medical Systems Corporation) was used in all of these determinations .
(7) Results Relative values of various levels of serum lipids in animals treated with each dose of pyridoxine hydrochloride, pravastatin sodium, simvastatin, or atorvastatin calcium alone as well as the medicinal compositions described above were calculated against each converted average value calculated from that determined 2 weeks and 1 week before the treatment into 100.
The results are summarized in Tables 1 - 6. The values indicate average results calculated from 5 dogs per a group.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 2 J.
Table 1 Percent changes of blood total cholesterol levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Simvastatin (1) 94.8 94.1 92.4 Pyridoxine hydrochloride 98.0 93.3 90.5 (50) Simvastatin (1) + Pyridoxine 88-5 83.6 80.0 hydrochloride (50) Table 2 Percent changes of blood LDL levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Simvastatin (1) 83.9 90.4 81.3 Pyridoxine hydrochloride 101.7 95.0 91.4 (50) Simvastatin (1) + Pyridoxine 83.0 70.4 70.4 hydrochloride (50) Table 3 Percent changes of blood triglyceride levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Simvastatin (1) 66.4 85.3 82.0 Pyridoxine hydrochloride 83.8 86.7 81.2 (50) Simvastatin (1) + Pyridoxine 50.1 54.4 65.1 hydrochloride (50) Table 4 Percent changes of blood LDL levels 4 Days 8 Days 12 Days Test substance (mg/Kg) after after after treatment treatment treatment Pravastatin sodium (2) 92.6 91.6 90.4 Pyridoxine hydrochloride 101.7 95.0 91.4 (50) Pravastatin sodium (2) +
50.1 54.4 65.1 Pyridoxine hydrochloride (50) FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 Table 5 Percent changes of blood LDL levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Atorvastatin calcium (2) 82.4 82.1 83.6 Pyridoxine hydrochloride 101.7 95.0 91.4 (50) Atorvastatin calcium (2) 76,1 73.8 66.2 +
Pyridoxine hydrochloride (50) Table 6 Percent changes of blood triglyceride levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Atorvastatin calcium (2) 77.2 86.3 86.4 Pyridoxine hydrochloride 83.8 86.7 81.2 (50) Atorvastatin calcium (2) 59,1 68.7 65.4 +
Pyridoxine hydrochloride (50) The various lipids in blood were remarkably reduced following combined administration of simvastatin, pravastatin, or atorvastatin with pyridoxine hydrochloride.
[Test Example 2]
(1) Test Substance Atorvastatin synthesized at Chemtech Labo., Inc. and pyridoxine hydrochloride manufactured at Nippon Roche K.K. were used.
(2) Animals Male Beagle dogs of 5 months of age were purchased from Covance Research Products Inc. as the test animals and were used after accommodation breeding for approximately 5 months.
(3) Dosage form, Preparation of the Formulation, and Storage The required amount of the test substance calculated based on the body weight of the test animals was weighed and put in gelatin capsules (TORPAC Inc. , 1/2 oz) . After filling up, the capsules were placed in a box divided up for every animal and stored under freezing until use.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.OA
(4) Route of Administration and Administration Period The capsules filled up with the test substance were orally administered to the test animals once daily via an oral gavage between 9:00 - 12:30. The test animals were fasted for 2-3 hrs prior to each administration. The administration period was 11 days.
(5) Preparation of the Test Samples Approximately 10 mL of blood was collected from the cephalic vein of each dog on -14 and -7 day (the 1st and the 2nd week prior to administration) as well as 4, 8, and 12 days after administration.
The animals were fasted for approximately 18 hrs before collection of the blood.
The collected blood was placed in a test tube and allowed to stand at room temperature for 30 min to 1 hour . Then the blood was centrifuged (approximately 1, 600 g, for 10 min) and the resultant serum obtained was used for assays.
(6) Test Procedure Blood homocysteine levels were determined by HPLC method used conventionally in current clinical examination.
(7) Results Relative values of blood homocysteine levels in animals treated with each dose of atorvastatin calcium or pyridoxine hydrochloride alone as well as the medicinal compositions of atorvastatin calcium pluspyridoxine hydrochloride were calculated against each converted average value calculated from that determined 2 weeks and 1 week before the treatment into 100.
The results are summarized in Tables 7. The values indicate average results calculated from 5 dogs per a group.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 Table 7 Percent changes of blood homocysteine levels (%) Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Atorvastatin calcium (2) + 97.4 101.2 93.0 Pyridoxine hydrochloride (5) Atorvastatin calcium (2) + 90.8 89.0 85.7 Pyridoxine hydrochloride (50) ~Comnarative examples Atorvastatin calcium (2) 107.2 106.3 106.9 Pyridoxine hydrochloride (5) 100.0 116.0 109.8 Pyridoxine hydrochloride (50)101.4 111.5 103.0 Remarkable ameliorating effects on blood homocysteine levels appeared by combined administration of atorvastatin calcium with pyridoxine hydrochloride.
[Industrial Applicability]
Since the medicinal compositionscomprising an HMG-CoA reductase inhibitor and a pyridoxine derivative of the present invention exert potent mitigating effects on blood lipid levels and reduce blood homocysteine levels, the medicinal compositions of the present invention are considered useful as preventive or therapeutic agents against cardiovascular diseases such as hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular disease, Burger's disease, Raynaud's disease, and the like, cerebrovascular diseases such as cerebral infarction, cerebrovascular disorders, senile dementia, and the like, and neurological diseases such as Alzheimer' s disease, Parkinson disease, and the like. Furthermore, the medicinal compositions of the present invention may also be useful as preventive or therapeutic agents against increased blood homocysteine levels caused by aging, smoking, nutrition impairment related to homocysteine metabolism, drugs, renal hypofunction, chronic renal dysfunction, diabetes mellitus, insulin resistance, malignant neoplasm, thyroidal hypofunction, pernicious anemia, and the like.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04
The present invention relates to a medicinal composition comprising an HMG-CoA reductaseinhibitor and a pyridoxine derivative as active ingredients (particularly a medicinal composition for mitigating blood lipid levels or lowering high blood homocysteine levels) .
