WO2008091870A2

WO2008091870A2 - Pharmaceutical compositions comprising atorvastatin and nicotinic acid

Info

Publication number: WO2008091870A2
Application number: PCT/US2008/051662
Authority: WO
Inventors: Magesh Kumar Devaraj; Vijayraghavan Thiruvur Panchanathan; Raja Kumar Seshadri; Venkata Nookaraju Sreedharala; Suman Sharma Ghati Sathyanarayana; Ratish Sashidharan Acharya; Raghava Raju Thummala Veera; Harish Kasam
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2007-01-24
Filing date: 2008-01-22
Publication date: 2008-07-31
Also published as: WO2008091870A3; EA200970708A1

Abstract

A solid pharmaceutical dosage form comprises a granulated powder mixture comprising atorvastatin or a salt thereof and a granulated powder mixture comprising nicotinic acid or a derivative thereof. The present invention further encompasses stabilized pharmaceutical compositions of atorvastatin or its salts and nicotinic acid or its derivatives.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ATORVASTATIN AND

NICOTINIC ACID

INTRODUCTION TO THE INVENTION The present invention relates to pharmaceutical fixed dose compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or its pharmaceutically acceptable derivatives. The invention further relates to processes to prepare such compositions, pharmacokinetic parameters of the compositions and method of using such compositions in treating hyperlipidemia. The present invention further relates to stabilized pharmaceutical compositions of atorvastatin or its salts and nicotinic acid or its derivatives.

Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

Atorvastatin calcium has a chemical name [R-(R^*,R^*)]-2-(4-fluorophenyl)-b,d- dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 - heptanoic acid, calcium salt (2:1 ) trihydrate. The empirical formula of atorvastatin calcium is (C₃3H₃₄ FN₂O₅)2Ca-3H₂O and its molecular weight is 1209.42. It has structural formula (1 ).

(1 )

Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4-phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol. Atorvastatin calcium is available commercially in LIPITOR tablets marketed by Pfizer. LIPITOR tablets for oral administration contain 10, 20, 40 or 80 mg of atorvastatin.

Nicotinic acid at therapeutic doses is an antihyperlipidemic agent. Nicotinic acid (niacin or 3-pyhdinecarboxylic acid) is a white, crystalline powder, very soluble in water, having structural formula (II).

(II) Nicotinic acid has the molecular formula C₆H₅NO₂ and the molecular weight

123.11. It is a white, crystalline powder, with an odour of slightly amine to odourless. It is soluble in boiling water and in boiling alcohol, sparingly soluble in water, dissolves in dilute solutions of the alkali hydroxides and carbonates. It has a melting point of 234°C to 240⁰C. Nicotinic acid, also known as niacin, has been used for many years in the treatment of hyperlipidemia or hypercholesteremia. This compound has long been known to exhibit the beneficial effects of reducing total cholesterol, VLDL-cholesterol and VLDL-cholesterol remnants, LDL-cholesterol, triglycerides and apolipoprotein a, known as "Lp(a)," in the human body, while increasing desirable HDL-cholesterol.

Nicotinic acid is available in several formulations that include immediate- release and sustained release formulations such as Niacore^®from Upsher-Smith Laboratories, Inc. and Niaspan^® as extended release formulation from Abbott Laboratories.

Combinations of atorvastatin and nicotinic acid have diminished side effects. Atorvastatin or its salts are very poorly in water. This results in low bioavailability. On the other hand nicotinic acid has a much higher solubility, but can be toxic or produce discomforting symptoms. Liver damage is a concern when treating for hyperlipedemia with nicotinic acid. In addition, nicotinic acid can produce gastrointestinal problems when taken in immediate release compositions administered several times daily. Flushing is another common occurrence in which painful swelling in the joints and elsewhere occurs for some minutes after ingestion.

Hyperlipidemia or an elevation in serum lipids is associated with an increased incidence of cardiovascular disease and atherosclerosis. It is well known that the likelihood of cardiovascular disease can be decreased, if the serum lipids, and in particular LDL-cholesterol, can be reduced.

Drugs that lower the concentration of serum lipoproteins or lipids include inhibitors of HMG-CoA reductase, the rate-controlling enzyme in the biosynthetic pathway of cholesterol. Other drugs, which lower serum cholesterol, include, for example, nicotinic acid, bile acid sequestrants.

Nicotinic acid has normally been administered three times per day after meals. This dosing regimen is known to provide a very beneficial effect on blood lipids. While such a regimen does produce beneficial effects, cutaneous flushing still often occurs in the hyperlipidemics to whom the nicotinic acid is administered. In order to avoid or reduce the cutaneous flushing resulting from nicotinic acid therapy, one method is use of agents such as guar gum, inorganic magnesium salts, and non-steroidal anti-inflammatory agents. Another method of avoiding or reducing the side effects associated with immediate release niacin is the use of controlled or sustained release formulations. Statins generally are relatively unstable in acidic environments and usually require a basic excipient to maintain pH of at least 9. Atorvastatin can degrade to the corresponding lactone in an acidic environment, wherein hydroxy acids of atorvastatin are degraded into the corresponding lactone.

International Application Publication Nos. WO 2005/011737, WO 2006/006021 , WO 2004/110431 , WO 2004/071402, WO 2004/032920, WO 2003/068191 , WO 2003/097039, WO 2001/076566, WO 2001/093859, WO 2001/093860, and WO 2000/035425 disclose various stabilized pharmaceutical compositions of atorvastatin or its salts.

International Application Publication No. WO 2005/046662 discloses a combination of an HMG CoA reductase inhibitor and at least one additional therapeutic agent. U.S. Patent No. 6,469,035, U.S. Patent Application Publication Nos. 2005/0255158 and 2004/0053975, and International Application Publication No. WO 99/17774 disclose pharmaceutical compositions comprising an HMG CoA reductase inhibitor and a nicotinic acid component.

Saturated aqueous solutions of nicotinic acid have pH values about 2.7. Combinations of atorvastatin or its salts, which is sensitive to an acidic environment, and nicotinic acid, which has an acidic pH, result in compositions having diminished side effects, and are stabilized for an acceptable safety profile.

SUMMARY OF THE INVENTION The present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein the composition, after oral administration to a human, results in a t_max of atorvastatin from about 1 hour to about 4 hours, or from about 1 hour to about 3 hours.

The present invention further relates to pharmaceutical compositions for once- daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form wherein the composition after oral administration to a human results in a t_max of nicotinic acid from about 2 hours to about 8 hours, or from about 3 hours to about 7 hours.

An aspect of the present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein release of atorvastatin after 30 minutes is not less than about 80%, when tested in vitro using a USP Type Il apparatus with 900 ml of pH 6.8 phosphate buffer at 75 rpm, the procedure being described in Test 711 , "Dissolution," United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP").

