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:
STABILIZED FLUVASTATIN COMPOSITIONS
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 stabilized pharmaceutical composition
comprising fluvastatin or salts thereof, wherein the fluvastatin is coated with a
pharmaceutically acceptable polymer. The polymer coated fluvastatin is mixed
with pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides a stabilized pharmaceutical composition comprising fluvastatin or salts thereof, and a pharmaceutical^ acceptable polymer in admixture with pharmaceutical^ acceptable excipients wherein the composition is stabilized by coating fluvastatin with the said polymer.
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.

US Patent No 5,354,772 (the 772 Patent) discloses the process for synthesis of Fluvastatin, its sodium salt and pharmaceutical compositions thereof.
Fluvastatin is extremely susceptible to degradation at low pH value. Instability of fluvastatin is due to the extreme liability of the beta.delta-hydroxy groups on the heptenoic acid chain and the presence of the double bond, such that at neutral to
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acidic pH, the compounds readily undergo elimination or isomerization or oxidation reactions to form conjugated unsaturated aromatic compounds.
Several pharmaceutical compositions comprising fluvastatin have been disclosed in US patent no. 6,558,659, PCT application no. WO2006006021 and WO2005011737.
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.
EP patent no. 547000 and US patent no. 5,356,896 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.
The present inventors while working on stabilized pharmaceutical composition of fluvastatin have surprisingly found a pharmaceutical composition comprising
fluvastatin or salts thereof wherein the said composition comprises fluvastatin or
salts thereof coated with a suitable pharmaceutically acceptable polymer in admixture with pharmaceutically acceptable excipients. Fluvastatin or salts thereof are coated with the said polymer by granulating fluvastatin with a solution of the polymer. This granulation process results in the formation of a film over fluvastatin particles thereby imparting better stability to the composition.
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In one of the aspects of the present invention there is provided, a stabilized pharmaceutical composition comprising fluvastatin or salts thereof and a pharmaceutically acceptable polymer in admixture with pharmaceutically acceptable excipients, wherein the said composition comprises fluvastatin coated with the said pharmaceutically acceptable polymer.
The pharmaceutical composition comprising fluvastatin or salts thereof can be prepared by granulating fluvastatin with the polymer dissolved a pharmaceutically
acceptable vehicle. The granulating mixture may also comprise a plastisizer. The granules so obtained are dried and blended with pharmaceutically acceptable
excipients. This mixture can be formulated to tablets, pellets, capsules, sachets, minitablets and the like.
A stabilized pharmaceutical composition may be formulated as immediate release, delayed release, sustained release, controlled release or extended release.
The pharmaceutical composition of the present invention is stable at accelerated storage stability conditions of 40°C temperature and 75% relative humidity. The total impurity level after one-month storage was 0.823% whereas the impurity level in the commercially available product Lescol® was 0.979% at accelerated stability conditions.
Also the stability of the pharmaceutical composition is studied at extreme stability storage condition of 60°C temperature. The total impurity level after one-week storage was less than 2.5% whereas the impurity level in the commercially available product Lescol® was more than 5.5% after one week of storage at 60°C temperature.
The stabilized pharmaceutical composition comprising fluvastatin or salts thereof comprises fluvastatin sodium.
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The pharmaceutical composition comprises fluvastatin or salts thereof and a pharmaceutical^ acceptable "polymer" wherein the said polymer is capable of preventing the degradation of fluvastatin by forming a coat around drug particles. Fluvastatin is an acid labile drug. The "polymer" used herein coats the fluvastatin and thereby prevents its contact with the acidic environment. This results in the stable fluvastatin compositions.
The polymer may be one or more of ethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methyl cellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate, polyethylene glycol, methacrylic acid polymers and the like.
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.
Pharmaceutical^ 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 and hydroxypropyl cellulose and the like. Suitable fillers may be one or more of lactose, dicalcium phosphate, 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.
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White 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 1.
Table 1

