WO2009070974A1

WO2009070974A1 - Therapeutic composition containing amlodipine nicotinate and statins

Info

Publication number: WO2009070974A1
Application number: PCT/CN2008/001872
Authority: WO
Inventors: Haiyong Wang; Yanming Chen; Junchang Fu; Leibo Wang
Original assignee: Beijing Rock Pharmaceutical Co., Ltd.; Beijing Sl Pharmaceutical Co., Ltd.
Priority date: 2007-11-12
Filing date: 2008-11-12
Publication date: 2009-06-11
Also published as: CN101854931B; CN101433539A; CN101854931A

Abstract

The therapeutic composition containing amlodipine nicotinate and statins is provided in the present invention. The formulation containing the composition, method to prepare the composition, and kit for associated administering the composition are also provided. The composition contains the following components: 1) an amount of amlodipine nicotinate; 2) an amount of one kind or many kinds of statins compounds or pharmaceutical acceptable salts thereof; and 3) a pharmaceutically acceptable carrier or diluent. The said composition or kit can be used to treat the sufferers (including human) suffering from angina pectoris, atherosclerosis and/or hypertension and hyperlipidemia complication and cardio-risk symptoms.

Description

Therapeutic 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

As the structure of human disease changes, diseases caused by hyperlipidemia become a major threat to health. Every year, between 8 and 10 million people worldwide die from cardiovascular diseases and strokes. Arteriosclerosis caused by hyperlipidemia is the main cause of coronary heart disease, hypertension and cerebrovascular diseases. The main component of coronary atherosclerotic plaque is cholesterol. The higher the blood cholesterol level, the greater the risk of coronary heart disease. Therefore, lowering blood cholesterol levels is important for the prevention and treatment of coronary heart disease. Therefore, blood lipid regulating drugs have become a drug of great interest in the pharmaceutical market.

Conversion from 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) to 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. The end result is lower levels of LDL (low-density lipoprotein), TG (triglyceride) and TC (total cholesterol), and an increase in HDL (high-density lipoprotein). Therefore, statins are a class of drugs that have strong lipid-lowering properties.

Statins are sometimes divided into two types according to their structure. 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. The 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. Pharmacologically, colvastatin (Baycol, Lipobay) is a synthetic statin. However, due to the high incidence of serious side effects reported in patients, it is mainly caused by rhabdomyolysis and renal failure caused by single administration. And dose-dependent myopathy. Was withdrawn from the market in 2001. To date, seven commonly used statins have been marketed, including 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 and related dihydropyridine compounds are disclosed in US patents

4,572,909, which is incorporated herein by reference, is an effective anti-ischemic and anti-hypertensive agent. 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. Although people are trying to improve risk factors for secondary conditions, such as smoking, obesity and lack of exercise, and treatment of dyslipidemia through improved diets and medications, CHD remains the most common cause of death in the United States. High concentrations of blood cholesterol and blood lipids are responsible for atherosclerosis. It is well known that inhibitors of HMG-CoA reductase can effectively lower plasma cholesterol levels, especially in humans, low-density lipoprotein cholesterol (LDL-C) has now established a method to reduce LDL-C and thus prevent coronary heart disease (see, eg , The Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994,344,1383-89; and Shepherd, J. et al., Prevention Of coronary heart disease with pravastatin in men with hypercholesterolemia, New England Journal of Medicine, 1995, 333, 1301- 07).

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. The treatment of angina symptoms involves the use of a large number of drugs, usually in combination with two or more of the following classes of drugs: beta blockers, nitrates and calcium channel blockers. Most, if not all, patients generally need to be treated with hypolipidemic drugs. The National Cholesterol Education Program (NCEP) believes that patients with special types of coronary heart disease need to actively improve the treatment of LDL-C.

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. For patients with vasospasm angina, amlodipine has been shown to prevent contraction and thus restore the supply of myocardial oxygen. In addition, 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. In 2002, 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. 2004 Sep; 2(5): 675-81.) In addition, patients who are treated for hypertension are generally more responsive than those who are treated for hyperlipidemia. Therefore, a single treatment for both diseases is beneficial to the patient. 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. In order to reduce the risk of coronary heart disease for a long time, it is very important to control the entire risk spectrum. For example, 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.