The present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein nicotinic acid is released according to the following dissolution profile, when tested in vitro according to the USP procedure in 900 ml of pH 2.1 simulated gastric fluid for 1 hour, followed by 900 ml of pH 6.5 fasting simulated intestinal fluid for 5 hours, followed by 900 ml of pH 7.4 phosphate buffer for 18 hours, in a USP Type Il apparatus at 50 rpm: a) Not more than about 25% of nicotinic acid is released within about 1 hour. b) Not more than about 60%, or between about 25% and about 60%, or between about 30% and about 50%, of nicotinic acid is released within about 6 hours. c) Not more than about 80%, or between about 40% and about 80%, or between about 50% and about 70%, of nicotinic acid is released within about 12 hours. d) Not less than about 60%, or not less than about 70%, of nicotinic acid is released within about 24 hours.

In an embodiment, the present invention provides oral pharmaceutical compositions comprising atorvastatin or its salts and nicotinic acid or its derivatives and release rate controlling excipients, wherein the composition is adapted to release nicotinic acid in a controlled manner so as to provide a control over nicotinic acid plasma levels for about 24 hours.

In an embodiment, the present invention relates to stable pharmaceutical compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or derivatives thereof.

In an embodiment the invention includes alkalizing agents as stabilizers. In an embodiment, the present invention relates to stable pharmaceutical formulations comprising compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or derivatives, wherein a formulation is in the form of a multilayered tablet.

In an embodiment, the present invention relates to stable pharmaceutical formulations comprising compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or derivatives, wherein a formulation is in the form of a capsule or a capsule within a capsule.

In an embodiment, the present invention relates to stable pharmaceutical formulations comprising compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or derivatives, wherein a formulation is in the form of a multi-particulate system.

In another embodiment the invention includes processes for manufacturing pharmaceutical compositions of the present invention. In an embodiment the invention includes methods of using pharmaceutical compositions of the present invention for the treatment of hyperlipidema.

An embodiment of the invention provides a solid pharmaceutical dosage form comprising a granulated powder mixture comprising atorvastatin or a salt thereof and a granulated powder mixture comprising nicotinic acid or a derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION

An aspect of the present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein the composition after oral administration to a human results in a t_max of atorvastatin from about 1 hour to about 4 hours, or from about 1 hour to about 3 hours.

An aspect of the present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein the composition after oral administration to a human results in a t_max of nicotinic acid from about 2 hours to about 8 hours, or from about 3 hours to about 7 hours.

An aspect of the present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein release of atorvastatin within 30 minutes is not less than about 80%, when tested in vitro in USP Type Il apparatus using 900 ml of pH 6.8 phosphate buffer at 75 rpm.

An aspect of the present invention relates to pharmaceutical compositions for once-daily administration comprising atorvastatin or its salts in immediate release form and nicotinic acid or its derivatives in controlled release form, wherein nicotinic acid is released according to the following dissolution profile, when tested in vitro in 900 ml of pH 2.1 simulated gastric fluid for 1 hour, followed by 900 ml of pH 6.5 fasting simulated intestinal fluid for 2-5 hours, followed by 900 ml of pH 7.4 phosphate buffer for 6-24 hours, in USP Type Il apparatus at 50 rpm: a) Not more than about 25% of nicotinic acid is released within about 1 hour. b) Not more than about 60%, or between about 25% and about 60%, or between about 30% and about 50%, of nicotinic acid is released within about 6 hours. c) Not more than about 80%, or between about 40% and about 80%, or between about 50% and about 70%, of nicotinic acid is released within about 12 hours. d) Not less than about 60%, or not less than about 70%, of nicotinic acid is released within about 24 hours.

In an embodiment the present invention provides oral pharmaceutical compositions comprising atorvastatin or its salts and nicotinic acid or its derivatives and release rate controlling excipients, wherein a composition is adapted to release nicotinic acid in a controlled manner so as to provide desired nicotinic acid plasma levels over about 24 hours.

In an embodiment the present invention relates to stable pharmaceutical compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or derivatives.

In an embodiment the invention includes the use of alkalizing agents as stabilizers.

In another embodiment the invention includes processes for manufacturing pharmaceutical compositions.

In an embodiment the invention includes a method of using pharmaceutical compositions of the present invention for the treatment of hyperlipidema.

The various pharmaceutically acceptable salts of atorvastatin include 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, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, etc. The term "pharmaceutically acceptable amine salt" includes, but is not limited to, salts formed by reaction with ammonium hydroxide or organic amines such as for example methylglucamine, choline, arginine, 1 -deoxy-2-(methylamino)-D-glucitol, and the like. The amount of an active ingredient in the pharmaceutical compositions of the present invention will be a therapeutically effective amount. Generally, a therapeutically effective amount of an active ingredient can range from about 0.05% to about 70%, or from about 1 % to about 60%, or from about 5% to about 50%, by weight, based on the total weight of the pharmaceutical composition.

A derivative of nicotinic acid is a compound that is metabolized to nicotinic acid by the body or mixtures thereof, thus producing the same effect as described herein. The nicotinic acid derivatives and other compounds include, but are not limited to nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol, d,1 -alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, nicotinamide adenine dinucleotide (NAD), N-methyl-2-pyrhdine-δ-carboxamide, N-methyl-nicotinamide, N- ribosyl-2-pyhdone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradilian, sorbinicate, hexanicite, ronitol, and esters of nicotinic acid such as lower alcohol esters like methyl, ethyl, propyl or butyl esters.

In an embodiment, the invention includes a concentration of active ingredient in immediate release form ranging from about 5 mg to about 100 mg, or from about 5 mg to about 80 mg.

In an embodiment the invention includes a concentration of active ingredient in controlled release form ranging from about 100 mg to about 1000 mg, or from about 250 mg to about 750 mg, or from about 375 mg to about 500 mg. In one of the embodiments, the present invention includes solid oral dosage forms, which include but are not limited to tablets, capsules, granules, sachets and the like.

In an embodiment, the present invention includes pharmaceutical compositions, which are in the form of a multilayered tablet. In an embodiment, pharmaceutical compositions of the present invention include atorvastatin or its salts in immediate release form, such that not less than about 80% is released within 30 minutes in an in vitro dissolution test, and a t_max between from about 1 hour to about 4 hours is achieved when the composition is orally administered. In an embodiment, pharmaceutical compositions of present invention includes nicotinic acid or its derivatives in an controlled release form, such that a nicotinic acid t_max between from about 2 hours to about 8 hours is achieved when the composition is orally administered, and nicotinic acid is released according to the following dissolution profile when tested in in vitro: a) Not more than about 25% of nicotinic acid is released within about 1 hour. b) Not more than about 60%, or between about 25% and about 60%, or between about 30% and about 50%, of nicotinic acid is released within about 6 hours. c) Not more than about 80%, or between about 40% and about 80%, or between about 50% and about 70%, of nicotinic acid is released within about 12 hours. d) Not less than about 60%, or not less than about 70%, of nicotinic acid is released within about 24 hours.