[Background of the Invention]
An old proverb wisely says that a man is as old as his arteries .
Recently, it has been noted and become widely known that increased blood homocysteine levels are an independent risk factor for arteriosclerosis.
Homocysteine is an amino acid produced in the metabolism of methionine, which is one of the essential amino acids. It has been observed that blood homocysteine levels are increased by genetic factors, deficiencies in vitamin cofactors (folic acid, vitamin B6, and vitaminBl2) , aging, sex difference, renal hypofunction, diabetes mellitus and other diseases, some drugs, smoking, and the like (Progress in Medicine, vol. 19 No. 8, 1999, p. 49 - 52) . This symptom is called homocysteinemia. Treatment against homocysteinemia currently consists of folic acid to advance homocysteine metabolism as a first step, followed by treatment with vitamins B6 and B12 as second-step therapy (Progress in Medicine, vol. 19 No.B, 1999, p.
52 - 53 ) .
On the other hand statins, which reduce blood cholesterol levels by specifically and competitively inhibiting HMG-CoA reductase in vivo, have elicited the following effects on blood homocysteine levels:
1) Following administration of pravastatin for 8 successive weeks in 16 patients with hypercholesterolemia, blood homocysteine levels FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 were reduced (Nikkei Medical, November 2001, p. 73), 2) In 20,705 patients treated with lovastatin for one year, bloodhomocysteine levels decreased by 3 .7% on average (versus a 1.9%
decrease in the placebo control group) (Circulation, vol. 105, No.
15, 2002, p. 1778), 3) Three of 7 patients with cardiovascular diseases were treated with atorvastatin and the other 4 patients were treated with simvastatin for 6 successive weeks. Blood homocysteine levels in patients treated with atorvastatin were increased, while those in patients treated with simvastatin were decreased (31st Hemophilia Symposium Hamburg, 2000, p. 258).
Thus it would appear that the results are inconsistent and no clear conclusion has yet been reached.
Furthermore, combination therapy with statins plus folic acid has been disclosed to prevent or reduce the risk of developing arteriosclerosis (WO 97/38694).
Regarding combination therapy with a statin plus a pyridoxine derivative, it has also been described on page 17 of WO 97/38694 that some other agents selected from HMG-CoA synthetase inhibitors, squalene epoxidase inhibitors, squalene synthetase inhibitors, ACAT
inhibitors, probucol, niacin, fibrates, cholesterol-binding antagonists, bile acid sequestrants, LDL receptor inducers, vitamin B6, vitamin B12, aspirin, (3-blockers, vitamin C, vitamin E, and ~3-carotene may be contained in the combination therapy in addition to a statin and folic acid.
However, there is no description in WO 97/38694 of a combination therapy containing an HMG-CoA synthetase inhibitor and a pyridoxine derivative alone, which is the present invention. Furthermore, there are neither descriptions norsuggestions about remarkable mitigating effects on blood lipid levels or reducing blood homocysteine levels, which is the medical intention of the present invention.
On the other hand, a composition comprising an HMG-CoA reductase inhibitor (statin) and 7 supplements (omega-3 fatty acid, vitamin E, vitamin C, vitamin B6, vitamin B12, folic acid, and calcium) is disclosed in WO 02/43659 as a dietary supplement to reduce risk of FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 cardiovascular diseases. However, this composition was contrived from speculation based on the known efficacies of the various individual compositions, that is, statin and omega-3 fatty acid mitigate serum lipid levels, vitamin E and vitamin C exert anti-oxidant activities, a combination containing folic acid, vitamin B6, and vitamin B12 reduces blood homocysteine levels, and calcium is beneficial for the cardiovascular system due to decreases in blood pressure. No concrete data are disclosed in WO 02/43659.
Therefore the novel effects of the present invention, namely, the remarkable mitigating effects of the present invention on blood lipid levels and remarkable reducing effects on blood homocysteine levels are not described in WO 02/43659.
[Disclosure of the Invention]
In light of this background, the present inventors have diligently conducted research to discover new and safe drugs that mitigate blood lipid levels and reduce blood homocysteine levels, and found that a medicinal composition comprising an HMG-CoA
reductaseinhibitor and a pyridoxine derivative as activeingredients exerts good effects on mitigating blood lipids levels and reducing blood homocysteine levels, and thus completed the present invention.
The present invention relates to (1) a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative as active ingredients.
