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:
PROCESS FOR PREPARATION OF STABILIZED FLUVASTATIN COMPOSITION
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 process for preparing a stabilized pharmaceutical composition comprising fluvastatin or salts thereof, wherein the said process comprises the step of granulating fluvastatin or salts thereof with a suitable film forming polymer in admixture with an alkalizing agent followed by blending the fluvastatin granules with the granules comprising an acidic substance, such that the pH of pharmaceutical composition is 7.0 or less.
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 process for preparing a stabilized pharmaceutical composition comprising fluvastatin or salts thereof, wherein the said process comprises the step of granulating fluvastatin or salts thereof with a suitable film forming polymer in admixture with an alkalizing agent followed by blending the fluvastatin granules with the granules comprising an acidic substance, such that the pH of pharmaceutical composition is 7.0 or less.
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.

FORMULA 1
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 lability of the .beta.,.delta.-hydroxy groups on the
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heptenoic acid chain and the presence of the double bond, such that at neutral to acidic pH, the compounds readily undergo elimination or isomerization or oxidation reactions to form conjugated unsaturated aromatic compounds, as well as the threo isomer, the corresponding lactones, and other degradation products. Additionally, the heat and light sensitivity as well as hygroscopicity of the subject compounds impose particular requirements in the manufacture and storage of pharmaceutical dosage forms.
Several stabilized pharmaceutical compositions comprising fluvastatin have been disclosed in prior art such as 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 said 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.
The present inventors while working on stabilized pharmaceutical composition of fluvastatin have surprisingly found a process for the preparation of pharmaceutical composition comprising fluvastatin or salts thereof wherein the said process comprises the step of granulating fluvastatin or salts thereof with a suitable pharmaceutical vehicle wherein the vehicle comprises a film forming polymer, plasticizer and an alkalizing agent in admixture with pharmaceutical^ acceptable excipients. The granules so obtained are mixed with extragranular excipients and granules of an acidic substance followed by lubricating this blend with pharmaceutically acceptable lubricants and/or glidant. This blend may be formulated into capsules, tablets, minitablets, sachets, pellets and the like.
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In one of the aspects of the present invention there is provided, a process for the preparation of stabilized pharmaceutical composition comprising fluvastatin or salts thereof, wherein the said process comprises the steps of
a) granulating fluvastatin or salts thereof, an alkalizing agent and a film-forming polymer in admixture pharmaceutically acceptable excipients
b) mixing the granules of step (a) with the granules of a pharmaceutically acceptable acidic substance and a filler,
c) lubricating the granules of step (b) with pharmaceutically acceptable lubricant and/or glidant
wherein the pH of the pharmaceutical composition is 7.0 or less.
In yet another aspect of present invention, there is provided, a stabilized pharmaceutical composition comprising fluvastatin or salts thereof comprising a film-forming polymer, an alkalizing agent and an acidic substance in admixture with pharmaceutically acceptable excipients wherein the said pharmaceutical composition has total impurity level of less than 0.5% after one month of storage at 40°C temperature and 75% relative humidity.
The pharmaceutical composition comprising fluvastatin or salts thereof can be prepared in two parts. In the first part, fluvastatin or salts thereof, can be granulated using a pharmaceutically acceptable vehicle wherein the vehicle comprises of a suitable film-forming polymer, a alkalizing agent in admixture with suitable pharmaceutical excipients. The granules so obtained are dried and passed through 30 mesh. In the second part, the acidic substance is dissolved in a suitable vehicle and granulated with filler/s. The granules are dried and passed through 40 mesh. The granules of both the parts can be mixed together followed by addition of filler, lubricants and glidants. This mixture can be formulated to tablets, pellets, capsules, sachets, minitablets and the like.
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The pharmaceutical composition as prepared by the above-described process, is subjected to accelerated storage stability conditions of 40°C temperature and 75% relative humidity. The total impurity level after one-month storage was less than 0.5% whereas the impurity level in the commercially available product Lescol® was approximately 1 % after one month of storage at accelerated stability conditions.
The pH of the pharmaceutical composition comprising fluvastatin or salts thereof was 7.0 or less. The pH of the composition was measured by dissolving or dispersing 20 mg unit dosage form of fluvastatin in 10 to 100 ml water.
The pharmaceutical composition comprising fluvastatin or salts thereof comprises fluvastatin sodium.
The pharmaceutical composition comprising fluvastatin or salts thereof
comprises a suitable "film-forming polymer" to prevent the degradation of
fluvastatin. Fluvastatin is an acid labile drug. The film-forming polymer used
herein coats the fluvastatin and thereby prevent its contact with the acidic
environment. The film-forming layer 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, and methacrylic acid polymers.