In an embodiment the invention includes pharmaceutical formulations comprising atorvastatin or its salts and nicotinic acid, producing plasma C_maχ values of atorvastatin ranging from about 5 ng/mL to about 10 ng/mL after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

In an embodiment the invention includes pharmaceutical formulations comprising atorvastatin or its salts and nicotinic acid, producing plasma C_maχ values of nicotinic acid ranging from about 15 ng/mL to about 30 ng/mL after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

In an embodiment the invention includes pharmaceutical formulations comprising atorvastatin or its salts and nicotinic acid, producing plasma AUCo-t values of atorvastatin ranging from about 25 ng-hour/ml to about 40 ng-hour/ml after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

In an embodiment the invention includes pharmaceutical formulations comprising atorvastatin or its salts and nicotinic acid, producing plasma AUCo-t values of nicotinic acid ranging from about 100 ng-hour/ml to about 165 ng-hour/ml after administration of a single 10 mg atorvastatin and 500 mg of nicotinic acid dose to healthy humans.

In an embodiment the invention includes pharmaceutical formulations comprising atorvastatin or its salts and nicotinic acid, producing plasma AUCo-∞ values of atorvastatin ranging from about 30 ng-hour/ml to about 50 ng-hour/ml after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

In an embodiment the invention includes pharmaceutical formulations comprising atorvastatin or its salts and nicotinic acid, producing plasma AUCo-∞ values of nicotinic ranging from about 110 ng-hour/ml to about 180 ng-hour/ml after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

Nicotinic acid is in controlled release form when the composition comprises a dissolution rate controlling excipient that delays and/or reduces the rate of release of the drug from the dosage form. Usually, the rate controlling excipient is a polymer or a fatty compound, or a mixture thereof. It may also comprise an ion-exchange resin. Examples of rate controlling excipients that may be used in the present invention include, but are not limited to:

1 ) Cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hypromellose or HPMC, such as is sold by Dow Chemical Co. under the trade name METHOCEL™, various grades including METHOCEL K 4M, METHOCEL K 15M, METHOCEL K 100M, METHOCEL K100M CR, METHOCEL K100LV), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), crosslinked carboxymethyl cellulose (croscarmellose) and its alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxy ethyl cellulose (HMHEC), hydrophobically modified ethylhydroxy ethyl cellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and the like; vinylpyrrolidone polymers including polyvinylpyrrolidones (PVP or povidone), crosslinked polyvinylpyrrolidones or crospovidone, copolymers of vinylpyrrolidone and vinyl acetate; and alkylene oxide homopolymers such as polyethylene oxide and polypropylene oxide. In an embodiment, a rate-controlling polymer comprises an ethylene oxide homopolymer. 2) Super disintegrant polymers such as a crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohol, amylose, crosslinked amylose, starch derivative, microcrystalline cellulose and cellulose derivative, alpha-, beta-and gamma-cyclodextrin and dextrin derivatives such as crossl inked carboxymethylcellulose.

3) Gums of plant, animal, mineral or synthetic origin such as (i) agar, alginates, carrageenan, furcellaran derived from marine plants, (ii) guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, (iii) microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, and (iv) synthetic or semi-synthetic gums such as propylene glycol alginate, hydroxypropyl guar and modified starches like sodium starch glycolate, and the like; and an acrylic acid polymer such as cross-linked polymer available under the trade name Carbopol™ or homopolymers and copolymers of acrylate or methacrylate monomers for example polymethacrylates marketed by Evonic Industries under the brand name Eudragit™, particularly Eudragit™ RS and Eudragit™ RL.

4) Fatty compounds including, without limitation thereto, various waxes such as digestible, long chain (e.g., C₈-C₅₀ or Ci₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of between about 25 and 90⁰C are also useful. In one embodiment of the present invention, the release rate controlling excipient is a hydrophilic swellable polymer. In an embodiment the hydrophilic swellable polymer comprises a polyethylene oxide. Polyethylene oxide is a nonionic homopolymer of ethylene oxide, containing 2000 to over 100,000 repeating oxyethylene groups. The molecular weight of polyethylene oxide ranges between 100,000 Daltons and 7,000,000 Daltons. It is commercially available as Polyox™ from Union Carbide. The higher molecular weight polyethylene oxide grades (molecular weight 3,000,000 to 7,000,000 Daltons), such as Polyox™ WSR coagulant with an approximate molecular weight of 5,000,000 Daltons, are used in certain embodiments of the present invention to provide delayed, sustained or controlled drug release. The polymer swells upon contact with aqueous fluid from the environment of use to form a hydrophilic gel matrix. This matrix expands with time and permits diffusion of the drug at a predetermined rate, depending upon the concentration and grade of the polymer used. In an embodiment, Polyox™ WSR coagulant is used as the swelling agent in a concentration from about 20% to about 60% by weight of the tablet. The pharmaceutical compositions of the present invention further comprise one or more of various pharmaceutically acceptable excipients including but not limited to diluents, binders, disintegrants, surfactants, solvents, glidants, lubricants, colorants, opacifiers, and film coating polymers. Diluents:

Various useful diluents include but are not limited to starches, lactose, mannitol, cellulose derivatives and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle products), Pharmatose™ (available from DMV) and others. Different grades of starches included but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801 , Avicel™ PH 101 , PH102, PH301 , PH302 and PH-F20, microcrystalline cellulose 114,silicified microcrystalline cellulose (Prosolv SMCC 90) and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, Disodium hydrogen phosphate basic calcium phosphate, and tribasic calcium phosphate. Disinteq rants:

Various useful disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (FMC-Asahi Chemical Industry Co., Ltd.), crospovidone, examples of commercially available crospovidone products including but not being limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcellulose. Examples of low-substituted hydroxypropylcellulose include but are not limited to low-substituted hydroxypropylcellulose LH11 , LH21 , LH31 , LH22, LH32, LH20,

LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate (type A or type B), colloidal silicon dioxide (different grades which are commercially available such as syloid 244), and starch.

Binders:

Various useful binders include but are not limited to hydroxypropylcellulose

(Klucel™-LF), hydroxypropyl methylcellulose (Methocel™), polyvinylpyrrolidone or povidone (PVP-K25, PVP-K29, PVP-K30, PVP- K90D), powdered acacia, gelatin, guar gum, carbomer (e.g. carbopol), methylcellulose, polymethacrylates, and starch.

