WO2006006021A2

WO2006006021A2 - Stabilized pharmaceutical compositions of preferably a statin

Info

Publication number: WO2006006021A2
Application number: PCT/IB2005/001836
Authority: WO
Inventors: Arra Ganga Srinivas; Beena Amol Sapre; Yogesh Ananda Chachare; Anandi Krishnan
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2004-06-28
Filing date: 2005-06-28
Publication date: 2006-01-19
Also published as: WO2006006021A3

Abstract

Stabilized pharmaceutical composition comprising a therapeutically effective amount of one or more active pharmaceutical ingredients capable of degradation in a low pH environment and a stabilizing effective amount of one or more amino-group containing monomeric compounds and/or amido-group containing monomeric compounds for the stabilization of the active pharmaceutical ingredientare provided. The present invention also provides for the use of such stabilized pharmaceutical compositions for the treatment of dyslipidemias including, for example, hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. Preferred active pharmaceutical ingredients are a statin such as pravastatin or atorvastatin. Preferred stabilizing compounds are meglumine, triethanolamine, tromethamine or sodium chloride. The composition is preferably in form of a tablet or granules.

Description

STABILIZED PHARMACEUTICAL COMPOSITIONS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119 to Provisional

Application No. 60/583,550, filed June 28, 2004 and entitled "STABILIZED PHARMACEUTICAL COMPOSITIONS," the contents of which are incorporated by reference herein.

BACKGROUND OF INVENTION

1. Technical Field

[0002] The present invention relates generally to stabilized pharmaceutical compositions for an active pharmaceutical ingredient which is sensitive to a low pH environment.

2. Description of the Related Art

[0003] Complications of cardiovascular disease such as, for example, myocardial infarction, stroke, and peripheral vascular disease, account for about half of the deaths in the United States. A high level of low density lipoprotein (LDL) in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and can rupture and promote thrombosis. By reducing plasma LDL levels, it has been shown that the risk of clinical events can be reduced in patients with cardiovascular disease and in patients who are free of cardiovascular disease but who have hypercholesterolemia. See, e.g., Scandinavian Simvastatin Survival Study Group, 1994 and Lipid Research Clinics Program, 1984a, 1984b. In addition, low levels of high density lipoprotein (HDL) and high levels of triglycerides (TG) are also known to be associated with increased incidence of cardiovascular disease and primary and secondary coronary events such as, for example, myocardial infarction. [0004] Presently, statins are among the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. Statins are also known to raise HDL cholesterol levels and decrease total triglyceride levels. Representative examples of statins are compactin, lovastatin, mevastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, itavastatin and fluvastatin. The mechanism of action of statins has been elucidated in some detail. It is believed that statins disrupt the biosynthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, its inhibition can lead to a reduction in the rate of formation of cholesterol in the liver.

[0005] Pharmaceutical compositions that include a medicament that is relatively unstable in an acidic environment are believed to require a basic excipient to enhance storage stability. For example, pravastatin sodium is an HMG-CoA reductase inhibitor (also known as 1-Naphthalene-heptanoic acid, l,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8- (2-methyl-l-oxobutoxy)-, monosodium salt, {lS-[lalpha(betaS*, deltaS*),2 alpha, 6 alpha, 8 beta(R*),8a alpha]}-) sold in the U.S. under the brandname PRAVACHOL®. Pravastatin is sensitive to a low pH environment and will degrade to form its lactone and various isomers. U.S. Patent No. 5,180,589 ("the '589 patent") discloses that it is necessary to add one or more basifying agents to impart a desired pH of at least 9 to an aqueous dispersion of a pravastatin composition in order to stabilize it. Among the basifying agents disclosed in the '589 patent are magnesium oxide, aluminum oxide, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide and alkaline earth metal hydroxides such as calcium hydroxide or magnesium hydroxide.

[0006] Atorvastatin calcium, another HMG-CoA reductase inhibitor, is described in