Of the said description, the present invention includes (2) a medicinal composition as stated in (1) for mitigating blood lipid levels or reducing high blood homocysteine levels, (3) a medicinal composition as stated in (1) or (2), comprising one or more HMG-CoA reductase inhibitors selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, and rosuvastatin as active ingredients, (4) a medicinal composition as stated in (1) or (2), comprising one or more HMG-CoA reductase inhibitors selected from the group FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 consisting of pravastatin, simvastatin, and atorvastatin as active ingredients, (5) a medicinal composition as stated in (1) or (2), comprising an HMG-CoA reductase inhibitor of atorvastatin, as an active ingredient, (6) a medicinal composition according to any one selected from (1) to (5) described above, comprising one or more pyridoxine derivatives selected from the group consisting of pyridoxine, pyridoxal, pyridoxamine, and pharmacologically acceptable salts thereof, (7) a medicinal composition according to any one selected from (1) to (5) described above, comprising a pyridoxine derivative selected from pyridoxine and a pharmacologically acceptable salt thereof, (8) a medicinal composition as stated in (2) where the HMG-CoA
reductase inhibitor is atorvastatin or a pharmacologically acceptable salt thereof, and the pyridoxamine derivative is pyridoxine or a pharmacologically acceptable salt thereof, (9) a medicinal composition according to any one selected from (1) to (8) for mitigating blood lipid levels, (10) a medicinal composition according to any one selected from (1) to (8) for reducing high blood homocysteine levels, (11) a medicinal composition according to any one selected from (1) to (8) for therapy or prevention of diseases caused by high blood homocysteine levels, (12) a medicinal composition according to any one selected from (1) to (8) for therapy or prevention of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular diseases, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease, and (13) a medicinal composition as stated in (8) for prevention or therapy of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular diseases, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 Parkinson disease.
In addition, the present invention provides (14) combination use of an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels by administration of an HMG-CoA
reductase inhibitor and a pyridoxine derivative at the same time or independently at certain time intervals, and (15) combination use of an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels.
Furthermore, the present invention provides (16) a method to mitigate blood lipid levels or to reduce high blood homocysteine levels by administration of an HMG-CoA reductase inhibitor and a pyridoxine derivative at the same time or independently at certain time intervals.
The preferable methods in said (16) are (17) a method as stated in (16) for mitigating blood lipid levels, (18) a method as stated in (16) for reducing a high blood homocysteine levels, (19) a method as stated in ( 16 ) for therapy or prevention of diseases caused by high blood homocysteine levels, (20) a method as stated in (16) for prevention or therapy of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular diseases, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease, (21) a method according to any one selected from (16) - (20), in which a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative is administered, and (22) a method as stated in (20) , in which a medicinal composition comprising an HMG-CoA reductaseinhibitor and a pyridoxine derivative FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 is administered.
Furthermore, the present invention provides (23) the use of an HMG-CoA reductase inhibitor and a pyridoxine derivative in the manufacture of a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels.
"HMG-CoA reductase inhibitor", one component of the medicinal composition of the present invention, refers to agents that competitively and specifically inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, which is a rate limiting enzyme in the biosynthesis of cholesterol. Since such inhibitors suppress blood cholesterol levels, the inhibitors are used as therapeutic agents for patients with hypercholesterolemia. As such HMG-CoA
reductase inhibitors, natural products derived from microorganisms and semi-synthesized compounds derived from the natural products described above, and totally synthesized chemical compounds are all included. For instance, such compounds are (+)-(3R, 5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methy lbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphtyl] heptanoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Sho 57-2240 (USP 4346227) (hereinafter called pravastatin), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[
(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphth yl(S)-2-methylbutyrate which is disclosed in Japanese Patent Publication (Kokai) Number Sho 57-163374 (USP 4231938) (hereinafter called lovastatin), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[
(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphth yl 2,2-dimethylbutyrate which is disclosed in Japanese Patent Publication (Kokai) Number Sho 56-122375 (USP 4444784) (hereinafter called simvastatin), (~) (3R*, 5S*, 6E) -7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 -2-yl]-3,5-dihydroxy-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kohyo) Number Sho 60-500015 (USP
4739073) (hereinafter called fluvastatin), (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-di(1-methylethyl)-5-methoxy methylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 1-216974 (USP 5006530) (hereinafter called rivastatin), (3R,5S)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-pheny laminocarbonyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 3-58967 (USP 5273995) (hereinafter called atorvastatin), and (E)-3,5-dihydroxy-7-(4'-(4" -fluorophenyl)-2'-cyclopropyl-quinol in-3'-yl]-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 1-279866 (USP 5854259 and USP 5856336) (hereinafter called pitavastatin), or (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-meth anesulfonylamino)pyridin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 5-178841 (USP 5260440) (hereinafter called rosuvastatin). In addition, an HMG-CoA reductase inhibitor, which is one component of the medicinal composition of the present invention, refers to other HMG-CoA reductase inhibitors described in the disclosed patents described above.
Planar chemical structures of representative HMG-CoA reductase inhibitors are shown below:
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 . 8 )H
O
H3C' Y 'O
H3 IC ~ ~CH3 Pravastatin Lovastatin F
H3C ~ CH3 O O COOH
H3C m ig Si ~mva~s%tat~i%n Fluvastatin F
Rivastatin Atorvastatin COOH
N
H3C~ ~SOzCH3 Pitavastatin Rosuvastatin "Pyridoxine derivative", which is an active ingredient of the FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 medicinal composition of the present invention includes pyridoxine, pyridoxal, pyridoxamine, or salts thereof, and is preferably pyridoxine hydrochloride, pyridoxal phosphate, or pyridoxamine phosphate, and is more preferably pyridoxine hydrochloride.
Each active ingredient of the present invention described above may be present as pharmacologically acceptable salts thereof, and in the case that the active ingredients present a basic functional group, such salts are, for example, a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, or the like; an inorganic acid salt such as a nitrate, a perchlorate, a sulfate, a phosphate, or the like; a lower organic sulfonate such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, or the like; an arylsulfonate such as benzenesulfonate p-toluenesulfonate, or the like; an amino acid salt such as ornithine salt, glutamate, or the like; carboxylic acid salt such as a fumarate, a succinate, a citrate, a tartrate, an oxalate, a maleate, or the like, in the case that the active ingredients present an acidic functional group, such salts are, for example, an alkaline metal salt such as sodium salt, potassium salt, lithium salt, or the like; an alkaline earth metal salt such as calcium salt, magnesium salt, or the like; a metal salt such as an aluminium salt, an iron salt, a zinc salt, a copper salt, a nickel salt, a cobalt salt, or the like;
an amine salt, for example, an inorganic salt such as ammonium salt, an organic acid salt such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris(hydroxymethyl)aminomethane salt, or the like. For instance, in the case of pravastatin, a preferable salt is pravastatin sodium, and for instance, in the case of atorvastatin, a preferable salt is atorvastatin calcium salt hydrate.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 In the case that each active ingredient involved forms a hydrate or solvate, such hydrates or solvates are included in the medicinal compositions of the present invention.