Surfactants:

Various useful surfactants include but are not limited to sodium lauryl sulfate, polysorbate 80, poloxamer 188, poloxamer 407, sodium carboxy methylcellulose hydrogenated oil, polyoxyethylene glycol, and polyoxypropylene glycol, Polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides grades such as

GELUCIRE 40/14, GELUCIRE 42/12, GELUCIRE 50/13, Sinespum C (supplied by

Cobar Quimica SCP (spain) and so on.

Glidants:

Various glidants or anti-sticking agents that can be used include but are not limited to talc, silica derivatives, colloidal silicon dioxide.

Solvents:

Various solvents that are useful in processing include but are not limited to water, lower alcohols like methanol, ethanol, and isopropanol, acidified ethanol, acetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, isopropyl alcohol and tetrahydrofuran. pH Modifiers:

Various useful pH modifiers include but are not limited to citrates, phosphates, carbonates, tartrates, fumarates, acetates, amino acid salts, and meglumine. Lubricants:

Various useful lubricants that can be used include but are not limited to magnesium stearate, sucrose esters of fatty acid, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate, zinc stearate, and castor oils. Flavors:

The flavoring agents, which can be used in the present invention, include but are not limited to natural or synthetic or semi-synthetic flavors like menthol, fruit flavors, citrus oils, peppermint oil, spearmint oil, and oil of wintergreen (methyl salicylate). Colorants:

Various useful colorants include but are not limited to Food Yellow No. 5,

Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, ferric oxide, and sunset yellow FCF, sunset yellow FCF lake.

Stabilizers: Various useful stabilizers include but are not limited to disodium edetate, tocopherol, and cyclodextrins.

Antioxidants:

Various antioxidants that can be used include but are not limited to ascorbic acid or its derivatives (esters, salts and so on) like ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols/vitamin E or its derivatives

(esters, salts, etc.), propyl gallate, and sodium bisulphate.

Film-forming Agents:

Various useful film-forming agents include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyethyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate and methylhydroxypropylcellulose phthalate, polyvinyl acetate phthalate, etc., insoluble cellulose derivatives such as ethylcellulose and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinylalcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, and waxes and fat substances.

In the case of polymethacrylates, cationic copolymerizates of dimethylaminoethyl methacrylate with neutral methacrylic esters (Eudragit™ E/ Eudragit™ EPO), copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups (described in "Ammonio Methacrylate Copolymer Type A or Type B" USP/NF, Eudragit™ RL and RS, respectively), and copolymerizates of ethyl acrylate and methyl methacrylate with neutral character (in the form of an aqueous dispersion, described in "Polyacrylate Dispersion 30 Per Cent" Ph. Eur., Eudragit™ NE 30 D) are useful.

Anionic copolymerizates of methacrylic acid and methyl methacrylate (described in "Methacrylic Acid Copolymer, Type C" USP/NF, Eudragit™ L and S, respectively, or in the form of the Eudragit™ L 30 D aqueous dispersion), acidic cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate and methylhydroxypropylcellulose phthalate, polyvinyl acetate phthalate, etc. may be used for film coatings. Plasticizers:

Various useful plasticizers include but are not limited to castor oil, diacetylated monoglycehdes, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. A plasticizer is normally present in an amount ranging from 5% (w/w) to 30 (w/w) based on the total weight of the film coating.

An opacifier like titianium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating. When coloured tablets are desired then the colour is normally contained in the coating. Consequently, colouring agents and pigments may be present in the film coating. Various useful colouring agents include but are not limited to dyes, lakes, and pigments such as iron oxides, which can be red, yellow, black, or blends thereof. Anti-adhesives are routinely used in the film coating process to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc. The anti-adhesive is present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based upon the total weight of the coating. Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol mono-stearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myhstyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax). In an embodiment, polyethylene glycols having molecular weights of 3,000-20,000 are employed.

In addition to above the coating ingredients, sometimes commercially available ready mixed coating products such as those sold as Opadry™ (supplied by Colorcon) may conveniently be used. The products require only mixing with a liquid before use.

The percentages of particles with different sizes that exist in a total powder is called the particle size distribution. It is represented in certain ways. Particle size is the maximum dimension of a particle, normally measured in micrometers. Particle size distributions can be expressed in terms of, Di₀, D₅₀, D₉₀ and D[4,3]. The Di₀, D₅₀ and D₉₀ represent the 10th, median or the 50th percentile, and the 90th percentile of the particle size distribution, respectively, as measured by volume. That is, the Di₀, D₅O, D₉₀ are values of the distribution such that 10%, 50%, and 90% of the particles have a volume of this value or less, or is the percentage of particles smaller than that size. D₅₀ is also known as the median diameter of particles. It is one of the important parameters representing characteristics of particles of powders. For a sample, if D₅₀=5 μm, it means that 50% of the particles are smaller than 5 μm. Similarly, if Dio=5 μm, 10% of the particles are less than or equal to 5 μm, and if D₉₀=5 μm, 90% of the particles are less than or equal to 5 μm. D[4,3] is the volume moment mean of the particles or the volume weighted particle size. In one of the embodiments the invention includes a defined particle size distribution for atorvastatin calcium trihydrate. The particle size includes a plurality of atorvastatin calcium trihydrate particles wherein D₅₀ (mean particle size) is about 0.5 μm to about 5 μm, Di₀ is about 0.1 μm to about 4 μm, D₉₀ is about 1 μm to about 10 μm, and D[4,3] is about 1 μm to about 5 μm. In an embodiment, the invention includes an immediate release layer that comprises one or more active ingredients.

In another embodiment, the invention includes an controlled release layer that comprises one or more active ingredients. In another embodiment, the invention includes the use of packaging materials such as containers including lids, composed of polyethylene and/or polypropylene and/or glass, and blisters or strips composed of aluminium or high-density polypropylene, or polyvinyl chloride, or polyvinyl chloride coated with polyvinylidene dichloride, generally termed PVC/PVDC. Different grades of PVC/PVDC are available as PVC/PVDC 40 gsm, PVC/PVDC 60 gsm, PVC/PVDC 90 gsm, etc. PVC/PVDC 40 gsm means 40 grams of PVDC coating per square meter of PVC film. Similarly 60 gsm means 60 grams of PVDC coating per square meter of PVC film, 90 gsm means 90 grams of PVDC coating per square meter of PVC film, etc. In one of the embodiments, a method of preparing a pharmaceutical composition includes but is not limited to one or more of the steps of physical mixing, blending, dry granulation, wet granulation, and direct compression. Process for Preparing Compositions:

An embodiment of the present invention is directed to processes for preparing multi-layer tablets comprising one or more active ingredients in either or both of an immediate release layer and an controlled release layer, wherein an embodiment of a process comprises:

Immediate release portion: 1 ) Sift the excipients through a sieve; 2) Dry mix the sifted materials of step 1 ) in a granulator;

3) Prepare granulating solution by dissolving surfactant in a solvent and adding pH modifier and binding agent.