U.S. Patent No. 5,273,995. Atorvastatin calcium is [R-(R* ,R*)-2-(4-fluorophenyl)-beta,delta- dihydroxy-5-(l -methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]- lH-pyrrole- 1 -heptanoic acid, hemicalcium salt. Atorvastatin calcium is sold in the U.S. under the brandname LIPITOR® and is susceptible to a low pH environment and can degrade to the corresponding lactone in an acidic environment. For example, U.S. Patent No. 5,686,104 ("the ' 104 patent") discloses that this and similar compounds in an oral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia are stabilized by a combination with at least one basic inorganic pharmaceutically acceptable calcium, magnesium, aluminum or lithium salt. Examples of these salts are calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide or lithium hydroxide. Thus, as in the '589 patent, the stabilizing agents disclosed in the '104 patent are basic inorganic pharmaceutically acceptable salts. [0007] WO 00/35425 discloses the stabilization of an HMG-CoA reductase inhibitor in a solid formulation with a buffering agent. Among the buffering agents disclosed in WO 00/35425 are sodium or potassium citrate, sodium phosphate, dibasic sodium phosphate, calcium carbonate, hydrogen phosphate, phosphate, sulphate, sodium or magnesium carbonate, sodium ascorbinate, benzoate, sodium or potassium hydrogen carbonate, lauryl sulphate, or mixtures of such buffering agents. Among the HMG-CoA reductase inhibitors disclosed in WO 00/34525 are atorvastatin, pravastatin, fluvastatin and cerivastatin, which are said to be particularly sensitive to an acidic environment in which hydroxy acids are degraded into the corresponding lactone.

[0008] Although the prior art basifying agents can prevent the degradation of a statin such as pravastatin sodium, they are less desirable because some are strong bases which may have an adverse effect on excipients used with pravastatin sodium pharmaceutical compositions. Additionally, the high alkalinity occurring at dissolution of these formulations may disrupt the acidic pH milieu of the gastrointestinal (GI) mucosa and is problematic for patients with pre-existing GI mucosal damage.

[0009] U.S. Patent No. 6,558,659 discloses a stabilized pharmaceutical composition of a ring-opened 7-substituted-3,5-dihydroxyheptanoic or a ring-opened 7-substituted-3,5- dihydroxyheptenoic acid and a stabilizing effective amount of at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound. The stabilized pharmaceutical composition does not contain a stabilizing effective amount of another stabilizer or a combination of other stabilizers.

[0010] Accordingly, it would be desirable to provide an improved stabilizing agent for an active pharmaceutical ingredient capable of degrading in a low pH environment. SUMMARY QF INVENTION

[0011] In accordance with one embodiment of the present invention, a stabilized pharmaceutical composition is provided comprising a therapeutically effective amount of one or more active pharmaceutical ingredients capable of degradation in a low pH environment and a stabilizing effective amount of one or more amino-group containing monomeric compounds and/or amido-group containing monomeric compounds for the stabilization of the active pharmaceutical ingredient.

[0012] In a second embodiment of the present invention, a method for the treatment of dyslipidemia is provided comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a stabilized pharmaceutical composition comprising a therapeutically effective amount of one or more active pharmaceutical ingredients capable of degradation in a low pH environment and a stabilizing effective amount of one or more amino-group containing monomeric compounds and/or amido-group containing monomeric compounds for the stabilization of the active pharmaceutical ingredients therein.

[0013] By employing a stabilizing effective amount of one or more stabilizing amino- group containing monomeric compounds and/or amido-group containing monomeric compounds for the one or more active pharmaceutical ingredients capable of degradation in a low pH environment to form a stabilized pharmaceutical composition, an improved dosage form of the one or more active pharmaceutical ingredients capable of degradation in a low pH environment stabilized with the one or more amino-group containing monomeric compounds and/or amido-group containing monomeric compounds is achieved without the need to basify the composition beyond a pH of about 10 and preferably not beyond a pH of about 9. Furthermore, the present invention alleviates the need to use amino or amido group containing polymeric compounds or sodium stearyl fumarate to stabilize the active drug.

DEFINITIONS

[0014] As used herein, the term "dyslipidemia" refers to an abnormal level of one or more of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (Apo B), apolipoprotein A (Apo A), very low density lipoprotein cholesterol (VLDL-C), and intermediate density lipoprotein cholesterol (IDL-C). By "abnormal" is meant a level generally accepted by the relevant medical community as an undesirable level, which may be higher or lower than desirable, and which may be beneficially adjusted by treatment of a patient with a stabilized statin composition as disclosed herein. Guidelines for the detection, evaluation and treatment of dyslipidemias are promulgated by the National Institute of Health's National Cholesterol Education Program ("NCEP"). The NCEP guidelines suggest when treatment with therapeutic agents such as the statin compounds disclosed herein, are indicated for the treatment of a dyslipidemia such as hypercholesterolemia. Initiation of treatment with a statin compound, in accordance with the NCEP guidelines depends on numerous factors. Among such factors are included abnormal levels of one or more of Total- C, LDL-D, TG, Apo B, Apo A, VLDL-C and IDL-C; familial history of cardiovascular disease or event; prior cardiovascular disease; and, prior occurrence of an acute cardiovascular event, such as myocardial infarction, etc.

