FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
TITLE OF THE INVENTION: "PHARMACEUTICAL COMPOSITIONS"
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 particularly describes the invention.

Technical field:
The present invention relates to stable pharmaceutical compositions comprising the amorphous active substance which is a HMG CoA inhibitor and also the process of preparation of the same.
Background and prior art:
Cholesterol is a chemical that can both benefit and harm the body. On the good side, cholesterol plays important roles in the structure of cells and in the production of hormones. But too much cholesterol in the blood can lead to heart and blood vessel disease. One type, of cholesterol called high-density lipoprotein (HDL) cholesterol, or "good cholesterol," actually lowers the risk of these problems but the other type, low-density lipoprotein (LDL) cholesterol, or "bad cholesterol," is the type that threatens people's health.
Treatment for high cholesterol levels usually begins with changes in daily habits. However, some may need to use cholesterol-reducing drugs to reduce their risk of health problems. Cholesterol-reducing drugs are medicines that lower the amount of cholesterol (a fat-like substance) in the blood.
There are different types of cholesterol reducing agents that can be used to lower the amount of cholesterol in the blood.One such type is HMG-CoA reductase inhibitors, often called "statins"; these are drugs that block an enzyme called "3-hydroxy-3-methyl-glutaryl-coenzyme A reductase." This blocks one of the steps in converting fat to cholesterol. These are the most effective cholesterol lowering agents available and in recent years have received increased attention for their benefits beyond helping patients with high cholesterol. Drugs in this group include: atorvastatin; cerivastatin; fluvastatin; lovastatin; pravastatin; simvastatin; and rosuvastatin.
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.
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Atorvastatin calcium is chemically known as [R-(R*, R*)]-2-(4-fluorophenyl)-(beta), [delta ]-dihydroxy-5 -(1 -methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl] -1 H-pyrrole-1 -heptanoic acid, calcium salt (2:1) trihydrate.
Atorvastatin calcium as a new chemical entity is described in US 5273995.
US 7151183 relates to the preparation of amorphous atorvastatin calcium by dissolving the crystalline form in acetone and then recovering the amorphous form from acetone.
US7230120 discloses the preparation of atorvastatin calcium using methanol.
US6528660 describes the preparation of amorphous atorvastatin calcium by dissolving crystalline atorvastatin calcium in a non -hydroxylic solvent, adding non-polar hydrocarbon anti-solvent to precipitate out amorphous atorvastatin calcium.
US20070066835 discloses a process of making the amorphous form by dissolving the salt in a mixture of water and water miscible organic solvent.
Atorvastatin calcium can exist in an amorphous form or in different crystalline forms which are disclosed in the patent applications WO 97/3958; WO 97/3959; WO 01/36384; WO 02/41834; WO 02/43732; WO 02/51804; and WO 02/57229. The processes for the preparation of amorphous atorvastatin calcium are described in the patent applications WO 97/3960; WO 00/71116; WO 01/28999; WO 01/42209; WO 02/57228; and WO 02/59087.
It is well known that the active substances in an amorphous form are better soluble and dissolve more rapidly, respectively, than when they are in a crystalline form. The advantage of an amorphous active substance over a crystalline form is particularly evident in case of less soluble substances such as, for example, atorvastatin calcium, and it is manifested in better bioavailability of an active substance.
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It is known from the patent and relevant literature that atorvastatin calcium is an unstable substance which is susceptible to heat, moisture, light and low pH at which atorvastatin calcium is converted from the carboxylic acid form to the lactone form (U.S. Pat. No. 5,686,104). The problem of instability of atorvastatin calcium has been solved thus far by the addition of excipients to a pharmaceutical formulation with special emphasis to stabilization of atorvastatin calcium in the sense of conversion into the lactone form by the addition of a basifying or a buffering agent to a pharmaceutical composition (WO 00/35425; WO 94/16603). A procedure for stabilization of an active substance is known from WO 01/93860, where, in the final phase of synthesis an alkaline substance or a buffering solution is added to prepare an alkaline stabilized substance i.e HMG-CoA reductase inhibitor.