4) Granulate dry mix of step 2) using the granulating solution of step 3), and add an additional quantity of solvent if required; 5) Dry the wet mass in a drier until a desired loss on drying is achieved;

6) Sift the dried granules through a sieve;

7) Mill the retained fraction through a screen and pass them through a sieve.

8) Sift extra granular excipients through a sieve; 9) Add sifted step 8) excipients except lubricant to the above sifted granules and blend; and

10) Add sifted lubricant to unlubhcated blend of step 9) and blend. Controlled release portion:

1 ) Sift the excipients through a sieve;

2) Dry mix the sifted materials of step 1 );

3) Prepare granulating solution by dissolving binder in a solvent; 4) Granulate the dry mix of step 2) using the granulating solution of step

3), and add an additional quantity of solvent if required;

5) Dry the wet mass until desired moisture content is achieved;

6) Sift the dried granules through a sieve;

7) Mill the retained fraction through a screen and pass particles through a sieve;

8) Sift extra granular excipients through a a sieve;

9) Add sifted step 8) excipients except lubricant to the sifted granules and blend; and

10) Add sifted lubricant to the unlubricated blend of step 9) and blend. Compression:

Compress the immediate release portion over the controlled release portion using a compression machine, to form a layered tablet.

Optionally, the compressed tablets can be film coated. The coating may or may not comprise an active agent. In an embodiment, the solid dosage form compressed as above may comprise a third layer in addition to the two layers. This third layer may comprise an active ingredient or only excipients.

In an embodiment, the invention includes a process, wherein granules, or a final blend of both immediate release portion and controlled release portion, are filled into hard gelatin capsules.

In an embodiment, the present invention relates to stable solid dosage forms comprising compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or its derivatives, wherein a formulation is in the form of a multilayered tablet. In an embodiment, the present invention relates to stable solid dosage forms comprising compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or its derivatives, wherein a formulation is in the form of a capsule or a capsule within a capsule. In an embodiment, the present invention relates to solid dosage forms comprising compositions of atorvastatin or its pharmaceutically acceptable salts and nicotinic acid or its derivatives, wherein a formulation is in the form of a multiparticulate system. In an embodiment, the invention includes processes, wherein an immediate release portion is compressed into mini tablets and, along with granules or a blend of controlled release portion, is filled into hard gelatin capsules.

In an embodiment, the invention includes processes, wherein an immediate release portion is compressed into mini tablets and further compressed into a blend of a controlled release portion to form an inlay tablet.

In an embodiment of the invention, a controlled release portion is compressed into a solid dosage form and an immediate release active is dissolved or dispersed in a coating solution and coated over the controlled release compressed form.

In an embodiment, a controlled release portion is compressed into a tablet and an immediate release portion is layered onto the compressed tablet in the form of a powder, dispersion, or solution, or optionally an intermediate layer is applied between controlled and immediate release portions, wherein the intermediate layer may or may not comprise an active ingredient.

While the dosage forms of the invention are designed to be administered once daily to obtain the desired therapeutic effect, for certain patients a medical practitioner might determine that more frequent administration is required.

The following examples will further illustrate certain specific aspects and embodiments of the invention in greater detail. The examples are provided only for purposes of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1 : Composition of atorvastatin 10 mg and nicotinic acid 500 mg. A) Immediate release portion:

* Evaporates during processing. Manufacturing process:

1 ) Atorvastatin calcium trihydrate, microcrystalline cellulose, mannitol, sodium starch glycolate (first quantity), and microcrystalline cellulose 102 were sifted through a #40 mesh sieve.

2) Above sifted materials were dry mixed in a rapid mixer granulator for about 10 minutes.

3) Poloxamer was dissolved in warm water (40⁰C to 50⁰C) with continuous stirring. This solution was kept aside until the foam subsided. 4) Meglumine and hydroxy propylcellulose were added to the step 3) solution with continuous stirring for 30 minutes and kept aside for about 2 hours.

5) Step 2) materials were granulated with granulating solution of step 4).

6) The wet mass was dried in a fluid bed dryer at 60°C until loss on drying at 70⁰C was between 2-3% w/w. 7) Dried granules were sifted through a #25 mesh sieve.

8) Milled the 25 mesh retained material through a 1.5 mm screen.

9) Sifted the sized granules through a #25 mesh sieve. Milling and sizing were continued until all granules passed through a #25 mesh sieve.

10) Sodium starch glycolate (second quantity) was sifted through a #40 mesh sieve.

11 ) Magnesium stearate and Sunset yellow FCF were sifted through a #80 mesh sieve. 12) Sifted sodium starch glycolate of step 10) was added to sifted granules of step 9) in a double cone blender and blended for about 10 minutes.

13) Sifted magnesium stearate and Sunset yellow FCF were blended with an equal quantity of the step 12) blend and reloaded into the same blender and blended for about 5 minutes.

B) Controlled release portion:

* Evaporates during processing. Manufacturing process:

1 ) Nicotinic acid and HPMC K 100 M were sifted through a #40 mesh sieve.

2) Sifted materials were dry mixed in a rapid mixer granulator for about 10 minutes.

3) Povidone K 9OD was dissolved in a mixture of isopropyl alcohol and water (9:1 volume ratio) with continuous stirring, to completely dissolve. 4) Granulated step 2) materials with the granulating solution of step 3).

5) Dried the wet mass in a fluid bed drier at 60⁰C until loss on drying at 60⁰C was between 1 -2% w/w.

6) Dried granules were sifted through a #18 mesh sieve. Milled the 18 mesh retained fraction through a 1.5 mm screen in a multimill. Sifted the sized granules through the #18 mesh sieve. Milling and sifting were continued until all granules passed through the #18 mesh sieve.

7) Stearic acid was sifted through a #40 mesh sieve.

8) Sifted stearic acid was added to the sifted dried granules of step 6) in an octagonal blender and blended for about 5 minutes. Compression: compressed the immediate release portion over the controlled release portion using 13.5 mm round punches and dies, with a compression machine.

EXAMPLE 2: Composition of atorvastatin 10 mg and nicotinic acid 375 mg.

A) Immediate release portion composition and manufacturing process were the same as in Example 1.

B) Controlled release portion:

* Evaporates during processing. Manufacturing process: same as that of Example 1.

Compression: compressed the immediate release portion over the controlled release portion using 13 mm round punches and dies, with a compression machine.

EXAMPLE 3: Biopharmaceutical performance of compositions prepared according to Example 1.

