[go: up one dir, main page]

WO2009070974A1 - Composition thérapeutique à base d'amlodipine nicotinate et de statines - Google Patents

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

Info

Publication number
WO2009070974A1
WO2009070974A1 PCT/CN2008/001872 CN2008001872W WO2009070974A1 WO 2009070974 A1 WO2009070974 A1 WO 2009070974A1 CN 2008001872 W CN2008001872 W CN 2008001872W WO 2009070974 A1 WO2009070974 A1 WO 2009070974A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
amlodipine
pharmaceutically acceptable
amount
statin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2008/001872
Other languages
English (en)
Chinese (zh)
Inventor
Haiyong Wang
Yanming Chen
Junchang Fu
Leibo Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BEIJING ROCK PHARMACEUTICAL Co Ltd
BEIJING SL PHARMACEUTICAL Co Ltd
Original Assignee
BEIJING ROCK PHARMACEUTICAL Co Ltd
BEIJING SL PHARMACEUTICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BEIJING ROCK PHARMACEUTICAL Co Ltd, BEIJING SL PHARMACEUTICAL Co Ltd filed Critical BEIJING ROCK PHARMACEUTICAL Co Ltd
Priority to CN2008801155977A priority Critical patent/CN101854931B/zh
Publication of WO2009070974A1 publication Critical patent/WO2009070974A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/395—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
    • A61K31/435—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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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 statins
  • the present invention relates to a pharmaceutical composition of amlodipine niacin and a statin compound or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof, and to a kit comprising a combination of amlodipine niacin and a statin.
  • the above compositions or kits can be used to treat patients suffering from angina pectoris, atherosclerosis, and/or hypertension and hyperlipidemia and to treat patients (including humans) at risk for cardiac risk. Background technique
  • HMGCoA 3-hydroxy-3-methylglutaryl coenzyme A
  • mevalonate is an early rate-limiting step in the cholesterol biosynthetic pathway that is catalyzed by HMGCoA reductase.
  • Statins are a competing antagonist of HMGCoA because they compete directly with the endogenous substrate of the HMGR active site. The statins are also not competitively combined with the common substrate NADPH (nicotinamide adenine dinucleotide phosphate). Cholesterol is synthesized by the mevalonate pathway by blocking the HMGR enzyme.
  • statins are a class of drugs that have strong lipid-lowering properties.
  • Type 1 statins have a substitution The decahydronaphthalene ring structure, similar to the first one found in statins, mevastatin, is often listed for this type due to structural relationships.
  • Statins belonging to this class include lovastatin, pravastatin, and simvastatin.
  • Type 2 statins are fully synthesized, with larger groups attached to similar parts of HMG.
  • a major difference between type 1 and type 2 is that type 1 statin is a type 2 statin-substituted fluorophenyl group in the butyl group, which increases the polar interaction and binds more closely to the HGMR enzyme.
  • statins belonging to type 2 are fluvastatin, cerivastatin, atorvastatin, and rosuvastatin.
  • Lovastatin is derived from a fungus.
  • Simvastatin and pravastatin are derived from the chemical modification of lovastatin and are therefore structurally indistinguishable from lovastatin. All three are partially reduced naphthalene ring structures.
  • Simvastatin and lovastatin are inactive lactones, in the form of hydroxy acids which inhibit the metabolism of HMGR.
  • Type 2 statins are all present in the form of an active hydroxy acid.
  • Fluvastatin has an anthracene ring structure, while atorvastatin and lovastatin have a pyrrole and pyrimidine ring structure, respectively.
  • the lipophilic cerivastatin has a pyridyl ring structure.
  • colvastatin (Baycol, Lipobay) is a synthetic statin.
  • lovastatin simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and ivavastatin.
  • HMGCoA reductase inhibitors also known as statins, have been found to be a breakthrough in the prevention of hypercholesterolemia and related diseases.
  • Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis, often causing cardiovascular, cerebrovascular and peripheral vascular disease.
  • Statins inhibit the in vivo synthesis of cholesterol, causing a decrease in blood cholesterol levels, which is believed to reduce the risk of atherosclerosis and its secondary disease.
  • Statins are the most popular categories in the world in recent years. Atorvastatin, simvastatin, and pravastatin all rank among the top 20 sales in single-species sales, especially atorvastatin has been globally every year. More than 60 million patients are taking it, and atorvastatin calcium (Lipitor) was as high as $12.9 billion in 2006. It is the best-selling drug in the world.
