COMPLETE AFTER PROVISIONAL
LEFT ON.2 8 JUN 2005
FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
STABILIZED PHARMACEUTICAL COMPOSITIONS
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

STABILIZED PHARMACEUTICAL COMPOSITIONS
BACKGROUND OF INVENTION
1. Technical Field
[0001] 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
[0002] 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.
[0003] 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.
[0004] Pharmaceutical compositions that include a medicament that is relatively
unstable in an acidic environment have been thought 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, 1,2,6,7,8,8a-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 trademark 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.
[0005] 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-( 1 -methylethyl)-3-pheny l-4-[(phenylamino)-carbonyl]-1 H-pyrrole-1 -heptanoic acid, hemicalcium salt. Atorvastatin calcium is sold in the U.S. under the trademark 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.

[0006] 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.
[0007] 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. For example, lactose discolors and emits a caramelized odor in the presence of
certain basifying agents, e.g., piperazine. 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.
[0008] 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 OF INVENTION
[0009] 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.
[0010] 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.
[0011] 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 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
[0012] 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.
[0013] 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 la
and IIb primary hypercholesterolemia, Frederickson Type IV hypertriglyceridemia,
Frederickson Type III dysbetaliproteinemia, and Frederickson Type V hyperlipidemia.
[0014] 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.

[0015] By "stabilized pharmaceutical composition" as used herein is meant that after
storage for three months at 40°C and 75% relative humidity, no more than about 10%, preferably no more than about 5%, and more preferably, no more than about 2% 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.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.

[0025] 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.
[0026] 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
[0027] 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 monomeric compounds and/or amido-group containing monomeric compounds for the stabilization of the active pharmaceutical ingredient.

[0028] 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 pharmaceutical ly acceptable salts, esters, derivatives and isomers thereof and the like and mixtures thereof. Any HMG-CoA reductase inhibitor may be employed 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.
[0029] 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 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.
[0030] 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 50 %, and more preferably from about 5 to about 30 % by weight of the composition. It is understood that higher or lower weight percentages of the active ingredient may be present in the pharmaceutical compositions.
[0031] Also present in the stabilized pharmaceutical composition of the present
invention is a stabilizing effective amount of one or more amino-group containing monomeric
compounds or a stabilizing effective amount of one or more amido-group containing
monomeric compounds, or a stabilizing effective amount of a combination of at least one
amino-group and at least one amido-group containing monomeric compound.
[0032] 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 formula

wherein R1, R2 and R3 are independently hydrogen, a hydrocarbyl of 1 to about 30 carbon atoms optionally containing 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, R2 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.
[0033] 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 di isopropanolamine, ethanolamine, and triethanolamine.
[0034] 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").

[0035] 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 monomeric compounds and the active pharmaceutical ingredient used. For example, the stabilizing effective amount of the amino-group containing monomeric compounds can range from about O.Olto about 10% and preferably from about 0.1 to about 4 % by weight of the stabilized pharmaceutical composition.
[0036] 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, corn starch, modified corn starch, mannitol, sorbitol, silicon dioxide, and microcrystalline cellulose.
[0037] 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 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. Tablet dosage forms may further contain excipients such as any pharmaceutically acceptable lubricant, binder, disintegrant, diluent, carrier, preservative or combination thereof. Solid dosage forms that are not formulated as tablets typically do not need a lubricant component since this is typically added to facilitate manufacture of tablet dosage forms. 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.
[0038] 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.
[0039] Excipients typically used in tablet dosage forms include, but are not limited to,
carriers, lubricants, glidants, binders and fillers that facilitate compacting, shaping, and sizing.
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.
[0040] 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 of dosage form. .
[0041] 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.

[0042] 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.
[0043] 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.
[0044] 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.
[0045] The aqueous dispersion (1 mg of medicament /l gm water) of the above
pharmaceutical compositions gave a pH of less than 9.
[0046] The stabilizer such as monomeric amine used in the above pharmaceutical
compositions includes any or all of the following: Meglumine / Triethanolamine / TRIS All mesh sizes are U.S. Standard ASTM.
[0047] The pharmaceutical composition of the invention may be prepared as follows.
A mixture of the filler (Mannitol / dicalcium phosphate), a fraction of another filler (such as microcrystalline cellulose), binder (HPMC), and disintegrant (such as croscarmellose sodium)

