FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITION"


2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


Field of Invention:
The present invention relates to stable and improved pharmaceutical compositions of atorvastatin calcium. There is also provided a process for preparing a formulation and use thereof in the treatment and / or prevention of physiological conditions based on atorvastatin calcium such as hyperlipidemia, hypercholesterolemia.
Background and prior art:
Atorvastatin calcium, is the active pharmaceutical ingredient in Lipitor® and is chemically known as (R-(R*,R*))-2-(4- flurophenyl)- [beta] , [delta] -dihy droxy-5 -(1 -methy lethy l)-3 -pheny 1- 4((phenylamino)carbonyl)-lH-pyrole-l-heptanoic acid hemi calcium salt, is in particular known to inhibit intracellular synthesis of cholesterol, and is considered especially useful in the treatment of hypercholesterolaemia and hyperlipidaemia. In the formula stated, R and R* are moieties that can be any alkaline salt, such as calcium.

Atorvastatin and its pharmaceutically acceptable complexes, salts, solvates, and hydrates are selective, competitive inhibitors of HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate - an early and rate-limiting step in the cholesterol biosynthetic pathway. See U.S. Patent No. 5,273,995 (to Warner-Lambert Company filed on 26 February 1991) which is herein incorporated by reference.
2
-3 JUL 2009

It is known that the amorphous forms of a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to crystalline forms (Konno T., Chem. Phar. Bull. 1990, 38, 2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation.
Atorvastatin calcium exists in amorphous and also in crystalline form. And as mentioned earlier, the amorphous form dissolves more rapidly and is more soluble than the crystalline form, thus making the amorphous form therapeutically more desirable. However, amorphous form of the atorvastatin calcium is highly susceptible to instability brought on by heat, moisture, light and acidic environments (such as gastric content). The instability in acidic condition and poor bioavailability of atorvastatin calcium requires patients to consume higher dosages (ultimately increase in dosage form size, weight) and with greater frequency to achieve a desired therapeutic result, a problem known to result in poor patient compliance.
Various methods were also known in the art to enhance the solubility and bioavailablity of the drugs having poor aqueous solubility such as chemical modification using a prodrug concept; physical modification via size reduction and surface modification; pH control using a buffering system; use of surfactants, cosolvents as absorption enhancers, and complexation.
Complexation is a favorable method to enhance the physicochemical properties of pharmaceutical compounds. It is the reversible association of a substrate (drug molecule) and ligand (complexing agent) to form a new species. Cyclodextrins are the well known examples of complexing agents and the complex formed using cyclodextrins is known as 'inclusion complexes'. These complexes are formed when a drug molecule is partially or fully included inside the cavity of the cyclodextrin with no covalent bonding. When such inclusion complexes are formed, the physicochemical parameters of the drug molecule are altered, and improvements in the drug's solubility, stability, taste, safety and bioavailability is achieved.
3
- 3 JUL 2009

Chemically cyclodextrins are cyclic oligosaccharides containing at least 6 D-(+) glucopyranose units attached by α-(l, 4) glucosidic bonds. The most common cyclodextrins are α-, β-, and γ-cyclodextrins (with 6, 7, or 8 glucose units respectively), differ in their ring size and solubility. Cyclodextrins with fewer than 6 units cannot be formed due to steric hindrances while the higher homologs with 9 or more glucose units are very difficult to purify.
WO2006/059224 A (to Warner-Lambert Company LLC, filed on 23 November 2005) discloses a solid pharmaceutical composition comprising a solid dispersion of amorphous atorvastatin and one or more optional pharmaceutically acceptable excipients, the solid dispersion comprising amorphous atorvastatin or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof; and a melt-processible polymer which is present in the range of 10% to 90% by weight of the resulting dispersion. Such a high amount of melt-processible polymer is required for stabilization of the amorphous form of atorvastatin calcium in the solid dispersion. However, due to high amount of melt-processible polymer, amorphous atorvastatin calcium may prone for oxidative degradation.
U. S. Patent 4,727,064 (to United States of America, Health & Human Services, filed on 29 June 1985) describes pharmaceutical preparations consisting of a drug with substantially low water solubility and an amorphous, water-soluble eye lodextr in-based mixture. The drug forms an inclusion complex with the cyclodextrins of the mixture. In U. S. Patent 5,691,316 (to Hybridon Inc., filed on 17 November 1994), a cyclodextrin cellular delivery system for oligonucleotides is described. In such a system, an oligonucleotide is noncovalently complexed with a cyclodextrin or, alternatively, the oligonucleotide may be covalently bound to adamantane which in turn is non-covalently associated with a cyclodextrin.
WO2007/071012 (to Orbus Pharma Inc., filed on 2 February 2006) discloses a drug composition of improved bioavailability and stability, comprising a pharmaceutical, a complexing agent and surfactant. Particularly, the composition comprises atorvastatin calcium in amorphous form, a cyclodextrin, and a surfactant a-alpha tocopheryl polyethylene glycol 1000 succinate. The said composition is manufactured by dissolving
4