The study was designed as randomized, open label, balanced, two-treatment, two period, two-sequence, single-dose, crossover bioequivalence study, of the composition prepared in Example 1 with the commercial reference products LIPITOR^® atorvastatin 10 mg tablets, from Pfizer, and NIASPAN^® niacin 500 mg extended release tablets, from Abbott Laboratories.

Tablets were evaluated in single dose crossover bioequivalence study involving administration of test product to 24 healthy human volunteers under fasting conditions and determining drug plasma levels. Subjects were administered a tablet of the present invention after an overnight fast. Plasma samples were withdrawn at 0, 0.25, 0.5, 0.75, 1 , 1.25, 1.50, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours post-dosing. Washout period between doses during the study was 10 days.

The pharmacokinetic parameters for atorvastatin and nicotinic acid were calculated using WinNonlin™ Professional software version 5.1 (Pharsight Corporation, USA). The following parameters were calculated:

AUCo-t = area under plasma concentration versus time curve, from time zero to the last measurable concentration.

AUCo-∞ = area under the plasma concentrations versus time curve, from time zero to infinity.

Cmax = maximum plasma concentration. t_max = time to achieve the maximum plasma concentration.

The results of these pharmacokinetic parameters calculated from the study are given in Table 1.

Table 1

"T vs R" is a ratio of results for the Test product to results for the Reference product, expressed as a percentage.

EXAMPLE 4: Dissolution profile of tablets prepared in Example 1.

Dissolution profile for atorvastatin in 900 ml of pH 6.8-phosphate buffer at 75 rpm in USP paddle type Il apparatus is given in Table 2. Table 2

Dissolution profile for nicotinic acid in 900 ml of pH 2.1 SGF (simulated gastric fluid) for 1 hour, then 900 ml of pH 6.5 fasting SIF (simulated intestinal fluid) for 2- 5 hours, followed by 900 ml of pH 7.4 phosphate buffer for 6-24 hours, 50 rpm in USP type Il apparatus at 50 rpm is given in Table 3.

Table 3

EXAMPLES 5A and 5B: Trilayer compositions of atorvastatin 10 mg and nicotinic acid 500 mg, and atorvastatin 10 mg and nicotinic acid 375 mg. Intermediate layer is 100 mg/tablet of microcrystalline cellulose 102.

For Example 5A, tablets containing atorvastatin 10 mg and nicotinic acid 500 mg are prepared by compressing immediate release portion from Example 1 , intermediate layer, and controlled release portion from Example 1 in separate layers, using 13.5 mm round punches in a compression machine. For Example 5B, tablets having three layers and containing atorvastatin 10 mg and nicotinic acid 375 mg are prepared by compressing immediate release portion from Example 1 , intermediate layer, and controlled release portion from Example 2 using 13 mm round punches in a compression machine.

EXAMPLE 6: Composition of atorvastatin 10 mg and nicotinic acid 500 mg. Immediate release portion:

* Evaporates during processing.

Syloid products are supplied Grace Davison. Manufacturing process:

1. Atoravastatin calcium, mannitol, and sodium starch glycolate (first quantity) were sifted through a #40 mesh sieve.

2. Above sifted material was placed in a rapid mixer granulator and dry mixed for 10 minutes. 3. Klucel LF, poloxamer, and meglumine were dissolved in water with continuous stirring.

4. Granulated step 2) material using binder solution of step 3). 5. Wet mass from step 4) was dried in a fluid bed dryer at 60⁰C until loss on drying at 70⁰C was 1.5-2.5% w/w.

6. Dried granules were passed through a #25 mesh sieve and retained material was milled through a 1.5 mm screen and passed through the #25 mesh sieve.

7. Sifted microcrystalline cellulose 102, sodium starch glycolate (second quantity), light magnesium oxide, and Syloid 244 through a #40 mesh sieve, then added to sized granules of step 6) and blended for 10 minutes in a blender.

8. Magnesium stearate and Sunset yellow FCF lake were sifted through a #80 mesh sieve, added to the blender and blended for 5 minutes.

Controlled release portion: composition and process were the same as those of Example 1.

Compressed immediate release portion and controlled release portion into tablets with 13.5 mm round punches using a compression machine.

EXAMPLE 7: Composition for th-layer tablet. A) Immediate release portion:

* Evaporates during processing.

Prosolv SMCC 90 is supplied by Penwest Pharmaceuticals Flowlac is supplied by Meggle Products.

Sinespum C is a composition of PEG 40 stearate, 2-Bromo-2-nitropropane-1 , 3-diol, sorbitan tristearate, sucrose and silicon dioxide, supplied by Cobar Quimica SCP (Spain). Manufacturing process:

I ) Lactose monohydrate (60.09 mg) and sodium lauryl sulphate (1.5 mg) were sifted through a ASTM #40 mesh sieve in a mechanical sifter and were then placed into a rapid mixer granulator at impeller fast speed and chopper off for 15 minutes to blend uniformly. 2) Butylated hydroxyanisole was dissolved in ethanol using mechanical stirrer.

3) Step 2) was added to step 1 ) in a rapid mixer granulator and blended uniformly at slow speed for 3-5 minutes.

4) Step 3) was placed into a comminuting mill fitted with a screen with 3 mm openings at knife forward and medium speed and then was sifted.

5) The granules were placed in a fluid bed dryer and dried at 55°C for 25 minutes until the loss on drying was 1 %.

6) Step 5) was sifted through a ASTM #16 mesh sieve and placed into a mechanical sifter, then the retained fraction obtained was milled in a comminuting mill fitted with a 1.2 mm screen at knife forward and medium speed, again passed through the sieve, and combined with the sifter material.

7) Atorvastatin calcium together with step 6) was sifted through a ASTM #40 mesh sieve using a mechanical sifter and blended in a double cone blender for 5 minutes. 8) Step 7) was sifted through a ASTM #40 mesh sieve using a mechanical sifter.

9) Prosolv, lactose monohydrate (4.38 mg), sodium lauryl sulphate (1.25 mg), Sinespum C, sodium bicarbonate and crospovidone were sifted separately through a ASTM #20 mesh sieve using a mechanical sifter. 10) Blended the step 8) and step 9) ingredients in a double cone blender for 15 minutes.

I 1 ) Magnesium stearate was sifted through a ASTM #60 mesh sieve and mixed with step 10) in a double cone blender for 5 minutes. B) Intermediate layer portion:

Manufacturing process:

1 ) Flowlac 100, microcrystalline cellulose 102, crospovidone and disodium hydrogen phosphate were sifted seperately through a ASTM #40 sieve twice.

2) Ingredients of step 1 ) were blended uniformly in A double cone blender for 10 minutes.

3) Magnesium stearate was sifted through a ASTM #60 mesh sieve.