[0015] The term "dyslipidemia" thus encompasses "hyperlipidemia",

"hypercholesterolemia" and "hypertriglyceridemia" which terms as used herein refer to abnormally high levels of one or more of Total-C, LDL-C, TG, Apo B, VLDL-C and IDL-C. Thus, the term "dyslipidemia" includes all of the dyslipidemias classified by the Frederickson Classification System, including Frederickson Type I hyperlipidemia, Frederickson Types Ia and lib primary hypercholesterolemia, Frederickson Type IV hypertriglyceridemia, Frederickson Type III dysbetaliproteinemia, and Frederickson Type V hyperlipidemia. [0016] By "therapeutically effective amount" as used herein is meant an amount of active component in the stabilized pharmaceutical compositions of the present invention which, when administered to a mammal for treating a state, disorder or condition such as dyslipidemia, is sufficient to effect such treatment is effective to beneficially treat a disorder. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. [0017] By "stabilized pharmaceutical composition" as used herein is meant that after storage for six months at 40⁰C and 75% relative humidity, no more than about 10%, preferably no more than about 5%, and more preferably, no more than about 1% by weight of the active component initially present in the composition degrades into a derivative of the active compound, e.g., pravastatin is sensitive to a low pH environment and will degrade to form its lactone and various isomers.

[0018] By "stabilizing effective amount" as used herein is meant an amount by weight of a stabilizing compound present in the pharmaceutical composition which is effective to provide a stabilized pharmaceutical composition, i.e., effective to stabilize the active pharmaceutical ingredient against degradation.

[0019] As used herein, the term "buffering agent" is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.

[0020] As used herein, the term "sweetening agent" is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art. [0021] As used herein, the term "binders" is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.

[0022] When needed, other binders may also be included in the present invention.

Exemplary binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly(propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, polyvinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.

[0023] As used herein, the term "diluent" or "filler" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

[0024] As used herein, the term "glidant" is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art. [0025] As used herein, the term "lubricant" is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

[0026] As used herein, the term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art. [0027] As used herein, the term "wetting agent" is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.

[0028] Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0030] The present invention relates to stabilized pharmaceutical compositions. In one embodiment, the stabilized pharmaceutical compositions include at least a therapeutically effective amount of one or more active pharmaceutical ingredients capable of degradation in a low pH environment and a stabilizing effective amount of one or more amino-group containing monomelic compounds and/or amido-group containing monomelic compounds for the stabilization of the active pharmaceutical ingredient. The terms "active pharmaceutical ingredient", "medicament", "drug" and "active" and the like are used interchangeably herein. [0031] Active pharmaceutical ingredients capable of degradation in a low pH environment, i.e., a pH of no more than about 10 and preferably no more than about 9, for use herein can be any active pharmaceutical ingredient capable of degrading in a low pH environment. Representative examples of such active pharmaceutical ingredients include, but are not limited to, one or more HMG-CoA reductase inhibitors or pharmaceutically acceptable salts, esters, derivatives and isomers thereof and the like and mixtures thereof. Any HMG- CoA reductase inhibitor may be employed as the active pharmaceutical ingredient capable of degrading in a low pH environment including, by way of example, statins such as, for example, pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin) and pharmaceutically acceptable salts, esters, derivatives and isomers thereof.

[0032] As one skilled in the art would readily appreciate, the foregoing statins can be employed in the stabilized pharmaceutical composition of the present invention either as the free acid or as any pharmaceutically acceptable salt, ester, derivative or isomer thereof. The free acid can be prepared, for example, by hydrolysis of the corresponding lactone form or by treatment of the salt form of the acid with cationic exchange resin and evaporating the water portion. The free acid can be used to form the pharmaceutically acceptable salt form, by conventional methods known in the art. Among preferred pharmaceutically acceptable salts are metal and amine salts. The term "pharmaceutically acceptable metal salt" thus includes, but is not limited to, sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or zinc salts. Such salts may be derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, l-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, and ammonium hydroxide. The term "pharmaceutically acceptable amine salt" includes, but is not limited to, salts formed by reaction with ammonium hydroxide or organic amine salt or for example methylglucamine, choline, arginine, l-deoxy-2-(methylamino)-D-glucitol and the like. [0033] The amount of the active ingredient in the stabilized pharmaceutical compositions of the present invention will be a therapeutically effective amount. Generally, a therapeutically effective amount can range from about 0.05% to about 70%, preferably from about 1% to about 60%, and more preferably from about 5% to about 50% by weight, based on the total weight of the stabilized pharmaceutical composition. It is understood that higher or lower weight percentages of the active ingredient may be present in the pharmaceutical compositions.

