HK1117398A - Pharmaceutical compositions of amlodipine and atorvastatin - Google Patents

Description

Pharmaceutical composition of amlodipine and atorvastatin

The invention is a divisional application of Chinese patent application 02815040.6 filed on 7, 29/2002, and the invention of the original application is named as a pharmaceutical composition of amlodipine and atorvastatin.

Technical Field

The present invention relates to pharmaceutical compositions containing amlodipine (amlodipine) and pharmaceutically acceptable salts thereof, and atorvastatin (atorvastatin) and pharmaceutically acceptable salts thereof, methods of preparing such compositions, kits containing such compositions, and methods of using such compositions for the treatment of patients suffering from angina pectoris, atherosclerosis, hypertension and hyperlipidemia complications and/or hypercholesterolemia, and for the treatment of patients, including human subjects, at risk of developing cardiac symptoms.

Background

In the early and rate-limiting step in the cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) is converted to mevalonate. This step is catalyzed by HMG-CoA reductase. Statins inhibit this conversion by HMG-CoA reductase. Because of this, statins are all potent lipid lowering agents.

Atorvastatin calcium disclosed in U.S. Pat. No.5,273,995, which is incorporated herein by reference, is currently available as Lipitor^®Sold under the name of (Liputa), having the chemical name [ R- (R, R)]-2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and the following structural formula:

atorvastatin and pharmaceutically acceptable salts thereof are selective competitive inhibitors of HMG-CoA reductase. Because of this, atorvastatin calcium is a potent lipid lowering agent and is therefore useful as a hypolipidemic and/or hypocholesterolemic agent.

U.S. Pat. No. 4,681,893, which is incorporated herein by reference, discloses some trans-6- [2- (3-or 4-formylamino-substituted-pyrrol-1-yl) alkyl ] -4-hydroxy-pyran-2-ones, including trans (±) -5- (4-fluorophenyl-2- (1-methylethyl) -N, 4-diphenyl-1- [ (2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl ] -1H-pyrrole-3-carboxamide.

U.S. Pat. No.5,273,995, which is incorporated herein by reference, discloses the R-form enantiomer of the open cyclic acid having trans-5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1- [ (2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl ] -1H-pyrrole-3-carboxamide, i.e., [ R- (R, R) -2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (phenylamino) -carbonyl ] -1H-pyrrole-1-heptanoic acid, it is atorvastatin.

U.S. Pat. nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482, respectively; 5,149,837, respectively; 5,155,251, respectively; 5,216,174, respectively; 5,245,047, respectively; 5,248,793, respectively; 5,280,126, respectively; 5,397,792, respectively; 5,342,952, respectively; 5,298,627, respectively; 5,446,054, respectively; 5,470,981, respectively; 5,489,690, respectively; 5,489,691, respectively; 5,510,488, respectively; 5,998,633 and 6,087,511, which are incorporated herein by reference, disclose various processes and key intermediates for the preparation of atorvastatin.

Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461, incorporated herein by reference.

Stable oral dosage forms of atorvastatin calcium are disclosed in U.S. Pat. nos. 5,686,104 and 6,126,971.

Amlodipine and related dihydropyridine compounds are disclosed in U.S. patent No. 4,572,909, which is incorporated herein by reference, as being effective anti-ischemic and anti-hypertensive agents. U.S. Pat. No. 4,879,303, incorporated herein by reference in its entiretyAmlodipine besylate (also known as amlodipine besylate) is disclosed. Amlodipine and amlodipine besylate are effective and durable calcium channel blockers. Because of this, other pharmaceutically acceptable acid addition salts of amlodipine, amlodipine besylate and amlodipine have utility as antihypertensive agents and anti-ischemic agents. U.S. patent No.5,155,120 also discloses that amlodipine and its pharmaceutically acceptable salts have utility in the treatment of congestive heart failure. Amlodipine besylate is currently available as Norvasc^®(amlodipine besylate) is sold. Amlodipine has the following formula:

atherosclerosis is a condition characterized by an irregularly distributed lipid deposition in the intima of arteries, including the coronary, carotid and peripheral arteries. Coronary atherosclerotic heart disease (hereinafter "CHD") accounts for 53% of all deaths due to cardiovascular disease. CHD accounts for approximately half the annual total us cardiovascular health care expenditure (approximately $500- $600 billion) and 6% of the global medical costs. Despite efforts to alleviate secondary risk factors such as, inter alia, smoking, obesity and lack of exercise, and treatment of dyslipidemia with dietary modification and drug therapy, CHD remains the leading cause of death in the united states.

High levels of blood cholesterol and blood lipids are symptoms involved in the development of atherosclerosis. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) are known to be effective in lowering male plasma cholesterol levels, particularly low density lipoprotein cholesterol (LDL-C) (Brown and Goldstein, New England Journal of medicine, 1981; 305 (9): 515-. It has now been determined that lowering LDL-C levels provides protection against coronary heart disease (see, for example, The Scandinavian Simvastatin Study group.4444 randomized trials of cholesterol lowering in patients with coronary heart disease: Scandinavian simvastatin Survival Study (4S), Lancet, 1994; 344: 1383-.

Angina is a severe systolic pain in the chest that often radiates from the precordial region to the left shoulder and lower left arm. Angina pectoris is often due to cardiac ischemia and is often a coronary disease.

At present, angina pectoris is treated in different countries. In the united states, symptomatic stable angina patients are often treated with surgical procedures or Percutaneous Transluminal Coronary Angioplasty (PTCA). Patients receiving PTCA or other surgical procedures designed to treat angina pectoris often develop complications such as restenosis. This restenosis occurs either as a short-term diffuse response to angioplasty-induced trauma or as a long-term progression through the process of atherosclerosis in the implanted vessel and bypass segment of angioplasty.

Symptomatic treatment of angina pectoris involves the use of a wide variety of drugs, often as a combination of two or more of the following classes: beta blockers, nitrates and calcium channel blockers. Most, if not all, patients also require treatment with lipid lowering drugs. The national Cholesterol reduction Program (NCEP) acknowledges that patients with coronary artery disease are a specific group of people who require supra-routine management of elevated LDL-C.

Amlodipine helps prevent myocardial ischemia in patients with exercise-induced angina by reducing overall peripheral resistance, or after administration, it reduces rate pressure products (rate pressure products) requiring oxygen at any particular level of exercise. Amlodipine has been shown to block stenosis in vasospastic angina patients, thus restoring myocardial oxygen supply. In addition, amlodipine has been shown to increase myocardial oxygen supply by dilating coronary arteries.