In the present invention, "mitigating blood lipid levels" means reducing bloodlipidlevelsto clinically significant values, namely, reducing blood triglyceride levels, reducing blood LDL levels, or reducing blood total cholesterol levels.
In the present invention, "reducing blood homocysteine levels"
means suppressing increases in high blood homocysteine levels, and reducing blood homocysteine levels. Factors that increase homocysteine levels in the blood are, for example, aging, smoking, nutritionimpairment related to homocysteine metabolism, some drugs, renal hypofunction, chronic renal dysfunction, diabetes mellitus, insulin resistance, malignant neoplasm, thyroidal hypofunction, pernicious anemia, and the like.
"Diseases caused by high blood homocysteine levels" described in the present invention have no limitation so long as the diseases derive from high blood homocysteine levels . They are, for example, cardiovascular diseases such as arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular disease, Burger's disease, Raynaud's disease, and cerebrovascular diseases such as cerebral infarction, cerebrovascular disorders, senile dementia, neurological diseases such as Alzheimer' s disease, Parkinson disease, and the like.
Since the early stages of the said diseases exhibit few subjective symptoms, it is difficult for patients themselves to become aware of having these diseases in the early stages . The subj ective symptoms of the "diseases caused by high blood homocysteine levels" in the present invention are, for example, headache, migraine, dizziness, numbness or feeling of numbness, cold sensation of the four limbs, shoulder stiffness, and the like. Therefore the said diseases may possibly be treated at their early stages by taking the medicinal composition of the present invention when such subjective symptoms first appear.
FP0330s.doc Sankyo/PB8879/PCT specification/ACF/29.12.04 [Mode for carrying out the Invention]
HMG-CoA reductase inhibitors used as an active ingredient in the medicinal composition of the present invention, for example, pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, or rosuvastatin, can be easily prepared according to the methods described hereinafter in Japanese Patent Publication (Kokai) Number Sho57-2240 (USP 4346227), Japanese Patent Publication (Kokai) Number Sho 57-16337 (USP 4231938), Japanese Patent Publication (Kokai) Number Sho 56-122375 (USP 4444784), Japanese Patent Publication (Kohyo) Number Sho 60-500015 (USP
4739073), Japanese Patent Publication (Kokai) Number Hei 1-216974 (USP5006530), Japanese Patent Publication (Kokai) Number Hei3-58967 (USP 5273995), Japanese Patent Publication (Kokai) Number Hei 1-279866 (USP 5854259 and USP 5856336), or Japanese Patent Publication (Kokai) Number Hei 5-178841 (USP 5260440).
In addition, pyridoxine derivatives used in the medicinal compositions of the present invention as an active ingredient can be easily obtained as commercially available products, or can be easily manufactured by previously known methods. For example, since pyridoxine hydrochloride is disclosedin"The Japanese Pharmacopoeia (JP) 14th Edition", the compound can be easily obtained.
The medicinal compositions of the present invention comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative as active ingredients contain both an HMG-CoA reductase inhibitor and a pyridoxine derivative as essential active ingredients. Additive agents may be contained in the formulation, when required. In addition, other inactive ingredients included in the medicinal compositions are not particularly restricted provided that they have no adverse effects when they are co-administered with the HMG-CoA reductase inhibitor and the pyridoxine derivative contained in the present medicinal composition. The preferable medicinal composition is restricted to an HMG-CoA reductase inhibitor and a pyridoxine derivative alone as active ingredients, and it may contain additive FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 agents for its formulation.
The concrete preparations of the medicinal composition of the present invention are, for example, tablets, granules (including powders), capsules, liquids and solutions (including syrups), and the like. These preparations are prepared by conventionally known methods disclosed in "The Japanese Pharmacopoeia (JP)" or the like using additive agents and bases that are suitable for each preparation, as necessary.
In each preparation, various conventionally used additive agents suitable for each preparation may also be used.
For example, in the case of tablets, diluents such as lactose, crystalline cellulose or the like, stabilizers such as magnesium aluminometasilicate, magnesium oxide orthelike, coating agentssuch as hydroxypropylcellulose or the like, and lubricants such as magnesium stearate or the like may be used.
In the case of granules and capsules, diluents such as lactose, purified sucrose, or the like, stabilizers such as magnesium aluminometasilicate, magnesium oxide, or the like, adsorbents such as corn starch, or the like, binders such as hydroxypropylcellulose, or the like may be used.
In each preparation described above, disintegrants such as crospovidone, or the like; surfactants such as polysorbate, or the like; adsorbents such as calcium silicate, or the like; colouring agents such as red ferric oxide, caramel, or the like; stabilizers such as sodium benzoate, or the like; pH modifiers; flavours; or the like, may be added as necessary.
In the present invention, "co-administration" means methods of administration of more than the 2 active ingredients to humans at the same time, or independent administration of more than the 2 active ingredients described above at a certain time interval.
When the 2 active ingredients of the present invention are administered, each active ingredient of the medicinal composition may be administered at the same time or independently at a certain time interval.
