FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&.
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)


"STABLE ORAL PHARMACEUTICAL COMPOSITION COMPRISING
ATORVASATEV"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAJ - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
1526 MUM 2009
29 JUN 2009

FIELD OF THE INVENTION
The present invention relates to a stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt
BACKGROUND OF THE INVENTION
Atorvastatin calcium, an HMG-CoA reductase inhibitor, disclosed in the U. S. Pat. No.
5,273,995, is currently sold in United States of America as Lipitor® having chemical
name Ql-(R*,R*)]-2-(4-fluorophenyl)-l3,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino) carbonyi]lH-pyrrole-l-heptanoic acid, calcium salt (2:1) trihydrate. It is indicated for prevention of cardiovascular disease and hypercholesterolemia. Atorvastatin is susceptible to a low pH environment and can degrade to the corresponding lactone in an acidic environment.
Amlodipine besylate, a long-acting calcium channel blocker is chemically described as 3-Ethyl-5- methyl (±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-l,4-dihydro-6-methyl-3;5-pyridinedicarboxylate; monobenzenesulphonate. Amlodipine may readily be prepared as described in U.S. Pat. No. 4,572, 909. Amlodipine besylate, which is currently sold as Norvasc®, may be prepared as described in U.S. Pat. No. 4,879,303, which is incorporated herein by reference. Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers. A combination of amlodipine besylate and atorvastatin calcium tablets is available as CADUET® tablets in the United States of America. This combination is indicated in treatment of cardiovascular disease, hypercholesterolemia, hypertension and Coronary Artery Disease (CAD).
U.S. Patent No. 5,686,104 discloses that HMG-CoA reductase inhibitors in an oral pharmaceutical composition for the treatment of hypercholesterolemia or hyperlipidemia are stabilized by combination with at least one alkaline earth metal salt such as calcium

< carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminium magnesium hydroxide.
U.S. Patent No. 6,680,341 discloses a stabilized pharmaceutical formulation containing as an active ingredient an HMG-CoA reductase inhibitor, and a buffering agent, wherein the active composition has a pH in the range from 7 to 11; at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent and a glidant; and additional buffering agent, wherein the pharmaceutical formulation has a pH below 9.
U.S. Patent No. 6,531,507 discloses a composition comprising a homogeneous mixture of a HMG-CoA reductase inhibitor with a buffering substance or a basifying substance in a finely distributed form, obtained by co-crystallization and/or co-precipitation of said HMG-CoA reductase inhibitor and said buffering substance or basifying substance. The basifying substance used for co-crystallization and/or co-precipitation is selected from the group consisting of metal oxides, inorganic bases, organic bases and organic acids with basic character.
U.S. Patent No. 7,030,151 discloses a pharmaceutical formulation comprising atorvastatin calcium as active ingredient and a pH adjusting substance to provide the pharmaceutical formulation when dissolved in a liquid aqueous medium increases the pH of said medium to a pH equal to or greater than pKa+l of atorvastatin calcium. The pH adjusting substance is selected from the group consisting of metal oxides, inorganic bases, organic bases, and salts of organic and inorganic aids.
U.S. Patent Application No. 2003175338 discloses a pharmaceutical formulation comprising atorvastatin and an alkali metal salt additive, the alkali metal salt additive being present at a concentration of between approximately 1.2% w/w and less than 5% w/w by weight of the formulation.

* U.S. Patent Application No. 2004247673 discloses a wet granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof with less than about 5 weight % of an alkaline earth metal salt additive with a disintegrant which provides the atorvastatin with not more than about 3% atorvastatin lactone based on the ratio of lactone peak area compared to the total drug-related peak integrated areas. The alkalizing agents include inorganic and organic bases (buffers).
U.S. Patent Application No. 2004072894 discloses a stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor which is capable of providing a pH in the range from 7 to 11. The active substance is contained the buffering agent having an amount of less than 1% w/w.
PCT Application No. 2003097039 discloses solid compositions for oral administration comprising atorvastatin calcium and a sodium or potassium compound which is capable of producing an aqueous dispersion having a pH above 11. The sodium or potassium compound may be a hydroxide or a salt of a weak acid.
SUMMARY OF THE INVENTION
The present invention provides a stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
The present invention also provides a stable oral pharmaceutical composition comprising a combination of atorvastatin or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.

Additionally, the present invention provides a process for preparing a stable oral pharmaceutical composition of atorvastatin or its pharmaceuticaly' acceptable salt comprising mixing atorvastatin or its pharmaceutically acceptable salt with alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt; and other excipients and converting the mixture into a pharmaceutical composition.
DESCRIPTION OF THE INVENTION
Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may. of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein

are incorporated herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual
publication dates which may need to be independently confirmed.
The term "stable" as used herein refers to chemical stability of atorvastatin in solid dosage forms wherein there is no change in assay values, impurities percentages and dissolution data when kept at 40°C /75% RH for 3 months.
The present invention provides a stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
The present invention also provides a stable oral pharmaceutical composition comprising a combination of atorvastatin or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
Additionally, the present invention provides a process for preparing a stable oral pharmaceutical composition of atorvastatin or its pharmaceutically acceptable salt