[0034] Also present in the stabilized pharmaceutical composition of the present invention is a stabilizing effective amount of one or more amino-group containing monomelic compounds or a stabilizing effective amount of one or more amido-group containing monomelic compounds, or a stabilizing effective amount of a combination of at least one amino-group and at least one amido-group containing monomeric compound. [0035] By "amino-group containing monomeric compound" as used herein is meant a pharmaceutically acceptable monomeric compound containing as a component of the monomer, an amino group, i.e., a group having the formula

wherein the nitrogen atom is bonded to three different atoms. The term "amino-group containing monomeric compound" is meant to include combinations of different amino-group containing monomeric compounds. Thus, for example, an amino-group containing monomeric compound for use herein can be of the general formula

wherein R¹, R² and R³ are independently hydrogen, a hydrocarbyl of 1 to about 30 carbon atoms optionally containing hydroxy groups or one or more heterocyclic groups or R¹ and R² or R¹ and R³ or R² and R³ together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms. Specific amines include those in which R¹, R and R³ are independently selected to be hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, dodecyl, stearyl, oleyl, phenyl, benzyl, and the like, containing e.g., 1 to about 30 carbon atoms, preferably no more than 1 to about 18 carbon atoms and more preferably no more than 1 to about 12 carbon atoms. Useful amines in which R¹ and R² or R¹ and R³ or R² and R³ together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic compound include cyclic amines such as pyrrolidine, piperidine, piperazine, morpholine, and the like.

[0036] Specific examples of useful amino-group containing monomeric compounds as stabilizers for the pharmaceutical compositions of the present invention include, but are not limited to, hydrocarbyl amines, hydroxy substituted hydrocarbyl amines and the like and mixtures thereof. The hydrocarbyl group of the hydrocarbyl amines and hydroxy substituted hydrocarbyl amines can be, for example, an alkyl, an alicyclic or an alkylalicyclic radical having from 1 to about 30 carbon atoms or an alkylaryl where the alkyl group is from about 4 to about 30 carbon atoms including, by way of illustration, straight or branched aliphatic, cycloaliphatic and aromatic groups and cycloaliphatic and aromatic groups substituted with one or more straight or branched aliphatic, cycloaliphatic and/or aromatic groups. Examples of such hydrocarbyl amines include, but are not limited to, isopropyl amine and dibutyl amine. Examples of hydroxy substituted hydrocarbyl amines include those containing hydrocarbyl groups as described above and from one to six hydroxyl groups. Examples of hydroxy substituted hydrocarbyl amines include diisopropanolamine, ethanolamine, and triethanolamine.

[0037] It is to be understood that the amino-group containing monomeric compounds useful to provide stabilized pharmaceutical compositions in accordance with the present invention are not to be construed as limited to the foregoing exemplary monomeric compounds. Thus, any pharmaceutically acceptable amino-group containing monomeric compound that provides an effective stabilized pharmaceutical composition of the present invention may be employed. Such pharmaceutically acceptable amino-group containing monomeric compounds are commercially available. Preferred amino-group containing monomeric compounds for use herein are meglumine, triethanolamine, and tromethamine

("TRIS").

[0038] By "amido-group containing monomeric compound" as used herein is meant a pharmaceutically acceptable monomeric compound containing as a component of the monomer, an amido group, i.e., a group having the formula:

wherein the carbon atom is bonded to another atom and the nitrogen atom is bonded to two other atoms. The term "amido-group containing monomeric compound" is meant to include combinations of different amido-group containing monomeric compounds. Thus, for example, the amido-group containing monomeric compound can be of the general formula

wherein R⁴, R⁵ and R⁶ are independently hydrogen, a hydrocarbyl of 1 to about 30 carbon atoms optionally containing one or more heterocyclic groups or R⁵ and R⁶ together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms. Specific amines include those in which R⁴, R⁵ and R⁶ are independently selected to be hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, dodecyl, stearyl, oleyl, phenyl, benzyl, and the like, containing e.g., 1 to about 30 carbon atoms, preferably no more than 1 to about 18 carbon atoms and more preferably no more than 1 to about 12 carbon atoms. Useful amines in which R⁵ and R⁶ together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic compound include cyclic amines such as pyrrolidine, piperidine, piperazine, morpholine, and the like. [0039] Generally, a stabilizing effective amount of the amino-group containing monomeric compounds and/or amido-group containing monomeric compounds employed in the stabilized pharmaceutical composition of the present invention will vary widely according to the amino-group containing monomeric compounds and/or amido-group containing monomelic compounds and the active pharmaceutical ingredient used. For example, a stabilizing effective amount of the amino-group containing monomeric compounds and/or amido-group containing monomeric compounds can range from about 0.01% to about 10% and preferably from about 0.1% to about 4% by weight, based on the total weight of the stabilized pharmaceutical composition.