surfactant in water to form slurry, mixing drug and complexing agent to form a mixture and adding mixture to the slurry to form complex mass drying it to form granules. However, this process may not be recommended for commercial production of the said formulation. It has been found, however, that the manufacturing process of WO2007/071012 was not suitable for large scale production due to high amount of cyclodextrin and solvent required, increased solvent evaporation time and also requirement of extensive blending of surfactant-water slurry and mixture of drug & complexing agent.
Hence, there is a constant need of a stabilized and improved pharmaceutical composition of atorvastatin calcium and an improved manufacturing process therefor which would enable in the formulation of Atorvastatin eventually having amorphous atorvastatin calcium and alleviate the above mentioned problems of the prior art formulations.
Objects of the invention:
The object of the present invention is to provide a stabilized and improved pharmaceutical composition comprising complex of atorvastatin calcium and hydroxypropyl- p-cyclodextrin.
Another object of the present invention is to provide a process of manufacturing the pharmaceutical composition comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextr in.
Another object of the present invention is to provide a pharmaceutical composition comprising complex of atorvastatin calcium and hydroxypropyl- p-cyclodextrin having enhanced solubility and bioavailability.
Yet another object of the present invention is to provide a process of substantially preventing the oxidative degradation of atorvastatin calcium in acidic environment of stomach.
5
-3 JUL 2009

Summary of the invention:
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextrin, with one or more pharmaceutically acceptable excipients wherein the atorvastatin calcium and hydroxypropyl-p-cyclodextrin is present in the weight ratio ranging from 1:0.5 to upto 1:6.
In further aspect of the present invention, there is provided a process of substantially preventing the formation of oxidative degradation products of atorvastatin calcium which process comprises complexing the atorvastatin calcium with hydroxypropyl-p-cyclodextrin.
In another aspect of the present invention, there is provided a process of substantially preventing the acid degradation of atorvastatin calcium which process comprises complexing the atorvastatin calcium with hydroxypropyi-p-cyclodextrin.
In another aspect of the present invention, there is provided a process of manufacturing the pharmaceutical composition which process comprises forming the granules comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextrin with one or more pharmaceutically acceptable excipients using hot melt granulation.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextrin, with one or more pharmaceutically acceptable excipients for use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of atorvastatin calcium.
Detailed description of the invention:
There is now provided a pharmaceutical composition comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextrin, with one or more pharmaceutically acceptable excipients.
6
-3 JUL 2009

In particular, the present inventers have surprisingly found that the pharmaceutical composition of comprising atorvastatin calcium with improved stability can be achieved by complexing the atorvastatin calcium with hydroxypropyl-p-cyclodextrin wherein the atorvastatin calcium and hydroxypropyl-p-cyclodextrin is present in the weight ratio ranging from 1:0.5 to upto 1:6, preferably 1:0.5 to 1: 4, more preferably 1:0.5 to 1:2.
The term "improved stability" or "stabilized" as used herein denotes the presence of minimal impurities, such as the above mentioned oxidative and/ or acidic degradation products of amorphous atorvastatin calcium, or at least denotes the presence of impurities in an amount within or below the pharmaceutically defined or recognized level of impurities acceptable for amorphous atorvastatin calcium or amorphous atorvastatin calcium containing formulations.
By "pharmaceutically acceptable" it means that a carrier, diluent or excipient must be compatible with atorvastatin calcium as employed according to the present invention.
The term "complex" or "inclusion complex" as used herein can be a solid solution in which molecules of one compound occupy places in the crystal lattice of another compound. A complex or inclusion complex can also be formed from molecular encapsulation, e.g. one compound trapped within another. Additionally, both forms of complex may be present in the solid and/or amorphous form, wherein a first compound is trapped within a second compound, or the first and/or second compound may be trapped within a lattice formed by the complexed compounds.
According to the present invention, when an inclusion complex is formed between atorvastatin calcium and hydroxypropyl- p-cyclodextrin, the hydroxypropyl- p-cyclodextrin molecule may encapsulate the atorvastatin calcium molecule and/or may occupy places in the crystal lattice of the hydroxypropyl- p-cyclodextrin/ atorvastatin calcium - hydroxypropyl- p-cyclodextrin complex.
It would be appreciated to the skilled artisan that cyclodextrin for the purpose of the present may be selected from, but not limited to Hydroxyethyl-p-cyclodextrin, Hydroxypropy-β-cyclodextrin, sulfoalkylether-βcyclodextrin (e.g. Sulfobutylether-p-cyclodextrin, Methyl-β-cyclodextrin, Dimethyl-β-cyclodextrin, Randomly dimethylated -
7
-3 JUL 2009

