FORM 2
THE PATENT ACT 1970
(39 of 1970)&The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS COMPRISING FLUVASTATIN AND
GLYCINE AND CALCIUM CARBONATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition of fluvastatin or
salts thereof comprising glycine and calcium carbonate in an amount sufficient
of impart a pH between 6 and 8 to an aqueous solution or dispersion of said
composition.
The following specification particularly describes the invention and the manner
in which it is to be performed.

4. DESCRIPTION
The present invention provides a pharmaceutical composition comprising fluvastatin or salts thereof, and a combination of glycine and calcium carbonate as stabilizing agents capable of imparting a pH between 6 and 8 to an aqueous solution or dispersion of said composition.
Fluvastatin is [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H -indol-2-yl]-3,5-dihydroxy-6-heptenoic acid of Formula I. Fluvastatin, is commercially available as Lescol® Capsules and extended release Tablets in form of its sodium salt. It is indicated for the treatment of hypercholesterolemia (heterozygous familial and non familial), mixed dyslipidemia, secondary prevention of coronary events and atherosclerosis.

CHJ CH3
FORMULA 1
US Patent No 5,354,772 (the 772 Patent) discloses the compound and process for synthesis of Fluvastatin, its sodium salt and pharmaceutical compositions thereof.
EP patent no. 547000 and US patent no. 5,356,896 (Kabadi & Vivilecchia) disclose a stabilized pharmaceutical composition fluvastatin and an alkaline medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition. Kabadi & Vivilecchia described that fluvastatin is
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extremely susceptible to degradation at low pH value. Instability of fluvastatin is due to the extreme liability of the p,8-hydroxy groups on the heptenoic acid chain and the presence of the double bond, such that at acidic pH, the compounds readily undergo elimination or isomerization or oxidation reactions to form conjugated unsaturated aromatic compounds. The fluvastatin compositions having pH between 1.0 & 7.8 have been described as unstable (Table 1) by Kabadi & Vivilecchia.
Table 1

