CA2430764A1 - Blood lipid ameliorant composition - Google Patents
Blood lipid ameliorant composition Download PDFInfo
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- CA2430764A1 CA2430764A1 CA002430764A CA2430764A CA2430764A1 CA 2430764 A1 CA2430764 A1 CA 2430764A1 CA 002430764 A CA002430764 A CA 002430764A CA 2430764 A CA2430764 A CA 2430764A CA 2430764 A1 CA2430764 A1 CA 2430764A1
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- Prior art keywords
- tocopherol
- riboflavin
- derivative
- atorvastatin
- ascorbic acid
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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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- 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
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
Abstract
A blood lipid ameliorant composition which comprises atorvastatin and one or more members selected from the group consisting of a riboflavine compound, a tocopherol compound, an ascorbic acid compound, pantethine, and taurine.
Description
SPECIFICATION
BLOOD LIPID AMELIORATING COMPOSITION
[TECHNICAL FIELD]
The present invention relates to blood lipid ameliorating compositions that contain atorvastatin in combination with one or more ingredients selected from the group consisting of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine.
[BACKGROUND ART]
Atorvastatin reduces total cholesterol levels in the blood by inhibiting HMG-CoA
reductase activity.
It is known that each of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine alone reduces cholesterol levels in the blood.
Furthermore, it is known that a co-administration of a HMG-CoA reductase inhibitors with either a tocopherol derivative or an ascorbic acid derivative reduces total cholesterol levels in the blood in addition to counteracting decrease of tocopherol or ascorbic acid that were decreased in the organism (Japanese Patent Kohyo No. Hei 8-505853).
However, it remains unknown whether co-administration of atorvastatin with one of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine or taurine synergistically decreases total cholesterol levels in the blood.
Furthermore, although atorvastatin is a highly safe remedy, it is desirable that atorvastatin can reduce total cholesterol levels in the blood when administered at lower doses, because it is necessary to administer atorvastatin for a long period.
[DISCLOSURE OF THE INVENTION]
The present inventors investigated drug compositions that decrease total cholesterol levels in the blood, and found that co-administration of atorvastatin with a certain vitamin or taurine reduces the total cholesterol levels in the blood at further lower doses, and completed the present invention.
The present invention comprises a serum lipid ameliorating composition comprising atorvastatin and one or more ingredients selected from the group consisting of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine.
The term 'atorvastatin' includes [R-(R*,R*)]-2-{4-fluorophenyl)-(3,8-dihydroxy-Doc. FP0143s.doc SankyolP853621English translationIGAD/22.05.03 (1-methylethyl)-3-phenyl-4-[phenylamino]carbonyl]-1 H-pyrrole-1-heptanoic acid and its salt (particularly calcium salt).
The term 'riboflavin derivative' includes riboflavin and riboflavin esters such as riboflavin butyrate. Among these compounds riboflavin, riboflavin sodium phosphate, riboflavin butyrate, flavin-adenine dinucleotide, or flavin-adenine dinucleotide sodium salt are preferred. Riboflavin sodium phosphate and riboflavin butyrate are more preferred, and riboflavin butyrate is the most preferred compound.
The term 'tocopherol derivative' includes tocopherol (the racemate and its optical enantiomers) and esters of tocopherol such as tocopherol acetate (the racemate and its optical enantiomers). Among these substances d-a-tocopherol succinate, dl-a-tocopherol succinate, dl-a-tocopherol calcium succinate, d-a-tocopherol acetate, dl-tocopherol acetate, d-a-tocopherol or dl-a-tocopherol are preferred, dl-a-tocopherol succinate or d-a-tocopherol acetate are more preferred, and d-a-tocopherol acetate is the most preferred compound.
The term 'ascorbic acid derivative' includes ascorbic acid, ascorbates such as sodium ascorbate, and ascorbic acid esters such stearyl ascorbate. Among these compounds ascorbic acid, sodium ascorbate or calcium ascorbate are preferred and ascorbic acid is more preferred.
Pantethine is 2,4-dihydroxy-N-[3-[(2-mercaptoethyl)amino]-3-oxopropyl]-3,3-dimethylbutanamide.
The term 'taurine' includes 2-aminoethanesulfonic acid and salts thereof.
The term 'total cholesterol in the blood' includes the total levels of cholesterol and cholesterol esters in the blood.
The term 'ameliorating' in the expression 'blood lipid ameliorating composition' indicates that the levels are decreased by clinically significant amounts following administration of the composition.
The weight percent of atorvastatin contained in solid preparations of the blood lipid ameliorating composition of the present invention is 0.01 to 5%, preferably 0.05 to 3%.
The weight percent of riboflavin derivative in the solid preparations is typically 0.002 to 40%, preferably 0.01 to 20.0%. Furthermore, the weight percent of ascorbic acid derivative is typically 0.05 to 50.0%, preferably 0.5 to 25.0%. The weight percent of tocopherol derivative is typically 0.002 to 40.0%, preferably 0.02 to 20%, the weight percent of pantethine is typically 0.3 to 50%, preferably 1.0 to 20%, and that of taurine is typically 0.3 to 50%, preferably 1 to 25%.
Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03 The content of atorvastatin contained in liquid and solution preparations of the blood lipid ameliorating composition of the present invention is typically 0.05 to 2 mg/mL, and preferably 0.1 to 1 mg/mL; that of riboflavin derivative is typically 0.05 to mglmL, preferably 0.1 to 3 mg/mL. In addition, the content of ascorbic acid derivative is typically 1 to 20 mglmL, preferably 2 to 10 mglmL. The content of tocopherol derivative is typically 0.5 to 5 mg/mL, preferably 1.5 to 3 mg/mL.