comprising mixing atorvastatin or its phannaceutically acceptable salt with alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its phannaceutically acceptable salt; and other excipients and converting the mixture into a pharmaceutical composition.
It has been surprisingly found that a stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt can be obtained by providing, in a pharmaceutical composition, suitable alkali metal salt additives in a stabilizing effective
amount of more than 5 % w/w.
The present invention is particularly adapted to stable oral pharmaceutical compositions comprising atorvastatin or its phannaceutically acceptable salt, as the active component of the composition. Among the preferred pharmaceutically acceptable salts are metal and amine salts. The term "phannaceutically acceptable salt" thus includes, but is not limited to sodium, potassium, lithium, calcium, magnesium, aluminium, iron and zinc salts of atorvastatin. Preferably, the atorvastatin is in the form of calcium salt. The atorvastatin or its phannaceutically acceptable salt is used in a therapeutically effective amount in the stable oral pharmaceutical compositions of the present invention. The atorvastatin or its pharmaceutically acceptable salt will generally be present in an amount ranging from about 0.05 to about 70% w/w, preferably in an amount ranging from about 1.0 to about 60% w/w. and most preferably from about 1% to about 40% w/w of the composition. The therapeutic effective amount of atorvastatin or its pharmaceutically acceptable salt that may be used in the stable composition of the present invention is in the range from about 10 to about 100 mg, equivalent to the base.
The stable oral pharmaceutical compositions of the present invention may also include amlodipine or its pharmaceutically acceptable salt. The expression "pharrnaceutically-acceptable acid addition salts" is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, besylate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. Other acid addition salts of amlodipine may be

prepared by reacting the free base form of amlodipine with the appropriate acid. When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base of amlodipine and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent. A particularly preferred salt of amlodipine is the besyiate salt. The amlodipine or its pharmaceutically acceptable salt is used in a therapeutically effective amount in the stable oral pharmaceutical compositions of the present invention. The amlodipine or its pharmaceutically acceptable salt may generally be present in an amount ranging from about 0.01 to about 60% w/w, preferably in an amount ranging from about 0.05 to about 40% w/w, and most preferably from about 0.01% to about 20% w/w of the composition. The therapeutic effective amount of amlodipine or its pharmaceutically acceptable salt that may be used in the stable composition of the present invention is in the range from about 2.5 to about 20 mg, equivalent to the base.
Also present in the stable oral pharmaceutical composition of the present invention are suitable alkali metal salt additive(s) in a stabilizing effective amount of more than 5 % w/w. The suitable alkali metal salt additives are used in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt. The suitable alkali metals of the invention may be selected from the group comprising compounds of group IA of periodic table such as sodium, potassium or lithium & the suitable alkali metal salt additives of the invention may be selected from the group comprising one or more of disodium hydrogen phosphate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, sodium aluminate and the like or mixtures thereof. The amount of suitable alkali metal salt additives that may be used in the stable oral

pharmaceutical composition of the subject invention ranges from about 5 % w/w to about 25 % w/w of the total weight of the composition.
The pharmaceutical composition of the present invention may further comprise conventional pharmaceutically acceptable excipients. Conventional pharmaceutical excipients include those which function in a dosage form, for example, as a disintegrant lubricant, glidant, fillers or diluents, wicking agents, carrier, colorant or coating material.
In preferred embodiments the composition of the present invention is formed into tablets. The fillers or diluents that may be used in the stable oral pharmaceutical composiUon of the present invention include microcrystaUine cellulose, mannitol, dextrates, dextrins, dextrose, fructose, lactose, lactitol, maltitol, maltodextrins, maltose and the like and mixtures thereof. A preferred filler is microcrystaUine cellulose or lactose or a combination thereof The diluents or fillers may be used in amounts ranging from about 0.1 to about 80% w/w. It is preferred that the fillers are used in amounts ranging from about 1 to about 70% w/w of the composition.
The disintegrants that may be used in pharmaceutical composition of the present invention include carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum. magnesium aluminium silicate, methylcellulose, microcrystaUine cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, and starch and the like or mixtures thereof The disintegrants may be used in amounts ranging from about 0.1 to about 50% w/w. It is preferred that the fillers are used in amounts ranging from about 1 to about 20% w/w of the composition.
The lubricants used in the present invention may be selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycol and the like and mixtures thereof. Generally the amount of the lubricants used in the present invention may vary from about 0.001 to about 5 % w/w of the composition.