are mixed together and passed through a #40 mesh screen. The stabilizer (preferably Meglumine / Triethanolamine / TRIS), is dissolved in water and the above mixture is granulated, dried and sized. These granules are mixed with medicament (such as Pravastatin sodium), and protectant (such as hydrophobic colloidal silicon dioxide), and filler (microcrystalline cellulose), and disintegrant (such as croscarmellose sodium), and lubricants (magnesium stearate and / or colloidal silicon dioxide).
[0048] An alternative method for preparing the pharmaceutical composition of the
invention as follows. A mixture of the filler (Mannitol / dicalcium phosphate), a fraction of another filler (such as microcrystalline cellulose), are mixed together and passed through a #40 mesh screen. The stabilizer (preferably Meglumine / Triethanolamine / TRIS) and binder (HPMC), are dissolved in water and the above mixture is granulated by fluid bed granulation, dried and sized. From these granules about 15 to 25% fines (below #80mesh) are separated and mixed with the medicament (such as Pravastatin sodium), filler (such starch), disintegrant (such as crospovidone and / or starch) and lubricant (such as colloidal silicon dioxide and / or magnesium stearate). The resulting mixture may then be roll compacted and sized. These sized granules are mixed with disintegrant (such as crospovidone and / or starch) and lubricant (such as colloidal silicon dioxide and / or magnesium stearate). The resulting mixture may then be compressed into tablets of 0.8 gram in weight. All mesh sizes are U.S. Standard ASTM.
[0049] In accordance with the present invention, another pharmaceutical composition
is also provided which has excellent storage stability even though it includes a medicament which may degrade in a low pH environment. The pharmaceutical composition of the invention, which is preferably in the form of a tablet, includes a medicament which is sensitive to a low pH environment, such as pravastatin sodium, one or more fillers, such as mannitol, dicalcium phosphate and microcrystalline cellulose, binder, such as hydroxypropyl methylcellulose disintegrating agent such as croscarmellose sodium, one or more lubricants such as magnesium stearate and/or colloidal silicon dioxide, a stabilizer such as sodium salt of

an acid and a protectant such as hydrophobic colloidal silicon dioxide. The sodium salt of the acid may be expected to pick up moisture preferentially to the drug. It would then dissociate in the presence of moisture and the sodium ions thus formed would prevent dissociation of pravastatin sodium according to the principle of common ion effect. Thus, the instability of the drug which occurs mainly in the dissociated / ionized form could probably be greatly reduced.
[0050] The pharmaceutical composition of the invention will include from about
about 8 to about 12% by weight pravastatin sodium, from about 1.5 to about 10% by weight of the sodium salt of an acid, preferably sodium chloride, from about 1 to about 2.5% by weight hydrophobic colloidal silicon dioxide, from about 50 to about 75% by weight lactose monohydrate, from about 20 to about 25% by weight microcrystalline cellulose, from about 1 to 2.5 % by weight hydroxypropyl methylcellulose, from about 5% by weight croscarmellose sodium, from about 1.5 to 2.5% by weight magnesium stearate.
[0051] Another embodiment of the present invention includes from about 8 to about
12% by weight pravastatin or pharmaceutically acceptable salts thereof, from about 1.5 to
about 5% by weight of the sodium 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, from about 1 to
2.5 % by weight hydroxypropyl methylcellulose, from about 5% by weight croscarmellose
sodium, from about 1.5 to 2.5% by weight magnesium stearate, from about 1% by weight
colloidal silicon dioxide.
[0052] The pharmaceutical composition of the invention may be prepared as follows.
A mixture of the filler (Mannitol / dicalcium phosphate), a fraction of another filler (such as microcrystalline cellulose), binder (HPMC), and disintegrant (such as croscarmellose sodium) are mixed together and passed through a #40 mesh screen. The sodium salt is dissolved in water and the above mixture is granulated, dried and sized. These granules are mixed with medicament (such as Pravastatin sodium), and protectant (such as hydrophobic colloidal silicon dioxide), and filler (microcrystalline cellulose), and disintegrant (such as

[0053] 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

Brief Procedure:
All excipients were sifted through 40 mesh ASTM and granulated using water as binder in
rapid mixer granulator. Granules were dried and sized through 30 mesh ASTM. Extra granular materials were added to above granules along with API. This mass was then lubricated in suitable blender. The granules obtained were compressed into tablets using required tooling. pH of the tablets obtained by above process was 7.61.

Example: 2

s.
No. Ingredients Batch No 177

Mg/tab % w/w
1. Pravastatin Sodium 80.00 10.00
2. Mannitol 416.50 52.0625
3. MCC 140.00 17.50
4. Hydroxypropyl Methylcellulose 12.00 1.50
5. Meglumine 1.50 0.1875
6. Crospovidone 40.00 5.00
7. Colloidal silicon dioxide 8.00 1.00
8. Starch 82.00 10.25
9. Magnesium stearate 20.00 2.50
Tablet weight (mg) 800.00 100.00
Brief Procedure:
All excipients were sifted through 40 mesh ASTM and loaded in FBP. This mass was then granulated using binder solution of suitable concentration to obtain sufficiently hard granules. The granules obtained by the above process were then sized through 30 mesh ASTM. To the above granules extra granular rnaterials were added along with API. This mass was then lubricated for sufficient time. This blend was then compressed into tablets by using required tooling. The pH of the tablets obtained was 8.20.