Hypertension often occurs with hyperlipidemia, both of which are considered to be major risk factors for the development of heart disease, ultimately leading to adverse heart disease. This clustering of risk factors may be due to a common mechanism. Furthermore, patients receiving treatment for hypertension are generally better than patients receiving treatment for hyperlipidemia. Thus, it would be advantageous for a patient to receive a monotherapy that treats both symptoms.

Coronary heart disease is a multifactorial disease in which the occurrence and severity are influenced by lipid distribution, the presence of diabetes, and the sex of the patient. Its occurrence is also affected by smoking and left ventricular hypertrophy, the latter being a secondary disease to hypertension. In order to meaningfully reduce the risk of coronary heart disease, it is important to control the entire risk range. For example, hypertension intervention trials cannot demonstrate a complete normalization of cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the risk of cardiovascular morbidity and mortality.

Framingham cardiology, a continuing prospective study of adult males and females, suggests that several risk factors can be used to predict the development of coronary heart disease (see Wilson et al, am. J Cardiol, 1987; 59 (14): 91G-94G). These factors include age, sex, total cholesterol level, High Density Lipoprotein (HDL) level, systolic blood pressure, smoking, glucose intolerance, and cardiac hypertrophy (electrocardiogram, echocardiogram showing left ventricular hypertrophy, or chest X-ray showing cardiac enlargement). The calculator and computer are readily programmable using a multivariate logarithmic function that calculates the likelihood of cardiovascular disease events.

These measurements estimated coronary artery disease risk at an irregular follow-up period based on the history of 5,209 men and women participating in the Framingham study. During an arbitrarily selected 6 year interval, the incidence of the paradigm ranges from less than 1% to greater than 80%. However, these incidences are generally less than 10% and rarely exceed 45% for men and 25% for women.

Kramsch et al, Journal of Human Hypertension, 1995; (supplement 1): 53-59, discloses the use of calcium channel blockers, including amlodipine, to treat atherosclerosis. That reference further teaches the use of combinations of amlodipine and a lipid lowering agent to treat atherosclerosis. Human trials have shown beneficial effects of calcium channel blockers in the treatment of early atherosclerotic lesions (see, e.g., Lichtlen P.R. et al, Retardation of coronary artery disease angiography procedures by nifedipine, Lancet, 1990; 335: 1109-. U.S. Pat. No. 4,681,893 discloses that some statins, including atorvastatin, are hypolipidemic agents and are useful for treating atherosclerosis. Jukema et al, Circulation, 1995; (supplement 1): 1-197, discloses evidence of the presence of a calcium channel blocker synergistic with a lipid-lowering drug (e.g., an HMG-CoA reductase inhibitor), specifically pravastatin. Orekhov et al, Cardiovasular drugs and Therapy, 1997; 11: 350 discloses the use of amlodipine in combination with lovastatin for the treatment of atherosclerosis.

International published patent application WO99/11259 discloses therapeutic combinations comprising amlodipine and atorvastatin. It is therefore desirable to be able to administer both drugs to patients requiring dual therapy. Furthermore, it is even more desirable to administer both drugs in a single dosage form.

It is therefore an object of the present invention to provide stable dosage forms with good bioavailability. It is another object of the present invention to provide stable compositions with low levels of impurities and/or degradation products that may occur during preparation and/or subsequent storage of the composition. We have surprisingly and unexpectedly found that although it is known that there is incompatibility between amlodipine and atorvastatin, amlodipine and atorvastatin can be formulated in a single dosage form that is stable and has a bioavailability equivalent to the respective therapeutic agents administered in separate dosage forms and contains very low levels of impurities and/or degradation products.

Summary of The Invention

Accordingly, a first aspect of the present invention is a pharmaceutical composition comprising two components: (a) one component includes particles of atorvastatin or a pharmaceutically acceptable salt thereof and a carrier including an alkalizing agent that forms a pH greater than 5; and (b) a second component comprising amlodipine or a pharmaceutically acceptable salt thereof and a carrier, excluding alkalizing agents that form a pH greater than 5, wherein the two components are combined to form the final composition in a solid dosage form.

A second aspect of the invention is a method of preparing a pharmaceutical composition comprising:

[A] atorvastatin granularized comprising:

step (1) -dissolving a surfactant in water and adding a binder and hydrating;

step (2) -mixing atorvastatin calcium in a granulation device to form an alkalizing agent having a pH greater than 5, a filler/diluent/disintegrant, and a disintegrant;

step (3) -granulating the powder mixture from step (2) and the solution from step (1) in a granulator device; and

step (4) -drying the granules in a drying apparatus;

[B] and finally, preparing the composition, which comprises:

step (1) -adding amlodipine besylate, a filler/diluent, a disintegrant, and a glidant (glidant) to an atorvastatin formulation;

step (2) -passing the powder mixture through a mill; and

step (3) -mixing the milled powder mixture and the lubricant in a mixer to provide a homogeneously mixed pharmaceutical composition for solid dosage forms.

A third aspect of the invention is a pharmaceutical composition having low levels of degradation products and/or impurities.

A fourth aspect of the invention is a method of using the pharmaceutical composition for treating a patient suffering from angina pectoris, atherosclerosis, hypertension and hyperlipidemia complications and/or hypercholesterolemia and for treating a patient, including a human subject, exhibiting signs of cardiac risk.

A fifth aspect of the invention is a commercially suitable therapeutic package or kit comprising a container and a pharmaceutical composition having low levels of degradation products and/or impurities.

Drawings

The invention will be further described, by way of non-limiting example, with reference to the accompanying figures 1-18, which are briefly described below.

Figure 1 is a plot of amlodipine plasma concentration versus time following co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (filled symbols) and a 5-mg amlodipine/10-mg atorvastatin dual treatment tablet (open symbols). The upper and lower panels are linear and semi-logarithmic graphs, respectively.

Figure 2 is a graph of atorvastatin plasma concentration versus time following co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (filled symbols) and a 5-mg amlodipine/10-mg atorvastatin dual treatment tablet (open symbols). The upper and lower panels are linear and semi-logarithmic graphs, respectively.

Figure 3 is a graph of the individual amlodipine Cmax values after co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (reference) and 5-mg amlodipine/10-mg atorvastatin dual treatment tablets (test). Circles and triangles represent individual subjects and mean values, respectively.

Figure 4 is a graph of the individual amlodipine AUC (0- ∞) values after co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (reference) and 5-mg amlodipine/10-mg atorvastatin dual therapy tablets (trial). Circles and triangles represent individual subjects and mean values, respectively.

