WO2006033287A1 - PRÉPARATION PHARMACEUTIQUE CONTENANT UN INHIBITEUR DE LA HMG-CoA RÉDUCTASE ET DE LA GLUTATHIONE - Google Patents

PRÉPARATION PHARMACEUTIQUE CONTENANT UN INHIBITEUR DE LA HMG-CoA RÉDUCTASE ET DE LA GLUTATHIONE Download PDF

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WO2006033287A1
WO2006033287A1 PCT/JP2005/017106 JP2005017106W WO2006033287A1 WO 2006033287 A1 WO2006033287 A1 WO 2006033287A1 JP 2005017106 W JP2005017106 W JP 2005017106W WO 2006033287 A1 WO2006033287 A1 WO 2006033287A1
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pharmaceutical composition
composition according
disease
dartathione
blood
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PCT/JP2005/017106
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Japanese (ja)
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Yasuhiro Torizumi
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Sankyo Company, Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • 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
    • 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
    • A61K31/351—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 not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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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    • 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
    • A61K31/33—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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • HMG Pharmaceutical Composition Containing CoA Reductase Inhibitor and Gnoretathion
  • the present invention relates to a pharmaceutical composition for treating cardiovascular diseases.
  • Hcy is an amino acid produced in the metabolic process of methionine, which is one of the essential amino acids. Genetic predisposition, vitamin deficiency deficiency, aging, sex, decreased renal function, diabetes, other diseases, drugs, smoking, etc. have been found to increase blood Hcy levels (eg, Non-Patent Document 1 This condition is called hyperhomocystinemia.
  • folic acid administration is the first treatment for the treatment of hyperhomocystinemia, and Hcy metabolism is promoted smoothly.
  • the second step is vitamin B and vitamin B.
  • Non-Patent Document 1 Non-Patent Document 1
  • an HMG-CoA reductase inhibitor (hereinafter referred to as a statin) specifically and antagonistically inhibits the pathway from HMG-CoA to mevalonic acid in the living body to reduce the blood cholesterol level.
  • glutathione is known to have an antioxidative effect, and the effect on the blood Hcy level, which is also known as an antidote such as drug addiction, is unknown.
  • vascular aging is deeply related to decreased production of vascular endothelial cell-derived nitric acid-nitrogen (NO), that is, decreased endothelial NO synthase (eNOS) activity. This has also been found recently.
  • NO vascular endothelial cell-derived nitric acid-nitrogen
  • eNOS endothelial NO synthase
  • Vascular endothelial dysfunction is deeply related to the onset and progression of arteriosclerosis, and is thought to be caused mainly by a decrease in NO produced from eINOS. It is thought that vascular endothelial cell-derived NO force vascular relaxation, platelets Suppresses aggregation of neutrophils, suppresses adhesion of neutrophils to endothelial cells, prevents vascular smooth muscle cells
  • NO derived from vascular endothelial cells plays a multifaceted role in vascular protection, and is considered to play an important role in the treatment of cardiovascular diseases.
  • Glutathione peroxidase is an antioxidant enzyme important for the body that detoxifies hydrogen peroxide and peroxides in the presence of glutathione, and an artery in which an increase in blood lipid peroxide is observed. It is useful for the prevention or treatment of diseases such as sclerosis, cerebrovascular disease, myocardial infarction (see Non-Patent Document 5, for example).
  • statins or dartathione have an effect of increasing GPx activity.
  • Non-Patent Document 1 Progress in Medicine, Vol. 19 No. 8, 1999 p. 49-53
  • Non-Patent Document 2 Angiology, Vol. 38 No. 4 1998 p. 215-219
  • Non-Patent Document 3 Vascular Medicine, Vol. 2 No. 2 2001 p. 189-194
  • Non-Patent Document 4 Pharmacology and Treatment, Vol. 29 No. 10 2001 p. 715-718
  • Non-patent document 5 http: z / www. Nokudai. Ac. Jpz pharma / eisei / takanasi. Ht m