p-cyclodextrin, Randomly methylated-β-cyclodextrin, Carboxymethyl-p-cyclodextrin, Carboxymethyl ethyl- β-cyclodextrin, Diethyl-β-cyclodextrin, Tri-O-methyl-β-cyclodextrin, Tri-O-ethyl-β-cyclodextrin, Tri-O-butyryl-β-cyclodextrin, Tri-O-valeryl-β-cyclodextrin, Di-O-hexanoyl-β-cyclodextrin, Glucosyl-β-cyclodextrin, Maltosyl-β-cyclodextrin, -hydroxy-3-trimethyl-ammoniopropyl-β-cyclodextrin. Hydroxypropyl-β-cyclodextrin and/ or sulfoalkylether-β-cyclodextrin (e.g. Sulfobutylether-β-cyclodextrin) may be preferred because it possesses high aqueous solubility and relatively less toxic.
Examples of suitable excipients for use in the pharmaceutical composition according to the present invention include, but not limited to diluents, disintegrants, binders, lubricants, glidants, and surfactants.
Diluents suitable for the pharmaceutical composition of the present invention comprises lactose (for example, spray-dried lactose, a-lactose, p-lactose, lactose available under the trade mark Tabletose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose), lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethyl en e, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, maize starch and rice starch), and the like. Particularly preferred diluent is mannitol and/ or its different grades, for example Pearlitol SD 200. The amount of diluent may be present in the range upto about 90 % by weight of the pharmaceutical composition, preferably in the range of about 2 % to about 70 % by weight of the pharmaceutical composition.
Glidants or lubricants suitable for the pharmaceutical composition of the present invention comprises stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon
8
-3 JUL 2009

dioxide, colloidal silicon dioxide and polymers thereof, magnesium aluminosilicate and / or magnesium aluminometasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) , or mixtures thereof or any other suitable lubricant. Particularly preferred lubricant for the pharmaceutical composition of the present invention is mixture of calcium stearate and talc.
The amount of lubricant may be present in the range upto about 5% by weight of the pharmaceutical composition, preferably in the range of about 0.25% to about 2% by weight of the pharmaceutical composition.
Disintegrants suitable for pharmaceutical composition according to the present invention comprises hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and any combination thereof. The preferable disintegrant is croscarmellose sodium.
The amount of disintegrant may be present in the range of upto about 20% by weight of the pharmaceutical composition, preferably about 2% to about 10% by weight of the pharmaceutical composition.
Binder suitable that may be present in the pharmaceutical composition according to the present invention comprises polyvinyl pyrrolidone (also known as povidone), acacia, alginic acid, agar, calcium carrageenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic* guar gum, tragacanth, sodium alginate, or mixtures thereof or any other suitable binder.
The amount of binder may be present in the range of upto about 10% by weight of the pharmaceutical composition, preferably in the range of about 2% to about 6% by weight of the pharmaceutical composition.
Moreover, atorvastatin calcium composition may require use of additives (for example surfactants) to achieve solubility that is sufficient to achieve bioavailability in human subjects. But the commonly used surfactants may react with atorvastatin calcium
9
- 3 JUL 2009