  • Amlodipine sulfonate (also known as amlodipine sulfonate) is disclosed in U.S. Patent 4,879,303, the disclosure of which is incorporated herein by reference. Amlodipine sulfonate is currently sold under the trade name "Norvasc”. Amlodipine sulfonate and amlodipine and other pharmaceutically acceptable acid addition salts are useful as antihypertensive and anti-ischemic agents. Amlodipine niacin is disclosed in Chinese Patent Application No. 00,124,812, which is incorporated herein by reference.
  • Atherosclerosis is a disease characterized by irregularly distributed fat deposits in the intima of the arteries, including the coronary arteries, the carotid arteries, and the peripheral arteries.
  • Atherosclerotic coronary heart disease (herein referred to as "CHD") accounts for 53% of total cardiovascular disease mortality.
  • the cost of CHD accounts for nearly half of the total US cardiovascular health expenditure (approximately $50-60 billion) and approximately 6% of annual national medical expenses.
  • CHD remains the most common cause of death in the United States. High concentrations of blood cholesterol and blood lipids are responsible for atherosclerosis.
  • LDL-C low-density lipoprotein cholesterol
  • Angina is a pain that contracts severely in the chest, often radiating from the heart to the left shoulder. And down to the left arm. Usually angina is due to cardiac ischemia and is often caused by coronary heart disease. At present, the treatment of symptomatic angina is significantly different between countries. In the United States, patients with stable angina symptoms are treated with surgery or PTCA. Patients treated with PTCA or other surgical methods for treating angina are often associated with complications such as (heart valve) restenosis. This restenosis can manifest itself as a short-term proliferative response to wounds caused by angioplasty, or as a long-term development of the atherosclerotic process in grafted vessels and angioplasty segments.
  • NASH National Cholesterol Education Program
  • Amlodipine helps prevent myocardial ischemia in patients with exertional angina by reducing total peripheral resistance or afterload, and amlodipine reduces rate-pressure products, thereby reducing myocardial oxygen demand at any given exercise level. the amount.
  • amlodipine has been shown to prevent contraction and thus restore the supply of myocardial oxygen.
  • amlodipine has been shown to increase the activity of myocardial oxygen supply by dilating coronary arteries.
  • Hypertension often coexists with hyperlipidemia, both of which are considered to be major risk factors for developing heart disease and ultimately leading to adverse heart attacks. These risk factors are mainly attributed to the common mechanism.
  • WHO estimated that more than 58% of cardiovascular disease in North America was due to higher than optimal blood pressure and blood lipids. Unfortunately, less than one-third of patients with both diseases were found, and less than one-tenth of them achieved treatment goals. When both factors are treated simultaneously, the adherence to treatment is significantly improved (Frishman, W. et al., Amlodipine/atorvastatin: the first cross risk factor polyp ill for the prevention and treatment of cardiovascular disease. Expert Rev Cardiovasc Ther.
  • Coronary heart disease is a multifactorial disease whose incidence and severity are affected by fat profile, the presence of diabetes, and the gender of the patient. The incidence is also affected by smoking and left ventricular hypertrophy, and left ventricular hypertrophy is a secondary disease of hypertension.
  • hypertension intervention trials have failed to demonstrate the complete normalization of blood pressure due to cardiovascular death in coronary heart disease. Treatment of patients with and without coronary heart disease with cholesterol synthesis inhibitors reduces cardiovascular morbidity and mortality.
  • lipid-lowering agents eg, HMGCOA reductase inhibitors
  • pravastatin lipid-lowering agents
  • W09911259 which is incorporated herein by reference, discloses the use of amlodipine or a pharmaceutically acceptable acid salt thereof in combination with atorvastatin or a pharmaceutically acceptable salt thereof, and a kit for use in combination with a medicament for use thereof
  • Patients with angina pectoris, atherosclerosis, concomitant hypertension and hyperlipidemia and the main symptoms of treatment are patients with heart, dangerous symptoms (including humans).
  • WO03011283 which is incorporated herein by reference, discloses a composition comprising two components: a) a component comprising atorvastatin calcium or a pharmaceutically acceptable salt thereof and a carrier particle; b) another The component comprises amlodipine or a pharmaceutically acceptable salt thereof and a granule of a carrier, wherein the two components are combined to form the final solid formulation composition, and a method of preparing the composition, a kit comprising the composition, and A method of treating patients with angina pectoris, atherosclerosis, concomitant hypertension and hyperlipidemia and/or patients with hypercholesterolemia and cardiac risk symptoms (including humans).