[0040] The pharmaceutical compositions of the present invention may also contain one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients for use in the pharmaceutical compositions of the present invention include, but are not limited to, fillers, glidants, lubricants diluent, binder, disintegrant, carrier, colorant and the like and mixtures thereof that are typically used in the art for oral solid dosage forms. Examples of pharmaceutically acceptable excipients include, but are not limited to, lactose, sugar, cornstarch, modified cornstarch, mannitol, sorbitol, silicon dioxide, and microcrystalline cellulose.

[0041] The pharmaceutical compositions of the present invention can be formulated in any manner. The preferred dosage forms of the stabilized pharmaceutical compositions of the present invention are solid dosage forms adapted for oral administration. However, within the scope of the dosage forms useful for formulating the stabilized compositions of the present invention include, but are not limited to, suspensions, solutions, emulsions and the like. Tablet dosage forms are the particularly preferred solid dosage forms of the stabilized pharmaceutical compositions of the present invention. For the purpose of stable oral preparations of the present invention, pharmaceutically acceptable inert carriers can be either solid or liquid. Among other preferred dosage forms useful for formulating the stabilized pharmaceutical compositions of the present invention include powders, dispersible granules, dispersions, capsules, suspensions and cachets.

[0042] Tablets containing the compositions according to the present invention may be produced by any standard tabletting technique, e.g. by wet granulation, dry granulation or direct compression. For example, by granulating the active component with or without an excipient, followed by addition of any other excipient(s) and then compression to form a tablet. The tablets are preferably made by direct compression methods as are known in the art, e.g., mixing the solid excipients in one or more stages and compressing the uniform mixture into tablets.

[0043] Tablet dosage forms may further contain one or more excipients such as any pharmaceutically acceptable lubricant, binder, glidant, disintegrant, diluent, filler, carrier, preservative and the like and combinations thereof that facilitate compacting, shaping, and sizing. Solid dosage forms that are not formulated as tablets typically do not need a lubricant component since this is typically added to facilitate the manufacture of tablet dosage forms. In forming a powder preparation, a finely divided solid carrier is typically employed and is blended with finely divided active ingredient, and then filled into a packet, capsule, or any conventional device for containing the powder. Granular formulations may be similarly packaged. Suspensions or emulsions are obtained by suspending the active component, typically in the form of powder or granules, into a pharmaceutically acceptable liquid carrier which is conventionally adapted for administration orally or parenterally. [0044] Useful lubricants can be any lubricant typically used in the pharmaceutical art for oral solid dosage forms. Example include, but are not limited to, stearate salts such as calcium stearate, magnesium stearate, zinc stearate and stearic acid, talc, hydrogenated vegetable oil, vegetable oil derivatives, silica, silicones, high molecular weight polyalkylene glycols and saturated fatty acids alone or mixtures and the like and mixtures thereof. Typical amounts of lubricant used in a tablet dosage form range from about 0.1 to about 25% and preferably from about 0.25 to about 10% by weight, based on the total weight of the composition.

[0045] Useful glidants may be any glidant typically used in the pharmaceutical art for oral solid dosage forms. Examples include, but are not limited to, colloidal silicon dioxide, talc alone and the like or mixtures thereof. The amount of glidants can vary widely and will ordinarily range from about 0.1% to about 5.0% by weight, based on the total weight of the composition. [0046] Useful fillers may be inert fillers, either water soluble or water insoluble and selected from those typically used in the pharmaceutical art for oral solid dosage forms. Suitable fillers include, but are not limited to, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, monosaccharide, disaccharides, polyhydric alcohols, sucrose, dextrose, lactose, fructose, mannitol, sorbitol, alone or mixtures thereof and the like or mixtures thereof. The amount of fillers can vary widely and will ordinarily range from about 1% to about 90% by weight, based on the total weight of the composition. [0047], An aqueous dispersion of the stabilized pharmaceutical compositions of the present invention will generally exhibit of a pH in the range of about 6.5 to about 10. It is preferred that an aqueous dispersion of a composition of the present invention exhibits a pH of not greater than about 10, preferably not greater than about 9.

