WO2009070973A1 - Composition thérapeutique à base d'amlodipine nicotinate et de sartans - Google Patents

Composition thérapeutique à base d'amlodipine nicotinate et de sartans Download PDF

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Publication number
WO2009070973A1
WO2009070973A1 PCT/CN2008/001871 CN2008001871W WO2009070973A1 WO 2009070973 A1 WO2009070973 A1 WO 2009070973A1 CN 2008001871 W CN2008001871 W CN 2008001871W WO 2009070973 A1 WO2009070973 A1 WO 2009070973A1
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Prior art keywords
amlodipine
composition
compound
hypertension
sartan
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PCT/CN2008/001871
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English (en)
Chinese (zh)
Inventor
Haiyong Wang
Yanming Chen
Junchang Fu
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Beijing Rock Pharmaceutical Co., Ltd.
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Priority to CN200880115206A priority Critical patent/CN101854934A/zh
Publication of WO2009070973A1 publication Critical patent/WO2009070973A1/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61P3/08—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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • composition containing amlodipine niacin and sartan
  • the present invention relates to a pharmaceutical composition of amlodipine niacin and a sartan compound or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof, and to a combination comprising a combination of amlodipine niacin and a composition of a sartan compound. Pill box.
  • the above compositions or kits can be used to treat patients suffering from hypertension, angina pectoris, atherosclerosis, and/or hypertensive blood pressure and patients (including humans) having cardiac risk symptoms. Background technique
  • Hypertension has become one of the main killers of human health. At present, the incidence of hypertension in some countries in Europe and America has reached 20%. According to statistics, there are 43 million people suffering from hypertension in the United States; the average incidence of hypertension in China is 11.88%, and more than 140 million people in China suffer from high blood pressure, such as Beijing. , Shanghai, Guangzhou) has reached 14%, in recent years, and is still growing at a rate of more than 3 million per year.
  • Hypertension is classified into primary hypertension and secondary hypertension according to the incidence, of which 90% is essential hypertension and 5% to 10% is secondary hypertension. Elevated blood pressure is a manifestation of certain diseases, such as secondary to renal artery stenosis, renal parenchymal disease, pheochromocytoma, pregnancy, or due to drugs. Essential hypertension is caused by various factors, and the blood pressure regulation function is imbalanced. The cause is not fully elucidated, but its drug treatment has made significant progress in recent decades.
  • antihypertensive drugs which lower blood pressure by various means. There is evidence that lowering blood pressure by 5-6mmHg reduces the risk of stroke
  • the target blood pressure should be lower in certain situations, such as diabetes or kidney disease (some experts recommend blood pressure levels below 120/80).
  • Common antihypertensive drugs include:
  • ACE inhibitors such as croctopril creatine, enalapril, fosinopril, lisinopril, quinapril, rallipril (Altace); angiotensin II receptor antagonism Agents: for example, telmisartan, irbesartan, losartan, valsartan, kan; alpha blockers such as prazosin or terazosin; beta-blockers such as adi Lol, labetalol, metoprolol, propranolol; calcium channel blockers such as nifedipine, amlodipine, diltiazem, verapamil; direct renin inhibitors such as aliskiren; diuretic Agents: such as benzyl fluorothiazide, chlorthalidone, hydrochlorothiazide.
  • Angiotensin-receptor antagonists also known as angiotensin II receptor blockers (ARBs), AT type I receptor antagonists or sartans, are a group that regulates renin-angiotensin-aldosterone Systematic drugs. Its main uses are high blood pressure (high blood pressure), diabetic nephropathy (diabetes caused by diabetes) and congestive heart failure. In 2008, they reportedly had a significant negative correlation with Alzheimer's disease. The US Department of Veterans Affairs systematically analyzed the medical records of 5 million patients and found that different types of commonly used antihypertensive drugs have very different findings. These patients taking angiotensin receptor blockers (ARBs) are 35-40% less likely to develop AD than those who use other antihypertensive drugs.
  • ARBs angiotensin II receptor blockers
  • Angiotensin receptor blockers are lower incidence, progression of Alzheimer's Disease ).