Ingredients Example 1 (mg/Cap) Example 2 (mg/Cap)
Fluvastatin sodium 21.68 43.36
Hydroxy Propyl Cellulose 0.65 1.30
Polyethylene Glycol 6000 0.065 0.13
Microcrystalline Cellulose 73.855 147.71
Lactose anhydrous 25.00 50.00
Purified Talc 2.50 5.00
Magnesium Stearate 1.25 2.50
Water q.s q.s
Isopropyl Alcohol q.s q.s
Total Weight 125.00 250.00
Procedure:
Fluvastatin sodium is accurately weighed and passed through #60 mesh. PEG is dissolved in water followed by adding isopropyl alcohol and hydroxypropyl cellulose. Fluvastatin is granulated by using above solution. The granules are dried and passed through #30 mesh. Microcrystalline cellulose and lactose are weighed accurately and sifted though #30 mesh and mixed with the fluvastatin granules. Further this blend is lubricated by mixing it with accurately weighed and
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sifted amount of talc and magnesium stearate. This mixture can be filled into hard gelatin capsules.
Example 3
Fluvastatin pharmaceutical composition is prepared as explained in example 2. The pharmaceutical composition of Example 2 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 2 shows the comparative impurity profile of Lescol® and the pharmaceutical composition of present invention.
Table 2: Impurity profile of the pharmaceutical composition of the present
invention and the commercially available product Lescol® marketed by Novartis.
Table 2:

Name of Impurity USP Limit Lescol 40 mg Initial Lescol40 mgI week at 60°C Example 2 40 mg Initial Example 240 mgI week at 60°C
Fluvastatin anti isomer 1.5 0.263 2.272 0.000 1.592
Fluvastatinhydroxy-diene 1.0 0.000 0.000 0.000 0.000
Fluvastatin short chain aldehyde 0.5 0.000 0.056 0.000 0.000
3-Hydroxy-5-ketoFluvastatin 1.0 0.044 0.463 0.000 0.054
HighestUnknown(RRT1.83) 0.5 0.075 2.226 0.041 0.378
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Total Unknown 1.5 0.234 2.861 0.140 0.665
TotalRelatedSubstances 4.0 0.541 5.652 0.140 2.331
Example 4
Fluvastatin pharmaceutical composition is prepared as explained in example 2. The pharmaceutical compositions of the present invention and the commercially available product of Novartis i.e. Lescol® are stored at accelerated stability condition of 40°C temperature and 75% RH. The compositions are analyzed at day 0 and after 1 month, for percent amount of impurities. The entire impurity profile of the composition is studied and Table 3 shows the comparative impurity profile of Lescol® and the pharmaceutical composition of present invention. Table 3: Impurity profile of the pharmaceutical composition of the present invention and the commercially available product Lescol® marketed by Novartis.
Table 3:

Name of Impurity USP Limit Lescol 40 mg Initial Lescol40 mg1MACC Example 2 40 mg Initial Example 240 mg1MACC
Fluvastatin anti isomer 1.5 0.263 0.353 0.000 0.309
Fluvastatinhydroxy-diene 1.0 0.000 0.000 0.000 0.117
Fluvastatin short chain aldehyde 0.5 0.000 0.000 0.000 0.015
3-Hydroxy-5-keto 1.0 0.044 0.098 0.000 0.026
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Fluvastatin
HighestUnknown(RRT1.83) 0.5 0.075 0.420 0.041 0.094
Total Unknown 1.5 0.234 0.528 0.140 0.356
TotalRelatedSubstances 4.0 0.541 0.979 0.140 0.823
Example 5
The pharmaceutical composition of fluvastatin is provided in 4.
Table 4

Ingredients Example 5
Fluvastatin Sodium 43.36
Povidone K-30 1.30
Isopropyl alcohol q.s
Micro crystalline cellulose 147.84
Lactose anhydrous 50.00
Purified Talc 5.00
Magnesium Stearate 2.50
Total Weight 250.00
Procedure:
Fluvastatin sodium is accurately weighed and passed through #60 mesh. Povidone is dissolved in isopropyl alcohol. Fluvastatin is granulated by using above solution. The granules are dried and passed through #30 mesh. Microcrystalline cellulose and lactose are weighed accurately and sifted though #30 mesh and mixed with the fluvastatin granules. Further this blend is lubricated
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by mixing it with accurately weighed and sifted amount of talc and magnesium stearate. This mixture can be filled into hard gelatin capsules.
Example 6
The pharmaceutical composition of fluvastatin is provided in 5.
Table 5