[0048] In accordance with the present invention, the pharmaceutical compositions are useful for the treatment of dyslipidemia including, for example, hypercholesterolemia, hyperlipoproteinemia and/or hypertriglyceridemia. While one of ordinary skill in the art will understand that dosages will vary according to the particular requirements and bioavailability of the active ingredient, the indication, age of the patient, and other factors, the compositions of the present invention will generally be administered at a daily dosage of the active ingredient between about 10 to about 80 mg per day. In any event, the amount administered per dosage will be a therapeutically effective amount of the active components. [0049] In accordance with an alternative embodiment of the present invention, a pharmaceutical composition is provided which has excellent storage stability. The pharmaceutical composition of the invention, which is preferably in the form of a tablet, includes a therapeutically effective amount of any of the aforementioned active pharmaceutical ingredients which are sensitive to a low pH environment, such as pravastatin sodium, and a stabilizing effective amount of an alkali metal salt of an acid, e.g., a sodium salt of hydrochloric acid (sodium chloride). The alkali metal salt of the acid may be capable to pick up moisture preferentially to the drug. It would then dissociate in the presence of moisture and the alkali metal (e.g., sodium) ions thus formed would prevent dissociation of the active such as pravastatin sodium according to the principle of common ion effect. Thus, the instability of the drug which occurs mainly in the dissociated/ionized form is believed to be greatly reduced. The pharmaceutical composition can further include one or more pharmaceutically acceptable excipients as discussed above. For example, the pharmaceutical composition can include one or more fillers, e.g., mannitol, dicalcium phosphate, microcrystalline cellulose and the like and mixtures thereof; binders, e.g., hydroxypropyl methylcellulose and the like and mixtures thereof; disintegrating agents, e.g., croscarmellose sodium and the like and mixtures thereof, one or more lubricants, e.g., magnesium stearate, colloidal silicon dioxide and the like and mixtures thereof, and a protectant, e.g., hydrophobic colloidal silicon dioxide and the like and mixtures thereof. Any of the aforementioned dosage forms can be used for the alternative pharmaceutical compositions.

[0050] In one embodiment, the alternative pharmaceutical compositions of the invention can include from about 8 to about 12% by weight of the active pharmaceutical ingredient, e.g., pravastatin or pharmaceutically acceptable salts, esters, derivatives or isomers thereof, from about 1.5 to about 10% by weight of the alkali metal salt of an acid, preferably sodium chloride, from about 1 to about 2.5% by weight protectant, e.g., hydrophobic colloidal silicon dioxide, from about 50 to about 75% by weight lactose monohydrate, from about 20 to about 25% by weight filler, e.g., microcrystalline cellulose, from about 1 to 2.5 % by weight binder, e.g., hydroxypropyl methylcellulose, from about 5% by weight croscarmellose sodium, from about 1.5 to 2.5% by weight magnesium stearate.

[0051] In yet another embodiment of the present invention, the alternative phamaceutical compositions can include includes from about 8 to about 12% by weight of the active pharmaceutical ingredient, e.g., pravastatin or pharmaceutically acceptable salts thereof, from about 1.5 to about 5% by weight of the alkali metal salt of an acid, preferably sodium chloride, from about 2% by weight hydrophobic colloidal silicon dioxide, from about 40 to about 55% by weight mannitol, from about 15 to about 25% by weight microcrystalline cellulose (MCC), from about 1 to 2.5 % by weight hydroxypropyl methylcellulose (HPMC), about 5% by weight croscarmellose sodium, from about 1.5 to 2.5% by weight magnesium stearate, and about 1% by weight colloidal silicon dioxide. [0052] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.

EXAMPLE 1

[0053] The stabilized pharmaceutical composition of Example 1 was prepared by sifting all excipients through a 40 mesh ASTM and granulated using water as a binder in a rapid mixer granulator. The granules were dried and sized through a 30 mesh ASTM. Extra granular materials were added to the above granules along with the API. This mass was then lubricated in suitable blender and compressed into tablets using required tooling. The pH of the tablets was 7.61. The ingredients and amounts used for this example are set forth below in Table 1.

TABLE l

EXAMPLE 2

[0054] The stabilized pharmaceutical composition of Example 9 was prepared by sifting all excipients through 40 mesh ASTM and loaded in a fluid bed processor (FBP). The mass was granulated using a binder solution of suitable concentration to obtain sufficiently hard granules. The granules were then sized through a 30 mesh ASTM. To the above granules, extra granular materials were added along with the API. This mass was then lubricated for a sufficient time and compressed into tablets using required tooling. The pH of the tablets was 8.20. The ingredients and amounts used for this example are set forth below in Table 2.

TABLE 2

EXAMPLE 3

[0055] The stabilized pharmaceutical composition of Example 10 was prepared by sifting all excipients through a 40 mesh ASTM. The mass was loaded in an FBP to obtain granules by top spray granulation. The granules were then sized using a 30 mesh ASTM. A part of above granules and API were mixed together. This mass was roll compacted to obtain compacts with sufficient hardness. Next, the compacts were passed through a 16 mesh ASTM by using an oscillating granulator and then through a 30 mesh ASTM. The granules obtained were lubricated along with extra granular materials and then compressed into tablets. The pH of the tablets was 8.15. The ingredients and amounts used for this example are set forth below in Table 3.