Figure 5 is the individual atorvastatin Cmax values after co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (reference) and 5-mg amlodipine/10-mg atorvastatin dual treatment tablets (test). Circles and triangles represent individual subjects and mean values, respectively.

Figure 6 is the individual atorvastatin AUC (0- ∞) values after co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (reference) and 5-mg amlodipine/10-mg atorvastatin dual therapy tablets (trial). Circles and triangles represent individual subjects and mean values, respectively.

Figure 7 is a graph of mean amlodipine plasma concentration versus time following co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (filled symbols) and a 10-mg amlodipine/40-mg atorvastatin dual treatment tablet (open symbols). The upper and lower panels are linear and semi-logarithmic graphs, respectively.

Figure 8 is a graph of mean atorvastatin plasma concentration versus time after co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (filled symbols) and a 10-mg amlodipine/40-mg atorvastatin dual treatment tablet (open symbols). The upper and lower panels are linear and semi-logarithmic graphs, respectively.

Figure 9 is the individual amlodipine Cmax values after co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/40-mg atorvastatin dual treatment tablets (test). Circles and triangles represent individual subjects and mean values, respectively.

Figure 10 is a graph of the individual amlodipine AUC (0- ∞) values after co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/40-mg atorvastatin dual therapy tablets (trial). Circles and triangles represent individual subjects and mean values, respectively.

Figure 11 is the individual atorvastatin Cmax values after co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/40-mg atorvastatin dual treatment tablets (test). Circles and triangles represent individual subjects and mean values, respectively.

Figure 12 is the individual atorvastatin AUC (0- ∞) values after co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/40-mg atorvastatin dual therapy tablets (trial). Circles and triangles represent individual subjects and mean values, respectively.

Figure 13 is a plot of mean amlodipine plasma concentration versus time following co-administration of 10-mg amlodipine and 2 x 40-mg atorvastatin tablets (filled symbols) and a 10-mg amlodipine/80-mg atorvastatin dual treatment tablet (open symbols). The upper and lower panels are linear and semi-logarithmic graphs, respectively.

Figure 14 is a plot of mean atorvastatin plasma concentration versus time after co-administration of 10-mg amlodipine and 2 x 40-mg atorvastatin tablets (filled symbols) and a 10-mg amlodipine/80-mg atorvastatin dual treatment tablet (open symbols). The upper and lower panels are linear and semi-logarithmic graphs, respectively.

Figure 15 is the individual amlodipine Cmax values after co-administration of 10-mg amlodipine and 2 x 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/80-mg atorvastatin dual treatment tablets (test). Circles and triangles represent individual subjects and mean values, respectively.

FIG. 16 is the individual amlodipine AUC (0- ∞) values after co-administration of 10-mg amlodipine and a 2X 40-mg atorvastatin tablet (reference) and a 10-mg amlodipine/80-mg atorvastatin dual therapy tablet (trial). Circles and triangles represent individual subjects and mean values, respectively.

Figure 17 is the individual atorvastatin Cmax values after co-administration of 10-mg amlodipine and 2 x 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/80-mg atorvastatin dual treatment tablets (test). Circles and triangles represent individual subjects and mean values, respectively.

Figure 18 is a graph of the individual atorvastatin AUC (0- ∞) values after co-administration of 10-mg amlodipine and 2 x 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/80-mg atorvastatin dual therapy tablets (trial). Circles and triangles represent individual subjects and mean values, respectively.

Detailed description of the invention

The pharmaceutical composition of the present invention contains amlodipine or a pharmaceutically acceptable acid addition salt thereof and atorvastatin or a pharmaceutically acceptable base addition salt thereof.

Amlodipine can be readily prepared as described in U.S. patent No. 4,572,909, which is incorporated herein by reference. At present, the Norvasc is adopted^®Amlodipine besylate is sold and can be prepared as described in U.S. patent No. 4,879,303, which is incorporated herein by reference. Amlodipine and amlodipine besylate are effective long-acting calcium channel blockers.

Atorvastatin can be readily prepared as described in U.S. Pat. Nos. 5,273,995 and 5,969,156, both of which are incorporated herein by reference. The hemicalcium salt of atorvastatin is currently expressed as lipitor^®And (5) selling.

Pharmaceutically acceptable acid addition salts of the compounds of this invention include those derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphoric and the like, as well as those derived from non-toxic organic acids such as aliphatic mono-and dibasic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Such salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, toluenesulfonate, and the like. Also included are salts of amino acids such as arginine salts and the like and gluconate, galacturonate (see, e.g., Berge S.M.et., "Pharmaceutical salts," J.of Pharma.Sci., 1977; 66: 1).

The acid addition salts of the basic compounds are prepared in a conventional manner by contacting the free base form with a sufficient amount of the desired acid. The free base may be prepared by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ from their respective salt forms in more or less physical properties, such as solubility in polar solvents, on the other hand, the salts are equivalent to their respective free bases for the purposes of the present invention.

Forming pharmaceutically acceptable base addition salts with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of the metal used as the cation include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, e.g., Berge et al, supra, 1977).

The base addition salts of the acidic compounds are prepared in a conventional manner by contacting the free acid form with a sufficient amount of the desired base to prepare the salt. The free acid may be prepared by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms in more or less different physical properties, such as solubility in polar solvents, on the other hand, the salts are equivalent to their respective free acids for the purposes of the present invention.

In addition, the compounds of the present invention can exist in unsolvated and solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Amlodipine is a racemic compound due to the symmetry at the 4-position of the dihydropyridine ring. According to Arrowsmith et al, J.Med.chem., 1986; 29: 1696 the R and S enantiomers can be prepared. The calcium channel blocking activity of amlodipine is substantially limited to the S (-) isomer and to racemic mixtures containing the R (+) and S (-) forms [ see International patent application No. PCT/EP94/02697(WO95/05822) ]. The R (+) isomer has little or no calcium channel blocking activity. However, the R (+) isomer is a potent inhibitor of smooth muscle cell migration. Thus, the R (+) isomer is useful in the treatment or prevention of atherosclerosis [ see International patent application No. PCT/EP95/00847(WO95/25722) ]. On the basis of the above, the skilled person will be able to select the R (+) isomer, the S (-) isomer or a racemic mixture of the R (+) isomer and the S (-) isomer to be used in the combination of the present invention.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier is a solid. Solid form preparations include powders, tablets, pills, capsules, cachets, and suppositories. A solid carrier can be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