The pharmaceutical formulation comprising amorphous atorvastatin calcium as the active substance is advantageous over a pharmaceutical formulation comprising a crystalline substance because the amorphous substance dissolves faster and better which is an important factor for bioavailability of the active substance in the body. It is well known that the stability of an active substance depends on a polymorphous form in which it exists and that an amorphous form is less stable than a crystalline form indicating that an amorphous form compared to a crystalline form is even more susceptible to heat, light, moisture and low pH. All these factors are of key importance for the stability of a pharmaceutical formulation comprising an amorphous substance. Impurities generated at degradation of an active substance reduce a therapeutic effect of an active substance and additionally unnecessarily burden the body with unnecessary degradation products. To date an appropriate and useful pharmaceutical composition containing atorvastatin calcium has not been described so far.
US20040077708 relates to a process for preparation of the stable pharmaceutical formulation comprising atorvastatin calcium in an amorphous form and pharmaceutically acceptable excipients by storing the pharmaceutical formulation in an inert atmosphere thereby achieving the stability which is superior and/or equal to the stability of the pharmaceutical formulation comprising the crystalline active substance
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Therefore, there is a constant need for preparing a stable pharmaceutical composition comprising amorphous atorvastatin calcium. Thus the present invention provides pharmaceutical composition comprising, atorvastatin calcium in amorphous form being advantageous over a crystalline substance by having better bioavailability prepared according to the process which is simple and economically convenient.
Objectives of the invention:
The basic objective of the present invention is to prepare a stable pharmaceutical formulation comprising an active substance which is amorphous atorvastatin calcium.
A further object of the present invention is to achieve the object by producing the amorphous atorvastatin in-situ during the manufacturing of the formulation.
Yet another object of the present invention is to manufacture a pharmaceutical formulation comprising amorphous atorvastatin calcium as the active substance and pharmaceutically acceptable excipients.
Summary of the invention:
It is provided by the present invention a stable pharmaceutical formulation comprising an active substance which is amorphous atorvastatin calcium.
In another aspect of the present invention, there is provided a stable pharmaceutical formulation comprising an active substance which is amorphous atorvastatin calcium, wherein the amorphous atorvastatin is formed in-situ during the manufacturing of the formulation.
In yet another aspect of the present invention there is provided a method to manufacture the formulation according to the present invention.
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Description of the invention:
As described above a major problem with formulations containing atorvastatin is its stability.
We have surprisingly found that when crystalline atorvastatin calcium is formulated by hot melt extrusion, the resultant product is a formulation containing amorphous atorvastatin calcium which remains stable.
Thus the present invention provides an economical and easy way to formulate a stable formulation.
Hot melt extrusion is a process that involves embedding a drug in a polymeric carrier while shaping the composite material to form a pharmaceutical product. The process according to the present invention comprises melt extrusion of crystalline atorvastatin calcium with one or more polymer(s). The melt extrudates thus obtained can be compressed as such to form tablets or incorporated as granules into various pharmaceuticals compositions that include, but are not limited to, tablets, capsules, pellets sprinklers, oral suspensions.
According to the present invention various statins or HMG CoA reductase inhibitors can be used. These include lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, cerivastatin, pitavastatin, rosuvastatin, atorvastatin and combinations thereof. The preferred HMG CoA reductase inhibitor is atorvastatin. The various available salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof of the various HMG CoA reductase inhibitors mentioned above may be used.
The term HMG CoA reductase inhibitors and the various statins are mentioned in the description as well as the claims in a broad sense to include not only HMG CoA reductase inhibitors and the various statins per se but also their salts, solvates, derivatives, prodrugs, enantiomers, racemic mixtures, polymorphs thereof.
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During the hot melt extrusion process, The polymers that can be used according to the
present invention, include, water soluble and water insoluble drugs but are not limited to
Homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP),
copolymers of N- vinyl pyrrolidone and vinyl acetate or vinyl propionate,Cellulose esters
and cellulose ethers, in particular methylcellulose and ethylcellulose,
hydroxyalkylcelluloses, in particular hydroxypropylcellulose,
hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate ,high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, Polyacrylates and polymethacrylates such as methacrylic acid / ethyl acrylate copolymers , methacrylic acid / methyl methacrylate copolymers, butyl methacrylate / 2- dimethylaminoethyl methacrylate copolymers , poly(hydroxylkyl acrylates), poly (hydroxyalkyl methacrylates), Polyacrylamides, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified ("polyvinyl alcohol") polyvinyl alcohol, Preferably homopolymers or copolymers of N-vinyl pyrrolidone, hydroxyalkylcelluloses, polyacrylates may be used.