TABLE 3

EXAMPLES 4-8 AND COMPARATIVE EXAMPLE A

[0056] Examples 4-8 include stabilized pharmaceutical compositions within the scope of the present invention. Comparative Example A includes a pharmaceutical composition outside the scope of the present invention. The aqueous dispersion (1 mg of medicament/ 1 gm water) of the above pharmaceutical compositions gave a pH of less than 9. [0057] The stabilized pharmaceutical compositions of Examples 4 and 6-8 and

Comparative Example A were generally prepared as follows. A mixture of filler (mannitol or dicalcium phosphate), a fraction of another filler (microcrystalline cellulose (MCC), a binder (hydroxypropyl methylcellulose (HPMC)), and disintegrant (croscarmellose sodium) were mixed together and passed through a #40 mesh screen. The stabilizer (meglumine, triethanolamine or TRIS), was dissolved in water and the above mixture was granulated, dried and sized. The granules were mixed with pravastatin sodium, a protectant (hydrophobic colloidal silicon dioxide), a filler (microcrystalline cellulose), a disintegrant (croscarmellose sodium) and a lubricant (magnesium stearate and/or colloidal silicon dioxide). [0058] The sodium chloride stabilized pharmaceutical composition of Example 5 may be prepared as follows. A mixture of the filler (lactose hydrous), a fraction of another filler (microcrystalline cellulose), a binder (HPMC), and disintegrant (croscarmellose sodium) were mixed together and passed through a #40 mesh screen. The sodium salt was dissolved in water and the above mixture was granulated, dried and sized. The granules were mixed with pravastatin sodium, a protectant (hydrophobic colloidal silicon dioxide), a filler (microcrystalline cellulose), a disintegrant (croscarmellose sodium) and a lubricant (magnesium stearate).

[0059] The resulting mixtures were then compressed into tablets. All mesh sizes are

U.S. Standard ASTM. The ingredients and amounts of Examples 1-7 and Comparative Example A are set forth below in Table 4.

TABLE 4

[0060] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A stabilized pharmaceutical composition comprising a therapeutically effective amount of one or more active pharmaceutical ingredients capable of degradation in a low pH environment and a stabilizing effective amount of one or more amino-group containing monomeric compounds and/or amido-group containing monomelic compounds for the stabilization of the active pharmaceutical ingredient.

2. The stabilized pharmaceutical composition of Claim 1, wherein the active pharmaceutical ingredient capable of degradation in a low pH environment is a HMG-CoA reductase inhibitor.

3. The stabilized pharmaceutical composition of Claim 2, wherein the HMG-CoA reductase inhibitor is a statin or a pharmaceutically acceptable salt, ester, derivative or isomer thereof.

4. The stabilized pharmaceutical composition of Claim 3, wherein the statin is selected from the group consisting of pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, itavastatin, nisvastatin, nisbastatin, rosuvastatin, atavastatin, visastatin and a pharmaceutically acceptable salts, esters, derivatives and isomers thereof.

5. The stabilized pharmaceutical composition of Claim 1, wherein the active pharmaceutical ingredient capable of degradation in a low pH environment is selected from the group consisting of pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, itavastatin, nisvastatin, nisbastatin, rosuvastatin, atavastatin, visastatin and a pharmaceutically acceptable salts, esters, derivatives and isomers thereof.

6. The stabilized pharmaceutical composition of Claims 1-5, wherein the amino- group containing monomelic compound is of the general formula

wherein R¹, R² and R³ are independently hydrogen, a hydrocarbyl of 1 to about 30 carbon atoms optionally containing one or more hydroxy groups or heterocyclic groups or R¹ and R²

1 "X O ¹X or R and R or R and R together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms.

7. The stabilized pharmaceutical composition of Claims 1-5, wherein the amino- group containing monomelic compound is selected from the group consisting of a hydrocarbyl amine, hydroxy substituted hydrocarbyl amine and mixtures thereof.

8. The stabilized pharmaceutical composition of Claims 1-5, wherein the amino- group containing monomelic compound is an alkyl amine having from 1 to about 30 carbon atoms.

9. The stabilized pharmaceutical composition of Claims 1-5, wherein the amino- group containing monomelic compound is selected from the group consisting of isopropyl amine, dibutyl amine and mixtures thereof.

10. The stabilized pharmaceutical composition of Claim 7, wherein the hydroxy substituted hydrocarbyl amine contains 1 to about 30 carbon atoms and from about 1 to about 6 hydroxyl groups.

1.1. The stabilized pharmaceutical composition of Claim 7, wherein the hydroxy substituted hydrocarbyl amine is selected from the group consisting of diisopropanolamine, ethanolamine and triethanolamine.