(especially amorphous form) to cause destabilization by oxidation. This situation, further, may exaggerate if the atorvastatin calcium does not form complex with hydroxypropyl-p-cyclodextrin, which may ultimately render atorvastatin calcium in the composition more prone for oxidative degradation in the acidic environment of stomach.
Examples of various antioxidants comprises ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, a-tocopherol, tocopherol acetate, tocopherol hemisuccinate, or other tocopherol derivatives, or mixtures thereof. The amount of antioxidant may be present in the range of about 0.001 to 1.5 % by weight of the solid dosage form, preferably about 0.01% to about 1% by weight of the pharmaceutical composition.
There is further provided by the present invention a pharmaceutical composition comprising atorvastatin calcium, hydroxypropyl-p-cyclodextrin, atleast one surfactant, and optionally one or more pharmaceutically acceptable excipients wherein the atorvastatin calcium: hydroxypropyl-p-cyclodextrin is present in the weight ratio ranging from 1:0.5 to upto 1:6, preferably 1:0.5 to 1: 4, more preferably 1:0.5 to 1:2.
Examples of surfactants suitable for use in the pharmaceutical composition of the present invention comprises polyoxyethylenated esters of sorbitan (for example, polysorbate 20, polysorbate 60 & polysorbate 80), sorbitan fatty acid esters (for example, Span 20, Span 40, Span 60 & Span 85), polyoxyethylene-polyoxypropylene block copolymers, sodium lauryl sulphate, propylene glycols and fatty acid esters of propylene glycol (for example, propylene glycol monocaprylate, propylene glycol monolaurate); oleoyl macrogol glycerides (for example, Labrafil); Caprylocaproyl macrogol glycerides (e.g. Labrasol); polyethylene glycols or its derivatives (for example, PEG 600, PEG 6000); polyoxyethylene-polyoxypropylene block copolymers generically known as "poloxamers"; polyoxyethylene castor oil derivatives (commercially available as Cremophor®), or combinations thereof. Particularly preferred surfactant for use in the pharmaceutical composition of the present invention is selected from polyoxyethylenated
10
-3 JUL 2009

esters of sorbitan, sorbitan fatty acid esters, polyoxyethylene castor oil derivatives or their mixtures.
The amount of surfactant may be present in the range of upto about 1% by weight of the solid dosage form, preferably in the range of about 0.3% to 0.7% and more preferably in the range of about 0.7% by weight of the solid dosage form.
In a particularly preferred embodiment, the pharmaceutical composition according to the present invention further comprises surfactant α-tocopheryl polyethylene glycol 1000 succinate (commercially available as Vitamin E-TPGS®).Vitamin E properties of α-tocopheryl polyethylene glycol 1000 succinate stabilizes atorvastatin calcium from degradation by oxidation without causing impurities to occur in greater than acceptable amounts, while also enhancing the bioavailability of atorvastatin calcium.
Alternatively, the surfactant, if present in the pharmaceutical composition of the present invention, may be present intra-granularly and/ or extra-granularly.
There is also provided by the present invention a process of substantially preventing the formation of oxidative degradation products and/ or acidic degradation products of amorphous atorvastatin calcium which process comprises complexing the atorvastatin calcium in hydroxypropyl-p-cyclodextrin.
There is also provided by the present invention a process of preparing the solid dosage form which process comprises preparing granules comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextrin, with one or more pharmaceutically acceptable excipients using hot melt granulation.


Typically the pharmaceutical composition of the present invention is prepared by forming granules comprising complex of atorvastatin calcium and hydroxypropyl-p-cyclodextrin, with one or more pharmaceutically acceptable excipients via hot melt granulation; blending the granules with one or more pharmaceutically acceptable excipients followed by compression of the lubricated granules into the desired dosage form.

The hot melt granulation is a well known granulation technique in the art. The entire process is simple, continuous and efficient. In the hot melt granulation process, neither solvent nor water is required during the process. It also takes fewer processing steps and thus the time consuming drying steps eliminated, compared to other convention granulation techniques such as wet granulation. The granules obtained via hot melt granulation are having uniform dispersion of fine drug particle (known as solid solution or solid dispersion), which posses good stability at varying pH and moisture levels and may ultimately render improvement to the dissolution rate and/or bioavailability of the formulation.
The process of hot melt granulation comprises basic steps of preparing atleast partially molten mixture comprising atorvastatin calcium, hydroxypropyl- p-cyclodextrin and one or more pharmaceutical excipients; preparing the granules, which further may be cooled and milled.
Typical melt granulation systems capable of carrying-out the present invention include a suitable extruder drive motor having variable speed and constant torque control, start-stop controls, and temperature zone controls. In addition, the system will include a temperature control console which includes temperature sensors, cooling means and temperature indicators throughout the length of the extruder. In addition, the system will include an extruder such as twin-screw extruder which consists of two co-rotating or counter-rotating intermeshing screws enclosed within a cylinder or barrel having an aperture or die at the exit thereof. The feed material is added through a feed hopper and is forced out in the form of free flowing uniform granules that are allowed to cool and further sized and blended. Suitable instruments and systems are available from distributors such as C.W. Brabender Instruments, Inc. of South Hackensack, N.J. and Eurolab Pharma Twin Screw Extruders. Other suitable apparatus will be apparent to those of ordinary skill in the art.
In order to carry out the hot melt granulation process of the invention, a melt granulating medium comprising crystalline atorvastatin calcium, hydroxypropyl-p-cyclodextrin, span 20 and optionally one or more pharmaceutically acceptable excipient is heated to a temperature at which the medium is at least partially in a molten state. As the granulating
12
-3 JUL 2009