Evidence suggests that calcium channel blockers are associated with lipid-lowering agents (eg, HMGCOA reductase inhibitors), particularly pravastatin, in combination with synergistic therapy (Jukema et al. Circulation, 1995 (Suppl. 1), 1-197 )·. 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). In addition, 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).

However, 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.

Thus, a first aspect of the invention provides a "composition" involving the following ingredients:

a) - a quantitative amount of amlodipine niacin;

b) - a quantity of one or more statins or a pharmaceutically acceptable salt thereof;

C) a pharmaceutically acceptable carrier or diluent,

The amlodipine niacin in the composition has significantly improved solubility and photostability compared to cisplatin benzenesulfonate, thereby enhancing the pharmacological activity of the composition. In addition, salt-forming niacin is not only an auxiliary component of salt formation, but also has a beneficial pharmacological effect. At the same time, 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:

1. The preparation of a composition by an alkalizing agent method, comprising:

[A] granulation of statins or their salts

[B] Final formulation.

2. Preparation of a composition by a package, including:

[A] Preparation of inclusion complex

[B] The final configuration.

3. Preparation of a composition by micro-deuteration, comprising:

[A] Preparation of micro *

[B] The final configuration.

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) a first unit dosage form containing a certain amount of amlodipine niacin and a pharmaceutically acceptable carrier or diluent;

b) 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;

c) a container for holding said first and second unit dosage forms.

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.

Due to the 4-position asymmetry of the dihydropyridine ring, 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) There are not many R isomers, or no calcium channel blocking activity at all. However, 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). Based on the above, 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;

Figure 2a: 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;

Figure 4a: HPLC diagram of the relevant substance at 4 weeks;

Figure 4b: HPLC plot of the relevant substance at 4 weeks;

Figure 5: Structural formula of amlodipine niacin

The present invention relates to 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.

The "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.

The term "pharmaceutically acceptable salts," includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The term "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.

Other 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. Typical 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. In most cases, it is preferred to mix 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.

The 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. Alternatively, the compound may be administered in a local rather than systemic manner, for example, in the form of a depot or sustained release formulation. In addition, 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.

The pharmaceutical 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.

Thus, the pharmaceutical 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.

For oral administration, the 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. In particular, 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). If necessary, 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, nectar Sugar alcohol, microcrystalline cellulose, polymethacrylate, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, talc and tribasic calcium phosphate; disintegrants include Carboxymethylcellulose calcium, sodium carboxymethylcellulose, colloidal silica, polyvinylpyrrolidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, powdered cellulose, pregelatinization Starch, sodium alginate, sodium glycolate starch and starch; flavoring agents include ethyl maltitol, ethyl vanillin, maltol, menthol and vanillin; glidants include colloidal silica, magnesium trisilicate , powdered cellulose, starch, talc and calcium dihydrogen phosphate; granulating agents include gum arabic, glucose, gelatin, polyvinylpyrrolidone, starch and yellow gum; lubricants include calcium stearate, glyceryl stearate, Palmitoyl stearyl glyceride, hydrogenated castor oil, hydrogenated vegetable oil, stearin, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc And zinc stearate; nonionic surfactants including glyceryl oleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters: preservatives including alcohols, benzalkonium chloride, Benzethonium chloride, benzyl alcohol, bromide, butyl p-hydroxybenzoate, cetyltrimethylammonium bromide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethyl p-hydroxybenzoate, Glycerin, methyl paraben, phenol, phenoxyethanol, phenylhexyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylene glycol, propyl paraben, sodium benzoate, c Sodium and mercaprous; solubilizers include benzalkonium chloride, benzethonamine, benzyl benzoate, cyclodextrin, glyceryl stearate, lecithin, poloxamer, polyoxyethylene alkyl ether, Polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan ester and stearic acid; suspending agent including gum arabic, bentonite, charcoal, carboxymethyl Fiber Calcium, sodium carboxymethyl cellulose; colloidal silica, dextrin, gelatin, guar, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, magnesium aluminum silicate , maltitol solution, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, powdered cellulose, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, yellow gum and xanthan gum.

A suitable coating is provided for the tablet core. For this purpose, 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.

Pharmaceutical preparations 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. In soft gels * the active compound can be dissolved or suspended in a suitable fluid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in a form suitable for oral administration.

For buccal administration, the 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.