The content of pantethine is typically 0.5 to 20 mg/mL, preferably 1 to 10 mg/mL;
and that of taurine is typically 1.0 to 50 mglmL, preferably 2 to 35 mglmL.
Practical preparations of the blood lipid ameliorating compositions are tablets, granules (involving powders), capsules, and liquids and solutions, etc., and are manufactured following addition of the required additive agents or materials, if desired, according to conventional methods described in The Pharmacopeia of Japan.
In the preparations described above, additive agents that are conventionally used can be employed based on the preparation.
For instance, in the case of tablets, lactose and crystalline cellulose are used as diluents, magnesium aluminometasilicate, etc., are used as stabilizing agents, hydroxypropylcellulose, etc., are used as binders, and magnesium stearate is used as a lubricant.
In granules and capsules, lactose and purified sucrose are used as diluents, magnesium aluminometasilicate is used as a stabilizing agent, cornstarch, etc., are used as adsorbents, and hydroxypropylcellulose and polysorbate, etc., are used as binders.
In liquids and solutions, D-sorbitol solution and honey, etc., are used as sweeteners, dl-malic acid, etc., are used as flavoring agents, disodium dihydrogen ethylenediamine tetraacetate, etc., are used as stabilizing agents, ethanol is used as a co-solvent, and polyoxyethylene hydrogenated castor oil stearate 60, etc., are used as a solubilizer.
In the preparations described above, a disintegrator such as crospovidone, etc.; an adsorbent such as calcium silicate, etc.; a coloring agent such as red ferric oxide and caramel, etc.; a pH modifier such as sodium benzoate, etc.; and a flavor may be used.
When the composition in the present invention is administered, each component of the composition can be administered at the same time or individually at certain intervals.
The term "administration at the same time" described above has no particular limitation, provided that each component of the composition is administered at Doc. FP0143s.doc SankyolP85362/English transla6onIGAD/22.05.03 roughly the same time. However, it is desirable that a single composition containing all components is administered.
The term "administration of individual components at certain intervals"
described above has no particular limitation, provided that each component of the composition is individually administered at different times. In this case, one component is administered and the other components can then be administered within a certain defined time period.
In the case that 3 or more components in total are contained in the composition, the term "administration of these components at the same time or individually at different times" described above involves the following ways of administration: all components are administered at the same time; all components are administered individually at different times; 2 or more components are administered at the same time and the remaining components) are administered at different times; 2 or more components are administered at different times and the remaining components are administered at the same time; and so on.
[BEST MODE FOR CARRYING OUT THE INVENTION]
The present invention is described in more detail by way of the following examples. However, the present invention is not limited to these examples TEST EXAMPLE 1. TABLETS
(1 ) Composition Table 1 RFV AA Tocoph Pant Taurine 4 tabs 4 tabs 4 tabs 4 tabs 4 tabs (800 (1200 (900 (1200 (1200 mg) mg) mg) mg) mg) Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFVb 100 - - - -mg Ascorbic acid - 500 mg - - -dl-a-Tocopherol - - 200 mg - -succinate Pantethine - - - 500 mg -Taurine - - - - 500 mg (Aminoethanesulfonic acid) Crystalline cellulose120 12 mg 12 mg 12 mg 120 mg mg Magnesium 144 - - - 144 mg mg aluminometasilicate Sucrose esters - 140 mg 108 mg 140 mg -fatty acids Hydroxypropylcellulose96 mg 48 mg 48 mg 48 mg 96 mg Magnesium stearate 24 mg 24 mg 24 mg 24 mg 24 mg Crospovidone 100 48 mg 48 mg 48 mg 100 mg mg Lactose aq aq aq aq aq Doc. FP0143s.doc Sankyo/P85362IEnglish translationlGADI22.05.03 RFVb: Riboflavin butyrate, RFV: Riboflavin, AA: Ascorbic acid, Tocoph:
Tocopherol, Pant: Pantethine, tabs: tablets, aq: appropriate quantity (2) Manufacturing Methods The amount of each component described above is weighed and prepared according to the methods described in the "General Rules for Preparation of Tablets"
in The Pharmacopeia of Japan.
TEST EXAMPLE 2. GRANULES
(1 ) Composition Table 2 RFV AA Tocoph Pant Taurine 4 packs 4 packs 4 packs4 packs 4 packs (4 g) (5.2 g) (4.2 (4.6 g) (5.2 g) g) Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFVb 100 mg - - - -Ascorbic acid - 1.0 g - - -dl-a-Tocopherol - - 200 - -mg succinate Pantethine - - - 500 mg -Taurine - - - - 1.0 g (Aminoethanesulfonic acid) Purified sucrose 1.4 g 1.6 g 1.4 1.6 g 1.4 g g Stevia extracts - 16 mg - 16 mg -Cornstarch 1.2 g 1.2 g 1.2 1.2 g 1.2 g g Polysorbate 80 80 mg 48 mg 48 mg 48 mg 80 mg Magnesium 144 mg - 128 - 144 mg mg aluminometasilicate Magnesium stearate 24 mg 24 mg 24 mg 24 mg 24 mg Lactose aq aq aq aq aq RFVb: Riboflavin butyrate, RFV: , Tocoph:
Riboflavin, AA: Ascorbic acid Tocopherol, Pant: Pantethine, packs: packages, quantity aq: appropriate (2) Manufacturing Methods The amount of each component described ghed and above is wei prepared according to the methods described Preparations in the "General Rules for of Granules" in The Pharmacopeia of Japan.