  • These sartans are AT type 1 receptor antagonists that block angiotensin II AT type I receptor activation. Blocking AT type I receptors directly causes vasodilation, reduces the secretion of angiotensin, and reduces the production and secretion of aldosterone. The combined effect is to lower blood pressure.
  • losartan potassium Since the first drug, losartan potassium, was introduced in 1994, many researchers have continuously modified their mother nucleus and developed many new sartans, including losartan potassium, irbesartan, candesartan, and he. Esometan, eprosartan, telmisartan, valsartan and olmesartan medoxomil.
  • Amlodipine and related dihydropyridine compounds are disclosed in U.S. Patent No. 4,572,909, the disclosure of which is incorporated herein by reference.
  • Amlodipine sulfonate also known as amlodipine sulfonate
  • Amlodipine niacin and ammonia benzene sulfonate are on average a potent and persistent calcium channel antagonist.
  • Amlodipine nicotinate also known as amlodipine niacin
  • Chinese Patent Application No. 00,124,812 which is incorporated herein by reference.
  • amlodipine, amlodipine besylate, amlodipine niacin and other pharmaceutically acceptable acid addition salts are useful as antihypertensive agents and anti-ischemic agents.
  • Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in U.S. Patent No. 5,155,120 for the treatment of congestive heart failure.
  • the current trade name of amlodipine besylate is known as Luohu.
  • hypertension is a syndrome with a very complicated etiology and pathogenesis, it has both neurological and humoral abnormalities, and often affects the structure and function of various organs and systems of the body. Most of the patients are accompanied by other diseases such as heart and brain. Kidney or vascular disease, decreased insulin sensitivity, dyslipidemia, etc. Therefore, the combination of antihypertensive drugs with different mechanisms of action can enhance the therapeutic effect, and at the same time take care of the different links in the pathogenesis of hypertension, so that various risk factors or comorbid diseases can be optimally controlled, which is more conducive to the target structure of hypertension.
  • the combination can be administered once without administration twice or more, so that the patient's treatment compliance is greatly increased and the quality of life is significantly improved.
  • Antihypertensive small-dose fixed combination preparations can be used not only as second-line drugs, but also as first-line drugs for the treatment of hypertension, especially when patients have other complications at the same time.
  • Chinese Patent Application No. 99,809,776 and its divisions 200,510,072,738 describe pharmaceutical compositions of amlodipine besylate and valsartan, and methods of using such compositions to treat patients suffering from hypertension or heart failure.
  • Chinese Patent Application No. 200,510,098,619 describes a composition comprising amlodipine besylate and an angiotensin II receptor inhibitor and methods for treating hypertension, individuals suffering from cardiac risk symptoms, including humans.
  • the albino sulfonate amlodipine is as high as 60. C has low light stability and thermal stability at high temperatures. Further, the pH of the saturated solution of amlodipine besylate is not close enough to the pH of the human blood (pH 7.4 ⁇ 0.5). Thus, there is a need to find a better alternative to amlodipine besylate, which provides a better feature of the amlodipine besylate valsartan compound. Summary of invention
  • Niacin also known as vitamin B3, is an organic compound having the C 5 H 4 NC0 2 H formula.
  • Niacin is a derivative of pyridine which is a colorless, water-soluble solid characterized by having a carboxylic acid at the 3-position of the pyridine.
  • Niacin is converted to niacinamide in the body, both of which have the same vitamin function.
  • Niacin is a precursor of NADK, NAD, and NADP, which plays a fundamental role in living cells, DNA repair, and the production of steroid hormones in the adrenal gland.
  • Nicotinic acid is chemically and chemically stable and is not easily destroyed under acid, alkali, oxygen, light or heating conditions.
  • Amlodipine niacin has the same excellent stability as niacin. Compared with amlodipine besylate, amlodipine urate has improved photostability and thermal stability Sex, as well as better physicochemical properties, such as solubility.
  • a first aspect of the invention provides a "composition" involving the following ingredients:
  • amlodipine niacin in the composition has significantly improved solubility and photostability compared to amlodipine besylate, thereby enhancing the pharmacological activity of the composition.
  • salt-forming niacin is not only an auxiliary component of salt formation, but also has a beneficial pharmacological effect.