  • Amlodipine besylate (Norvasc, Pfizer) and atorvastatin calcium (Lipitor, Pfizer) are the first dual-effect combination for the treatment of hypertension and/or angina and dyslipidemia. Once in the drug, there are multiple dose combinations to choose from. Amlodipine/atorvastatin maintains the safety and efficacy of its parent drug, but simplifies the treatment of these diseases and can be considered as a multi-drug The preliminary version of (Polypill).
  • amlodipine besylate 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 that makes amlodipine besylate atorvastatin calcium a better feature. 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 to amlodipine besylate, amlodipine niaminate has improved photostability and thermal stability, 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 cisplatin benzenesulfonate, 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 corrosivity and toxicity, enabling industrial operations. Difficulties, benzenesulfonic acid is hygroscopic and requires special storage, transportation and use. In addition, the available benzenesulfonic acid contains about 10% water, which is easy to cause loading errors in production.
  • a second aspect of the invention relates to a method of preparing the above composition, comprising:
  • composition by an alkalizing agent method comprising:
  • composition by a package including:
  • a third aspect of the invention relates to the preparation of a composition of the composition which achieves a therapeutic effect in a mammal.
  • a fourth aspect of the invention relates to a kit called "Pill Box A" which has a therapeutic effect in a mammal, which consists of the following parts:
  • a second unit dosage form containing an amount of one or more statins or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;
  • a fifth aspect of the invention relates to the use of the above composition or kit for treating angina pectoris, atherosclerosis and/or in combination with hypertension and hyperlipidemia in a mammal.
  • amlodipine is a racemic compound.
  • the R and S enantiomers can be prepared as described by Arrow smith et al. (J Med Chem, 1986, 26, 1696).
  • the calcium channel blocking activity of amlodipine is essentially limited to the S-isomer, in the racemic mixture of isomers (see International Patent Application) PCT/EP94/02697)
  • 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).
  • the skilled person can select the R (+) isomer, the S (-) isomer and the racemic mixture of the R (+) isomer and the S (-) isomer in combination for use in the present invention. . BRIEF abstract
  • Figure la HPLC diagram of related substances at 0 days
  • Figure lb Amlodipine niacin tablets HPLC plot of related substances at 0 days;
  • FIG. 1a HPLC diagram 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 product of the study substance at 0 days
  • FIG. 4a HPLC diagram of the relevant substance at 4 weeks
  • Figure 4b HPLC plot of the relevant substance at 4 weeks
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising nicotinic acid nicotinic acid and/or a statin 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.
  • statin a compound refers to lovastatin, pravastatin, simvastatin, rosuvastatin, pitavastatin, fluvastatin, and atorvastatin or a pharmaceutically acceptable salt thereof, Atorvastatin and its calcium salt are preferred.
  • Lovastatin, pravastatin, simvastatin, fluvastatin can be readily prepared by the methods described in U.S. Patent Nos. 4,342,767, 4,346,227, 4,444,784 and 4,739,073, each of which is incorporated herein by reference. This is cited as a reference.
  • Atorvastatin can be readily prepared by the method described in U.S. Patent No. 4,681,892, the disclosure of which is incorporated herein by reference.
  • the atorvastatin hemi-calcium salt currently sold under the trade name Lipitor can also be readily prepared by the method described in U.S. Patent No. 5,273,995, the disclosure of which is incorporated herein by reference.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
  • pharmaceutically acceptable cationic salts is defined, 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 Ethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (ie N-methylglucamine), benzylethylamine (ie N-benzylethylamine), diethylamine, piperazine, ammonia Butanetriol (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
  • atorvastatin pharmaceutically acceptable cationic salts can be readily prepared by reacting the free acid form of atorvastatin with a suitable typically two equivalents of base in a cosolvent.
  • bases include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzoquinone, choline, diethanolamine, and meglumine.