Suitably homopolymers or copolymers of N-vinyl pyrollidone may include a copolymer of N-vinyl pyrrolidone & Vinyl acetate. A preferred polymer is a copolymer N-vinyl pyrollidone and about 40% by weight of the copolymer, vinyl acetate. Suitably polyacrylates may include cationic copolymers based on dimethylaminoethyl, methacrylate and neutral methacrylic esters may be used. More preferably the polymer can be Eudragit El 00.
Suitably the hydroxyalkycellulose may be hydroxypropylcellose.
A single polymer may be used or a combination of one or more polymers may be used.
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Different ratios of the drug: polymer may be used. Suitably the ratio may be 1:1 to 1:6, more preferably 1:2 to 1:5.
In addition to the drug and polymer, the matrix may further comprise additional excipients like plasticizers, disintegrants, flow regulators, lubricants, fillers, stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.
Suitable plasticizers which can be used in the present invention, include, but are not limited to, sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; low molecular weight polyethylene glycol; triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate. It is present in an amount ranging from 0% to 10% to the weight of polymer.
Suitable flow regulators are selected from highly dispersed silica (Aerosil)), and animal or vegetable fats or waxes.
Various other additives may be used, for example dyes such as azo dyes, organic or inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.
The present invention also provides a process to manufacture of a composition according to the present invention. The process involves forming a powder blend, transferring the blend through a heated barrel of the extruder, whereby the powder blend melts and molten solution product is collected on a conveyor whereby it is allowed to cool and form an extrudate. Alternatively, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms. More preferably the extrudates thus finally obtained from the above process are then milled and ground to granules by the means known to a person skilled in the art.
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The extrudates so obtained may then be admixed with other suitable pharmaceutically acceptable excipients. The present invention may comprise one or more of pharmaceutically acceptable excipients.
Suitable diluents may include one or more of but not limited to calcium phosphate-dibasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, isomalt, PVA, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents thereof.
Suitable binders may include one or more of but not limited to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof.
Suitable disintegrants may include one or more of but not limited to hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium , starch, crystalline cellulose, sodium starch glycollate, hydroxypropyl starch, partly pregelatinized starch, crospovidone and equivalents thereof.
Suitable lubricants/glidants may include one or more of but not limited to stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, PEG microcrystalline wax, colloidal silicon dioxide and equivalents thereof.
Optionally suitable coloring agents may be added.
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 scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional
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features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention.
Exemplary compositions of the present invention for melt extrusion of atorvastatin calcium with one or more polymer (s) are shown below in table 1.
Tahlel:

Sr. No. Ingredients Example (mg)
1 2 3 4 5 6
1 Atorvastatin Ca 80 80 80 80 80 80
2 Hydroxypropyl cellulose 320 - - 80 - 160
3 Copolymer of N-vinyl pyrrolidone & vinyl acetate (Kollidon VA 64 320 80 160
4 Dimethyl aminoethyl methacrylate ester (EudragitElOO®) 320 160 80
Process:
The drug and polymer(s) are passed individually through 20 mesh. The drug(s) and polymer(s) are mixed and again passed through 20 mesh. The mixture was hot melt extruded at a temperature ranging from 60 - 160°C; most preferably at a temperature between 90- 120°C. Optionally, suitable plasticizers and surfactants are added in the hot melt extrusion process.

Sr. No. Ingredients Qty/Unit (mg)
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1 Atorvastatin Calcium 82.87
2 PVP VA 64 320.00
3 Span 20 32.00
4 Calcium carbonate 30.00
5 LHPC 80.00
6 Crosscarmellose sodium 50.00
7 Talc 16.00
8 Pearlitol DC 400 (Mannitol) 369.13
9 Calcium Stearate 20.00
Total 1000.00
Process
Atorvastatin Calcium , PVP VA-64 and Span 20 are hot melt extruded. The extrudates are sized and mixed with calcium carbonate, crosscarmellose sodium and LHPC. This is then diluted with Perlitol DC 400 and lubricated with talc and calcium stearate.
Experiment:
It was observed that when Crystalline Atorvastatin was processed using hot-melt extrusion, there was a conversion of the crystalline form to amorphous form and the final formulation that was obtained contained the amorphous Atorvastatin. Figure I indicates an X-ray powder diffractogram (XRD) of crystalline atorvastatin calcium and X-ray powder diffractograms (XRD) of amorphous atorvastatin calcium obtained as per the examples 1-3 of table 1 above.
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.
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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.
Dated this 27th day of July 2007
Dr. Gopakumar G. Nair Agent for the Applicant
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