TEST EXAMPLE 3. CAPSULES
(1 ) Components Table 3 RFV AA Tocoph Pant Taurine 4 caps 4 caps 4 caps 4 caps 4 caps Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFVb 100 mg - - - -- 500 mg - - -Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03 dl-a-Tocopherol - - 200 mg - -succinate Pantethine - - - 500 mg -Taurine - - - - 500 mg (Aminoethanesulfonic acid) Cornstarch 960 960 mg 840 mg 960 mg 960 mg mg Polysorbate 80 80 mg 48 mg 48 mg 48 mg 80 mg Magnesium 144 - 128 mg - 144 mg mg aluminometasilicate Magnesium stearate 24 mg 24 mg 24 mg 24 mg 24 mg -Lactose_______________________________________ ____a~l_~________a~L~_______ aq___~______ aq_______ ~a4______.
Subtotal 1520 1940 1580 1940 mg 2008 mg mg mg mg _Capsule__~____~________~_________.__-__320__mg640 _mg~_ 320 _640_mg______ ~ mg- 640 ~ mg Total 1840 2580 1900 2580 mg 2648 mg mg mg mg RFVb: Riboflavin butyrate, RFV: Riboflavin, AA: Ascorbic acid, Tocoph:
Tocopherol Pant: Pantethine, caps: capsules, aq: appropriate quantity (2) Manufacturing Methods The amount of each component described above is weighed and prepared according to the methods described in the "General Rules for Preparations of Granules" in The Pharmacopeia of Japan, and hard capsules are prepared by filling the granules into capsules.
TEST EXAMPLE 4. LIQUIDS AND SOLUTIONS
(1 ) Components Table 4 RFV AA Tocoph Pant Taurine 100 100 mL 100 mL 100 mL 100 mL mL
Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFV sodium 200 - - - -mg Ascorbic acid - 500 mg - - -dl-a-Tocopherol - - 50 mg - -acetate Pantethine - - - 500 mg -Taurine - - - - 500 mg (Aminoethanesulfonic acid) D-Sorbitol solution 4 g 6 g 4 g 6 g 4 g Honey 7g 8g 7g 8g 7g dl-Malic acid 200 - 200 mg - 200 mg mg DDEDTA 20 mg 20 mg 20 mg 20 mg 20 mg Ethanol 2 mL 2 mL 2 mL 2 mL 2 mL
PEHCO 100 100 mg 100 mg 100 mg 100 mg rng Sodium benzoate 60 mg 60 mg 60 mg 60 mg 60 mg Flavor trace trace trace trace trace Distilled water aq aq a4 ag as RFV: Riboflavin, AA: Ascorbic acid, Tocoph: Tocopherol, Pant: Pantethine, D-Sorbitol solution: D-Sorbitol solution (70%), DDEDTA: Disodium dihydrogen ethylenediamine tetraacetate, PEHCO: Polyoxyethylene hydrogenated castor oil stearate 60, aq:
appropriate quantity Doc. FP0143s.doc Sankyo/P853621English translation/GADl22.05.03 (2) Manufacturing Methods The amount of each component described above is weighed and prepared according to the methods described in the "General Rules for Preparations of Liquids and Solutions" in The Pharmacopeia of Japan.
TEST EXAMPLES ASSAY OF BLOOD LIPID AMELIORATING EFFECTS
< Test Methods >
(1 ) Test Compounds Atorvastatin was synthesized at Chemtech Labo. Inc., and riboflavin butyrate, d-a-tocopherol acetate, ascorbic acid, pantethine and taurine were purchased from Mitsubishi-Tokyo Pharmaceutical Inc., Eisai Co., Ltd., NIPPON ROCHE K.K., Nacalai Tesque, Inc. and Dai-ich Pharmaceutical Co., Ltd., respectively.
(2) Test Animals Beagle dogs aged 5 months were purchased from Covance Research Products Inc. and used after 1 month of quarantine and acclimatisation breeding.
(3) Preparation forms for administration, methods for preparing the formulation, and method for stocking the formulation The required amounts of atorvastatin or each component of the combination drug calculated from the body weight of each dog were weighed and filled in a gelatin capsule (112 ounce) purchased from TORPAC Inc. Capsules filled with atorvastatin were stocked in a refrigerator and those filled with combination drugs stocked at room temperature until use.
The combination drugs were filled in identical gelatin capsules.
(4) Route of administration and administration period Atorvastatin or combination drug capsules were forcibly orally administered to each of the test animals once daily between 9:00 and 12:30. Animals were fasted for 2 or 3 hr prior to administration of the capsules.
The administration period was 11 successive days.
BLOOD LIPID AMELIORATING COMPOSITION
[TECHNICAL FIELD]
The present invention relates to blood lipid ameliorating compositions that contain atorvastatin in combination with one or more ingredients selected from the group consisting of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine.
[BACKGROUND ART]
Atorvastatin reduces total cholesterol levels in the blood by inhibiting HMG-CoA
reductase activity.
It is known that each of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine alone reduces cholesterol levels in the blood.
Furthermore, it is known that a co-administration of a HMG-CoA reductase inhibitors with either a tocopherol derivative or an ascorbic acid derivative reduces total cholesterol levels in the blood in addition to counteracting decrease of tocopherol or ascorbic acid that were decreased in the organism (Japanese Patent Kohyo No. Hei 8-505853).
However, it remains unknown whether co-administration of atorvastatin with one of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine or taurine synergistically decreases total cholesterol levels in the blood.
Furthermore, although atorvastatin is a highly safe remedy, it is desirable that atorvastatin can reduce total cholesterol levels in the blood when administered at lower doses, because it is necessary to administer atorvastatin for a long period.