Ingredients Example 6
Fluvastatin Sodium 43.36
Povidone K-30 1.30
Crospovidone 1.30
Isopropyl alcohol q.s
Micro crystalline cellulose 146.54
Lactose 50.00
Purified Talc 5.00
Magnesium Stearate 2.50
Total Weight 250.00
Procedure:
Fluvastatin sodium is accurately weighed and passed through #60 mesh. Povidone is dissolved in isopropyl alcohol followed by addition of crosspovidone. Fluvastatin is granulated by using above suspension. The granules are dried and passed through #30 mesh. Microcrystalline cellulose and lactose are weighed accurately and sifted though #30 mesh and mixed with the fluvastatin granules. Further this blend is lubricated by mixing it with accurately weighed and sifted amount of talc and magnesium stearate. This mixture can be filled into hard gelatin capsules.
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Example 7
Fluvastatin pharmaceutical composition is prepared as explained in example 5 and 6. The pharmaceutical composition of Example 5 and 6 and the commercially available product of Novartis i.e. Lescol® are stored at 40°C and 75% RH. The compositions are analyzed at day 0 and after 1 month, for percent amount of impurities. The entire impurity profile of the compositions was studied and Table 6 shows the comparative impurity profile of Lescol® and the pharmaceutical composition of example 5.
Table 6: Impurity profile of the pharmaceutical composition of Example 5 and the commercially available product Lescol® marketed by Novartis.
Table 6

Name of Impurity USP Limit Lescol 40 mg Initial Lescol40 mg1MACC Example 540 mg Initial Example 540 mg 1MACC
Fluvastatin anti isomer 1.5 0.263 0353 0.051 0.099
Fluvastatin hydroxy-diene 1.0 0.000 0.000 0.012 0.051
Fluvastatin short chain aldehyde 0.5 0.000 0.000 0.006 0.011
3-Hydroxy-5-keto Fluvastatin 1.0 0.044 0.098 0.000 0.009
Highest Unknown (RRT1.83) 0.5 0.075 0.420 0.096 0.091
Total Unknown 1.5 0.234 0.528 0.135 0.187
Total Related Substances 4.0 0.541 0.979 0.204 0.357
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Table 7: impurity profile of the pharmaceutical composition of Example 6 and the commercially available product Lescol9 marketed by Novartis.
Table 7

Name of Impurity USP Limit Lescol 40 mg Initial Lescol40 mg1MACC Example 6 40 mg Initial Example 640 mg1MACC
Fluvastatin anti isomer 1.5 0.263 0353 0.054 0.109
Fluvastatin hydroxy-diene 1.0 0.000 0.000 0.011 0.066
Fluvastatin short chain aldehyde 0.5 0.000 0.000 0.004 0.007
3-Hydroxy-5-keto Fluvastatin 1.0 0.044 0.098 0.000 0.016
Highest Unknown (RRT1.83) 0.5 0.075 0.420 0.096 0.099
Total Unknown 1.5 0.234 0.528 0.139 0.228
Total Related Substances 4.0 0.541 0.979 0.208 0.426
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WE CLAIM:
1. A stabilized pharmaceutical composition comprising fluvastatin or salts thereof and a pharmaceutically acceptable polymer in admixture with pharmaceutically acceptable excipients, wherein the said composition comprises fluvastatin coated with the said pharmaceutically acceptable polymer.
2. A stabilized pharmaceutical composition comprising fluvastatin or salts thereof, polyvinyl pyrrolidone and/or cross polyvinyl pyrrolidone in admixture with pharmaceutically acceptable excipients, wherein the said composition comprises fluvastatin coated with polyvinyl pyrrolidone.
3. A stabilized pharmaceutical composition according to claim 1, wherein fluvastatin or salts thereof is fluvastatin sodium.
4. A stabilized pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable excipients include a filler, binder, glidant, lubricant, a vehicle, plastisizer and the like.
5. A stabilized pharmaceutical composition according to claim 1, is formulated as an immediate release, delayed release, sustained release, controlled release or extended release.
6. A stabilized pharmaceutical composition according to claim 1, is a tablet, capsule, suspension, sachet, beads, granules, minitablets and pellets.
Dated this 19th day of January, 2007

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