medium is heated and becomes molten, it forms liquid bridges between the particles of the composition which change to solid bonds upon cooling. A solid mass is thereby formed in which the granulating medium and the remaining components of the composition are closely bound together, forming agglomerations or granules.
It will be within the skill of the artisan to devise techniques for ordering the heating and mixing of the various constituents of the granulate comprising active ingredients of the invention to result in the formation of a suitable melt granulation.
It would further be appreciated to the skilled artisan that the temperature of the hot melt granulator may be adjusted equal to or less than or more than, preferably less than or equal to the softening temperature of atorvastatin calcium and/or pharmaceutical excipient.
Further, it would be within the grasp of the skilled artisan to optimize the feed rate; extruder zone temperatures; and residence time of the material in each extruder zone, which is guided by rotation speed of the screw to achieve granules according to the present invention.
The compositions are maintained at an elevated temperature for a time sufficient to substantially completely liquify the composition of the invention. The length of time that the molten mixture is maintained at an elevated temperature can vary widely. The time will be such that degradation of the components of the mixture will be substantially minimized or avoided. The appropriate time can be readily determined experimentally and will vary according to the particular mixture being granulated. The time of exposure of the components to the elevated temperature is less than 5 minutes and preferably less than 2 minutes.
The resulting composition is then cooled or allowed to cool, preferably to room temperature. If necessary, the composition is also dried (air dried or possibly in an oven).
13
-3 JUL 2009

The cooled mixture is then broken into small chunks and milled using standard procedures. The resulting granulate is suitable for use in the preparation of pharmaceutical compositions.
The resulting granules of the invention can be processed further into various ora! pharmaceutical compositions such as tablets, mouth dissolving tablets; dispersible tablets; effervescent tablets; chewable tablets, minitablets, tablet filled capsules, pellets, granules, that can be incorporated in capsules or sachets. Preferably the oral dosage form according to the present invention is in the form of tablet and tablet filled capsules.
The resultant tablets were optionally seal coated. Alternatively, the tablet may be seal coated and finally film coated. The formulation may be further coated with Ready colour mix systems (such as Opadry colour mix systems).
. The tablet cores may be provided with suitable enteric coatings. For the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate may also be used. Alternatively, the tablet cores may be provided with sugar coating using concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
Orally administrate pharmaceutical compositions in the form of hard gelatin capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules may contain the active ingredient in the form of granules prepared via hot melt granulation as described above, which may optionally be admixed and filled with suitable pharmaceutically acceptable excipients.
There is further provided by the present invention a pharmaceutical composition
comprising atorvastatin calcium, hydroxypropyl-p-cyclodextrin and with one or more
-pharmaceutically acceptable excipients for use in treating disorders or conditions that
14
- 3 JUL 2009

respond to, or are prevented, ameliorated or eliminated by, the administration of atorvastatin calcium.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.
Example

Sr. no. Ingredient Qty (mg/tab)
Dry mix for HMG
1. Atorvastatin Calcium (Crystalline) 86.74
2. Hydroxypropyl-β-cyclodextrin 160.0
3. Span 20 8.4
^Mending & Lubrication
4. Pearlitol SD 200 796.86
5. Calcium carbonate 20.0
6. Ac-di-sol 80.0
7. Calcium stearate 32.0
8. Talc 16.0
Total 1200.0 mg/tab
Procedure:
Mixture of crystalline atorvastatin calcium, HP p-cyclodextrin and span 20 was extruded
by melt granulation process to prepare granules.
The above granules then sized through 30 mesh sieve.
Sized granules were then blended with Pearlitol SD 200, calcium carbonate, Ac-di-sol
and talc.
Finally, the granules were blended and lubricated with calcium stearate. The lubricated granules were then compressed into tablets.
15
- 3 JUL 2009

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more different polymers; reference to a "plasticizer" refers to a single plasticizer or to combinations of two or more plasticizer, and the like.

Dr. Gopakumar G. Nair Gopakumar Nair Associates