[DISCLOSURE OF THE INVENTION]
The present inventors investigated drug compositions that decrease total cholesterol levels in the blood, and found that co-administration of atorvastatin with a certain vitamin or taurine reduces the total cholesterol levels in the blood at further lower doses, and completed the present invention.
The present invention comprises a serum lipid ameliorating composition comprising atorvastatin and one or more ingredients selected from the group consisting of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine.
The term 'atorvastatin' includes [R-(R*,R*)]-2-{4-fluorophenyl)-(3,8-dihydroxy-Doc. FP0143s.doc SankyolP853621English translationIGAD/22.05.03 (1-methylethyl)-3-phenyl-4-[phenylamino]carbonyl]-1 H-pyrrole-1-heptanoic acid and its salt (particularly calcium salt).
The term 'riboflavin derivative' includes riboflavin and riboflavin esters such as riboflavin butyrate. Among these compounds riboflavin, riboflavin sodium phosphate, riboflavin butyrate, flavin-adenine dinucleotide, or flavin-adenine dinucleotide sodium salt are preferred. Riboflavin sodium phosphate and riboflavin butyrate are more preferred, and riboflavin butyrate is the most preferred compound.
The term 'tocopherol derivative' includes tocopherol (the racemate and its optical enantiomers) and esters of tocopherol such as tocopherol acetate (the racemate and its optical enantiomers). Among these substances d-a-tocopherol succinate, dl-a-tocopherol succinate, dl-a-tocopherol calcium succinate, d-a-tocopherol acetate, dl-tocopherol acetate, d-a-tocopherol or dl-a-tocopherol are preferred, dl-a-tocopherol succinate or d-a-tocopherol acetate are more preferred, and d-a-tocopherol acetate is the most preferred compound.
The term 'ascorbic acid derivative' includes ascorbic acid, ascorbates such as sodium ascorbate, and ascorbic acid esters such stearyl ascorbate. Among these compounds ascorbic acid, sodium ascorbate or calcium ascorbate are preferred and ascorbic acid is more preferred.
Pantethine is 2,4-dihydroxy-N-[3-[(2-mercaptoethyl)amino]-3-oxopropyl]-3,3-dimethylbutanamide.
The term 'taurine' includes 2-aminoethanesulfonic acid and salts thereof.
The term 'total cholesterol in the blood' includes the total levels of cholesterol and cholesterol esters in the blood.
The term 'ameliorating' in the expression 'blood lipid ameliorating composition' indicates that the levels are decreased by clinically significant amounts following administration of the composition.
The weight percent of atorvastatin contained in solid preparations of the blood lipid ameliorating composition of the present invention is 0.01 to 5%, preferably 0.05 to 3%.
The weight percent of riboflavin derivative in the solid preparations is typically 0.002 to 40%, preferably 0.01 to 20.0%. Furthermore, the weight percent of ascorbic acid derivative is typically 0.05 to 50.0%, preferably 0.5 to 25.0%. The weight percent of tocopherol derivative is typically 0.002 to 40.0%, preferably 0.02 to 20%, the weight percent of pantethine is typically 0.3 to 50%, preferably 1.0 to 20%, and that of taurine is typically 0.3 to 50%, preferably 1 to 25%.
Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03 The content of atorvastatin contained in liquid and solution preparations of the blood lipid ameliorating composition of the present invention is typically 0.05 to 2 mg/mL, and preferably 0.1 to 1 mg/mL; that of riboflavin derivative is typically 0.05 to mglmL, preferably 0.1 to 3 mg/mL. In addition, the content of ascorbic acid derivative is typically 1 to 20 mglmL, preferably 2 to 10 mglmL. The content of tocopherol derivative is typically 0.5 to 5 mg/mL, preferably 1.5 to 3 mg/mL.
The content of pantethine is typically 0.5 to 20 mg/mL, preferably 1 to 10 mg/mL;
and that of taurine is typically 1.0 to 50 mglmL, preferably 2 to 35 mglmL.
Practical preparations of the blood lipid ameliorating compositions are tablets, granules (involving powders), capsules, and liquids and solutions, etc., and are manufactured following addition of the required additive agents or materials, if desired, according to conventional methods described in The Pharmacopeia of Japan.
In the preparations described above, additive agents that are conventionally used can be employed based on the preparation.
For instance, in the case of tablets, lactose and crystalline cellulose are used as diluents, magnesium aluminometasilicate, etc., are used as stabilizing agents, hydroxypropylcellulose, etc., are used as binders, and magnesium stearate is used as a lubricant.
In granules and capsules, lactose and purified sucrose are used as diluents, magnesium aluminometasilicate is used as a stabilizing agent, cornstarch, etc., are used as adsorbents, and hydroxypropylcellulose and polysorbate, etc., are used as binders.
In liquids and solutions, D-sorbitol solution and honey, etc., are used as sweeteners, dl-malic acid, etc., are used as flavoring agents, disodium dihydrogen ethylenediamine tetraacetate, etc., are used as stabilizing agents, ethanol is used as a co-solvent, and polyoxyethylene hydrogenated castor oil stearate 60, etc., are used as a solubilizer.
In the preparations described above, a disintegrator such as crospovidone, etc.; an adsorbent such as calcium silicate, etc.; a coloring agent such as red ferric oxide and caramel, etc.; a pH modifier such as sodium benzoate, etc.; and a flavor may be used.
When the composition in the present invention is administered, each component of the composition can be administered at the same time or individually at certain intervals.
The term "administration at the same time" described above has no particular limitation, provided that each component of the composition is administered at Doc. FP0143s.doc SankyolP85362/English transla6onIGAD/22.05.03 roughly the same time. However, it is desirable that a single composition containing all components is administered.