% Fluvastatin remaining at 37C
PH After 1 h After 24 h
7.8 98.3 98.0
6.0 99.6 97.1
4.0 86.7 25.2
1.0 10.9 0
US Patent no. 6,531,507 and 6,806,290 disclose the composition obtained by co-crystallization and/or co-preciptation of HMG-CoA reductase inhibitor and buffering substance or basifying substance.
US application no. 2005214372 and 2005214371 discloses a process for preparing stable pharmaceutical compositions of acid labile drugs wherein the drug is coated over an inert core followed by two subsequent coatings devoid of an alkaline stabilizing agent to prevent the degradation of the acid labile drug.
Several pharmaceutical compositions comprising fluvastatin have been disclosed in US patent no. 6,558,659, 6,911,472 European application no. EP1755587, EP1703911, EP1641440, EP1296672; PCT application no. W02006006021, WO2006105643, WO2007016757 and WO2005011737.
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The present inventors while working on stabilized pharmaceutical composition of fluvastatin have surprisingly found stable pharmaceutical composition comprising fluvastatin or salts thereof and a combination of glycine and calcium carbonate as stabilizing agents wherein the pH of aqueous solution or dispersion of the said composition is between 6 and 8. Fluvastatin is an acid labile drug and it undergoes degradation at acidic pH. Glycine and calcium carbonate in the pharmaceutical composition impart pH between 6 and 8 around the fluvastatin particle thereby preventing the degradation of fluvastatin.
In one of the aspects of the present invention there is provided, a stabilized pharmaceutical composition comprising fluvastatin or salts thereof, and a mixture of glycine or salts thereof and calcium carbonate along with pharmaceutically acceptable excipients wherein the mixture of glycine or salts thereof and calcium carbonate is present in an amount capable of imparting a pH between 6 and 8 to the aqueous solution or dispersion of the said composition.
In yet another aspect of the present invention is provided, a method for stabilizing a pharmaceutical composition comprising fluvastatin or salts thereof by adding a effective stabilizing amount of mixture of glycine or salts thereof and calcium carbonate wherein the mixture of glycine or salts thereof and calcium carbonate is capable of imparting a pH between 6 and 8 to the aqueous solution or dispersion of the said composition.
Glycine and calcium carbonate are present in an amount effective to impart a pH between 6 and 8 to the aqueous solution of fluvastatin. Total amount of glycine and calcium carbonate may vary from 0.001 to 90% by weight of the total composition. Further, the glycine to calcium carbonate ratio may be between 1:1 & 1:100 and vice versa.
Glycine also known as aminoethanoic acid, is a neutral nonpolar amino acid. Glycine has both the active groups of an amine and a carboxylic acid and it can
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be considered both acid and base. Calcium carbonate is poorly soluble in water. Saturated solution of calcium carbonate has a pH of more than 8 at 25°C. When dissolved in water it dissociates to strongly basic calcium cations and carbonate ions thereby raising the pH of water. When the pharmaceutical composition of present invention comprising glycine and calcium carbonate is dispersed or dissolved in water, calcium carbonate raises the pH of the water to more than 8. Simultaneously glycine, which is zwitterion, acts as an acid and neutralizes calcium ions to achieve a pH between 6 and 8. Thus the required pH of 6 to 8 is maintained around the fluvastatin particle and this prevents the degradation of fluvastatin. The pH of the pharmaceutical dosage form may be determined by taking a unit dosage of the composition containing e.g. 20 mg of fluvastatin and dispersing or dissolving the composition in 10 to 100 ml of water.
Glycine and Calcium carbonate are capable of imparting a pH between 6 and 8, thereby preventing the degradation of fluvastatin in aqueous and/or acidic environment. When the said composition is dissolved or dispersed in simulated gastric acidic media of pH 1 to 2, glycine and calcium carbonate neutralize the acidic groups present in the composition and surrounding media thereby maintaining a pH between 5 and 6.5 around the fluvastatin particles. This pH around fluvastatin helps to prevent its degradation in acidic gastric condition thereby assisting the absorbance of fluvastatin into systemic circulation.
Glycine and Calcium carbonate exert stabilizing action in the stored fluvastatin composition. The stabilized pharmaceutical composition of the present invention contains at least 80% of undegraded fluvastatin after storage for three months at about 40°C and 75% relative humidity. The in vitro stability of the pharmaceutical composition is also studied at extreme stability storage condition of 60°C temperature. The total impurity level after one-week storage is not more than 1% whereas the impurity level in the commercially available product Lescol® is more than 5.5% after one week of storage at 60°C temperature. Thus, the stabilizing agent is capable of providing both in vitro and in vivo stabilization of fluvastatin.
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Other suitable equivalents of potassium hydrogen tartrate may be used as stabilizing agent/s. The pharmaceutical composition may comprise one or more but not limited to salts of organic acid or base and salts of an inorganic acid or base and inorganic or organic bases. Suitable salts of inorganic acids include alkali metal salts of phosphoric acid, carbonic acid, like calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, anhydrous sodium, potassium or calcium dibasic phosphate, or trisodium phosphate. The organic base may be one or more of amino acids like glycine, alanine, asparginine, cysteine, glutamine, leucine, isoleucine, proline, phenylalanine and the like. The salts of organic acid include sodium citrate, sodium acetate, sodium tartrate and the like. Salts of organic acids include sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate and the like.
The stabilized compositions of the invention may be prepared by various techniques and manufacturing processes generally known to the art. The pharmaceutical composition can be prepared by dry or wet granulation method. Fluvastatin may be granulated with a suitable binder/binders dissolved a pharmaceutically acceptable vehicle. The granulating mixture may also comprise a plastisizer. The granules so obtained are dried and blended with a stabilizing agent and other pharmaceutically acceptable excipients. Alternatively the fluvastatin or salts thereof can be mixed directly with a stabilizing agent and other pharmaceutically acceptable excipients. This mixture can be formulated to tablets, pellets, capsules, sachets, minitablets and the like.
The stabilized pharmaceutical composition comprising fluvastatin or salts thereof comprises fluvastatin sodium. The pharmaceutical composition of this invention contains 10 mg to 100 mg of fluvastatin or salts thereof.
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The pharmaceutical composition comprising fluvastatin or salts thereof comprises a pharmaceutical^ acceptable vehicle wherein the vehicle may be one or more selected from a group comprising water, isopropyl alcohol, dichloromethane, acetone, chloroform and the like.
Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, glidant, plastisizer and the like. Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, crosspovidone and hydroxypropyl cellulose and the like. Suitable fillers may be one or more of lactose, dicalcium phosphate, pregelatinized starch, microcrystalline cellulose, mannitol and the like. Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate and the like. Suitable glidants may be one or more of microcrystalline cellulose, colloidal silicon dioxide, talc, magnesium stearate and the like. Suitable plastisizer may be one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples
Example 1 and 2
The pharmaceutical composition of fluvastatin is provided in Table 2.
Table 2

Ingredients Example 1 Example 2
rng/cap mg/cap

Fluvastatin sodium 22.09 44.18
Microcrystalline Cellulose 52.04 104.07
Pregelatinized Starch 30.00 60.00
Glycine 15.00 30.00
Calcium Carbonate 50.00 100.00
Purified Talc 5.00 10.00
Magnesium Stearate 0.875 1.75
Procedure:
Fluvastatin sodium is accurately weighed and passed through #60 mesh.
Accurately weighed microcrystalline cellulose, pregelatinized starch, glycine and
calcium carbonate are sifted through #40 mesh followed by mixing with
Fluvastatin sodium. Further this blend is lubricated by mixing it with accurately
weighed and sifted amount of talc and magnesium stearate. This mixture is filled
into hard gelatin capsules.
A dispersion of this composition in 10-100 ml. of water has a pH of 6.8-7.2.
The degradation analysis of the pharmaceutical composition prepared as per formula 2 is carried out by incubating 3 capsules in 60 ml of 0.01 N HCI for a period of 1 h. The samples were withdrawn at regular intervals and analyzed for the percentage fluvastatin remaining by HPLC (Column: Hypersil, BDS, C 18, 50 X 4.6 mm, 5 micron). The results are compared to the commercially available pharmaceutical composition of fluvastatin Lescol® marketed by Novartis.
Table 3