The pharmaceutical composition comprising fluvastatin or salts thereof comprises a suitable "alkalizing agent" to prevent the degradation of fluvastatin. Fluvastatin is stable at alkaline pH values. By using a suitable alkalizing agent during the preparation of fluvastatin granules, a microenvironment around fluvastatin particles is created which has a pH of about 8.0 to 9.0. A suitable alkalizing agent may be one or more Diethanolamine, Monoethanolamine, Potassium citrate,Sodium bicarbonate,Sodium Citrate dihydrate, Triethaolamine,
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Sodium Carbonate, Potassium carbonate,anhydrous sodium.Trisodium
Phosphate, Sodium Hydroxide,Potassiun Hydroxide, Magnesium
oxide.Magnesium hydroxide,Magnesium carbonate.Magnesium hydrogen carbonate,Calcium hydroxide.Calcium carbonate,Magnesium aluminium hydroxide and the like.
The pharmaceutical composition comprising fluvastatin or salts thereof comprises an "acidic s.ubstance". The acidic substance may be one or more of citric acid, lactic acid, ascorbic acid, aspartic acid and the like.
The pharmaceutical composition comprising fluvastatin or salts thereof comprises a pharmaceutically 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 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, and dibutyl sebacate
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those
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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 120 mg (mg/Cap) Example 240 mg (mg/Cap)
Stage A
Fluvastatin sodium * 21.68 43.36
Hydroxy Propyl Cellulose 0.325 0.650
Polyethylene Glycol 0.0325 0.065
Hydroxymethyl methylamine 1.10 2.2
Water q.s q.s
Isopropyl Alcohol q.s q.s
Stage B
Lactose 18.95 37.90
Citric acid 0.350 0.700
Water q.s q.s
Stage C
Microcrystalline Cellulose 72.76 145.52
Lactose anhydrous 6.05 12.10
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Purified Talc 2.50 5.00
Magnesium Stearate 1.25 2.50
Total Weight 125.00 250.00
Procedure:
Fluvastatin sodium is accurately weighed and passed through #60 mesh, hydroxymethyl methylamine and PEG are dissolved in water followed by adding isopropyl alcohol and hydroxypropyl cellulose. Sifted fluvastatin is granulated by using above solution. The granules are dried and passed through #30 mesh. Citric acid and lactose are weighed accurately. Citric acid is dissolved in water and then lactose is granulated using water having citric acid. The granules are dried and passed through #40 mesh. The lactose and citric acid granules are mixed with accurately weighed microcrystalline cellulose and lactose. Talc and magnesium stearate are weighed accurately and mixed with the blend of lactose-citric acid granules and fluvastatin granules. This blend is then filled into hard gelatin capsules.
An aqueous dispersion of the composition as per example 1 in 10-100 ml water has a pH of 7.0.
Example 3
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 for one months at 40°C and 75% relative humidity. The compositions are analyzed at day 0 and after 1 month, 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.
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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 Lescol 40 mg Initial Lescol40 mg1MACC Example 2 40 mg Initial Example 240 mg1MACC
Fluvastatin anti isomer 0.263 0353 0.091 0.134
Fluvastatin hydroxy-diene 0.000 0.000 0.030 0.000
Fluvastatin short chain aldehyde 0.000 0.000 0.000 0.000
3-Hydroxy-5-keto Fluvastatin 0.044 0.098 0.041 0.102
Highest Unknown (RRT1.83) 0.075 0.420 0.093 0.074
Total Unknown 0.234 0.528 0.234 0.258
Total Related Substances (w/w) 0.541 0.979 0.396 0.494
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WE CLAIM:
1. A process for the preparation of stabilized pharmaceutical composition
comprising fluvastatin or salts thereof, wherein the said process
comprises the steps of:
a) granulating fluvastatin or salts thereof, an alkalizing agent and a film-forming polymer in admixture pharmaceutically acceptable excipients
b) mixing the granules of step (a) with the granules of a pharmaceutically acceptable acidic substance and a filler,
c) lubricating the granules of step (b) with pharmaceutically acceptable lubricant and/or glidant,
wherein the pH of the pharmaceutical composition is 7.0 or less.
2. A stabilized pharmaceutical composition comprising fluvastatin or salts thereof comprising a film-forming polymer, an alkalizing agent and an acidic substance in admixture with pharmaceutically acceptable excipients wherein the said pharmaceutical composition has total impurity level of less than 0.5% after one month of storage at 40°C temperature and 75% relative humidity.
3. The process and the stabilized pharmaceutical composition according to claim 1 and 2, wherein fluvastatin or salts thereof is fluvastatin sodium.
4. The process and the stabilized pharmaceutical composition according to claim 1 and 2, wherein an alkalizing agent is hydroxymethyl methylamine.
5. The process and the stabilized pharmaceutical composition according to claim 1 and 2, wherein a film-forming polymer is hydroxypropyl cellulose.
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6. The process and the stabilized pharmaceutical composition according to claim 1 and 2, wherein an acidic substance is citric acid.
7. The process and the stabilized pharmaceutical composition according to claim 1 and 2, wherein pharmaceutical^ acceptable excipients include a filler, binder, glidant, lubricant, a vehicle, plastisizer and the like.
8. A stabilized pharmaceutical composition according to claim 2, wherein the total impurity level is 0.49% after one of storage at 40°C temperature and 75% relative humidity.
Dated this 30th day of October, 2006
For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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