4) Step 2) was uniformly blended with step 3) in a double cone blender for 5 minutes.

C) Controlled release portion:

* Evaporates during processing. Manufacturing process:

1 ) Nicotinic acid and hydroxypropyl methylcellulose K 100M were sifted through a ASTM #40 mesh sieve and uniformly blended for 10 minutes.

2) Povidone was dissolved in isopropyl alcohol and water in the ratio of 9:1 and used to granulate step 1 ).

3) Granulated material from step 2 was placed in a fluidized bed dryer and dried until loss on drying was less than 1 % w/w at 60⁰C. 4) Step 3) granules were sifted through a ASTM #18 mesh sieve and retained material was milled in a comminuting mill through a 1.5 mm screen with knife forward and medium speed to pass through the sieve.

5) Stearic acid was sifted through an ASTM #40 mesh sieve and blended uniformly with the granules for 5 minutes.

Compression of trilayer tablet:

Final blend of the controlled release portion of nicotinic acid was first pre- compressed in a compression machine, followed by addition of intermediate layer portion and pre-compression, followed by addition of immediate release portion. Finally the three blends (controlled release blend, intermediate layer blend, immediate release blend) were compressed together into a tri-layer tablet.

EXAMPLE 8: Composition for tri-layer tablet. A) Immediate release portion:

* Evaporates during processing.

Manufacturing process: same as Example 7 immediate release portion, with mannitol replacing lactose. B) Intermediate layer portion:

*Evaporates during processing. Manufacturing process:

1 ) Microcrystalline cellulose 114, microcrystalline cellulose 102, mannitol powder and sodium starch gylcolate type A (10 mg) were sifted through a ASTM #40 mesh sieve and blended uniformly for 10 minutes in a rapid mixer granulator.

2) Binder solution of meglumine and hydroxypropyl cellulose LF was prepared in water.

3) Step 1 ) was granulated with step 2) and the granules were dried in a fluid bed dryer until loss on drying was between 1.5 -2.5% at 70⁰C.

4) Step 3) was sifted through a ASTM #25 mesh sieve and retained particles were milled through a multi-mill with a 1.5 mm screen with knife forward and medium speed, then added to the fraction passing through the sieve.

5) Sodium starch glycolate type A (second quantity of 10 mg) was sifted through a ASTM #40 mesh sieve and blended with the material from step 4) for 10 minutes in a double cone blender.

6) Magnesium stearate was sifted through an ASTM #60 mesh and blended with step 5) for 5 minutes.

C) Controlled release portion:

* Evaporates during processing.

Manufacturing process: same as controlled release portion of Example 7.

Compression of trilayer tablet:

EXAMPLE 9: Composition for tri-layer tablet. A) Immediate release portion:

* Evaporates during processing. Manufacturing process: 1 ) Atorvastatin calcium, microcrystalline cellulose 114, microcrystalline cellulose 102, mannitol powder and sodium starch glycolate (10 mg) were sifted through a ASTM #40 mesh sieve and blended uniformly in a rapid mixer granulator.

2) Hydroxypropylcellulose LF, poloxamer and meglumine were dissolved in hot water.

3) Step 1 ) was granulated with step 2) and the mixture was dried in a fluid bed dryer until loss on drying was 1.5-2.5% at 70⁰C.

4) Step 3) was sifted through ASTM #25 mesh sieve and the retained particles were milled through a 1.5 mm screen with knife forward and medium speed, to pass through the sieve, then was combined with the sifted material.

5) Sodium starch glycolate (second quantity of 10 mg) was sifted through a ASTM #40 mesh sieve. Magnesium stearate and sunset yellow lake were blended uniformly and sifted through a ASTM #80 mesh sieve.

6) Step 5) ingredients were blended with step 4). B) Intermediate layer portion:

* Evaporates during processing. Manufacturing process:

2) Binder solution of meglumine and hydroxypropyl cellulose LF was prepared in water. 3) Step 1 ) was granulated with step 2) and the granules so obtained were dried in a fluid bed dryer until loss on drying was between 1.5-2.5% at 70 ⁰C.

4) Step 3) was sifted through a ASTM #25 mesh sieve and retained particles were milled through a multi-mill having a 1.5 mm screen with knife forward and medium speed, then added to the material passing through the sieve.

5) Sodium starch glycolate type A (second quantity of 10 mg) was sifted through a ASTM #40 mesh sieve and blended with ASTM #25 passed materials from 4) for 10 minutes in a double cone blender.

6) Magnesium stearate was sifted through a ASTM #60 mesh sieve and blended with step 5) for 5 minutes.

C) Controlled release portion:

* Evaporates during processing.

Manufacturing procedure: same as controlled release portion of Example 7. Compression of Thlayer tablet:

EXAMPLE 10: Composition for tri-layer tablets. A) Immediate release portion:

* Evaporates during processing. Manufacturing process:

1 ) Atorvastatin calcium Form P, microcrystalline cellulose 114, crospovidone, mannitol and sodium lauryl sulphate were sifted through a ASTM #40 mesh sieve and blended for 10 minutes in a rapid mixer granulator.

2) Butylated hydroxyanisole was dissolved in isopropyl alcohol and moistened with step 1 ) with impeller at slow speed.

3) Binder solution was prepared by dissolving hydroxypropyl cellulose in water, the moistened dry mix of 2) was granulated using the solution and granules were dried in a fluid bed dryer to a loss on drying of 1.5-2.5% at 70⁰C.

4) Dried granules were sifted through a ASTM #25 mesh sieve, followed with sifting the retained particles through a multimill having a 1.5 mm screen with knife forward and medium speed. Milled particles were combined with the sieved material. 5) Crospovidone was sifted through a ASTM #40 mesh sieve and sodium bicarbonate through was sifted through a ASTM #80 mesh sieve, and they were blended with ASTM #25 passed materials of step 4) for 10 minutes in a double cone blender.

6) Magnesium stearate and Sunset yellow FCF Lake were sifted through through a ASTM #80 mesh sieve and blended with step 5) for 5 minutes. B) Intermediate layer portion:

* Evaporates during processing. Manufacturing process:

1 ) Microcrystalline cellulose 114, microcrystalline cellulose 102, mannitol powder and sodium starch glycolate type A (first quantity) were sifted through a

ASTM #40 mesh sieve and blended uniformly for 10 minutes in a rapid mixer granulator.

2) Binder solution of meglumine and hydroxypropyl cellulose LF was prepared in water. 3) Step 1 ) was granulated with step 2) and the granules were dried in a fluid bed dryer until loss on drying was 1.5-2.5% at 70 ⁰C.