Time (min) Percentage Fluvastatin remaining
Lescol® Example 2
15 32 100
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30 39 95
45 48 78
60 46 80
Example 3 &4
The pharmaceutical composition of fluvastatin is provided in Table 4.
Table 4

Ingredients Example 3 mg/cap Example 4 mg/cap
Fluvastatin sodium 22.09 44.18
Povidone K-30 0.65 1.30
Crosspovidone 0.65 1.30
Isopropyl Alcohol qs Qs
Microcrystalline Cellulose 50.73 101.47
Pregelatinized Starch 25.00 50.00
Glycine 15.00 30.00
Calcium Carbonate 50.00 100.00
Purified Talc 5.00 10.00
Magnesium Stearate 0.875 1.75
Procedure:
Fluvastatin sodium is accurately weighed and sifted through #60 mesh. Povidone and crosspovidone are dissolved in isopropyl alcohol and fluvastatin is granulated with this solution. The granules are dried and passed through ASTM
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#36 mesh. Accurately weighed microcrystalline cellulose, pregelatinized starch, glycine and calcium carbonate are sifted through #40 mesh followed by mixing with granules of fluvastatin sodium. Further this blend is lubricated by mixing it with accurately weighed and sifted amount of talc and magnesium stearate. This mixture is filled into hard gelatin capsules.
A dispersion of this composition in 10-100 ml. of water has a pH of 6.8-7.2.
The degradation analysis of the pharmaceutical composition prepared as per formula 4 is carried out by incubating the 3 capsules in 60 ml of 0.01 N HCI for a period of 1 h. the samples were withdrawn a regular intervals and analyzed for the percentage fluvastatin remaining by HPLC (Column: Hypersil, BDS, C 18, 50 X 4.6 mm, 5 micron). The results are compared to the commercially available pharmaceutical composition of fluvastatin Lescol® marketed by Novartis.
Table 5

Time (min) Percentage Fluvastatin remaining
Lescol® Example 4
15 32 100
30 39 93
45 48 92
60 46 84
Example 5
To evaluate the release properties of the pharmaceutical composition of present invention (Example 2 and 4), USP apparatus II is used, at 50 rpm and using 500 ml dissolution liquid of deaerated water at 37 °C. The release of the active
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substance is monitored by HPLC (Column: Hypersil, BDS, C 18, 50 X 4.6 mm, 5 micron)
The results of the tests carried out are given in Table 6.
Table 6

Time Cumulative percent release
(min) Lescol Example 2 Example 4
5 59 3(3 27
10 95 77 61
15 99 94 85
20 100 100 99
30 100 101 103
45 100 105 104
Example 6
The stabilization effect of the added stabilizing agent in the pharmaceutical composition of Example 2 & 4 is tested by dispersing the pharmaceutical composition in 20 ml water followed by titration with 0.1 N HCI. The stabilizing effect is measured in terms of the pH of the solution with every addition of 0.1 N HCI by a pH meter (Orion Research Inc., Boston (model 310). The results are compared to the commercially available pharmaceutical composition of fluvastatin Lescol® marketed by Novartis.
Table 7

S.No. 0.1N HCI added(in ml) Lescol (20ml Water) Example 2 (20 ml Water) Example 4 (20ml Water)
Initial pH 0 8.20 7.22 6.87
1. 0.1 6.72 6.16 5.91
2. 0.2 6.36 5.96 5.62
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3. 0.3 6.06 5.82 5.41
4. 0.4 5.85 5.64 5.17
5. 0.5 5.68 5.39 4.96
6. 1.0 4.96 4.93 4.31
7. 1.5 4.05 4.00 3.73
8. 2.0 5.54 5.45 3.64
9. 2.5 5.66 5.69 3.57
10. 3.0 5.60 5.50 3.53
11. 3.5 5.52 5.49 3.51
12. 4.5 5.51 5.47 3.50
13. 6.5 5.44 5.42 3.36
14. 11.5 5.23 4.87 3.11
15. 16.5 4.92 3.30 2.80
16. 21.5 3.40 2.54 2.61
17. 31.5 2.15 2.12 2.27
18. 41.5 2.02 2.02 2.02
Example 7
The stabilization effect of the added stabilizing agent in the pharmaceutical composition of example 2 & 4 is tested by dispersing the pharmaceutical composition in 20 ml water followed by titration with 0.01 N HCI. The stabilzing effect is measured in terms of the pH of the solution with every addition of 0.01 N HCI by pH meter (Orion Research Inc., Boston (model 310). The results are compared to the commercially available pharmaceutical composition of fluvastatin Lescol® marketed by Novartis.
Table 8