  • the salt is isolated by concentration or by addition of a non-solvent.
  • the acid solution with a different cationic salt (e.g., sodium or potassium hexyl hexanoate, magnesium oleate) in a solvent such as ethyl acetate to obtain the desired salt by precipitation. It is also possible to separate the salt by concentrating the reaction solution and/or adding a non-solvent.
  • a different cationic salt e.g., sodium or potassium hexyl hexanoate, magnesium oleate
  • a solvent such as ethyl acetate
  • compositions described herein can be administered to a human 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. Organs will target liposomes and selectively absorb them.
  • compositions of the present invention can be produced in a known manner, for example, by conventional methods of mixing, dissolving, granulating, tableting, milling, emulsifying, encapsulating 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 can be used in the form of tablets, pills, powders, troches, capsules, gels, syrups, bones, suspensions, elixirs, suppositories, and the like, 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 methyl cellulose, magnesium aluminum silicate, maltodextrin, methyl fiber Vitamins, polydecyl acrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, starch and zein; cationic surfactants, including benzalkonium chloride, benzethonamide; diluents included Calcium carbonate, calcium sulfate, dextrose, dextrin, dexamethasone, dibasic calcium phosphate dihydrate, palmitoyl stearyl glyceride, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, nec
  • 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 capsules may contain 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.
  • a suitable fluid such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
  • stabilizers can be added. All formulations for oral administration should be in a form suitable for oral administration.
  • compositions may take the form of tablets or lozenges prepared in conventional manner.
  • 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 ice-clearing 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.
  • other delivery systems of hydrophobic pharmaceutical compounds can be used. Liposomes and emulsions are well known examples of media or carriers for the delivery of hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, 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. A variety of materials have been established which are continuously dry and are well known to those skilled in the art. Depending on its chemical nature, a sustained release capsule can release the compound for several weeks, up to more than 100 days. Other strategies for stabilizing proteins can be used depending on the chemical nature and biostability of the therapeutic agent.
  • the compounds used in the pharmaceutical compositions of the present invention can be salts having pharmaceutically acceptable equilibrium ions.
  • the pharmaceutically acceptable salts can be formed from a wide variety of acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid and the like.
  • the solubility of the salt in aqueous or other protic solvents tends to be greater than the corresponding free acid or base form.
  • 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 containing a dispersion of the preparation, such as a small package, a capsule and a vial or a powder in an ampoule.
  • the unit dosage form may itself be a gel, tablet, tablet or lozenge, or it may be in the appropriate number of packages.
  • compositions containing the following ingredients:
  • statins b) - a quantity of one or more statins or a pharmaceutically acceptable salt thereof; C) a pharmaceutically acceptable carrier or diluent.
  • the amount of amlodipine niacin is from 0.1 to 100 mg, preferably from 1 to 25 mg, more preferably from 2.5 to 10 mg.
  • the “statin”, the compound refers to lovastatin, pravastatin, simvastatin, fluvastatin and atorvastatin or a pharmaceutically acceptable salt thereof, preferably atorvastatin and its calcium salt.
  • the amount of the compound is, for example, 0.1 to 1000 mg, preferably 1 to 200 mg, more preferably 2.5 to 100 mg, for example, the amount of the atorvastatin calcium salt is 0.1 to 1000 mg, preferably 1 to 100 mg, more preferably 5 to 80 mg.
  • a pharmaceutically acceptable carrier or diluent is as described above or as described in Remington's Pharmacy.
  • the invention also relates to a method of preparing the above composition, comprising:
  • Granules of statins or their salts including:
  • Step 1 Dissolve the surfactant in water and add the binder
  • Step 2 Mix the statin or its salt in the granulation equipment and form an alkalizing agent with a pH between 4 and 10 for different statins
  • the pH at which the compound or its salt needs to be adjusted depends on its structure. For example, the pH at which atorvastatin calcium needs to be adjusted should be greater than 5, filler/diluent, filler/diluent/disintegrant, and disintegrant