For example, anionic surfactants include docusate sodium and sodium lauryl sulfate; binders include acacia, charcoal (carbomer), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type 1), hydroxyethyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, starch, and zein; cationic surfactants including benzalkonium chloride, benzethonium chloride, and cetrimide; diluents include calcium carbonate, calcium sulfate, dextrose, dextrin, dextran, dibasic calcium phosphate dihydrate, palmitoyl stearoyl glyceride, hydrogenated vegetable oil (type 1), kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, talc and tribasic calcium phosphate; disintegrants include calcium carboxymethylcellulose, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium glycolate starch and starch; the flavoring agent comprises ethyl maltitol, ethyl vanillin, maltol, menthol and vanillin; glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and calcium phosphate tribasic; granulating agents including acacia, glucose, gelatin, povidone, starch and tragacanth; lubricants include calcium stearate, glyceryl monostearate, palmitoyl stearoyl glyceride, hydrogenated castor oil, hydrogenated vegetable oil (type 1), light mineral oil, lubritab, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate; nonionic surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, and sorbitan esters; preservatives include alcohols, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, butyl paraben, cetyltrimethylammonium bromide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethyl paraben, glycerol, imidurea, methyl paraben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylene glycol, propyl paraben, sodium benzoate, sodium propionate and thimerosal; solubilizers include benzalkonium chloride, benzethonium chloride, benzyl benzoate, cyclodextrin, glycerol monostearate, lecithin, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan esters, and stearic acid; suspending agents include acacia, bentonite, charcoal, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl methylcellulose, kaolin, magnesium aluminum silicate, maltitol solutions, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, powdered cellulose, propylene glycol alginate, sodium starch glycolate, starch, tragacanth and xanthan gum.

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

In solid dosage forms, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain from 5% to about 70% of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, coconut oil and the like. The term "formulation" is intended to encompass the formulation of the active compound with an encapsulating material as a vehicle for providing a capsule with or without other vehicles around which the active ingredient is coated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges are used as solid dosage forms suitable for oral administration.

The pharmaceutical preparations are preferably in unit dosage form containing a suitable amount of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, for example, in the form of tablets, capsules, and powders in vials or ampoules.

Also, the unit dosage form may itself be a capsule, tablet, cachet, or lozenge, or it may be the appropriate number of packaged forms.

Specifically, the following general procedure is used to prepare the pharmaceutical compositions of the present invention:

[A] atorvastatin granules were prepared as follows:

step (1) -a surfactant such as polysorbate 80, sodium lauryl sulfate, etc. is dissolved in water, and a binder such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), starch 1500, starch, etc. is added and hydrated;

step (2) -mixing atorvastatin calcium and alkalizing agents that form a pH greater than 5, such as calcium carbonate, dicalcium phosphate and tricalcium phosphate and the like, fillers/diluents such as microcrystalline cellulose, silicified microcrystalline cellulose, starch 1551, sorbitol, mannitol, and the like, fillers/diluents/disintegrants such as croscarmellose sodium, sodium starch glycolate, polyplasdone, starch, carboxymethylcellulose (CMC), and the like, in a granulation apparatus such as a fluid bed granulator/dryer, high shear mixer/granulator, double wall mixer/granulator, ribbon mixing granulator, and the like;

step (3) -granulating the powder mixture from step (2) and the solution from step (1) in a granulation apparatus; and

step (4) -drying the granules in a drying apparatus such as a fluid bed granulator/dryer, oven, conveyor dryer, microwave dryer, or the like;

[B] the final formulation was prepared as follows:

step (1) -adding amlodipine besylate, a filler/diluent such as microcrystalline cellulose, silicified microcrystalline cellulose, starch 1551, a disintegrant such as croscarmellose sodium, sodium starch glycolate, polyplasdone, starch, CMC, etc., and a glidant such as silicon dioxide, talc, sterotex, stearic acid, syloid, etc., to the atorvastatin granules and milling by a mill such as a Comil mill, Fritz mill, Oscillator mill, Pin mill, etc.;

step (2) -mixing the ground powder material with a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, talc, etc., in a mixer such as described above, and

step (3) -compressing the blended granulation into tablets in a tableting apparatus.

Preferably, the granulation dryer used in preparing the pharmaceutical composition is a Fluid Bed Granulation Dryer (FBGD).

Thus, the pharmaceutical compositions of the present invention contain, in addition to the active pharmaceutical agent, an alkalizing agent which is used as a "bioavailability modifier" to modify the solubility and bioavailability of the formulation and as a "stability enhancer". The term "bioavailability modulator" means a substance used in a formulation that has an effect on the solubility of an active pharmaceutical agent and is therefore used to modulate the pharmacokinetic parameters of the drug. The term "stability enhancer" refers to the use of an alkalizing agent that stabilizes atorvastatin or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention.

"bioavailability modulators" may be used in a forward sense, i.e., their presence serves to increase blood levels of the formulation, or they may be used in a reverse sense, in which case their presence inhibits blood levels of the formulation. Thus, it is possible to optimize the bioavailability of a particular formulation by using an appropriate amount of a bioavailability modulator.

As indicated, the compositions of the present invention employ alkalizing agents such as calcium carbonate, dicalcium carbonate, tricalcium carbonate, and the like, as bioavailability modifiers.

In the tablets prepared according to the invention, the alkalizing agent serves as a positive meaning and serves to increase the bioavailability of the atorvastatin component. Preferably, calcium carbonate is used in a weight/weight ratio (w/w) of atorvastatin calcium to calcium carbonate of about 1: 1 to 1: 4. More preferably the ratio of atorvastatin calcium to calcium carbonate is 1: 3 w/w.

In addition, other preferred carriers for use in the pharmaceutical compositions of the present invention include microcrystalline cellulose, starch 1551, starch 1500, croscarmellose sodium, polysorbate 80, hydroxypropyl cellulose, silicon dioxide, and magnesium stearate.

The pharmaceutical composition of the present invention contains about 0.25% to about 10% amlodipine or a pharmaceutically acceptable salt thereof and about 2.5% to about 20% atorvastatin or a pharmaceutically acceptable salt thereof; preferably from about 0.5% to about 7% amlodipine besylate and from about 10% to about 20% atorvastatin calcium.

The following are fixed dual therapeutic dose combinations used in preferred pharmaceutical compositions according to the present invention.