  • the present inventors have (1) decreased blood Hcy amount, (2) increased eNOS activity and increased blood concentration of Z or vascular endothelial cell-derived NO, and (3) GPx activity. We have conducted intensive research to find safe drugs that can simultaneously increase.
  • the present invention provides:
  • a pharmaceutical composition comprising an HMG-CoA reductase inhibitor and dartathione, preferably
  • HMG—CoA reductase inhibitor potency The drug according to (1), which is one or more selected from the group power consisting of pravastatin, oral pastatin, sympastatin, flupastatin, atorvastatin, pitapastatin and rospastatin Composition,
  • HMG—CoA reductase inhibitory power A pharmaceutical composition according to (1), which is pravastatin,
  • vascular endothelial cell-derived nitric oxide Diseases caused by decreased blood concentration of vascular endothelial cell-derived nitric oxide are hypertension, exertional hypertension, arteriosclerosis, ischemic heart disease, heart failure, myocardial infarction, thrombosis, peripheral vascular disorder, pulmonary hypertension , Birja's disease, Reino's disease, cerebral ischemia, cerebral infarction, cerebral insufficiency, cerebrovascular dementia, impotence, pregnancy toxemia, diabetic power, one or more selected (13 ) Pharmaceutical composition according to:
  • the present invention provides:
  • HMG A method for administering CoA reductase inhibitor and dartathione simultaneously, sequentially or separately, and
  • a method for preventing or treating arteriosclerosis comprising administering an effective amount of the pharmaceutical composition according to any one of (1) to (3) above, wherein a force is also selected for the mammal (1) to (3) I will provide a.
  • the “HMG—CoA reductase inhibitor” is a drug that specifically and antagonistically inhibits HMG (3-hydroxy-3-methyldaritalyl) CoA reductase, which is the rate-limiting enzyme of the cholesterol biosynthesis system ( It is a generic name for this drug and is called a statin as a general term for this drug), and it is used as a therapeutic agent for hyperlipidemia because it lowers blood cholesterol.
  • statins include all natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all synthetic compounds, such as pravastatin, oral pastatin, simpastatin, flupastatin, atorvastatin, pitapastatin. Or it may be rospastatin.
  • statins pravastatin, sympastatin or atorvastatin is preferred, and pravastatin is more preferred.
  • glutathione is a tripeptide consisting of three amino acids such as glutamic acid, cysteine, and glycine.
  • the amount of homocysteine in blood refers to the weight of homocysteine present in blood.
  • “maintaining the amount of blood homocystine” refers to maintaining an original state by suppressing an increase in the amount of homocysteine in blood.
  • “hyperhomocystinemia” refers to, for example, vitamin B in the body
  • B, or 12 is a condition in which abnormalities in metabolism occur due to lack of folic acid, etc., resulting in an increase in the amount of homocysteine in the blood.
  • the “disease caused by hyperhomocystinemia” is not particularly limited as long as it is a disease that develops due to an increase in the amount of Hcy in the blood.
  • arteriosclerosis Cardiovascular diseases such as ischemic heart disease, myocardial infarction, thrombosis, peripheral vascular disorder, Birja's disease, Reino's disease, and cerebral infarction, cerebral circulatory failure, cerebrovascular dementia, etc., Alzheimer's disease, Parkinson Neurological diseases such as diseases, and more preferably arteriosclerosis.
  • factors causing hyperhomocystinemia include, for example, aging, smoking, nutritional disorders related to Hcy metabolism, drug properties, decreased renal function, chronic renal failure, diabetes, insulin resistance, malignant tumors, Examples include hypothyroidism and pernicious anemia.
  • “to promote the synthesis of nitric acid and nitrogen in vascular endothelial cells” means to promote the synthesis of NO by activating eNOS present in vascular endothelial cells.
  • maintaining the blood concentration of vascular endothelial cell-derived nitric oxide refers to suppressing the decrease of vascular endothelial cell-derived monoxide-nitrogen in the blood, Is to keep.
  • disease caused by a decrease in blood concentration of vascular endothelial cell-derived monoxide and nitrogen monoxide refers to a decrease in eNOS activity and a decrease in blood concentration of Z or vascular endothelial cell-derived NO.