  • Step 3 granulating the powder mixture from step 2 and the solution from step 1 in a granulator apparatus;
  • Step 4 Dry the granules in a drying device
  • Step 1 Add amlodipine niacinate, a filler/diluent, a disintegrant, and a glidant to the statin formula.
  • Step 2 The powder mixture is over 80 mesh
  • Step 3 Mixing the homogeneous composition and lubricant in a mixer for providing a uniformly mixed pharmaceutical composition in solid dosage form.
  • Step 1 Prepare a saturated aqueous solution of the main body.
  • the main body may be a homologue of cyclodextrin or urea.
  • the main body may be used singly or in combination.
  • a quantitative guest substance is added to the saturated aqueous solution of the host and dissolved.
  • the guest substance may be amlodipine niacin or a statin such as atorvastatin calcium.
  • Step 3 a clathrate is prepared by a method which is any one of a recrystallization method, an ultrasonic method, a grinding method, a freeze drying method, a spray drying method, and a solution-stirring method.
  • Step 4 The temperature of the dried clathrate should be controlled between 0-100 degrees Celsius, preferably between 10-60 degrees Celsius.
  • Step 1 The clathrate is comminuted and the mesh is controlled between 60 and 120 mesh.
  • Step 2 Mixing the clathrate fine powder with another uncoated guest fine powder (between 60 and 120 mesh) in a mixer and uniformly mixing the lubricant to provide a uniform mixed pharmaceutical composition in a solid dosage form. Things.
  • Step 1 Prepare a solution of the host material, which may be gelatin, gum arabic, alginate, protein, starch, carboxymethyl cellulose salt, cellulose acetate phthalate, ethyl cellulose, hyprothenol One or a combination of cellulose, polyester, polymer anhydride, and the like.
  • the host material which may be gelatin, gum arabic, alginate, protein, starch, carboxymethyl cellulose salt, cellulose acetate phthalate, ethyl cellulose, hyprothenol One or a combination of cellulose, polyester, polymer anhydride, and the like.
  • Step 2 adding a quantitative amount of the guest substance to the solution of the host material to dissolve or disperse into a suspension or emulsion.
  • the guest substance may be amlodipine niacin or a statin such as Ato. Vitastatin calcium.
  • Step 3 Preparation of micro-invasion by sheep coagulation method, it is possible to reduce the temperature, adjust the pH or add a dehydrating agent, a non-solvent and other coagulants to reduce the solubility of the polymer and make the high score.
  • the sub-material is precipitated from the solution to form a new condensed liquid sphere, or a polymer in the condensed liquid phase is deposited on the capsular core, wherein the temperature control range is between 0-100 degrees Celsius, preferably between 10-80 degrees Celsius, acid
  • the pH should be controlled between 1.5 and 6.5, preferably between 2 and 5.
  • the pH of the base should be controlled between 5 and 11, preferably between 7 and 10.
  • the present invention also includes a phase separation complex coacervation method, a solvent-nonsolvent method, and a microcapsule for preparing a guest by a temperature changing method, and a liquid drying method, a spray drying method, and a polycondensation method to prepare a guest micro-twist.
  • Step 4 The obtained micro* is dried at a low temperature, and the temperature is controlled between 10-70 degrees Celsius, preferably between 20-60 degrees Celsius.
  • Step 1 The dried micro-smash is crushed and the mesh is controlled between 60-120 mesh.
  • Step 2 Mix the microencapsulated fine powder with another guest fine powder (between 60 and 120 mesh) which has not been microencapsulated in a mixer and uniformly mix the lubricant to provide uniform mixing of the solid dosage form.
  • Pharmaceutical composition
  • the present invention also relates to a preparation of the composition for obtaining a therapeutic effect in a mammal, which is treated by the above method and used for preparation including ordinary tablets, pills, powders or granules, tablets, gels, gels, syrups. Agents, bones, suspensions, cachets and suppositories.
  • kit A which achieves a therapeutic effect in a mammal, which consists of the following components:
  • a fifth aspect of the invention relates to the use of the above composition or kit for treating angina pectoris, atherosclerosis and/or hypertension and hyperlipidemia in a mammal.
  • the present invention taking atorvastatin calcium as an example, the following is a fixed dual therapeutic dose combination for use in a preferred pharmaceutical composition.
  • Atorvastatin calcium amlodipine niacin as an active ingredient as an active ingredient as an active ingredient