  • benzenesulfonic acid has many disadvantages, such as strong corrosiveness and toxicity, which makes industrial operation difficult, and benzoic acid is hygroscopic, thus requiring special storage, transportation and use. Further, the available benzenesulfonic acid contains about 10%. The water is easy to cause loading errors in production.
  • a second aspect of the present invention relates to a kit called "Pill Box A" which has a therapeutic effect on a mammal, and which is composed of the following parts:
  • a unit dosage form containing a certain amount of amlodipine niacin and a pharmaceutically acceptable carrier or diluent;
  • a second unit dosage form containing an amount of one or more sartan compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;
  • a third aspect of the invention relates to the use of the above composition or kit for the treatment of hypertension, angina pectoris, atherosclerosis and/or hypertension and hyperlipidemia in a mammal.
  • amlodipine is a racemic compound.
  • the R and S enantiomers can be prepared as described by Arrowsmith et al. (J Med Chem, 1986, 26, 1696.
  • the calcium channel blocking activity of amlodipine is essentially limited to the S-isomer, in the isomer In the racemic mixture (see International Patent Application PCT/EP94/02697), there are not many R isomers, or no calcium channel resistance at all. Broken activity.
  • the R(+) isomer is a potent inhibitor of smooth muscle cell migration. Therefore, the R (+) isomer is used to treat or prevent atherosclerosis (see International Patent Application PCT 95/00847).
  • Figure la HPLC diagram of related substances at 0 days
  • Figure lb Amlodipine niamin tablets. Related materials at 0 days HPLC chart; Figure 2a: HPLC chart of related substances at 4 weeks;
  • Figure 2b Amlodipine niamin tablets. Related materials at 4 weeks HPLC chart; Figure 3a: Reference material HPLC material at 0 days;
  • Figure 3b HPLC plot of related substances at 0 days
  • FIG. 4a HPLC diagram of related substances at 4 weeks
  • FIG. 4b HPLC diagram of related substances at 4 weeks
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amlodipine niacin and/or a sartan compound or a pharmaceutically acceptable salt thereof.
  • Amlodipine can be readily prepared by the method described in U.S. Patent No. 4,572,909, which is incorporated herein by reference.
  • Amlodipine niacin can be readily prepared by the method described in Chinese Patent Application No. 00,124,812, which is incorporated herein by reference.
  • Amlodipine and amlodipine niacin are both effective and long-acting calcium channel blockers.
  • the “sartan” compound refers to losartan potassium, irbesartan, candesartan, tamsartan, eprosartan, telmisartan, olmesartan and valsartan or Its medicine With a salt, preferably irbesartan, olmesartan medoxomil and valsartan or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
  • pharmaceutically acceptable cationic salts used to define, but not limited to, the following salts: alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), aluminum salts, ammonium salts and salts with organic amines, organic amines including benzoquinone (ie N, N, - dibenzyl B Diamine), choline, diethanolamine, ethylenediamine, meglumine (ie N-methylglucamine), benzylethylamine (ie N-benzylethylamine), diethylamine, piperazine, tromethamine Triol (ie 2-amino-2-hydroxymethyl-1, 3-propanediol) and procaine.
  • alkali metal salts Such as sodium and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • aluminum salts such as
  • compositions described herein can be administered to a patient by themselves, or mixed with other active ingredients, or a suitable carrier or excipient, in a pharmaceutical composition for combination therapy.
  • Formulation and administration of the compounds of the present application techniques may be found in "Remington's pharmaceutical” Mack Publishing Co. , Easton, PA, 18 th edition, 1990.
  • Suitable routes of administration may include oral, rectal, transmucosal or enteral administration.
  • the compound may be administered in a local rather than systemic manner, for example, in the form of a depot or sustained release formulation.
  • the drug can be administered to a target drug delivery system, for example, in the form of a liposome coated with tissue-specific antibodies.
  • compositions of the present invention can be produced in a known manner, for example, by conventional methods of mixing, dissolving, granulating, tableting, milling, emulsifying, budding, or tabletting.
  • compositions used in accordance with the present invention can be prepared in a conventional manner using one or more physiologically acceptable carriers including pharmaceutically acceptable excipients and excipients which facilitate processing of the active compounds into preparations. .