"Administration at the same time" described above includes FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 administration of each active ingredient at a pharmacologically acceptable time interval in addition to administration of all active ingredients at the same time . There is no restriction provided that their pharmaceutical preparations are to be taken at roughly the same time. Nevertheless, it is favourable to take the 2 active ingredients as a single pharmaceutical preparation.
"Independent administration of the more than 2 active ingredients described above at a certain time interval" described above hasno restriction provided thattheir available pharmaceutical preparations are to be taken independently at different times. For instance, it indicates that first one active ingredient is administered, and then after a defined time delay, the other active ingredient is administered.
Furthermore, in the case that the medicinal composition contains more than 3 active ingredients, "simultaneous administration or independent administration at certain time intervals" includes all cases wherein all active ingredients contained in the medicinal composition are taken at the same time, each composition is taken independently at certain time intervals, more than 2 active ingredients contained in the medicinal composition are simultaneously taken and the rest of them are independently taken at certain time intervals, or more than 2 active ingredients in the medicinal composition are simultaneously taken and the rest of them are simultaneously taken at a certain time interval.
Since the medicinal composition of the present invention exerts remarkable mitigating effects on blood lipid levels and reducing effects on high blood homocysteinelevels, the medicinalcompositions of the present invention are useful as pharmaceutical agents for mitigating blood lipid levels and reducing high blood homocysteine levels. Thus the medicinal compositions of the present invention are useful as preventive or therapeutic agents against diseases, for example, hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 disease, Burger' s disease, Raynaud' s disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease.
In the present invention, the dosage of HMG-CoA reductase inhibitors varies depending on the types of HMG-CoA reductase inhibitors used, the formulations, and the like. It is usual to administer 1 rng - 200 mg per day and preferably 5 mg - 160 mg per day.
In the present invention, the dosage of pyridoxine derivative varies depending on the type of pyridoxine derivative used, its formulation, and the like. It is usual to administer 0.1 mg - 1,200 mg per day and preferably 1 mg - 800 mg per day.
In the case that the dosage form of the medicinal composition of the present invention is a solid dosage form, the weight percentages of the active ingredients contained in the medicinal composition are, for example, usually 0.01 - 5% in the case of atorvastatin or pravastatin, and preferably 0.05 - 3%. In the case of simvastatin, the weight percentage is usually 0.005 - 3%, preferably 0.03 - 2%. Furthermore, weight percentage of pyridoxine derivative is usually 0.01 - 30%, and preferably it is 0.1 - 20%.
In the case that the dosage form of the medicinal composition of the present invention is a liquid or solution, the percentages of the active ingredients contained in the medicinal composition are, for example, usually 0 .O1 - 10 mg/mL for atorvastatin andpravastatin, and preferably 0.05 - 5 mg/mL. In the case of simvastatin, the percentage is usually 0.005 - 5 mg/mL, and preferably 0.03 - 3 mg/mL.
Furthermore, the percentage of pyridoxine derivative is usually 0.1 - 20 mg/mL, and preferably 0.1 - 10 mg/mL.
[Best Mode for carrying out the Invention]
The present invention will further be exemplified in more detail by the Examples . However, the scope of the present invention is not limited by these Examples.
[Examples]
(Example 1) Tablets FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (1) Compositions 6 Tablets 6 Tablets 6 Tablets (mg) (mg) (mg) Pravastatin sodium 20 - -Simvastatin - 10 -Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Magnesium oxide 400 400 400 Magnesium 140 140 140 aluminometasilicate Crystalline cellulose 120 120 120 Corn starch 140 140 140 Hydroxypropylcellulose 60 60 60 Croscarmellose sodium 15 15 15 Magnesium stearate 25 25 25 Glycerin triacetate 6 6 6 A suitable A suitable A suitable Lactose amount amount amount Total 1,200 1,200 1,200 (2) Manufacturing methods Each active ingredient described above is weighed and the tablets are manufactured according to methods described in General Rules for Preparation (tablets) of the Japanese Pharmacopoeia.
(Example 2) Granules (1) Compositions 3 Packages 3 Packages 3 Packages (mg) (mg) (mg) Pravastatin sodium 20 - -Simvastatin - 10 -Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Magnesium oxide 400 400 400 Magnesium aluminometasilicate 140 140 140 Purified sucrose 1400 1400 1400 Extracted products from 15 15 15 stevia Corn starch 1200 1000 1100 Polysorbate 80 80 80 80 Magnesium stearate 25 25 25 A suitable A suitable A suitable Lactose amount amount amount Total 4,300 4,300 4,300 FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (2) Manufacturing methods Each active ingredient described above is weighed and the granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia.
(Example 3) Capsules (1) Compositions 6 Capsules 6 Capsules 6 Capsules (mg) (mg) (mg) Pravastatin sodium 20 - -Simvastatin - 10 -Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Magnesium oxide 400 400 400 Corn starch 600 400 500 Polysorbate 80 50 50 50 Magnesium stearate 25 25 25 A suitable A suitable A suitable Lactose amount amount amount Capsule 480 480 480 Total 2,300 2,300 2,300 (2) Manufacturing methods Each active ingredient described above is weighed and granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia. The capsules are manufactured by filling the granules in hard capsules.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (Example 4) Syrups (1) Compositions 60 mL (mg) 60 mL (mg) 60 mL (mg) Pravastatin sodium 20 - -Simvastatin - 10 Atorvastatin calcium - - 20 Pyridoxine hydrochloride 100 100 -Pyridoxal phosphate - - 60 Sodium benzoate 240 240 240 Citric acid 60 60 60 Sucrose 1,500 1,500 1,500 Conc. Glycerin 1,800 1,800 1,800 Polyvinylalcohol 120 120 120 Ethanol (95%) 500 9,000 4,500 Hydrochloric acid A suitable A suitable A suitable amount amount amount Sodium hydroxide A suitable A suitable A suitable amount amount amount Purified water A suitable A suitable A suitable amount amount amount (2) Manufacturing methods Each active ingredient described above is weighed and the syrups are manufactured according to methods described in General Rules for Preparation (syrups) of the,lapanese Pharmacopoeia. The syrups are kept in brown glass bottles.