In addition to the formulations described above, the compounds can also be formulated as depot preparations. These long acting formulations can be implanted, for example, subcutaneously or intramuscularly. Thus, for example, 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.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient. Alternatively, 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. In addition, 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.

Many of 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.

Pharmaceutical 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. Also, the unit dosage form may itself be a gel, tablet, tablet or lozenge, or it may be in the appropriate number of packages.

In particular, the invention relates to "compositions" containing the following ingredients:

a) a certain amount of amlodipine niacin;

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:

1. Preparation of composition by alkalizing agent method

[A] 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;

[B] Final formulation, including:

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; and

Step 3: Mixing the homogeneous composition and lubricant in a mixer for providing a uniformly mixed pharmaceutical composition in solid dosage form.

2. Preparation of a composition by a package, including: [A] Preparation of inclusion complex

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.

In step 2, 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.

[B] final configuration

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.

3. Preparation of composition by microencapsulation

[A] Preparation of microcapsules

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.

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. N2008/001872

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. Further, 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.

[B] final configuration

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.

The present invention also relates to a kit, hereinafter referred to as "kit A," which achieves a therapeutic effect in a mammal, which consists of the following components:

a) a first unit dosage form containing a quantity of amlodipine niacin and a pharmaceutically acceptable carrier or diluent;

b) two unit dosage forms containing an amount of one or more statins or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

c) a container for holding the first and second unit dosage forms.

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. According to 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

10 2.5

20 2.5

40 2.5

80 2.5

10 5

20 5

40 5

80 5

10 10

20 10

40 10

80 10 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. Typically, 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.

The pharmaceutical 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 people, angina, arterial porridge Sclerotherapy is characterized by the presence of hypertension and hyperlipidemia.

Furthermore, because 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.

The term "heart risk" as used herein 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.

The lower doses mentioned in the specification and claims and other doses mentioned elsewhere are for patients whose average body weight is about 65 kg-70 kg. Depending on the patient's medication history and the presence of the subject's disease, such as diabetes, the skilled person can easily determine the dose required for a subject who is outside of 65 kg-70 kg. All doses mentioned in the specification and claims are daily doses. For example, those skilled in the art recognize that the free base form of atorvastatin calcium or other salt forms can be used in the present invention. The following non-limiting examples detail the methods of making and using the pharmaceutical compositions of the present invention. Example

Example 1 General Method for Preparation of Atorvastatin Calcium Microcapsules

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. Adding a mass concentration of 20% formaldehyde and a 5% concentration of glutaraldehyde Solution, then adjust the pH of the system to 8.5-9.5, cross-link solidify for 2 hours, rinse the product 2-3 times with distilled water, remove residual formaldehyde and glutaraldehyde, and place the washed micro-microspheres in a three-necked flask. The bath temperature is kept at 20. C-25 ° C, then a tannin solution at a concentration of 5% was added dropwise, and after treatment for 10 hours, the final product was washed with water and then allowed to air dry at room temperature. Example 2 General Method for Preparation of Atorvastatin Calcium / Amlodipine Tablets Using Atorvastatin Calcium Micro*

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.

Table 1. Atorvastatin calcium micro-attack / niacin cefodipine tablets (g / 1000

Film)

Example 3 General method for preparing amlodipine octachlorate inclusion compound: β-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 β-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

General method for calcium/nicotinic acid amlodipine tablets

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. Add water as a wetting agent and binder to make soft material, granulate, and add a prescription amount of strontium stearate. The specific specifications are shown in Table 2.

Table 2. Amlodipine octoate inclusion compound / atorvastatin calcium tablets (g / 1000 tablets)

Example 5 Light resistance test

The pharmaceutical compositions of the study products 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. As is apparent from the above results, the research product exhibited improved light resistance as compared with the control, and the improved light resistance of amlodipine niacin in a single conjugate was also exhibited in the compound.

Claims

1. A composition comprising the following ingredients:

a) a certain amount of amlodipine niacin;

b) - a quantity of one or more statins or a pharmaceutically acceptable salt thereof; and C) a pharmaceutically acceptable carrier or diluent.

2. The composition of claim 1 wherein the amount of amlodipine niacin (in terms of amlodipine, the same below) is from 1 to 25 mg.