  • the present invention relates to the use of a combination of active ingredients as described above which can be administered in the form of a solid dosage form which has low levels of degradation products and/or impurities in a therapeutic pack or kit, for example suffering from angina pectoris, atherosclerosis, high Treatment of diseases and symptoms of patients with high blood pressure and 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.
  • people, especially for people, angina, arterial porridge Sclerotherapy is characterized by the presence of hypertension and hyperlipidemia.
  • these diseases and conditions are closely related to the occurrence of heart disease and the appearance of adverse cardiac conditions, these combinations and methods are useful in heart risk management by virtue of their role as anti-angina and anti-hyperlipemia.
  • heart risk means that the patient suffers from adverse cardiac symptoms, such as myocardial infarction, cardiac arrest, heart failure, myocardial ischemia.
  • the heart risk is calculated using the Framingham risk equation given above. Danger management, meaning that the risk of adverse cardiac symptoms in the future is substantially reduced.
  • Gelatin and gum arabic were respectively dissolved in distilled water, stirred and fully dissolved. Add atorvastatin calcium, hydroxyethyl cellulose, and emulsification for 30 min in gum arabic. Mix gelatin solution and gum arabic solution into three-necked flask. In the control, the stirring speed is 300 rpm, the water bath is heated, the temperature is maintained at 50 ° C _ 5 5 ° C, the pH of the system is adjusted to 3.8-4.2, the condensation reaction is carried out for 1 hour, and the temperature of the system is lowered to 5 ° C - 10 ° C.
  • the dried atorvastatin calcium micro-sprayed dry fine powder is passed through an 80 mesh sieve, and an appropriate amount of amlodipine niacin and an appropriate amount of excipients are hooked in a mixer to obtain a uniformly mixed drug composition in a solid dosage form.
  • Objects, tableting, specific specifications are shown in Table 1.
  • Example 3 General method for preparing amlodipine octachlorate inclusion compound: ⁇ -cyclodextrin was weighed and dissolved in distilled water heated to 60 ° C in an appropriate amount, and otherwise taken amlodipine niacin, dissolved in water, and added under stirring Aqueous ⁇ -cyclodextrin, and after sonication for 30 min, was filtered to obtain a solution. The resulting solution was freeze-dried to give a white powder.
  • Example 4 Preparation of Atorvastatin Using Amlodipine Niacinate
  • the white powder of the above dried amlodipine acenapine inclusion compound is passed through an 80 mesh sieve, and mixed with an appropriate amount of atorvastatin calcium and an appropriate amount of excipients in a mixer to obtain a uniformly mixed drug composition in a solid dosage form.
  • Table 2 The specific specifications are shown in Table 2.
  • amlodipine citrate (5 mg) and atorvastatin calcium (20 mg) are as described in Examples 1-4.
  • Reference substance clomlpine besylate (5mg) and 72
  • the pharmaceutical composition of atorvastatin calcium (20 mg) was prepared according to Chinese patent application 98,808,460, the reference product (5 mg) was commercially available, and the reference product amlodipine tablet (5 mg) was self made.
  • the study materials and the reference materials and the reference materials were exposed to incandescent lamps (220 V, 100 W) at 50 ° C and 30 cm above the sample for 4 weeks, and the result was that the reference substance and the reference product were discolored to a pale yellow color.
  • the study and the reference product amlodipine tablet did not change 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 of the relevant substance 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 profile of the study at 0 weeks
  • Figure 4a shows after 4 weeks HPLC plot of the control
  • Figure 4b shows the HPLC profile of the study after 4 weeks.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition thérapeutique à base d'amlodipine nicotinate et de statines. L'invention concerne également une formulation contenant la composition, un procédé de préparation de la composition et un kit pour l'administration associée de la composition. La composition contient les ingrédients suivants: 1) une quantité d'amlodipine nicotinate; 2) une quantité d'un type de composés statines parmi de nombreux types de composés statines, 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'angine de poitrine, d'athérosclérose et/ou d'hypertension et de complications liées à l'hyperlipidémie et de symptômes de risque cardiaque.
PCT/CN2008/001872 2007-11-12 2008-11-12 Composition thérapeutique à base d'amlodipine nicotinate et de statines Ceased WO2009070974A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008801155977A CN101854931B (zh) 2007-11-12 2008-11-12 含有烟酸氨氯地平和他汀类药物的治疗组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2007101771849A CN101433539A (zh) 2007-11-12 2007-11-12 含有烟酸氨氯地平和他汀类药物的治疗组合物
CN200710177184.9 2007-11-12