(Example 5) Tablets (1) Compositions 6 Tabl__ets (mg) Atorvastatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Magnesium aluminometasilicate 140 Crystalline cellulose 120 Corn starch 140 Hydroxypropylcellulose 60 Croscarmellose sodium 15 Magnesium stearate 25 Glycerin triacetate 6 Lactose A suitable amount Total 1,200 FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 (2) Manufacturing methods Each active ingredient described above is weighed and the tablets are manufactured according to methods described in General Rules for Preparation (tablets) of the Japanese Pharmacopoeia.
(Example 6) Granules (1) Compositions 3 Packages (mg) Atorvastatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Magnesium aluminometasilicate 140 Purified sucrose 1400 Extracted products from stevia 15 Corn starch 1200 Polysorbate 80 80 Magnesium stearate 25 Lactose A suitable amount Total 4,300 (2) Manufacturing methods Each active ingredient described above is weighed and the granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia.
(Example 7) Capsules (1) Compositions 6 Capsules (mg) Atorvastatin calcium 20 Pyridoxine hydrochloride 100 Magnesium oxide 400 Corn starch 600 Polysorbate 80 50 Magnesium stearate 25 Lactose A suitable amount Capsule 480 Total 2,300 (2) Manufacturing methods Each active ingredient described above is weighed and granules are manufactured according to methods described in General Rules for Preparation (granules) of the Japanese Pharmacopoeia. The capsules FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 are manufactured by filling the granules in hard capsules.
(Example 8) Syrups (1) Compositions _ 60 mL (mg) Atorvastatin calcium 20 ~
Pyridoxine hydrochloride 100 Sodium benzoate 240 Citric acid 60 Sucrose 1,500 Conc. Glycerin 1,800 Polyvinylalcohol 120 Ethanol (95%) 500 Hydrochloric acid A suitable amount Sodium hydroxide A suitable amount Purified water A suitable amount (2) Manufacturing methods Each active ingredient described above is weighed and the syrups are manufactured according to methods described in General Rules for Preparation (syrups) of the Japanese Pharmacopoeia. The syrups are kept in brown glass bottles.
[Test Examples]
[Test Example 1]
(1) Test Substance Pravastatin sodium manufactured at Sankyo Co., Ltd. was used.
Simvastatin and atorvastatinsynthesized at Chemtech Labo., Inc.were used. Pyridoxine hydrochloride manufactured at Nippon Roche K.K. was used.
(2) Animals Male Beagle dogs of 5 months of age were purchased from Covance Research Products Inc. as the test animals and were used after accommodation breeding for approximately 5 months.
(3) Dosage form, Preparation of the Formulation, and Storage The required amount of the test substance calculated based on the body weight of the test animals was weighed and put in gelatin capsules (TORPAC Inc., 1/2 oz) . After filling up, the capsules were placed in a box divided up for every animal and stored under freezing FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 until use.
(4) Route of Administration and Administration Period The capsules filled up with the test substance were orally administered to the test animals once daily via an oral gavage between 9:00 - 12:30. The test animals were fasted for 2-3 hrs prior to each administration. The administration period was 11 days.
(5) Preparation of the Test Samples Approximately 10 mL of blood was collected from the cephalic vein of each dog on -14 and -7 day (the 1st and the 2nd week prior to administration) as well as 4, 8, and 12 days after administration.
The animals were fasted for approximately 18 hrs before collection of the blood.
The collected blood was placed in a test tube and allowed to stand at room temperature for 30 min to 1 hour. Then the blood was centrifuged (approximately 1, 600 g, for 10 min) and the resultant serum obtained was used for assays.
(6) Test Procedure Total cholesterol content was assayed by enzymatic assay method, while HDL, LDL, and triglyceride were determined by homogeneous method, chemically modified method, and enzymatic techniques, respectively. Clinical Laboratory System (TBA-120FR, Toshiba Medical Systems Corporation) was used in all of these determinations .
(7) Results Relative values of various levels of serum lipids in animals treated with each dose of pyridoxine hydrochloride, pravastatin sodium, simvastatin, or atorvastatin calcium alone as well as the medicinal compositions described above were calculated against each converted average value calculated from that determined 2 weeks and 1 week before the treatment into 100.
The results are summarized in Tables 1 - 6. The values indicate average results calculated from 5 dogs per a group.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 2 J.