4) Step 3) was sifted through a ASTM #25 mesh sieve, and retained particles were milled through a multi-mill having a 1.5 mm screen with knife forward and medium speed, then the milled particles were combined with the sifted material. 5) Sodium starch glycolate type A (second quantity) was sifted through a

ASTM #40 mesh sieve and blended with step 4) material for 10 minutes in a double cone blender.

6) Magnesium stearate was sifted through an ASTM #60 mesh sieve and blended with step 5) for 5 minutes. C) Controlled release portion:

* Evaporates during processing.

EXAMPLE 11 : Composition for tri-layer tablets. A) Immediate release portion:

*Evaporates during processing.

"Atorvastatin calcium-BHA premix is a mixture of atorvastatin calcium and less than about 5% w/w, or less than about 3% w/w, of butylated hydroxyanisole as an antioxidant. Manufacturing process:

1 ) Microcrystalline cellulose and lactose monohydrate were sifted through a ASTM # 40 mesh sieve in a mechanical sifter and blended uniformly for 5 minutes.

2) Eudragit EPO was sifted through ASTM #40 mesh.

3) Atorvastatin calcium-BHA premix (first quantity) and Eudragit EPO were dissolved in methanol and stirred until a clear solution was obtained.

4) Step 1 ) was loaded in a fluidized bed processor and step 3) was sprayed using the top spray configuration for 20 minutes and dried until loss on drying was less than 2%.

5) Step 4) was sifted through a ASTM #30 mesh sieve in a mechanical sifter.

6) Atorvastatin calcium BHA premix (second quantity), lactose monohydrate, sodium starch glycolate,were sifted through a ASTM #40 mesh sieve and blended with granules of step 5) for 7 minutes in a double cone blender.

7) Magnesium stearate is sifted through ASTM #60 mesh sieve and lubricated the blend of step 6 for about 5 minutes in a double cone blender.

B) Intermediate layer:

Manufacturing process:

1 ) Flowlac 100, microcrystalline cellulose 102, crospovidone and disodium hydrogen phosphate were sifted through a ASTM #40 sieve separately.

2) Step 1 ) ingredients were blended uniformly for 10 minutes in a double cone blender.

3) Magnesium stearate was sifted through a ASTM #60 mesh sieve and blended with step 2) for 5 minutes. C) Controlled release layer:

* Evaporates during processing.

Manufacturing process: same as controlled release portion of Example 7. Compression of trilayer tablet:

EXAMPLE 12: Comparative stability data for Example 1 , Example 2, Example 7 and Example 9 products.

Tablets of Examples 1 , 2, 7, and 9 were packaged in aluminium foil blister packaging and stored under accelerated stability conditions (40⁰C and 75% relative humidity) for one month, samples were analyzed for atorvastatin lactone impurity content, highest individual impurity ("HM"), and total impurities other than lactone ("Tl"), and the data are given in the Table 4 where values are percentages of the initial atorvastatin content.

Table 4

Claims

CLAIMS:

1. A solid pharmaceutical dosage form comprising a granulated powder mixture comprising atorvastatin or a salt thereof and a granulated powder mixture comprising nicotinic acid or a derivative thereof.

2. The solid pharmaceutical dosage form of claim 1 , wherein a granulated powder mixture comprising atorvastatin and a granulated powder mixture comprising nicotinic acid are mixed and compressed to form a tablet.

3. The solid pharmaceutical dosage form of claim 1 , wherein a granulated powder mixture comprising atorvastatin, a granulated powder mixture comprising nicotinic acid, and an intermediate pharmacologically inert separating powder are compressed to form a three-layer tablet.

4. The solid pharmaceutical dosage form of claim 1 , wherein a granulated powder comprising atorvastatin and a granulated powder comprising nicotinic acid are mixed and filled into a capsule.

5. A solid pharmaceutical dosage form of any of claims 1 -4, wherein a granulated powder mixture comprising nicotinic acid comprises a polymer to control dissolution of nicotinic acid.

6. A solid pharmaceutical dosage form comprising a granulated powder mixture comprising atorvastatin or its salts and a granulated powder mixture comprising nicotinic acid.

7. The solid pharmaceutical dosage form of any of claims 1 -6, producing C_maχ values of atorvastatin ranging from about 5 ng/mL to about 10 ng/mL and C_maχ values of nicotinic acid ranging from about 15 ng/mL to about 30 ng/mL, after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

8. The solid pharmaceutical dosage form of any of claims 1 -6, producing AUCo-t values of atorvastatin ranging from about 25 ng-hour/ml to about 40 ng-hour/ml and AUCo-_t values of nicotinic acid ranging from about 100 ng-hour/ml to about 165 ng-hour/ml, after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

9. The solid pharmaceutical dosage form of any of claims 1 -6, producing AUCo-∞ values of atorvastatin ranging from about 30 ng-hour/ml to about 50 ng-hour/ml and AUCo-co values of nicotinic ranging from about 110 ng-hour/ml to about 180 ng-hour/ml, after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

10. The solid pharmaceutical dosage form of any of claims 1 -6, producing t_max values of atorvastatin from about 1 hour to about 4 hours, after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

11. The solid pharmaceutical dosage form of any of claims 1 -6, producing t_max values of atorvastatin from about 1 hour to about 3 hours after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

12. The solid pharmaceutical dosage form of any of claims 1 -6, producing t_max values of nicotinic acid in the range of about 2 hours to about 8 hours, after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

13. The solid pharmaceutical dosage form of any of claims 1 -6, producing t_max values of nicotinic acid in the range of about 3 hours to about 7 hours, after administration of a single 10 mg atorvastatin and 500 mg nicotinic acid dose to healthy humans.

14. The solid pharmaceutical dosage form of any of claims 1 -6, for which dissolution testing in vitro in pH 2.1 simulated gastric fluid for 1 hour, followed by pH 6.5 fasting simulated intestinal fluid for 5 hours, followed by pH 7.4 phosphate buffer for 18 hours, gives release of nicotinic acid from the dosage form of: a) not more than about 25% released within about 1 hour; b) not more than about 60% released within about 6 hours; c) not more than about 80 % released within about 12 hours; and d) not less than about 60 % released within about 24 hours.

15. The solid dosage form of claim 14, wherein dissolution testing gives release of nicotinic acid from the dosage form between about 25% and about 60% within about 6 hours.

16. The solid dosage form of claim 14, wherein dissolution testing gives release of nicotinic acid from the dosage form between about 30% and about 50% within about 6 hours.

17. The solid dosage form of claim 14, wherein dissolution testing gives release of nicotinic acid from the dosage form between about 40% and about 80% within about 12 hours.

18. The solid dosage form of claim 14, wherein dissolution testing gives release of nicotinic acid from the dosage form between about 50% and about 70% within about 12 hours.

19. The solid dosage form of claim 14, wherein dissolution testing gives release of nicotinic acid from the dosage form not less than about 70% within about 24 hours.