Publications (1)

Publication Number Publication Date
WO2009070974A1 true WO2009070974A1 (fr) 2009-06-11

Family

ID=40708281

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001872 Ceased WO2009070974A1 (fr) 2007-11-12 2008-11-12 Composition thérapeutique à base d'amlodipine nicotinate et de statines

Country Status (2)

Country Link
CN (2) CN101433539A (fr)
WO (1) WO2009070974A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2423123C1 (ru) * 2009-10-26 2011-07-10 Государственное образовательное учреждение высшего профессионального образования "Мордовский государственный университет им. Н.П. Огарева" Способ профилактики нарушений липидного обмена

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101780081B (zh) * 2010-03-31 2013-03-06 海南美兰史克制药有限公司 烟酸辛伐他汀药物组合物缓释片
CN103861117B (zh) * 2014-03-18 2016-03-30 王洪安 一种普伐他汀钠分散片及其制备方法
CN109925295A (zh) * 2017-12-18 2019-06-25 江苏开元药业有限公司 一种HMG-CoA还原酶抑制剂微囊制剂及其制备方法
CN110812326B (zh) * 2019-11-04 2022-04-22 黑龙江省农业科学院畜牧兽医分院 一种辛伐他汀混悬乳剂及其制备方法和应用
RU2741689C1 (ru) * 2020-07-17 2021-01-28 Инна Александровна Семенец Способ оптимизации кислородзависимых процессов при длительном введении симвастатина животным с использованием липоевой кислоты