The term "administration of individual components at certain intervals"
described above has no particular limitation, provided that each component of the composition is individually administered at different times. In this case, one component is administered and the other components can then be administered within a certain defined time period.
In the case that 3 or more components in total are contained in the composition, the term "administration of these components at the same time or individually at different times" described above involves the following ways of administration: all components are administered at the same time; all components are administered individually at different times; 2 or more components are administered at the same time and the remaining components) are administered at different times; 2 or more components are administered at different times and the remaining components are administered at the same time; and so on.
[BEST MODE FOR CARRYING OUT THE INVENTION]
The present invention is described in more detail by way of the following examples. However, the present invention is not limited to these examples TEST EXAMPLE 1. TABLETS
(1 ) Composition Table 1 RFV AA Tocoph Pant Taurine 4 tabs 4 tabs 4 tabs 4 tabs 4 tabs (800 (1200 (900 (1200 (1200 mg) mg) mg) mg) mg) Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFVb 100 - - - -mg Ascorbic acid - 500 mg - - -dl-a-Tocopherol - - 200 mg - -succinate Pantethine - - - 500 mg -Taurine - - - - 500 mg (Aminoethanesulfonic acid) Crystalline cellulose120 12 mg 12 mg 12 mg 120 mg mg Magnesium 144 - - - 144 mg mg aluminometasilicate Sucrose esters - 140 mg 108 mg 140 mg -fatty acids Hydroxypropylcellulose96 mg 48 mg 48 mg 48 mg 96 mg Magnesium stearate 24 mg 24 mg 24 mg 24 mg 24 mg Crospovidone 100 48 mg 48 mg 48 mg 100 mg mg Lactose aq aq aq aq aq Doc. FP0143s.doc Sankyo/P85362IEnglish translationlGADI22.05.03 RFVb: Riboflavin butyrate, RFV: Riboflavin, AA: Ascorbic acid, Tocoph:
Tocopherol, Pant: Pantethine, tabs: tablets, aq: appropriate quantity (2) Manufacturing Methods The amount of each component described above is weighed and prepared according to the methods described in the "General Rules for Preparation of Tablets"
in The Pharmacopeia of Japan.
TEST EXAMPLE 2. GRANULES
(1 ) Composition Table 2 RFV AA Tocoph Pant Taurine 4 packs 4 packs 4 packs4 packs 4 packs (4 g) (5.2 g) (4.2 (4.6 g) (5.2 g) g) Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFVb 100 mg - - - -Ascorbic acid - 1.0 g - - -dl-a-Tocopherol - - 200 - -mg succinate Pantethine - - - 500 mg -Taurine - - - - 1.0 g (Aminoethanesulfonic acid) Purified sucrose 1.4 g 1.6 g 1.4 1.6 g 1.4 g g Stevia extracts - 16 mg - 16 mg -Cornstarch 1.2 g 1.2 g 1.2 1.2 g 1.2 g g Polysorbate 80 80 mg 48 mg 48 mg 48 mg 80 mg Magnesium 144 mg - 128 - 144 mg mg aluminometasilicate Magnesium stearate 24 mg 24 mg 24 mg 24 mg 24 mg Lactose aq aq aq aq aq RFVb: Riboflavin butyrate, RFV: , Tocoph:
Riboflavin, AA: Ascorbic acid Tocopherol, Pant: Pantethine, packs: packages, quantity aq: appropriate (2) Manufacturing Methods The amount of each component described ghed and above is wei prepared according to the methods described Preparations in the "General Rules for of Granules" in The Pharmacopeia of Japan.
TEST EXAMPLE 3. CAPSULES
(1 ) Components Table 3 RFV AA Tocoph Pant Taurine 4 caps 4 caps 4 caps 4 caps 4 caps Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFVb 100 mg - - - -- 500 mg - - -Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03 dl-a-Tocopherol - - 200 mg - -succinate Pantethine - - - 500 mg -Taurine - - - - 500 mg (Aminoethanesulfonic acid) Cornstarch 960 960 mg 840 mg 960 mg 960 mg mg Polysorbate 80 80 mg 48 mg 48 mg 48 mg 80 mg Magnesium 144 - 128 mg - 144 mg mg aluminometasilicate Magnesium stearate 24 mg 24 mg 24 mg 24 mg 24 mg -Lactose_______________________________________ ____a~l_~________a~L~_______ aq___~______ aq_______ ~a4______.
Subtotal 1520 1940 1580 1940 mg 2008 mg mg mg mg _Capsule__~____~________~_________.__-__320__mg640 _mg~_ 320 _640_mg______ ~ mg- 640 ~ mg Total 1840 2580 1900 2580 mg 2648 mg mg mg mg RFVb: Riboflavin butyrate, RFV: Riboflavin, AA: Ascorbic acid, Tocoph:
Tocopherol Pant: Pantethine, caps: capsules, aq: appropriate quantity (2) Manufacturing Methods The amount of each component described above is weighed and prepared according to the methods described in the "General Rules for Preparations of Granules" in The Pharmacopeia of Japan, and hard capsules are prepared by filling the granules into capsules.