Atorvastatin calcium as active ingredient (mg)	Amlodipine besylate as active ingredient (mg)
		510204080510204080510204080	2.52.52.52.52.5555551010101010

The present invention relates to the treatment of diseases and conditions, for example in patients suffering from angina pectoris, atherosclerosis, hypertension and hyperlipidemia complications and/or hypercholesterolemia and in patients presenting with signs of cardiac risk, with a combination of active ingredients as described above, which can be administered in the form of a solid dose with low levels of degradation products and/or impurities in a therapeutic package or kit. The kit includes a solid dosage form and a container. Typically, the kit includes instructions for administration of the dosage form. The container may be of any conventional shape or form known in the art, for example a carton, glass or plastic bottle, or a single dose pressed out from behind according to a treatment regimen.

The pharmaceutical compositions and methods of the present invention are all suitable for use as a treatment for angina pectoris, atherosclerosis and complications characterized by the presence of hypertension and hyperlipidemia in mammals, particularly in humans. Furthermore, because these diseases and symptoms are closely related to the occurrence of heart disease and the appearance of adverse cardiac conditions, these combinations and methods are useful in the management of cardiac risk by virtue of their action as anti-angina and anti-hyperlipidemia.

The term "cardiac risk" as used herein means that the patient suffers from future adverse cardiac symptoms, e.g. myocardial infarction, cardiac arrest, heart failure, myocardial ischemia. The cardiac risk was calculated using the Framingham Risk equation given above. The term "cardiac risk management" means that the risk of future adverse cardiac symptoms is substantially reduced.

The activity of the compounds of the present invention in routine testing and in the clinical methods described in International published patent application No. WO99/11259T, which is incorporated herein by reference, demonstrates the utility of the compounds of the present invention as pharmaceutical agents in the treatment of atherosclerosis in mammals, such as humans.

The following doses mentioned in the specification and claims and other doses mentioned elsewhere are for human subjects having a weight average of about 65kg to about 70 kg. The skilled person can readily determine the dosage required for a subject weighing outside of 65kg to 70kg, based on the history of the subject's medication and the disease, e.g. diabetes, present in the subject. All doses mentioned in the specification and claims are daily doses.

In general, amlodipine besylate is generally administered in a dosage of from about 0.5mg to about 20mg of the active ingredient according to the present invention. Preferably, amlodipine besylate is administered at a dose of about 5mg to about 10mg of the active ingredient. Those skilled in the art will recognize that the free base form or other salt forms of amlodipine besylate may be used in the present invention. The calculation of the dosage of the free base form or other salt forms of amlodipine besylate is easily accomplished by implementing simple ratios with respect to the molecular weight of the substances involved. Typically, according to the present invention, atorvastatin is administered at a dose of about 0.5mg to about 160mg of the active ingredient. Preferably, atorvastatin is administered at a dose of about 10mg to about 80mg of the active ingredient. One skilled in the art will recognize that atorvastatin calcium in its free base form or other salt forms may be used in the present invention. The calculation of the dosage of atorvastatin calcium in its free base form or in other salt forms of these other forms is easily accomplished by performing simple ratios with respect to the molecular weight of the substances involved.

Biological equivalence study

A single dose bioequivalence study was conducted comparing amlodipine besylate/atorvastatin calcium dual treatment tablets with co-administered amlodipine besylate and atorvastatin calcium tablets.

Specifically, a comparison was made between the following dosing regimens:

(1)5-mg amlodipine/10-mg atorvastatin dual therapy tablet versus 5-mg amlodipine and 10-mg atorvastatin tablet

(2)10-mg amlodipine/40-mg atorvastatin dual therapy tablet versus 10-mg amlodipine and 40-mg atorvastatin tablet

(3)10-mg amlodipine/80-mg atorvastatin dual treatment tablet versus 10-mg amlodipine and two 40-mg atorvastatin tablets

In all cases, the dual therapy tablets were bioequivalent to the amlodipine and atorvastatin tablets separate from the co-administration. Examples 2-4 and tables 1-3 describe the details of this study.

Stability study

The total impurities and/or degradation products from atorvastatin after 24 months of storage of the pharmaceutical composition at 25 ℃/60% Relative Humidity (RH) should not exceed 2.0%. In addition, the following specific impurities and/or degradation products should not exceed 0.5%:

5- (4-fluorophenyl) -9, 3-dihydro- β, δ -dihydroxy-3- (1-methylethyl) -2-oxo-4-phenyl-3- [ (phenylamino) carbonyl ] -1H-pyrrole-1-heptanoic acid;

(2R-trans) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl-1H-pyrrole-3-carboxamide; and

3- [ (4-fluorophenyl) carbonyl ] -2- (2-methyl-1-oxopropyl) -N, 3-diphenyl-2-oxiranecarboxamide.

The total impurities and/or degradation products from amlodipine should not exceed 2.0% after 24 months of storage of the pharmaceutical composition at 25 ℃/60% RH. In addition, the following specific impurities and/or degradation products should not exceed 1.0%:

2- (2-amino-ethoxymethyl) -4- (2-chloro-phenyl) -6-methyl-pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester; and

6- (2-chloro-phenyl) -8-methyl-3, 4,6, 7-tetrahydro-2H-1, 4-benzoxazine-5, 7-dicarboxylic acid 5-ethyl ester 7-methyl ester.

The stability of atorvastatin/amlodipine dual therapy tablets during storage at 40 ℃/75% RH was evaluated. Specifically, the following combinations were evaluated:

(1) 5mg amlodipine/10 mg atorvastatin

(2)10mg amlodipine/40 mg atorvastatin

(3)10mg amlodipine/80 mg atorvastatin

Table 4 shows that the dual treatment tablets are compatible with commercial Lipitor after 3 months of stability at 40 ℃/75% RH^®Analysis of the degradation products of the (atorvastatin calcium) tablets. In thatIn all cases, with Lipitor^®The total degradation products of the dual therapy tablet are comparable or better than the case.

This accelerated study of 3 months stability at 40 ℃/75% RH is the standard method for determining the shelf-life stability of a drug at 25 ℃/60% RH for 24 months.

The above results show that the pharmaceutical compositions of the present invention are not only stable but also have a bioavailability comparable to the respective therapeutic agents administered in divided dosage forms.

The following non-limiting examples detail the inventors' preferred methods of making and using the pharmaceutical compositions of the present invention.