  • suitable formulations depend on the route of administration chosen. Any suitable well-known techniques, carriers and excipients in the art can be used as described in Remington's Pharmacy above.
  • compositions can be readily prepared by combining the active compounds withpharmaceutically acceptable carriers which are known in the art. These carriers are capable of forming the compounds of the present invention into tablets, pills, powders, troches, capsules, gels, syrups, greens, suspensions. Liquid, flat attack and suppository, etc., for oral administration to patients.
  • a pharmaceutical preparation for oral use can be obtained by mixing one or more solid excipients with the pharmaceutical composition of the present invention, optionally grinding the resulting mixture after adding a suitable excipient as needed, and treating the mixture of the granules to obtain a tablet. Or lozenge core.
  • suitable excipients especially fillers such as sugars, include lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, and tragacanth , methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP).
  • a disintegrating agent such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.
  • Anionic surfactants include sodium docusate, sodium lauryl sulfate; binders include gum arabic, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl fiber , hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, decyl cellulose, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate , starch and zein; cationic surfactants, including benzalkonium chloride, benzethonamide; diluents including calcium carbonate, calcium sulfate, dextrose, dextrin, glucosinolate, dibasic calcium phosphate Hydrate, palmitoyl stearyl glyceride, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mann
  • a suitable coating is provided for the tablet core.
  • a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize combinations of different active compound doses.
  • compositions which can be used orally include a plug-in capsule made of gelatin and a sealant made of gelatin* and a plasticizer such as glycerin or sorbitol.
  • the plug-in capsule may comprise the active ingredient in admixture with a filler such as lactose, a binder such as a starch and/or a lubricant such as talc or magnesium stearate and optionally a stabilizer.
  • the active compound can be dissolved or suspended in a suitable fluid, such as fatty oils, liquid paraffin Or in liquid polyethylene glycol.
  • stabilizers can be added. All formulations for oral administration should be in a form suitable for oral administration.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example, including conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds can also be formulated as depot preparations. These long acting formulations can be implanted, for example, subcutaneously or intramuscularly.
  • the compound can be prepared from a suitable polymeric or hydrophobic material (e.g., an emulsion in a suitable oil) or an ion exchange resin, or a sparingly soluble derivative, for example, a sparingly soluble salt.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.
  • hydrophobic pharmaceutical compounds can be used.
  • Liposomes and emulsions are well known examples of media or carriers for the delivery of hydrophobic drugs.
  • Some organic solvents, such as dimercaptosulfoxide, may also be used, although generally with greater toxicity.
  • a sustained release system can be used to deliver a compound, such as a semipermeable matrix of a solid hydrophobic polymer comprising a therapeutic agent.
  • sustained release materials have been established and are well known to those skilled in the art.
  • the sustained release capsule can be used to release the compound for several weeks, up to more than 100 days.
  • Other strategies for stabilizing proteins can be used depending on the chemistry and biostability of the therapeutic agent.
  • compositions suitable for use in the present invention include compositions comprising an effective amount of the active ingredient to achieve its intended purpose. More specifically, an effective therapeutic amount refers to an amount of a compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease or prolong the survival of the treated patient. Determination of the effective therapeutic amount is well within the abilities of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the pharmaceutical preparation is preferably in unit dosage form containing the appropriate amount of active ingredient.
  • the unit dosage form can be a package preparation, the package containing the dispersion of the preparation, such as a packet of tablets, a gum*, and a powder in a vial or ampule.
  • the unit dosage form itself may be a capsule, a tablet, a sputum or lozenge, or it may be an appropriate number package style.
  • compositions containing the following ingredients:
  • the dosage of the active ingredient necessary for the desired therapeutic effect depends on the species, age and individual condition of the subject, and the mode of administration.
  • the approximate daily dose for oral administration of amlodipine citrate is -25 mg, preferably 2.5-10 mg, for a patient weighing about 70 kg.
  • the "sartan”, the compound refers to irbesartan, telmisartan, valsartan, losartan, candesartan or a pharmaceutically acceptable salt thereof, which is used in an amount of from 1 to 500 mg per day, more preferably 10-320 mg.