3. The composition of claim 2, wherein the amount of amlodipine niacin is 2.5-10 mg.

The composition according to any one of claims 1 to 3, wherein the statin compound is selected from the group consisting of lovastatin, pravastatin, simvastatin, rosuvastatin, pitavastatin, fluvastatin, Atorvastatin and their pharmaceutically acceptable salts.

5. The composition of claim 4 wherein said statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin and pharmaceutically acceptable salts thereof.

The composition according to any one of claims 1 to 3, wherein the amount of the statin compound is 1-200 m o

7. The composition of claim 1 wherein the statin is atorvastatin calcium and is present in an amount of 10-80 mg based on atorvastatin.

8. The composition of claim 1 wherein the statin is rosuvastatin calcium and is present in an amount of from 5 to 80 mg based on rosuvastatin.

9. A process for the preparation of a composition according to any one of claims 1 to 8 which comprises: (1) preparing a composition by an alkalizing agent method

[A] Granules of statins or their salts, including:

Step 1: dissolving the surfactant in water and adding a binder;

Step 2: Mix the statin compound or its salt in a granulation apparatus and form an alkalizing agent with a pH between 4 and 10, for different statins or their salts. The adjusted pH depends on its structure, 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;

[B] Final formulation, including:

Step 1: Add clopiate penicillin, filler/diluent, disintegrant, and glidant to the statin formula.

Step 2: The powder mixture is passed through an 80 mesh screen; and

Step 3: mixing the homogeneous composition and the lubricant in a mixer for providing a uniformly mixed pharmaceutical composition in the form of a solid dosage form; or

(2) A package preparation composition comprising:

[A] Preparation of inclusion complex

Step 1: preparing a saturated aqueous solution of the main body, the main body may be a homologue of cyclodextrin, or may be urea, and the main body may be used alone or in combination;

Step 2: adding a quantitative guest substance to the saturated aqueous solution of the main body and dissolving, the guest substance may be amlodipine niacin or a statin such as atorvastatin calcium;

Step 3: The 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 dry clathrate should be controlled between 10-60 degrees Celsius; [B] Final configuration

Step 1: The clathrate is pulverized, and the U number is controlled between 60-120; Step 2: The clathrate fine powder and another uncontained guest fine powder (between 60 and 120 mesh) in the mixer The neutralizing lubricant is uniformly mixed and used to provide a uniform mixed pharmaceutical composition in a solid dosage form; or (3) Preparation of composition by micro-chemical method

[A] Preparation of micro-attack

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 more of cellulose, polyester, polymer anhydride, etc.;

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-yuan by single coacervation method, which can reduce the temperature, adjust the pH or add a dehydrating agent, non-solvent and other coagulant to reduce the solubility of the polymer, and precipitate the polymer material from the solution to form a new condensed liquid sphere. , or the polymer in the condensed liquid phase is deposited on the attack substance, wherein the temperature control range is between 0-100 degrees Celsius, preferably between 10-80 degrees Celsius, and the acid-adjusted pH value is controlled between 2-5, the alkali adjustment The pH should be controlled between 7-10;

Step 4: Perform low temperature drying on the obtained micro*, and control the temperature between 20-60 degrees Celsius;

[B] final configuration

Step 1: The dried microcapsules are pulverized, and the mesh number is controlled between 60 and 120 meshes; Step 2: The microencapsulated fine powder and another guest which is not microcapsuleized are fine.

^ (between 60 and 120 mesh) is uniformly mixed with the lubricant in a mixer for providing a uniformly mixed pharmaceutical composition in the form of a solid dosage.

10. A formulation comprising the composition of any one of claims 1 to 8 selected from the group consisting of a common tablet, a pill, a powder or granule, a lozenge, a gelatin, a gel, a syrup, a bone, a suspension Liquid, cachets and suppositories.

11. A kit comprising the composition of any one of claims 1 to 8, which consists of the following: a) a first unit dosage form containing a certain amount of amlodipine niacin and a pharmaceutically acceptable carrier or diluent;

c) a container for holding said first and second unit dosage forms.

12. A method of treating angina pectoris, atherosclerosis and/or hypertension and hyperlipidemia in a mammal, including a human, comprising administering an effective amount of the composition of any one of claims 1 to 8. The formulation of claim 10 or the kit of claim 11 administered to the mammal.

13. Use of a composition according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of angina pectoris, atherosclerosis and/or hypertension and hyperlipidemia in a mammal, including a human Blood.