TABLE 1 list of pharmacokinetic parameter values after co-administration of 5-mg amlodipine and 10-mg atorvastatin tablets (reference) and 5-mg amlodipine/10-mg atorvastatin dual treatment tablets (test)

Parameter(s)	Mean of minimum variance				Ratio of	90% confidence interval
								Co-administration of separate tablets (reference)	Double treatmentTherapeutic tablet (test)
	Amlodipine, standard assay
Cmax，ng/mLtmax，hrAUC(0-tlqc)，ng·hr/mLAUC(0-∞)，ng·hr/mLt*，hr		2.797.4113615251.6	2.778.0613414949.5		99.110998.198.296.1		95.7 to 103 do not apply 94.9 to 10194.8 to 10288.8 to 103
	Amlodipine, normalized for content
nCmax，ng/mLnAUC(0-tlqc)，ng·hr/mLnAUC(0-∞)，ng·hr/mL		2.79136152	2.94142159		105104104	102 to 109101 to 108101 to 108
	Atorvastatin
Cmax，ng/mLtmax，hrAUC(0-tlqc)，ng·hr/mLAUC(0-∞)，ng·hr/mLt*，hr		2.520.62412.818.49.12	2.301.1212.318.410.2	91.018095.8100112	82.0 to 101 do not apply 88.6 to 10490.2 to 11182.0 to 142

AUC (0- ∞) — the area under the plasma concentration-time curve where time is extrapolated from zero to infinity.

T^*Terminal half-life (terminating half-life).

ncax and nAUC are values normalized for amlodipine content.

Ratio-ratio of treatment mean expressed as a percentage (100% × test/reference).

The 90% confidence interval is the 90% confidence interval estimated for the ratio to the treatment mean (trial/reference), expressed as a percentage of the reference mean.

TABLE 2 summary of pharmacokinetic parameter values after co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/40-mg atorvastatin dual treatment tablets (test)

Parameter(s)	Mean of minimum variance			Ratio of	90% confidence interval
							Co-administration of separate tablets (reference)	Dual therapeutic tablet (test)
	Aminopodipine
Cmax，ng/mLtmax，hrAUC(0-tlqc)，ng·hr/mLAUC(0-∞)，ng·hr/mLt*，hr		5.777.2828732051.7	6.267.3329833151.6	10910110410399.7	105 to 113 do not apply 101 to 107100 to 10794.6 to 105
	Atorvastatin
Cmax，ng/mLtmax，hrAUC(0-tlqc)，ng·hr/mLAUC(0-∞)，ng·hr/mLt*，hr		15.00.64171.580.412.3	14.21.0979.188.215.3	95.0170111110124		82.1 to 110 do not apply 104 to 117103 to 11698.2 to 149

Cmax is the maximum plasma concentration.

tmax is the time to reach Cmax.

AUC (0-tlqc) — the area under the plasma concentration-time curve from zero to the last quantifiable concentration in time.

AUC (0- ∞) — the area under the plasma concentration-time curve where time is extrapolated from zero to infinity.

T^*Terminal half-life.

Ratio-ratio of treatment mean expressed as a percentage (100% × test/reference).

The 90% confidence interval is the 90% confidence interval estimated for the ratio to the treatment mean (trial/reference), expressed as a percentage of the reference mean.

TABLE 3 summary of pharmacokinetic parameter values after co-administration of 10-mg amlodipine and 2X 40-mg atorvastatin tablets (reference) and 10-mg amlodipine/80-mg atorvastatin dual treatment tablets (test)

Parameter(s)	Mean of minimum variance				Ratio of	90% confidence interval
							Co-administration of separate tablets (reference)		Dual therapeutic tablet (test)
	Amlodipine (I) salt
Cmax，ng/mLtmax，hrAUC(0-tlqc)，ng·hr/mLAUC(0-∞)，ng·hr/mLt*，hr		5.087.3927030352.6	5.007.4426229855.7	98.610197.098.4106		95.4 to 102 do not apply 94.2 to 99.995.4 to 10199.9 to 112
							Atorvastatin
Cmax，ng/mLtmax，hrAUC(0-tlqc)，ng·hr/mLAUC(0-∞)，ng·hr/mLt*，hr		33.71.0916817712.7	33.71.5817018115.51	10014410195122		87.8 to 114 do not apply 95.1 to 10894.8 to 109101 to 143

Cmax is the maximum plasma concentration.

tmax is the time to reach Cmax.

AUC (0-tlqc) — the area under the plasma concentration-time curve from zero to the last quantifiable concentration in time.

AUC (0- ∞) — the area under the plasma concentration-time curve where time is extrapolated from zero to infinity.

T^*Terminal half-life.

Ratio-ratio of treatment mean expressed as a percentage (100% × test/reference).

The 90% confidence interval is the 90% confidence interval estimated for the ratio to the treatment mean (trial/reference), expressed as a percentage of the reference mean.

TABLE 4 amlodipine/atorvastatin dual therapeutic tablets and Lipitor^®Stability comparison of tablets

Degradation of tablets stored at 40 ℃/75% RH for 3 months
										Product(s)	Amlodipine/atorvastatin dual therapeutic tablet						Lipitor®Tablet formulation
Dosage form	5mg/10mg		10mg/40mg		10mg/80mg		10mg	40mg	80mg
										Package (I)	Small bottle	Water bubble	Small bottle	Water bubble	Small bottle	Water bubble	Small bottle	Small bottle	Small bottle
Atorvastatin Total degradation product (%)	0.39	0.41	0.23	0.24	0.24	0.33	0.43-0.54	0.51-0.63	0.20
										Amlodipine total degradation product (%)	ND	ND	ND	ND	ND	ND	N/A	N/A	N/A

Not applicable to N/A

ND is not detected

Example 1

General procedure for the preparation of atorvastatin calcium/amlodipine besylate dual therapeutic tablets

[A] Process for granulating atorvastatin

Step 1-polysorbate 80 was dissolved in purified water at 50 ℃ and hydroxypropyl cellulose hydrate was added. The solution was allowed to cool to room temperature.

Step 2-mixing atorvastatin calcium, calcium carbonate, microcrystalline cellulose, starch 1500 and croscarmellose sodium in a fluid bed granulator/dryer (FBG/D) or high shear mixer/granulator.

Step 3-pelletize the powder mixture from step 2 and the solution from step 1 in FBG/D or high shear mixer/granulator.

Step 4-drying the particles in FBG/D or other drying equipment to a moisture content (loss on drying, LOD) of less than or equal to 2.0%.

[B] Finally, preparing

Step 1-adding amlodipine besylate, microcrystalline cellulose, croscarmellose sodium and silicon dioxide to the atorvastatin granules obtained in step [ a ].

Step 2-passing the powder mixture through a mill, such as a Comil mill.

Step 3-add magnesium stearate to the milled powder mixture from step 2 and mix in a box mixer, V-mixer, ribbon blender, etc.

Step 4-compressing the final blended granulate into tablets using a tabletting device.