TEST EXAMPLE 4. LIQUIDS AND SOLUTIONS
(1 ) Components Table 4 RFV AA Tocoph Pant Taurine 100 100 mL 100 mL 100 mL 100 mL mL
Atorvastatin 20 mg 20 mg 20 mg 20 mg 20 mg RFV sodium 200 - - - -mg Ascorbic acid - 500 mg - - -dl-a-Tocopherol - - 50 mg - -acetate Pantethine - - - 500 mg -Taurine - - - - 500 mg (Aminoethanesulfonic acid) D-Sorbitol solution 4 g 6 g 4 g 6 g 4 g Honey 7g 8g 7g 8g 7g dl-Malic acid 200 - 200 mg - 200 mg mg DDEDTA 20 mg 20 mg 20 mg 20 mg 20 mg Ethanol 2 mL 2 mL 2 mL 2 mL 2 mL
PEHCO 100 100 mg 100 mg 100 mg 100 mg rng Sodium benzoate 60 mg 60 mg 60 mg 60 mg 60 mg Flavor trace trace trace trace trace Distilled water aq aq a4 ag as RFV: Riboflavin, AA: Ascorbic acid, Tocoph: Tocopherol, Pant: Pantethine, D-Sorbitol solution: D-Sorbitol solution (70%), DDEDTA: Disodium dihydrogen ethylenediamine tetraacetate, PEHCO: Polyoxyethylene hydrogenated castor oil stearate 60, aq:
appropriate quantity Doc. FP0143s.doc Sankyo/P853621English translation/GADl22.05.03 (2) Manufacturing Methods The amount of each component described above is weighed and prepared according to the methods described in the "General Rules for Preparations of Liquids and Solutions" in The Pharmacopeia of Japan.
TEST EXAMPLES ASSAY OF BLOOD LIPID AMELIORATING EFFECTS
< Test Methods >
(1 ) Test Compounds Atorvastatin was synthesized at Chemtech Labo. Inc., and riboflavin butyrate, d-a-tocopherol acetate, ascorbic acid, pantethine and taurine were purchased from Mitsubishi-Tokyo Pharmaceutical Inc., Eisai Co., Ltd., NIPPON ROCHE K.K., Nacalai Tesque, Inc. and Dai-ich Pharmaceutical Co., Ltd., respectively.
(2) Test Animals Beagle dogs aged 5 months were purchased from Covance Research Products Inc. and used after 1 month of quarantine and acclimatisation breeding.
(3) Preparation forms for administration, methods for preparing the formulation, and method for stocking the formulation The required amounts of atorvastatin or each component of the combination drug calculated from the body weight of each dog were weighed and filled in a gelatin capsule (112 ounce) purchased from TORPAC Inc. Capsules filled with atorvastatin were stocked in a refrigerator and those filled with combination drugs stocked at room temperature until use.
The combination drugs were filled in identical gelatin capsules.
(4) Route of administration and administration period Atorvastatin or combination drug capsules were forcibly orally administered to each of the test animals once daily between 9:00 and 12:30. Animals were fasted for 2 or 3 hr prior to administration of the capsules.
The administration period was 11 successive days.
(5) Preparation of test samples and procedures Blood (10 mL) was collected from the superficial radial vein 2 or 1 weeks prior to administration and 4, 8, and 12 days after administration was started.
Animals were fasted for approximately 18 hr prior to blood collection. Collected blood was Doc. FP0143s.doc Sankyo/P85362/English translationIGAD/22.05.03 placed in a test tube, left at room temperature for 0.5-1 hr, then centrifuged (3,000 rpm for 10 min). The obtained serum was used for assays of blood levels of total cholesterol, lipid peroxides and triglycerides according to CEH-COD-POD
methods, Yagi's methods and GK-GPO-POD methods respectively.
All these levels were determined using a fluorometer (Hitachi, Ltd., F3000), a full automatic analyzer (Monarch, Instrumentation Laboratory), and an automatic analyzer (7170, Hitachi, Ltd.).
<RESULTS>
Total cholesterol levels and so forth in the blood collected from dogs treated with either atorvastatin alone or a combination drug consisting of atorvastatin plus one of riboflavin butyrate, d-a-tocopherol acetate, ascorbic acid, pantethine and taurine were determined. All these values were converted to their relative ratios against their averaged pre-dosing levels (100) determined 2 and 1 weeks prior to drug administration. The averaged value in each group was obtained from 5 animals per group.
(Effects of co-administration of atorvastatin and riboflavin butyrate) Table 5 Test Substance Dose Blood Total Cholesterol Levels (mglkg) after administration 4 days 8 days 12 days Atorvastatin 2 102.9 95.5 90.9 alone RFVb alone 200 99.5 99.0 97.2 Atorvastatin 2 94.9 88.0 89.3 + RFVb 200 RFVb: riboflavin butyrate (Effects of co-administration of atorvastatin and d-a-tocopherol acetate) Table 6 Test Substance Dose Blood Total Cholesterol Levels (mg/kg) after administration 4 days 8 days 12 days Atorvastatin alone2 102.9 95.5 90.9 Tocoph alone 300 97.7 95.1 97.5 Atorvastatin 2 93.7 84.2 87.7 + Tocoph 300 Tocoph: d-a-tocopherol acetate Doc. FP0143s.doc Sankyo/P853621English translation/GAD/22.05.03 Table 7 Test Substance Dose Blood Lipid Peroxide Levels (mg/kg) after administration 4 days 8 days 12 days Atorvastatin alone2 104.5 84.4 80.9 Tocoph alone 300 106.3 119.0 75.9 Atorvastatin 2 79.5 68.3 68.1 + Tocooh 300 Tocoph: d-a-tocopherol acetate (Effects of co-administration of atorvastatin and ascorbic acid) Table 8 Test Substance Dose Blood FFA Levels (mg/kg) after administration 4 days 8 days 12 days Atorvastatin alone2 102.9 95.5 90.9 AA alone 500 95.9 96.7 98.9 Atorvastatin 2 96.3 87.6 87.9 + AA 500 AA: ascorbic acid (Effects of co-administration of atorvastatin and pantethine) Table 9 Test Substance Dose GOT Levels (mglkg) after administration 4 days 8 days 12 days Atorvastatin alone2 102.9 95.5 90.9 Pantethine alone 300 94.0 87.6 85.2 Atorvastatin 2 88.7 78.2 70.7 + Pantethine 300 Table 10 Test Substance Dose Blood Lipid Peroxide Levels (mglkg) after administration 4 days 8 days 12 days Atorvastatin 2 104.5 84.4 80.9 alone Pantethine alone300 82.5 105.0 87.5 Atorvastatin 2 90.2 74.0 69.2 + Pantethine 300 (Effects of co-administration of atorvastatin and taurine) Table 11 Test Substance Dose Blood Total Cholesterol Levels (mg/kg) after administration 4 days 8 days 12 days Simvastatin alone 2 102.9 95.5 90.9 Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03 Taurine alone 1000 95.9 90.2 87.2 Atorvastatin 2 87.5 75.2 73.7 + Taurine 1000 Table 12 Test Substance Dose Blood Triglyceride Levels (mglkg) after administration 4 days 8 days 12 days Simvastatin 2 87.1 86.7 74.1 alone Taurine alone 1000 98.6 95.8 80.8 Atorvastatin 2 83.5 77.7 65.4 + Taurine 1000 POSSIBILITY OF INDUSTRIAL UTILIZATION
The present invention, drug compositions of atorvastatin plus ascorbic acid and so forth, exerts excellent blood total cholesterol-lowering effects and is useful as a blood lipid ameliorating agent.
Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03
Animals were fasted for approximately 18 hr prior to blood collection. Collected blood was Doc. FP0143s.doc Sankyo/P85362/English translationIGAD/22.05.03 placed in a test tube, left at room temperature for 0.5-1 hr, then centrifuged (3,000 rpm for 10 min). The obtained serum was used for assays of blood levels of total cholesterol, lipid peroxides and triglycerides according to CEH-COD-POD
methods, Yagi's methods and GK-GPO-POD methods respectively.
All these levels were determined using a fluorometer (Hitachi, Ltd., F3000), a full automatic analyzer (Monarch, Instrumentation Laboratory), and an automatic analyzer (7170, Hitachi, Ltd.).
<RESULTS>
Total cholesterol levels and so forth in the blood collected from dogs treated with either atorvastatin alone or a combination drug consisting of atorvastatin plus one of riboflavin butyrate, d-a-tocopherol acetate, ascorbic acid, pantethine and taurine were determined. All these values were converted to their relative ratios against their averaged pre-dosing levels (100) determined 2 and 1 weeks prior to drug administration. The averaged value in each group was obtained from 5 animals per group.
(Effects of co-administration of atorvastatin and riboflavin butyrate) Table 5 Test Substance Dose Blood Total Cholesterol Levels (mglkg) after administration 4 days 8 days 12 days Atorvastatin 2 102.9 95.5 90.9 alone RFVb alone 200 99.5 99.0 97.2 Atorvastatin 2 94.9 88.0 89.3 + RFVb 200 RFVb: riboflavin butyrate (Effects of co-administration of atorvastatin and d-a-tocopherol acetate) Table 6 Test Substance Dose Blood Total Cholesterol Levels (mg/kg) after administration 4 days 8 days 12 days Atorvastatin alone2 102.9 95.5 90.9 Tocoph alone 300 97.7 95.1 97.5 Atorvastatin 2 93.7 84.2 87.7 + Tocoph 300 Tocoph: d-a-tocopherol acetate Doc. FP0143s.doc Sankyo/P853621English translation/GAD/22.05.03 Table 7 Test Substance Dose Blood Lipid Peroxide Levels (mg/kg) after administration 4 days 8 days 12 days Atorvastatin alone2 104.5 84.4 80.9 Tocoph alone 300 106.3 119.0 75.9 Atorvastatin 2 79.5 68.3 68.1 + Tocooh 300 Tocoph: d-a-tocopherol acetate (Effects of co-administration of atorvastatin and ascorbic acid) Table 8 Test Substance Dose Blood FFA Levels (mg/kg) after administration 4 days 8 days 12 days Atorvastatin alone2 102.9 95.5 90.9 AA alone 500 95.9 96.7 98.9 Atorvastatin 2 96.3 87.6 87.9 + AA 500 AA: ascorbic acid (Effects of co-administration of atorvastatin and pantethine) Table 9 Test Substance Dose GOT Levels (mglkg) after administration 4 days 8 days 12 days Atorvastatin alone2 102.9 95.5 90.9 Pantethine alone 300 94.0 87.6 85.2 Atorvastatin 2 88.7 78.2 70.7 + Pantethine 300 Table 10 Test Substance Dose Blood Lipid Peroxide Levels (mglkg) after administration 4 days 8 days 12 days Atorvastatin 2 104.5 84.4 80.9 alone Pantethine alone300 82.5 105.0 87.5 Atorvastatin 2 90.2 74.0 69.2 + Pantethine 300 (Effects of co-administration of atorvastatin and taurine) Table 11 Test Substance Dose Blood Total Cholesterol Levels (mg/kg) after administration 4 days 8 days 12 days Simvastatin alone 2 102.9 95.5 90.9 Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03 Taurine alone 1000 95.9 90.2 87.2 Atorvastatin 2 87.5 75.2 73.7 + Taurine 1000 Table 12 Test Substance Dose Blood Triglyceride Levels (mglkg) after administration 4 days 8 days 12 days Simvastatin 2 87.1 86.7 74.1 alone Taurine alone 1000 98.6 95.8 80.8 Atorvastatin 2 83.5 77.7 65.4 + Taurine 1000 POSSIBILITY OF INDUSTRIAL UTILIZATION
The present invention, drug compositions of atorvastatin plus ascorbic acid and so forth, exerts excellent blood total cholesterol-lowering effects and is useful as a blood lipid ameliorating agent.