• The typical glidants that may be included in the present invention include colloidal silicon dioxide, talc and the like. The amounts of glidants used in the present invention may vary from about 0.1 to about 5% w/w of the composition.
Examples of wicking agents that may be used in the present invention include colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, m-pyrol, vinylpyrrolidone polymers such as povidone, or crossiinked polyvinylpyrrolidone such as crospovidone; cellulose and cellulose derivatives such as microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl cellulose, carboxyalicyl celluloses and their alkali salts; sodium starch glycolate, starch and starch derivatives, ion-exchange resins and the like and mixtures thereof.
The binders used in the present invention may be selected from the group comprising of starch, gelatin, dextrin, maltodextrin, natural and synthetic gums like acacia, alginic acid, sodium alginate, guar gum. extract of fish moss, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, veegum, arabogalactan and the like and mixtures thereof.
The film forming polymer used in the the present invention may be selected from the group comprising opadry®, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone; and the like and mixtures thereof.
The composition of the present invention may also use solubilizers known in the art such as polysorbate 80 and the like; and antioxidants known in the art such as butylated hydroxyl anisol, butylated hydroxyl toluene and the like.
The term "pharmaceutical composition" as used herein includes solid oral dosage forms such as pellets, beads, granules and the like, which may be encapsulated or compressed into tablets. The pellets, beads, granules in turn may be prepared by conventional

« methods known to a person skilled in the art. The compressed tablets may optionally be coated with film-coat.
The pharmaceutical compositions of the present invention, maybe prepared by the conventional processes such as wet granulation, dry granulation or direct compression. In wet granulation, atorvastatin or its pharmaceutically acceptable salt is mixed with suitable alkali metal salt additives and various excipients and granulated, followed by screening and drying of the damp mass. The dried mass may be screened, lubricated and compressed. Dry granulation can be done by two processes: (1) slugging, which involves mixing the atorvastatin or its pharmaceutically acceptable salt with suitable alkali metal salt additives and the excipients, slugging, dry screening, lubrication and compression, or (2) roller compaction process. Direct compression involves compressing tablets directly from the physical mixture of atorvastatin or its pharmaceutically acceptable salt, suitable alkali metal salt additives and the excipients. Alternatively the pharmaceutical compositions of the present invention may be obtained by preparing placebo granules comprising the suitable alkali metal salt additives and pharmaceutically acceptable excipients, and mixing these with atorvastatin to obtain a blend, which may be encapsulated or compressed into tablets. This method provides compositions of atorvastatin that are stable.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
EXAMPLE 1
The stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt may be prepared as given in Table 1.
Table 1

Name of Ingredients Quantity
(Mg/Tabtet) % w/w
Atorvastatin calcium (Amorphous) 80 6.53
Di-sodium hydrogen phosphate 66. 5.39
Microcrystaliine Cellulose 317.96 25.97
Lactose monohydrate 210. 17.15
Croscarmellose sodium 75 6.12
Poly sorb ate 80 04.80 0.39
Butylated hydroxyl anisol 00.24 0.0196
Purified water q.s
Extragranular
Croscarmellose sodium 36 2.94
Microcrystaliine Cellulose 334 2.72
Sodium hydrogen carbonate 66 5.39
Magnesium stearate 10 0,816
Total wt 1200.00 98.04
Coating
Opadry white 24 1.96
Purified water q.s
Total wt 1224.00 100.00
The atorvastatin calcium, di-sodium hydrogen phosphate, microcrystaliine cellulose, lactose monohydrate and Croscarmellose sodium were sifted through # 40 sieve and mixed for 10 minutes in a RMG. The binder solution was prepared by heating purified water to 40 - 50°C and polysorbate 80 added to it with stirring. The Butylated hydroxyl anisol (solution dissolved in ethanol) was added to the above solution to get a clear solution. Then the previously prepared blend was granulated in RMG using the binder solution prepared above. The granules were dried in rapid drier at 50°C till LOD below 4 % w/w was obtained and sifted through appropriate sieve. Then croscarmellose sodium, microcrystaliine cellulose and sodium hydrogen carbonate were mixed with the above blend. Also magnesium stearate was added to the above blend and mixed. The blend was then compressed blend using suitable punches. The tablets were then coated with opadry white ready mix.
EXAMPLE 2

The stable oral pharmaceutical composition as prepared in example 1 was subjected to dissolution. The results are given in Table 2.

Media 6.8 pH Phosphate buffer
Appratus USP Type II
Agitation 75RPM
Volume 900 ml
Table 2

Sr. No. Time in min Lipitor® 80 mg Tablet Composition of example -1

(% drug release) (% drug
1. 5 85.63 90.53
2. 10 94.08 95.67
3. 15 96.70 97.20
4. 30 98.73 98.17
EXAMPLE 3
The stable oral pharmaceutical compositions comprising atorvastatin or its pharmaceutically acceptable salt and amlodipine or its pharmaceutically acceptable salt may be prepared as given in Table 3.
Table 3

Name of Ingredients Quantity (mg/Tablet) %w/w
Atorvastatin calcium 80 9.80
Di-sodium hydrogen phosphate 50 6.12
Microcrystalline cellulose 371.76 45.55
Croscarmellose sodium 75 9.19
Polysorbate 80 3 0.36
Butylated hydroxy! toulene 00.24 0.029
Purified water q.s.
Extragranular
Amlodipine besylate 10 1.22

Croscarmetlose sodium 50 6.12
Presel starch 100 12.25
Sodium hydrogen carbonate 50 6.12
Magnesium stearate 10 1.22
Total wt 800 98.04
Coating
Opadry II Blue 16 1.96
Purified water q.s
Total wt 816 100
The composition was prepared as given as per the procedure given in example 1.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.