TABLE 5 formulation description of amlodipine besylate/atorvastatin calcium dual therapeutic tablet cores is provided

TABLE 5 amlodipine besylate/atorvastatin calcium dual therapeutic tablet core (g/1000 tablets)

Atorvastatin dose (mg)	10			20		40		80
										Amlodipine dosage (mg)	5		10	5	10	5	10	5	10
Atorvastatin particles
	Atorvastatin calcium carbonate Croscarmellose Sodium microcrystalline cellulose starch, pregelatinized, 1500 corn polysorbate 80 hydroxypropyl cellulose purified water USP/Epa	10.8533.153.0013.8515.000.402.0060.00	10.8533.153.0013.8515.000.402.0060.00		21.7066.306.0027.7030.000.804.00120.00	21.7066.306.0027.7030.000.804.00120.00	43.40132.6012.0055.4060.001.6012.00240.00	43.40132.6012.0055.4060.001.6012.00240.00	86.80265.2024.00110.80120.003.2024.00480.00	86.80265.2024.00110.80120.003.2024.00480.00
Final mixing
	Amlodipine besylate microcrystalline cellulose croscarmellosol Sodium silicon dioxide, colloidal magnesium stearate (non-bovine) tablet core weight (mg)	6.9410.413.000.650.75100	13.873.483.000.650.75100		6.9427.766.001.301.50200	13.8720.836.001 301.50200	6.9462.4612.002.603.00400	13.8755.5312.002.603.00400	6.94131.8624.005.206.00800	13.87124.9324.005.206.00800

^aFormulation aids that are removed during processing

Example 2

5-mg amlodipine/10-mg atorvastatin dual therapeutic tablets and co-administration of 5-mg amlodipine/10-mg atorvastatin dual therapeutic tablets

Single dose bioequivalence study comparing amlodipine and 10-mg atorvastatin tablets

The scheme is as follows: a randomized single dose two-way crossover study was performed on 36 healthy volunteers. After overnight fasting, each subject received a single dose of 5-mg amlodipine and 10-mg atorvastatin as a dual treatment tablet and the separate tablets were co-administered on days 1 and 15.

Blood samples were collected before and after each dose for 168 hours. Plasma samples were collected and stored frozen at-70 ℃ prior to analysis. Plasma amlodipine and atorvastatin concentrations were determined by an efficient method. Pharmacokinetic parameter values were evaluated from concentration-time curves by a non-compartmental method. The ANOVA (analysis of variance) results of the Cmax and AUC values of the logarithmic transformation were used to calculate the 90% confidence interval for the least variance treatment mean proportion. Bioequivalence if the confidence interval for the ratio of amlodipine and atorvastatin Cmax and AUC values is in the range of 80% to 125% based on log transformed values.

The trial tests in this study and the content uniformity for the dual treatment tablet indicated that the amlodipine fraction was 94% of the labeling requirement. The atorvastatin moiety ranged from 95% to 105%, which are commercially available amlodipine and atorvastatin tablets co-administered in the reference treatment. Thus, bioequivalence was evaluated after dividing test-treated amlodipine Cmax and AUC values by 0.94, giving the results of two assays.

And (4) conclusion: data obtained from 35 subjects completing the study and one subject receiving only separate tablet treatments prior to leaving the study were used in the evaluation. The mean plasma concentrations are detailed in figures 1 and 2. Pharmacokinetic parameter values are summarized in table 1. The respective Cmax and AUC values are detailed in figures 3 and 4.

Amlodipine, standard assay

The absorption rate after administration of the 5-mg amlodipine/10-mg atorvastatin dual treatment tablet is similar to that after co-administration of the separate 5-mg amlodipine and 10-mg atorvastatin tablets based on the amlodipine Cmax and tmax values. The difference in the mean tmax values was about 40 minutes. Mean Cmax values were nearly equal after each treatment was administered with 90% confidence intervals for Cmax values in the 80% to 125% bioequivalence range.

The extent of absorption after administration of the 5-mg amlodipine/10-mg atorvastatin dual therapeutic tablet is similar to that after co-administration of the separate 5-mg amlodipine and 10-mg atorvastatin tablets, based on the amlodipine AUC value. The mean AUC (0- ∞) values are nearly equal with a 90% confidence interval for the AUC (0- ∞) values in the 80% to 125% bioequivalence range.

Final elimination of average amlodipine^*Values are similar, averaging about 50 hours.

Normalized analysis of amlodipine content in test tablets

The average amlodipine content-normalized Cmax value after tablet administration was about 5% higher than after co-administration of each tablet. The 90% confidence interval for the normalized-Cmax value is in the 80% to 125% bioequivalence range.

The average amlodipine content-normalized AUC (0- ∞) values after administration of the tablets were about 4% higher than after co-administration of each tablet. The 90% confidence interval for normalized-AUC (0- ∞) values is in the 80% to 125% bioequivalence range.

Atorvastatin

The absorption rate after administration of the 5-mg amlodipine/10-mg atorvastatin dual treatment tablet is similar to that after co-administration of the separate 5-mg amlodipine and 10-mg atorvastatin tablets based on the atorvastatin Cmax and tmax values. The difference in the mean tmax values was about 30 minutes. The difference in mean Cmax values was approximately 9%, with 90% confidence intervals for Cmax values in the 80% to 125% bioequivalence range.

The extent of absorption after administration of the 5-mg amlodipine/10-mg atorvastatin dual treatment tablet was similar to that after co-administration of the separate 5-mg amlodipine and 10-mg atorvastatin tablets, based on the atorvastatin AUC values. The mean AUC (0- ∞) values are equal, with a 90% confidence interval for the AUC (0- ∞) values in the 80% to 125% bioequivalence range.

Average atorvastatin final elimination t^*Values are similar, averaging about 10 hours.

And (4) conclusion: the 5-mg amlodipine/10-mg atorvastatin dual therapy tablet is bioequivalent to co-administration of separate 5-mg amlodipine and 10-mg atorvastatin tablets.

Example 3

Single dose bioequivalence study of 10-mg amlodipine/40-mg atorvastatin dual treatment tablets compared to co-administration of 10-mg amlodipine and 40-mg atorvastatin tablets

The scheme is as follows: a randomized single dose two-way crossover study was performed on 36 healthy volunteers. After overnight fasting, each subject received a single dose of 10-mg amlodipine and 40-mg atorvastatin as a dual treatment tablet and the separate tablets were co-administered on days 1 and 15.