Table 1 Percent changes of blood total cholesterol levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Simvastatin (1) 94.8 94.1 92.4 Pyridoxine hydrochloride 98.0 93.3 90.5 (50) Simvastatin (1) + Pyridoxine 88-5 83.6 80.0 hydrochloride (50) Table 2 Percent changes of blood LDL levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Simvastatin (1) 83.9 90.4 81.3 Pyridoxine hydrochloride 101.7 95.0 91.4 (50) Simvastatin (1) + Pyridoxine 83.0 70.4 70.4 hydrochloride (50) Table 3 Percent changes of blood triglyceride levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Simvastatin (1) 66.4 85.3 82.0 Pyridoxine hydrochloride 83.8 86.7 81.2 (50) Simvastatin (1) + Pyridoxine 50.1 54.4 65.1 hydrochloride (50) Table 4 Percent changes of blood LDL levels 4 Days 8 Days 12 Days Test substance (mg/Kg) after after after treatment treatment treatment Pravastatin sodium (2) 92.6 91.6 90.4 Pyridoxine hydrochloride 101.7 95.0 91.4 (50) Pravastatin sodium (2) +
50.1 54.4 65.1 Pyridoxine hydrochloride (50) FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 Table 5 Percent changes of blood LDL levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Atorvastatin calcium (2) 82.4 82.1 83.6 Pyridoxine hydrochloride 101.7 95.0 91.4 (50) Atorvastatin calcium (2) 76,1 73.8 66.2 +
Pyridoxine hydrochloride (50) Table 6 Percent changes of blood triglyceride levels Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Atorvastatin calcium (2) 77.2 86.3 86.4 Pyridoxine hydrochloride 83.8 86.7 81.2 (50) Atorvastatin calcium (2) 59,1 68.7 65.4 +
Pyridoxine hydrochloride (50) The various lipids in blood were remarkably reduced following combined administration of simvastatin, pravastatin, or atorvastatin with pyridoxine hydrochloride.
[Test Example 2]
(1) Test Substance Atorvastatin synthesized at Chemtech Labo., Inc. and pyridoxine hydrochloride manufactured at Nippon Roche K.K. were used.
(2) Animals Male Beagle dogs of 5 months of age were purchased from Covance Research Products Inc. as the test animals and were used after accommodation breeding for approximately 5 months.
(3) Dosage form, Preparation of the Formulation, and Storage The required amount of the test substance calculated based on the body weight of the test animals was weighed and put in gelatin capsules (TORPAC Inc. , 1/2 oz) . After filling up, the capsules were placed in a box divided up for every animal and stored under freezing until use.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.OA
(4) Route of Administration and Administration Period The capsules filled up with the test substance were orally administered to the test animals once daily via an oral gavage between 9:00 - 12:30. The test animals were fasted for 2-3 hrs prior to each administration. The administration period was 11 days.
(5) Preparation of the Test Samples Approximately 10 mL of blood was collected from the cephalic vein of each dog on -14 and -7 day (the 1st and the 2nd week prior to administration) as well as 4, 8, and 12 days after administration.
The animals were fasted for approximately 18 hrs before collection of the blood.
The collected blood was placed in a test tube and allowed to stand at room temperature for 30 min to 1 hour . Then the blood was centrifuged (approximately 1, 600 g, for 10 min) and the resultant serum obtained was used for assays.
(6) Test Procedure Blood homocysteine levels were determined by HPLC method used conventionally in current clinical examination.
(7) Results Relative values of blood homocysteine levels in animals treated with each dose of atorvastatin calcium or pyridoxine hydrochloride alone as well as the medicinal compositions of atorvastatin calcium pluspyridoxine hydrochloride were calculated against each converted average value calculated from that determined 2 weeks and 1 week before the treatment into 100.
The results are summarized in Tables 7. The values indicate average results calculated from 5 dogs per a group.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04 Table 7 Percent changes of blood homocysteine levels (%) Test substance (mg/Kg) 4 Days 8 Days 12 Days after after after treatment treatment treatment Atorvastatin calcium (2) + 97.4 101.2 93.0 Pyridoxine hydrochloride (5) Atorvastatin calcium (2) + 90.8 89.0 85.7 Pyridoxine hydrochloride (50) ~Comnarative examples Atorvastatin calcium (2) 107.2 106.3 106.9 Pyridoxine hydrochloride (5) 100.0 116.0 109.8 Pyridoxine hydrochloride (50)101.4 111.5 103.0 Remarkable ameliorating effects on blood homocysteine levels appeared by combined administration of atorvastatin calcium with pyridoxine hydrochloride.
[Industrial Applicability]
Since the medicinal compositionscomprising an HMG-CoA reductase inhibitor and a pyridoxine derivative of the present invention exert potent mitigating effects on blood lipid levels and reduce blood homocysteine levels, the medicinal compositions of the present invention are considered useful as preventive or therapeutic agents against cardiovascular diseases such as hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular disease, Burger's disease, Raynaud's disease, and the like, cerebrovascular diseases such as cerebral infarction, cerebrovascular disorders, senile dementia, and the like, and neurological diseases such as Alzheimer' s disease, Parkinson disease, and the like. Furthermore, the medicinal compositions of the present invention may also be useful as preventive or therapeutic agents against increased blood homocysteine levels caused by aging, smoking, nutrition impairment related to homocysteine metabolism, drugs, renal hypofunction, chronic renal dysfunction, diabetes mellitus, insulin resistance, malignant neoplasm, thyroidal hypofunction, pernicious anemia, and the like.
FP0330s.doc Sankyo/P88879/PCT specification/ACF/29.12.04
Claims (23)
1. Medicinal compositions comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative.
2 . Medicinal compositions according to Claim 1 for mitigating blood lipid levels or reducing high blood homocysteine levels.
3. Medicinal compositions according to Claim 1 or Claim 2, in which the HMG-CoA reductase inhibitor is one or more HMG-CoA reductase inhibitors selected from the group consisting of pravastatin, lovastatin, simvastatin,fluvastatin, rivastatin, atorvastatin, pitavastatin, and rosuvastatin.
4. Medicinal compositions according to Claim 1 or Claim 2, in which the HMG-CoA reductase inhibitor is one or more HMG-CoA reductase inhibitors selected from the group consisting of pravastatin, simvastatin, and atorvastatin.