12. The stabilized pharmaceutical composition of Claim 1, wherein the amido-group containing monomeric compound is of the general formula

wherein R⁴, R⁵ and R⁶ are independently hydrogen, a hydrocarbyl of 1 to about 30 carbon atoms optionally containing one or more heterocyclic groups or R⁵ and R⁶ together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms.

13. The stabilized pharmaceutical composition of Claims 1-12, wherein the stabilizing effective amount of the amino-group containing monomeric compound and/or amido-group containing monomeric compound is about 0.01 to about 10% by weight based on the total weight of the stabilized pharmaceutical composition.

14. The stabilized pharmaceutical composition of Claim 1, wherein the active pharmaceutical ingredient capable of degradation in a low pH environment is a pharmaceutically acceptable acid salt of pravastatin and the amino-group containing monomeric compound is selected from the group consisting of meglumine, triethanolamine, tromethamine and mixtures thereof.

15. The stabilized pharmaceutical composition of Claim 14, wherein the pharmaceutically acceptable acid salt is pravastatin sodium.

16. The stabilized pharmaceutical composition of Claim 1, wherein the active pharmaceutical ingredient capable of degradation in a low pH environment is a pharmaceutically acceptable acid salt of atorvastatin and the amino-group containing monomeric compound is selected from the group consisting of meglumine, triethanolamine, tromethamine and mixtures thereof.

17. The stabilized pharmaceutical composition of Claim 16, wherein the pharmaceutically acceptable acid salt is atorvastatin calcium.

18. The stabilized pharmaceutical composition of Claims 1-17, further comprising one or more pharmaceutically acceptable excipients.

19. The stabilized pharmaceutical composition of Claims 1-18, which is in the form of a solid.

20. The stabilized pharmaceutical composition of Claims 1-19, which is in the form of a tablet.

21. The stabilized pharmaceutical composition of Claim 20, wherein the tablet contains at least a lubricant.

22. The stabilized pharmaceutical composition of Claim 21, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, polyethylene glycol, stearic acid, hydrogenated vegetable oil and talc.

23. The stabilized pharmaceutical composition of Claims 1-18, which is in the form of granules.

24. The stabilized pharmaceutical composition of Claim 23, wherein the granules are constituents of a dispersion.

25. The stabilized pharmaceutical composition of Claims 1-18, which is in the form of a suspension.

26. The stabilized pharmaceutical composition of Claims 1-18, which is in the form of a capsule.

27. The stabilized pharmaceutical composition of Claims 1-18, which is in the form of a cachet.

28. The stabilized pharmaceutical composition of Claims 1-18, wherein the amino- group containing monomeric compound and/or amido-group containing monomelic compound imparts a pH of not more than about 10 to an aqueous dispersion of the pharmaceutical composition.

29. The stabilized pharmaceutical composition of Claims 1-18, wherein the amino- group containing monomeric compound and/or amido-group containing monomeric compound imparts a pH of not more than about 9 to an aqueous dispersion of the pharmaceutical composition.

30. A stabilized pharmaceutical composition comprising (a) about 0.05 % to about 70 % by weight, based on the total weight of the composition, of one or more active pharmaceutical ingredients comprising a statin or a pharmaceutically acceptable salt, ester, derivative or isomer thereof and (b) about 0.01 to about 10% by weight, based on the total weight of the composition, of one or more amino-group containing monomeric compounds and/or amido-group containing monomeric compounds.

31. A stabilized pharmaceutical composition comprising a therapeutically effective amount of one or more active pharmaceutical ingredients capable of degradation in a low pH environment and a stabilizing effective amount of one or more alkali metal salts of an acid for the stabilization of the active pharmaceutical ingredient.

32. The stabilized pharmaceutical composition of Claim 31, wherein the active pharmaceutical ingredient capable of degradation in a low pH environment is a HMG-CoA reductaseinhibitor.

33. The stabilized pharmaceutical composition of Claim 32, wherein the HMG-CoA reductase inhibitor is a statin or a pharmaceutically acceptable salt, ester, derivative or isomer thereof.

34. The stabilized pharmaceutical composition of Claim 33, wherein the statin is selected from the group consisting of pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, itavastatin, nisvastatin, nisbastatin, rosuvastatin, atavastatin, visastatin and a pharmaceutically acceptable salts, esters, derivatives and isomers thereof.

35. The stabilized pharmaceutical composition of Claim 31, wherein the active pharmaceutical ingredient capable of degradation in a low pH environment is selected from the group consisting of pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, itavastatin, nisvastatin, nisbastatin, rosuvastatin, atavastatin, visastatin and a pharmaceutically acceptable salts, esters, derivatives and isomers thereof and the alkali metal salt of an acid is a sodium salt.

36. The stabilized pharmaceutical composition of Claims 31-34, wherein the alkali metal salt of an acid is sodium salt chloride.