S.No. 0.01N HCI Lescol Example 2 Example 4
added (in ml) (20ml Water) (20ml Water) (20ml Water)
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Initial pH 0 8.19 7.21 6.93
1. 0.1 7.56 7.02 6.87
2. 0.2 7.28 6.74 6.71
3. 0.3 7.17 6.56 6.54
4. 0.4 6.93 6.40 6.41
5. 0.5 6.77 6.28 6.39
6. 1.0 6.47 5.95 6.04
7. 1.5 6.23 5.80 5.88
8. 2.0 6.01 5.69 5.78
9. 2.5 5.83 5.62 5.65
10. 3.0 5.73 5.56 5.52
11. 3.5 5.65 5.52 5.48
12. 4.5 5.45 6.10 5.34
13. 6.5 5.09 6.04 4.99
14. 11.5 3.08 5.96 3.89
15. 16.5 5.02 5.86 3.40
16. 21.5 5.08 5.76 3.27
17. 31.5 5.12 5.60 3.06
18. 41.5 5.03 5.59 2.96
19. 61.5 4.70 5.58 2.85
20. 81.5 3.70 5.54 2.78
21. 101.5 3.40 5.44 2.65
22. 151.5 2.75 4.85 2.53
23. 201.5 2.65 2.98 2.39
Example 8
Fluvastatin pharmaceutical composition is prepared as explained in Example 2 and 4. The pharmaceutical composition of Example 2 & 4 and the commercially available product of Novartis i.e. Lescol® are stored at 60°C. The compositions are analyzed at day 0 and after 1 week, for percent amount of impurities. The entire impurity profile of the composition was studied and Table 9 shows the
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comparative impurity profile of Lescol® and the pharmaceutical composition of present invention.
Table 9: Impurity profile of the pharmaceutical composition of the present invention and the commercially available product Lescol® marketed by Novartis.
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Table 9

Name of impurity Lescol® Initial Lescol® 1 week Example 2 Initial Example 2 I week Example 4 Initial Example 4 1 week
Fluvastatin aniisomer 0.263 2.272 0.000 0.342 0.000 0.548
Fluvastatin hydroxydiene 0.000 0.000 0.000 0.293 0.000 0.209
Fluvastatin short chain aldehyde 0.000 0.056 0.000 0.000 0.000 0.000
3-hydroxy-5-ketofluvastatin 0.044 0.463 0.038 0.041 0.037 0.130
Highest Unknown 0.075 2.226 0.071 0.063 0.071 0.065
Total Unknown 0.234 2.861 0.071 0.108 0.071 0.113
Total Related Substances 0.543 5.652 0.109 0.784 0.108 1.000
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WE CLAIM:
1. A stabilized pharmaceutical composition comprising fluvastatin or salts thereof, and a mixture of glycine or salts thereof and calcium carbonate along with pharmaceutically acceptable excipients wherein the mixture of glycine or salts thereof and calcium carbonate is present in an amount capable of imparting a pH between 6 and 8 to the aqueous solution or dispersion of the said composition.
2. A method for stabilizing a pharmaceutical composition comprising fluvastatin or salts thereof by adding a effective stabilizing amount of mixture of glycine or salts thereof and calcium carbonate wherein the mixture of glycine or salts thereof and calcium carbonate is capable of imparting a pH between 6 and 8 to the aqueous solution or dispersion of the said composition.
3. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the stabilized pharmaceutical composition of fluvastatin or salts thereof, is such that at least about 80% of the potency of fluvastatin is maintained after storage for at least three month at 40°C and 75% relative humidity.
4. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, wherein the pH of the aqueous solution or dispersion of the said composition is between 6 and 8.
5. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, about 10 mg to 100 mg of fluvastatin or salt thereof is present.
6. A stabilized pharmaceutical composition according to claim 1, wherein fluvastatin or salts thereof is fluvastatin sodium.
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7. A stabilized pharmaceutical composition according to claim 1, wherein pharmaceutical^ acceptable excipients include a filler, binder, glidant, lubricant, a vehicle, plastisizer and the like.
8. A stabilized pharmaceutical composition according to claim 1, is formulated as an immediate release, delayed release, sustained release, controlled release or extended release.
9. A stabilized pharmaceutical composition according to claim 1, is a tablet, capsule, suspension, sachet, beads, granules, minitablets and pellets.
Dated this 20thday of April, 2007

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