Example 3

Sr. No. Ingredients Batch No 051
Mg/tab % w/w
1. Pravastatin Sodium 80.00 10.00
2. Mannitol 415.84 51.98
3. MCC 140.00 17.50
4. Hydroxypropyl Methylcellulose 12.00 1.50
5. Meglumine 1.50 0.1875
6. D&C Yellow No. 10 Alu Lake 0.48 0.06
7. FD&C Blue No. 1 Alu Lake 0.18 0.0225
8. Crospovidone 40.00 5.00
9. Colloidal silicon dioxide 8.00 1.00
10. Starch 82.00 10.25
11. Magnesium stearate 20.00 2.50
Tablet weight (mg) 800.00 100.00
Brief Procedure:
All excipients were sifted through 40 mesh ASTM. The mass is then loaded in FBP to obtain granules by top spray granulation. The granules obtained were then sized using 30 mesh ASTM. A part of above granules and API were mixed together. This mass was then roll compacted to obtain compacts with sufficient hardness. The compacts were then passed through 16 mesh ASTM by using Oscillating Granulator and then through 30 mesh ASTM. The granules obtained by above process were then lubricated along with extra granular materials. The granules obtained by this process were then compressed into tablets. The pH of the tablets was 8. J 5.

WHAT IS CLAIMED IS:
1. A stabilized pharmaceutical composition comprising a therapeutically effective amount of one or more HMG-CoA reductase inhibitor and a stabilizing effective amount of one or more amino-group containing monomeric compounds for the stabilization of the active pharmaceutical ingredient.
2. The stabilized pharmaceutical composition of Claim 2, wherein the HMG-CoA reductase inhibitor is a statin or a pharmaceutically acceptable salt thereof.
3. 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 pharmaceutically acceptable salts thereof.
4. The stabilized pharmaceutical composition of Claim 1, wherein the active
pharmaceutical ingredient is selected from the group consisting of pravastatin, lovastatin,
atorvastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, itavastatin, nisvastatin,
nisbastatin, rosuvastatin, atavastatin, visastatin and pharmaceutically acceptable salts thereof.

5. The stabilized pharmaceutical composition of Claim 1, wherein the amino-group
containing monomeric 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 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.
6. The stabilized pharmaceutical composition of Claim 1, wherein the amino-group containing monomeric compound is selected from the group consisting of a hydrocarbyl amine, hydroxy substituted hydrocarbyl amine and mixtures thereof.
7. The stabilized pharmaceutical composition of Claim 3, wherein the amino-group containing monomeric compound is an alkyl amine having from 1 to about 30 carbon atoms.
8. The stabilized pharmaceutical composition of Claim 1, wherein the amino-group containing monomeric compound is selected from the group consisting of isopropyl amine, dibutyl amine and mixtures thereof.
9. 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.
10. The stabilized pharmaceutical composition of Claim 7, wherein the hydroxy
substituted hydrocarbyl amine is selected from the group consisting of diisopropanolamine,
ethanolamine and triethanolamine.

11. The stabilized pharmaceutical composition of Claim 1, wherein the stabilizing
effective amount of the amino-group containing monomeric compound is about O.Olto about
10%.
12. The stabilized pharmaceutical composition of Claim 1, wherein the stabilizing
effective amount of the amino-group containing monomeric compound is more preferably
about O.Olto about 10%.
13. 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.
14. The stabilized pharmaceutical composition of Claim 14, wherein the
pharmaceutically acceptable acid salt is pravastatin sodium.
15. The stabilized pharmaceutical composition of Claim 1, wherein the active
pharmaceutical ingredient 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.
16. The stabilized pharmaceutical composition of Claim 16, wherein the
pharmaceutically acceptable acid salt is atorvastatin calcium.
17. The stabilized pharmaceutical composition of Claim 1, further comprising one or
more pharmaceutically acceptable excipients.

18. The stabilized pharmaceutical composition of Claim 1, which is in the form of a solid.
19. The stabilized pharmaceutical composition of Claim 1, which is in the form of a tablet.
20. The stabilized pharmaceutical composition of Claim 20, wherein the tablet
contains at least a lubricant.
21. 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.
22. The stabilized pharmaceutical composition of Claim 1, which is in the form of granules.
23. The stabilized pharmaceutical composition of Claim 23, wherein the granules are constituents of a dispersion.
24. The stabilized pharmaceutical composition of Claim 1, which is in the form of a suspension.
25. The stabilized pharmaceutical composition of Claim 1, which is in the form of a capsule.
26. The stabilized pharmaceutical composition of Claim 1, which is in the form of a cachet.

27. The pharmaceutical composition of Claim 1, wherein the amino-group containing monomeric compound containing monomeric compound imparts a pH of not more than about 10 to an aqueous dispersion of the pharmaceutical composition.
28. The pharmaceutical composition of Claim 1, wherein the amino-group containing monomeric compound containing monomeric compound imparts a pH of not more than about 9 to an aqueous dispersion of the pharmaceutical composition.
29. A method of treating dyslipidemia, comprising the step of orally administering to a patient in need of such treatment a therapeutically effective unit dosage of the pharmaceutical composition of Claim 1.
Dated this Twenty Eighth (28th) day of June 2005

(Signed)
GLENN SALDANHA MD & CEO Glenmark Pharmaceuticals Limited