  • the present invention also relates to the preparation of the composition for obtaining a therapeutic effect in a mammal, including common tablets, pills, powders or granules, troches, capsules, gels, syrups, bones, suspensions, blister Capsules and suppositories.
  • kit A which achieves a therapeutic effect in a mammal, which consists of the following components:
  • a second unit dosage form containing an amount of one or more sartan compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;
  • the compound preparation of amlodipine and sartan of the present invention is in accordance with the treatment principle of the combined use of hypertension.
  • the sartans act on the terminal action of the renin-angiotensin-boosting system, blocking the direct rise of angiotensin II (Aug 11).
  • pressure and reduce the tension of the sympathetic nervous system which plays an important role in blood pressure regulation; and amlodipine targets the calcium channel to regulate blood, so the two can complement each other from the pharmacological mechanism.
  • the combined use can reduce the relative amount of each drug, reduce the occurrence of adverse drug reactions, improve the patient's medication compliance, and achieve the goal of improving the control rate of hypertension; again, the pharmacokinetic characteristics of the second class of drugs are basically similar, It can maintain the 24-hour antihypertensive effect once a day, and has the characteristics of pharmacokinetic adaptation.
  • the present invention also relates to the use of the above composition or kit for the treatment of hypertension, angina pectoris, atherosclerosis and/or hypertension and hyperlipidemia in a mammal.
  • valsartan is exemplified below, and the following is a fixed dual therapeutic dose combination for use in a preferred pharmaceutical composition.
  • Valsartan amlodipine niacin is exemplified below, and the following is a fixed dual therapeutic dose combination for use in a preferred pharmaceutical composition.
  • the present invention relates to the use of a combination of active ingredients as described above which can be administered in a solid dosage form which has low levels of degradation products and/or impurities in a therapeutic pack or kit, for example for angina pectoris, atherosclerosis, hypertension and Treatment of diseases and symptoms of patients with hyperlipemia and/or hypercholesterolemia and treatment of patients with signs of heart disease.
  • the kit includes a solid dosage form and a container.
  • the kit includes instructions for administration in dosage form.
  • the container may be of any conventional shape or form known in the art, such as a carton, glass bottle or plastic bottle.
  • compositions and methods of the present invention are all suitable for use as a mammal, and the mammal may be selected from the group consisting of a mouse, a rat, a rabbit, a guinea pig, a dog, a cat, a sheep, a goat, a cow, a primate such as a monkey, a gorilla, and a donkey. And people, especially for human treatment, angina pectoris, atherosclerosis and characterized by hypertension and hyperlipidemia.
  • valsartan is used as an example to prepare amlodipine valsarate valsartan composition, and the antihypertensive effect of the composition on spontaneously hypertensive rats is examined.
  • Example 1 General Preparation Method of Valsartan/Amlodipine Nicotin Tablets Valsartan, amlodipine niacin, pulverized through 100 mesh, ready for use; lactose, microcrystalline cellulose, pregelatinized starch, carboxymethyl The sodium starch and magnesium stearate were sieved through an 80 mesh sieve, respectively.
  • the particle content was measured, and the tablet weight was adjusted within the indicated range based on the particle content. Tableting, the hardness of the control piece is 4 ⁇ 9k g . Table 1. Valsartan micro sputum / nicotinic acid amlodipine tablets 1000 tablets
  • the pharmaceutical composition of the study product amlodipine citrate (5 mg) and valsartan (80 mg) was as described in Example 1.
  • the pharmaceutical composition of the reference substance amlodipine besylate (5 mg) and valsartan (80 mg) was prepared according to Chinese Patent Application No. 99,809,776, and the reference product (5 mg) was commercially available, and the reference product was nicotinic acid ammonia chloride.
  • the ground film (5mg) is homemade. Expose the study and control and reference products to 50. C and incandescent lamp (220V, 100W) placed 30cm above the sample for 4 weeks, the result is that the reference substance and the reference product are discolored to light yellow, and the research product and the reference product amlodipine tablet have no color.