Doc. FP0143s.doc Sankyo/P85362/English translation/GAD/22.05.03
Claims (14)
1. A blood lipid ameliorating composition comprising atorvastatin and one or more ingredients selected from the group consisting of a riboflavin derivative, a tocopherol derivative, an ascorbic acid derivative, pantethine and taurine.
2. A composition according to claim 1 wherein the riboflavin derivative is riboflavin, riboflavin sodium phosphate, riboflavin butyrate, flavin-adenine dinucleotide or flavin-adenine dinucleotide sodium salt.
3. A composition according to claim 1 wherein the riboflavin derivative is riboflavin sodium phosphate or riboflavin butyrate.
4. A composition according to claim 1 wherein the riboflavin derivative is riboflavin butyrate.
5. A composition according to any one of claims 1 to 4 wherein the tocopherol derivative is d-.alpha.-tocopherol succinate, dl-.alpha.-tocopherol succinate, dl-.alpha.-tocopherol calcium succinate, d-.alpha.-tocopherol acetate, dl-.alpha.-tocopherol acetate, d-.alpha.-tocopherol or dl-.alpha.-tocopherol.
6. A composition according to any one of claims 1 to 4 wherein the tocopherol derivative is d-.alpha.-tocopherol succinate or d-.alpha.-tocopherol acetate.
7. A composition according to any one of claims 1 to 4 wherein the tocopherol derivative is d-.alpha.-tocopherol acetate.
8. A composition according to any one of claims 1 to 7 wherein the ascorbic acid derivative is ascorbic acid, sodium ascorbate, or calcium ascorbate.
9. A composition according to any one of claims 1 to 7 wherein the ascorbic acid derivative is ascorbic acid.
10. A blood lipid ameliorating composition containing atorvastatin and riboflavin succinate.
11. A blood lipid ameliorating composition containing atorvastatin and ascorbic acid.
12. A blood lipid ameliorating composition containing atorvastatin and d-.alpha.-tocopherol acetate.
13. A blood lipid ameliorating composition containing atorvastatin and pantethine.
14. A blood lipid ameliorating composition containing atorvastatin and taurine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000-379880 | 2000-12-14 | ||
| JP2000379880 | 2000-12-14 | ||
| PCT/JP2001/010913 WO2002047683A1 (en) | 2000-12-14 | 2001-12-12 | Blood lipid ameliorant composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2430764A1 true CA2430764A1 (en) | 2002-06-20 |
Family
ID=18848166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002430764A Abandoned CA2430764A1 (en) | 2000-12-14 | 2001-12-12 | Blood lipid ameliorant composition |
Country Status (6)
| Country | Link |
|---|---|
| CN (1) | CN1287787C (en) |
| AU (1) | AU2002221130A1 (en) |
| CA (1) | CA2430764A1 (en) |
| HK (1) | HK1061519A1 (en) |
| TW (1) | TWI292315B (en) |
| WO (1) | WO2002047683A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2491382A1 (en) * | 2002-07-03 | 2004-01-15 | Esperion Therapeutics, Inc. | Compositions comprising panthetine for the treatment of dyslipidemia |
| US20050159478A1 (en) * | 2003-12-23 | 2005-07-21 | Hunsicker Jeffrey C. | Compositions containing d-tocopherol compound polybasic acid partial esters |
| JP5080011B2 (en) * | 2005-02-28 | 2012-11-21 | 第一三共ヘルスケア株式会社 | Composition for increasing glutathione peroxidase activity |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6019891B2 (en) * | 1978-12-01 | 1985-05-18 | 第一製薬株式会社 | Drug-induced fatty liver agent |
| JPS5869813A (en) * | 1981-10-23 | 1983-04-26 | Sogo Yatsukou Kk | Serum lipid depressant |
| JPS6041611A (en) * | 1983-08-17 | 1985-03-05 | Sankyo Co Ltd | Blood lipid improving agent |
| US5662934A (en) * | 1993-01-05 | 1997-09-02 | Najarian; Thomas | Compositions and methods for lowering cholesterol while maintaining antioxidant levels |
| CA2251972A1 (en) * | 1996-04-17 | 1997-10-23 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardiovascular disease |
| AU5844196A (en) * | 1996-05-29 | 1998-01-05 | Taisho Pharmaceutical Co., Ltd. | Remedy or preventive for hyperlipemia |
-
2001
- 2001-12-12 WO PCT/JP2001/010913 patent/WO2002047683A1/en active Application Filing
- 2001-12-12 CA CA002430764A patent/CA2430764A1/en not_active Abandoned
- 2001-12-12 CN CNB018226442A patent/CN1287787C/en not_active Expired - Fee Related
- 2001-12-12 AU AU2002221130A patent/AU2002221130A1/en not_active Abandoned
- 2001-12-13 TW TW090130882A patent/TWI292315B/en active
-
2004
- 2004-06-17 HK HK04104417A patent/HK1061519A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| TWI292315B (en) | 2008-01-11 |
| HK1061519A1 (en) | 2004-09-24 |
| WO2002047683A1 (en) | 2002-06-20 |
| CN1287787C (en) | 2006-12-06 |
| CN1489464A (en) | 2004-04-14 |
| AU2002221130A1 (en) | 2002-06-24 |
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