  • eNOS activity a decrease in blood concentration of Z or vascular endothelial cell-derived NO.
  • eNOS activity a decrease in blood concentration of Z or vascular endothelial cell-derived NO.
  • Z or vascular endothelial cell-derived NO preferably high blood pressure, exertional hypertension, arteriosclerosis, ischemic heart disease, heart failure, thrombosis, pulmonary hypertension, cerebral ischemia.
  • cerebral infarction, cerebral circulatory failure, senile dementia, impotence, pregnancy toxemia, diabetes and the like arteriosclerosis is more preferable.
  • Examples of causes that cause a decrease in blood concentration of vascular endothelial cell-derived NO include, for example, aging, menopause, hypertension, hyperlipidemia, smoking, insulin resistance, diabetes, oxidative stress, pharmaceutical properties, etc. There is also a duplication of causes and results and a vicious circle.
  • “maintaining the activity of dartathione peroxidase” refers to maintaining a state in which the activity of glutathione peroxidase is suppressed by suppressing a decrease in activity of glutathione peroxidase.
  • the "disease caused by a decrease in the activity of dartathione peroxidase” is not particularly limited as long as it is a disease caused by an increase in active oxygen or an increase in peroxyphospholipid. Nonetheless, preferred are arteriosclerosis, cerebrovascular disease, ischemic heart disease, myocardial infarction, carcinogenesis, inflammation, aging, etc. More preferred is arteriosclerosis.
  • the respective components can be administered simultaneously, sequentially or separately.
  • "simultaneously" administration includes administration at exactly the same time as pharmacologically acceptable as well as administration at the same time.
  • the dosage form is not particularly limited as long as it can be administered at approximately the same time, but it is preferably a single composition.
  • “sequentially or separately” administration is not particularly limited as long as it can be administered separately at different times. For example, one ingredient is administered and then determined. There are ways to administer other components after a certain period of time.
  • treating means curing or ameliorating a disease or symptom or suppressing a symptom.
  • the pharmaceutical composition containing a statin and dartathione according to the present invention comprises (1) a decrease in blood Hcy level, (2) an increase in eNOS activity, and an increase in blood concentration of Z or vascular endothelial cell-derived NO. , And (3) the ability to simultaneously increase GPx activity and each phenomenon It is useful for treating or preventing diseases caused by.
  • Statin for example, pravastatin, oral pastatin, simpastatin, flupastatin, atorvastatin, pitapastatin or rospastatin contained in the composition of the present invention is disclosed in JP-A-57-2240 (USP4346227), JP-A-57357. — 163374 (USP4231938), JP 56-122375 (USP4444784), JP 60-500015 (USP4739 073), ⁇ 3- 58967 ⁇ -(USP5273995), ⁇ Fl- 279866 ⁇ -(USP5854) 259 and USP5856336) or JP-A-5-178841 (USP5260440) and the like.
  • dartathione is listed in the Japanese Pharmacopeia Standard 2002.
  • composition of the present invention containing a statin and dartathione contains statin and dartathion as essential components, and optionally further contains an additive for formulation. Other components may be contained as long as the combined action of statin and dartathione is not adversely affected.
  • a pharmaceutical composition containing only statin and dartathione as active ingredients, and further containing additives for formulation.
  • Specific dosage forms of the pharmaceutical composition of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups) and the like. It can be produced according to the usual methods described in the Japanese Pharmacopoeia, using additives and base materials suitable for the shape as appropriate.
  • magnesium metasilicate aluminate or magnesium oxide is used as a stabilizer
  • hydroxypropyl cellulose is used as a coating agent.
  • magnesium stearate can be used as a lubricant.
  • lactose or purified sucrose is used as an excipient
  • magnesium metasilicate or magnesium silicate as a stabilizer
  • corn denpene or the like as an adsorbent
  • Hydroxypropyl cellulose etc. can be used as a binder it can.
