Patent Application
20050182106
The present invention relates to a medicinal composition comprising an HMG-CoA reductase inhibitor and a pyridoxine derivative as active ingredients (particularly a medicinal composition for mitigating blood lipid levels or lowering high blood homocysteine levels).
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 vitamin B12), 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.8, 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:
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, β-blockers, vitamin C, vitamin E, and β-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 nor suggestions 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 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.
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 reductase inhibitor and a pyridoxine derivative as active ingredients exerts good effects on mitigating blood lipids levels and reducing blood homocysteine levels, and thus completed the present invention.
The present invention relates to
In addition, the present invention provides
Furthermore, the present invention provides
The preferable methods in said (16) are
Furthermore, the present invention provides
“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-methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphtyl]heptanoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Sho 57-2240 (U.S. Pat. No. 4,346,227) (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-naphthyl(S)-2-methylbutyrate which is disclosed in Japanese Patent Publication (Kokai) Number Sho 57-163374 (U.S. Pat. No. 4,231,938) (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-naphthyl 2,2-dimethylbutyrate which is disclosed in Japanese Patent Publication (Kokai) Number Sho 56-122375 (U.S. Pat. No. 4,444,784) (hereinafter called simvastatin), (±)(3R*,5S*,6E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kohyo) Number Sho 60-500015 (U.S. Pat. No. 4,739,073) (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 (U.S. Pat. No. 5,006,530) (hereinafter called rivastatin), (3R,5S)-7-(2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 3-58967 (U.S. Pat. No. 5,273,995) (hereinafter called atorvastatin), and (E)-3,5-dihydroxy-7-[4′-(4′-fluorophenyl)-2′-cyclopropyl-quinolin-3′-yl]-6-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 1-279866 (U.S. Pat. No. 5,854,259 and U.S. Pat. No. 5,856,336) (hereinafter called pitavastatin), or (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyridin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid which is disclosed in Japanese Patent Publication (Kokai) Number Hei 5-178841 (U.S. Pat. No. 5,260,440) (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:
“Pyridoxine derivative”, which is an active ingredient of the 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 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 blood lipid levels to 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, nutrition impairment 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 subjective 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.
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 Sho 57-2240 (U.S. Pat. No. 4,346,227), Japanese Patent Publication (Kokai) Number Sho 57-16337 (U.S. Pat. No. 4,231,938), Japanese Patent Publication (Kokai) Number Sho 56-122375 (U.S. Pat. No. 4,444,784), Japanese Patent Publication (Kohyo) Number Sho 60-500015 (U.S. Pat. No. 4,739,073), Japanese Patent Publication (Kokai) Number Hei 1-216974 (U.S. Pat. No. 5,006,530), Japanese Patent Publication (Kokai) Number Hei 3-58967 (U.S. Pat. No. 5,273,995), Japanese Patent Publication (Kokai) Number Hei 1-279866 (U.S. Pat. No. 5,854,259and U.S. Pat. No. 5,856,336), or Japanese Patent Publication (Kokai) Number Hei 5-178841 (U.S. Pat. No. 5,260,440).
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 disclosed in “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 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 or the like, coating agents such 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 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 has no restriction provided that their 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 homocysteine levels, the medicinal compositions 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 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 0.02 mg-3 mg/kg per day and preferably 0.08 mg-2.5 mg/kg per day. For example, in an adult human (about 60 kg), this is a dosage of approximately 1-200 mg per day preferably 5-160 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 0.002-20 mg/kg per day and preferably 0.02-13 mg/kg per day. For example, in an adult human (about 60 kg) this is a dosage of about 0.1 mg-1,200 mg per day and preferably about 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 0.01-10 mg/mL for atorvastatin and pravastatin, 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.
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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Compositions
(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.
(1) Test Substance
Pravastatin sodium manufactured at Sankyo Co., Ltd. was used. Simvastatin and atorvastatin synthesized 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., ½ oz). After filling up, the capsules were placed in a box divided up for every animal and stored under freezing 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.
The various lipids in blood were remarkably reduced following combined administration of simvastatin, pravastatin, or atorvastatin with pyridoxine hydrochloride.
(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., ½ oz). After filling up, the capsules were placed in a box divided up for every animal and stored under freezing 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
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 plus pyridoxine 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.
Remarkable ameliorating effects on blood homocysteine levels appeared by combined administration of atorvastatin calcium with pyridoxine hydrochloride.
Since the medicinal compositions comprising 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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2002-202121 | Jul 2002 | JP | national |
| 2002-343586 | Nov 2002 | JP | national |
This is a Continuation-in-Part application of International Application PCT/JP2003/008674 filed on Jul. 8, 2003, incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/JP03/08674 | Jul 2003 | US |
| Child | 11031105 | Jan 2005 | US |