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1268052A (zh) * 1997-08-29 2000-09-27 辉瑞大药厂 含有氨氯地平和阿多伐他丁的治疗组合物
CN1617717A (zh) * 2001-07-31 2005-05-18 沃尼尔·朗伯有限责任公司 氨氯地平和阿托伐他汀的药物组合物
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1268052A (zh) * 1997-08-29 2000-09-27 辉瑞大药厂 含有氨氯地平和阿多伐他丁的治疗组合物
CN1617717A (zh) * 2001-07-31 2005-05-18 沃尼尔·朗伯有限责任公司 氨氯地平和阿托伐他汀的药物组合物
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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2423123C1 (ru) * 2009-10-26 2011-07-10 Государственное образовательное учреждение высшего профессионального образования "Мордовский государственный университет им. Н.П. Огарева" Способ профилактики нарушений липидного обмена

Also Published As

Publication number Publication date
CN101433539A (zh) 2009-05-20
CN101854931A (zh) 2010-10-06
CN101854931B (zh) 2012-11-07

Similar Documents

Publication Publication Date Title
CN114159570B (zh) 含有葡萄糖激酶激活剂和dpp-iv抑制剂的药物组合及其制备方法和用途
JP4020863B2 (ja) アムロジピン及びアトルバスタチンの医薬組成物
EP1737847B1 (fr) Nebivolol et ses sels pharmaceutiquement acceptables, procede de preparation et compositions pharmaceutiques de nebivolol
HK1259458A1 (zh) 用於治疗心血管疾病的吉卡宾组合
CZ458199A3 (cs) Farmaceutický prostředek pro kombinování piperidinalkanolu s dekongestantem
AU2006212609A1 (en) A stable pharmaceutical composition comprising a fixed dose combination of fenofibrate and an HMG-CoA reductase inhibitor
JP2010532336A (ja) 水分散性の乾いた形態の医薬品の新規製造方法およびそれに伴い得られる医薬組成物
AU2002355680A1 (en) Pharmaceuticals compositions of amlodipine and atorvastatin
WO2009070974A1 (fr) Composition thérapeutique à base d'amlodipine nicotinate et de statines
CN101972260B (zh) 一种瑞舒伐他汀钙口服药物组合物
CN101804029A (zh) 阿托伐他汀脂质体、其制备方法及含有它的药物组合物
US20070027218A1 (en) Pharmaceutical compositions comprising higher primary alcohols and ezetimibe and process of preparation thereof
CA2534910C (fr) Compositions pharmaceutiques stables a liberation controlee contenant du fenofibrate et de la pravastatine
WO2007075009A1 (fr) Préparation complexe contenant de l'amlopidine camsylate et de la simvastatine, et procédé de production associé
CN101468001A (zh) 含有氨氯地平系列盐和他汀类药物的治疗组合物
CN101433538B (zh) 含有氨氯地平和烟酸的治疗组合物
CA2492781A1 (fr) Composition medicale pour reduire le taux de lipides sanguins ou le taux d'homocysteine sanguine
US20080070938A1 (en) Medicinal composition for mitigating blood lipid or lowering blood homocysteine
ES2387913T3 (es) Preparaciones de combinación de sales del ácido O-acetilsalicílico
US20130158084A1 (en) Pharmaceutical Composition Comprising Losartin For Treating or Preventing Statin BasedGrug-Induced Muscle Toxicity
WO2009070973A1 (fr) Composition thérapeutique à base d'amlodipine nicotinate et de sartans
CN107811989B (zh) 一种瑞舒伐他汀钙药物组合物及其制备方法
US20080207643A1 (en) Composition for Treating Hyperlipaemia
WO2015066784A1 (fr) Composition pharmaceutique, forme pharmaceutique orale, capsule, comprimé bicouche, utilisations, procédé de traitement de l'hypercholestérolémie, de l'hypertriglycéridémie et/ou de la dyslipidémie mixte, et procédé de prévention de l'athérosclérose, du diabète ou prévention secondaire d'autres maladies cardiovasculaires
AU2003254428B2 (en) Stable controlled release pharmaceutical compositions containing Fenofibrate and Pravastatin

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880115597.7

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08855968

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08855968

Country of ref document: EP

Kind code of ref document: A1