5. Medicinal compositions according to Claim 1 or Claim 2, in which the HMG-CoA reductase inhibitor is atorvastatin.
6. Medicinal compositions according to any one claim selected from Claim 1 to Claim 5, in which the pyridoxine derivative is one or more pyridoxine derivatives selected from a group consisting of pyridoxine, pyridoxal, pyridoxamine, and their salts.
7. Medicinal compositions according to any one claim selected from Claim 1 to Claim 5, in which the pyridoxine derivative is pyridoxine or its salts.
8 . Medicinal compositions according to Claim 2, in which the HMG-CoA
reductase inhibitor is atorvastatin or its salts and the pyridoxine derivative is pyridoxine or its salts.
reductase inhibitor is atorvastatin or its salts and the pyridoxine derivative is pyridoxine or its salts.
9. Medicinal compositions according to any one claim selected from Claim 1 to Claim 8 for mitigating blood lipid levels.
10. Medicinal compositions according to any one claim selected from Claim 1 to Claim 8 for reducing high blood homocysteine levels.
11 . Medicinal compositions according to any one claim selected from Claim 1 to Claim 8 for therapy or prevention of diseases caused by high blood homocysteine levels.
12. Medicinal compositions according to any one claim selected from Claim 1 to Claim 8 for prevention or therapy of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction,thrombosis,peripheral vascular disease, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease.
13. Medicinal compositions according to Claim 8 for prevention or therapy of hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular disease, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders, senile dementia, Alzheimer's disease, or Parkinson disease.
14. Combination therapies of an HMG-CoA reductase inhibitor and a pyridoxine derivative by simultaneous administration or independent administration at a certain time interval for mitigating blood lipid levels or reducing high blood homocysteine levels.
15. Combination therapies of an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels.
16 . Methods to mitigate blood lipid levels or reduction of high blood homocysteine levels by administration of an HMG-CoA reductase inhibitor with a pyridoxine derivative at the same time or independently at a certain time interval.
17. Methods according to Claim 16 to mitigate blood lipid levels.
18 . Methods according to Claim 16 to reduce high blood homocysteine levels.
19 . Methods according to Claim 16 to treat or prevent diseases caused by high blood homocysteine levels.
20. Methods according to Claim 16 to prevent or treat hypercholesterolemia, arteriosclerosis, ischemic heart disease, myocardial infarction,thrombosis,peripheral vascular disease, Burger's disease, Raynaud's disease, cerebral infarction, cerebrovascular disorders,senile dementia,Alzheimer's disease, or Parkinson disease.
21. Methods according to one Claim selected from Claim 16 to Claim 20 by administration of a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative.
22. Methods according to Claim 20 by administration of a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative.
23. Uses of an HMG-CoA reductase inhibitor and a pyridoxine derivative to manufacture medicinal compositions containing an HMG-CoA reductase inhibitor and a pyridoxine derivative for mitigating blood lipid levels or reducing high blood homocysteine levels.
Applications Claiming Priority (5)
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| JP2002-343586 | 2002-11-27 | ||
| PCT/JP2003/008674 WO2004006919A1 (en) | 2002-07-11 | 2003-07-08 | Medicinal composition for mitigating blood lipid or lowering blood homocystein |
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| AU2004305154A1 (en) * | 2003-12-23 | 2005-07-07 | Medicure International Inc. | Combination therapies employing a composition comprising a HMG CoA reductase inhibitor and a vitamin B6 related compound |
| JP4949661B2 (en) * | 2004-09-21 | 2012-06-13 | 第一三共株式会社 | Pharmaceutical composition containing HMG-CoA reductase inhibitor and glutathione |
| TW200612896A (en) * | 2004-09-21 | 2006-05-01 | Sankyo Co | Pharmaceutical compositions containing with HMG-CoA reductase inhibitor and glutathione |
| ES2385752T3 (en) * | 2006-04-26 | 2012-07-31 | Rosemont Pharmaceuticals Ltd | Oral Liquid Compositions |
| WO2015060317A1 (en) * | 2013-10-22 | 2015-04-30 | 長谷川亨 | Neurodegenerative disease testing method |
| JP6009050B1 (en) * | 2015-08-21 | 2016-10-19 | 国立大学法人東北大学 | Reducing or preventing sickness or hangover caused by drinking |
| WO2020046132A1 (en) | 2018-08-31 | 2020-03-05 | Leiden University | Pharmacological chaperones for enzyme treatment therapy |
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| ZA936723B (en) * | 1992-09-14 | 1995-08-14 | Vesta Med Pty Ltd | Pharmaceutical preparations for lowering homocysteine levels |
| JP2000508659A (en) * | 1996-04-17 | 2000-07-11 | メルク エンド カンパニー インコーポレーテッド | Combination therapy to reduce cardiovascular disease-related risks |
| AU753657B2 (en) * | 1997-10-22 | 2002-10-24 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardio-and cerebrovascular disease |
| GB9916536D0 (en) * | 1999-07-14 | 1999-09-15 | Scarista Limited | Nutritional or pharmaceutical compositions |
| EP1339429A4 (en) * | 2000-11-29 | 2007-03-14 | Smithkline Beecham Corp | Composition containing statins and calcium for improved cardiovascular health |
| US6669955B2 (en) * | 2001-08-28 | 2003-12-30 | Longwood Pharmaceutical Research, Inc. | Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin |
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| TW200403053A (en) | 2004-03-01 |
| TWI302457B (en) | 2008-11-01 |
| CN100341509C (en) | 2007-10-10 |
| AU2003281176A1 (en) | 2004-02-02 |
| HK1077232A1 (en) | 2006-02-10 |
| WO2004006919A1 (en) | 2004-01-22 |
| CN1681499A (en) | 2005-10-12 |
| JP2010077162A (en) | 2010-04-08 |
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