  • disintegrants such as crospovidone; surfactants such as polysorbate; adsorbents such as calcium silicate; colorants such as iron sesquioxide and caramel; sodium benzoate and the like as necessary Stabilizers; pH regulators; fragrances; etc. can also be added.
  • the single dose of statin varies depending on the type of statin, indication, purpose of use and age, preferably 1S, 0. Olmg / kg to 10mg / kg, more preferably 0. 05mg / kg to 5mgZkg, which is administered once to three times a day.
  • the content of the statin contained in the solid dosage form of the pharmaceutical composition of the present invention is usually 0.05 mg to 200 mg, preferably 0.5 mg to lOO mg.
  • the content of dartathione is 1 to 100 parts by weight, preferably 3 to 30 parts by weight, per 1 part by weight of the statin.
  • the statin contained when the composition of the present invention is a liquid preparation is usually 0.001 mg to 200 mgZmL, and preferably 0. OlmgZmL to 50 mgZmL.
  • the content of dartathione is 1 to 100 parts by weight, preferably 3 to 30 parts by weight, per 1 part by weight of the statin.
  • Pi Yupa Pass Yuchin-2 Glutathione 200 200 200 Sodium benzoate 180 180 180 White sugar 980 980 980 Concentrated glycerin 630 630 630 Polypinyl alcohol 120 120 120 Purified water Remainder Remainder
  • a syrup was prepared by taking the above ingredients and quantities, and preparing a syrup according to the section “General Syrup” in Japanese Pharmacopoeia, and then filling it into a brown glass bottle.
  • Test substance Pravastatin sodium was manufactured by Sankyo Co., Ltd., and Dartathion was manufactured by Kojin Co., Ltd.
  • beagle dogs were purchased from Covance Research Products Inc. at the age of 5 months and used after quarantine and acclimatization for about 1 month.
  • the required amount of the test substance calculated based on the body weight of each test animal was filled into a gelatin capsule (1Z2 ounce) manufactured by TORPAC. After filling, the capsules were placed in cases separated by animal and stored refrigerated until administration.
  • Capsules filled with the test substance were orally administered by gavage to test animals once a day between 9:00 and 12:30. The test animals were fasted for 2 to 3 hours before administration.
  • the administration period was 7 days.
  • the obtained blood is placed in a test tube, allowed to stand at room temperature for 30 minutes to 1 hour, and then centrifuged (about 1600
  • the blood GPx activity was determined by the NADPH method, and the total blood Hcy amount was determined by the HPLC method.
  • NO produced by eNOS was rapidly converted to nitrate ions (NO ”) and nitrite ions.
  • results of each test value for the single agent and combination drug at each dose of pravastatin sodium and dalutathion are the average of the test values on the 14th and 7th day before administration Calculated as 100.
  • Tables 5 to 7 show the obtained results. Each value is the average of 5 animals per group.
  • statin and dartathione according to the present invention comprises (1) a decrease in blood Hcy level, (2) an increase in eNOS activity and an increase in blood concentration of Z or vascular endothelial cell-derived NO, and (3) It is useful for simultaneously increasing GPx activity and for treating or preventing diseases caused by each phenomenon.

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Abstract

La présente invention a pour objet un médicament sans danger pour la santé qui permet à la fois de (1) diminuer le taux d'homocystéine sanguine, (2) augmenter l’activité de la monoxyde d’azote synthase présente dans les cellulaires endothéliales vasculaires et/ou augmenter le taux de monoxyde d’azote sanguin distribué aux cellules endothéliales vasculaires et (3) augmenter l’activité de la glutathione peroxydase. La présente invention a également pour objet une préparation pharmaceutique comprenant un inhibiteur de la HMG-CoA réductase ainsi que de la glutathione.
PCT/JP2005/017106 2004-09-21 2005-09-16 PRÉPARATION PHARMACEUTIQUE CONTENANT UN INHIBITEUR DE LA HMG-CoA RÉDUCTASE ET DE LA GLUTATHIONE WO2006033287A1 (fr)

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JP2004272770 2004-09-21
JP2004-272770 2004-09-21

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CN105175263A (zh) * 2015-09-28 2015-12-23 中国食品药品检定研究院 普伐他汀钠药物共晶及其制备方法和用途

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