Blood samples were collected before and after each dose for 168 hours. Plasma samples were collected and stored frozen at-70 ℃ prior to analysis. Plasma amlodipine and atorvastatin concentrations were determined by an efficient method. Pharmacokinetic parameter values were evaluated from concentration-time curves by a non-compartmental method. ANOVA results of Cmax and AUC values for logarithmic conversion were used to calculate 90% confidence intervals for the ratio of minimum variance treatment means. Bioequivalence if the confidence interval for the ratio of amlodipine and atorvastatin Cmax and AUC values is in the range of 80% to 125% based on log transformed values.

And (4) conclusion: data obtained from 36 subjects who completed the study were evaluated. The mean plasma concentrations are detailed in figures 5 and 6. Pharmacokinetic parameter values are summarized in table 2. The respective Cmax and AUC values are detailed in figures 7 and 8.

Amlodipine (I) salt

The absorption rate after administration of the 10-mg amlodipine/40-mg atorvastatin dual treatment tablet based on the amlodipine Cmax and tmax values was similar to that after co-administration of the separate 10-mg amlodipine and 40-mg atorvastatin tablets. The difference in mean tmax values was less than 10 minutes. The mean Cmax value difference was 9% with 90% confidence intervals for Cmax values in the 80% to 125% bioequivalence range.

The extent of absorption after administration of the 10-mg amlodipine/40-mg atorvastatin dual therapeutic tablet based on the amlodipine AUC value is similar to that after co-administration of the separate 10-mg amlodipine and 40-mg atorvastatin tablets. The difference in mean AUC (0- ∞) values was 3%, with a 90% confidence interval for AUC (0- ∞) values in the 80% to 125% bioequivalence range.

Final elimination of average amlodipine^*Values are similar, averaging about 51 hours.

Atorvastatin

The absorption rate after administration of the 10-mg amlodipine/40-mg atorvastatin dual treatment tablet based on the atorvastatin Cmax and tmax values was similar to that after co-administration of the separate 10-mg amlodipine and 40-mg atorvastatin tablets. The difference in mean tmax values was less than 30 minutes. The difference in mean Cmax values was 5% with 90% confidence intervals for Cmax values in the 80% to 125% bioequivalence range.

The extent of absorption after administration of the 10-mg amlodipine/40-mg atorvastatin dual treatment tablet based on the atorvastatin AUC values was similar to that after co-administration of the separate 10-mg amlodipine and 40-mg atorvastatin tablets. The difference in mean AUC (0- ∞) values was 10%, with a 90% confidence interval for AUC (0- ∞) values in the 80% to 125% bioequivalence range.

Average atorvastatin final elimination t^*Values are similar, averaging about 14 hours.

And (4) conclusion: the 10-mg amlodipine/40-mg atorvastatin dual therapy tablet is bioequivalent to co-administration of separate 10-mg amlodipine and 40-mg atorvastatin tablets.

Example 4

10-mg amlodipine/80-mg atorvastatin dual therapeutic tablets with a single dose bioequivalence to co-administration of 10-mg amlodipine and two 40-mg atorvastatin tablets

Study of

The scheme is as follows: a randomized single dose two-way crossover study was performed on 36 healthy volunteers. After overnight fasting, each subject received a single 10-mg amlodipine and 80-mg atorvastatin as a dual treatment tablet and the separate tablets were co-administered on days 1 and 15.

Blood samples were collected before and after each dose for 168 hours. Plasma samples were collected and stored frozen at-70 ℃ prior to analysis. Plasma amlodipine and atorvastatin concentrations were determined by an efficient method. Pharmacokinetic parameter values were evaluated from concentration-time curves by a non-compartmental method. ANOVA results of Cmax and AUC values for logarithmic conversion were used to calculate 90% confidence intervals for the ratio of minimum variance treatment means. Bioequivalence if the confidence interval for the ratio of amlodipine and atorvastatin Cmax and AUC values is in the range of 80% to 125% based on log transformed values.

And (4) conclusion: data obtained from 36 subjects who completed the study were evaluated. The mean plasma concentrations are detailed in figures 9 and 10. Pharmacokinetic parameter values are summarized in table 3. The respective Cmax and AUC values are detailed in figures 11 and 12.

Amlodipine (I) salt

The absorption rate after administration of the 10-mg amlodipine/80-mg atorvastatin dual treatment tablet based on the amlodipine Cmax and tmax values was similar to that after co-administration of the separate 10-mg amlodipine and two 40-mg atorvastatin tablets. The difference in mean tmax values was less than 5 minutes. Mean Cmax values differed by less than 2% with 90% confidence intervals for Cmax values in the 80% to 125% bioequivalence range.

The extent of absorption after administration of the 10-mg amlodipine/80-mg atorvastatin dual therapeutic tablet based on the amlodipine AUC value is similar to that after co-administration of the separate 10-mg amlodipine and the two 40-mg atorvastatin tablets. The difference in mean AUC (0- ∞) values is less than 2%, with a 90% confidence interval for AUC (0- ∞) values in the 80% to 125% bioequivalence range.

Final elimination of average amlodipine^*Values are similar, averaging about 54 hours.

Atorvastatin

The absorption rate after administration of the 10-mg amlodipine/80-mg atorvastatin dual treatment tablet based on the atorvastatin Cmax and tmax values was similar to that after co-administration of separate 10-mg amlodipine and two 40-mg atorvastatin tablets. The difference in mean tmax values was less than 30 minutes. The mean Cmax values were identical with 90% confidence intervals for Cmax values in the 80% to 125% bioequivalence range.

The extent of absorption after administration of 10-mg amlodipine/80-mg atorvastatin dual treatment tablets based on atorvastatin AUC values was similar to that after co-administration of 10-mg amlodipine and two 40-mg atorvastatin tablets taken separately. The difference in mean AUC (0- ∞) values is 2%, with a 90% confidence interval for AUC (0- ∞) values in the 80% to 125% bioequivalence range.

Average atorvastatin final elimination t^*Values are similar, averaging about 14 hours.

And (4) conclusion: amlodipine 10-mg/atorvastatin 80-mg dual treatment tablets are bioequivalent to co-administration of separate 10-mg amlodipine and two 40-mg atorvastatin tablets.

Claims (1)

1. A pharmaceutical composition comprising the following two components:

(a) one component includes particles of atorvastatin or a pharmaceutically acceptable salt thereof and a carrier including an alkalizing agent that forms a pH greater than 5; and (b) a second ingredient comprising amlodipine or a pharmaceutically acceptable salt thereof and a carrier that does not include an alkalizing agent that forms a pH greater than 5, wherein the two ingredients are mixed to form the final composition for use in a solid dosage form.