  • Figure la shows the HPLC profile of the reference product at 0 weeks
  • Figure lb shows the HPLC profile of the reference penicillin amlodipine tablet at 0 weeks
  • Figure 2a HPLC chart of related substances at 4 weeks
  • Figure 2b HPLC chart of related substances at 4 weeks of amlodipine niacin tablets
  • Figure 3a shows the HPLC profile of the control at 0 weeks
  • Figure 3b shows the HPLC of the study at 0 weeks pattern
  • FIG. 4 a showing the reference after 4 weeks the HPLC profile
  • Figure 4b shows the HPLC profile after 4 weeks of study product.
  • Amlodipine niacin, amlodipine besylate was purchased from hammer pharmcetical S.P.A (batch number: AB034K00).
  • the SHR is both male and female, weighing 250 to 280 g, and is provided by the Animal Experimental Center of the Academy of Military Medical Sciences. RBP21 type rat sphygmomanometer (China-Japan Friendship Clinical Medical Research Institute).
  • amlodipine niacindipine/valsartan After administration of amlodipine niacindipine/valsartan, the blood pressure gradually decreased. After 9 days, the blood pressure decreased significantly, reached a peak at 13 days, and the blood pressure remained stable afterwards.
  • the amlodipine niacin/valsartan group had the best blood pressure lowering effect after administration (P ⁇ 0.01). After 1 week of withdrawal, the blood pressure returned to normal at 25 days. The results are shown in Table 1.

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  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition thérapeutique à base d'amlodipine nicotinate et de sartans. L'invention concerne également un procédé de préparation de la composition et une formulation et un kit contenant la composition. La composition contient les ingrédients suivants: 1) une quantité d'amlodipine nicotinate; 2) une quantité d'un type de composés sartans parmi de nombreux types de composés sartans, ou de sels pharmaceutiquement acceptables de ceux-ci; et 3) un support ou diluant pharmaceutiquement acceptable. Ladite composition ou ledit kit peuvent être utilisés pour traiter les sujets (y compris humains) souffrant d'hypertension, d'angine de poitrine, d'athérosclérose et/ou de complications liées à l'hypertension et de symptômes de risque cardiaque.
PCT/CN2008/001871 2007-11-12 2008-11-12 Composition thérapeutique à base d'amlodipine nicotinate et de sartans WO2009070973A1 (fr)

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CN200880115206A CN101854934A (zh) 2007-11-12 2008-11-12 含有烟酸氨氯地平和沙坦类药物的治疗组合物

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CNA2007101771834A CN101433536A (zh) 2007-11-12 2007-11-12 含有烟酸氨氯地平和沙坦类药物的治疗组合物
CN200710177183.4 2007-11-12

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WO2009070973A1 true WO2009070973A1 (fr) 2009-06-11

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WO (1) WO2009070973A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN103006650B (zh) * 2012-12-31 2014-07-23 广州白云山天心制药股份有限公司 含氯化钠药物载体的复方降血压片剂
CN107033129A (zh) * 2017-02-28 2017-08-11 吉林修正药业新药开发有限公司 厄贝沙坦杂质的合成方法
CN112979617A (zh) * 2019-12-17 2021-06-18 中国科学院苏州纳米技术与纳米仿生研究所 一种厄贝沙坦哌嗪盐及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312715A (zh) * 1998-07-10 2001-09-12 诺瓦提斯公司 缬沙坦和钙通道阻断剂的抗超敏组合
CN1681785A (zh) * 2002-09-11 2005-10-12 韩林制药株式会社 S－(－)－氨氯地平烟酸盐及其制备方法
CN1765362A (zh) * 2004-09-30 2006-05-03 江苏恒瑞医药股份有限公司 包含氨氯地平和血管紧张素ⅱ受体抑制剂的组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312715A (zh) * 1998-07-10 2001-09-12 诺瓦提斯公司 缬沙坦和钙通道阻断剂的抗超敏组合
CN1681785A (zh) * 2002-09-11 2005-10-12 韩林制药株式会社 S－(－)－氨氯地平烟酸盐及其制备方法
CN1765362A (zh) * 2004-09-30 2006-05-03 江苏恒瑞医药股份有限公司 包含氨氯地平和血管紧张素ⅱ受体抑制剂的组合物

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CN101854934A (zh) 2010-10-06

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