FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification [See Sections 10 and rule 13]
TITLE: SUSTAINED RELEASE DOSAGE FORM OF HMG-CoA REDUCTASE INHIBITORS
Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10th Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
The following specification describes the invention:

Field of Invention
The present invention relates to stable sustained release formulations comprising HMG CoA reductase inhibitors preferably fluvastatin or its pharmaceutically acceptable salts.
Background and Prior Art
Fluvastatin hydrochloride is a water soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*, S*-(E)]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3, 5-dihydroxy-6-heptenoic acid, monosodium salt.
Fluvastatin is a competitive inhibitor of HMG-CoA reductase, which is responsible of the conversion of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. These biochemical processes results in reduction of plasma cholesterol concentration.
Sustained release formulation avoids the frequent administration of the medicament while maintaining a uniform and constant release of the active pharmaceutical ingredient over an extended period of time.
Sustained release formulation of HMG-CoA reductase inhibitors are of more importance because the site of action of statins is liver and conventional rapid release formulation of statin have side effects associated with systemic delivery of the statins. EP0375156 describes the necessity of sustained release formulation of statin class of drugs to prevent the side effects associated with systemic entry of the statins.
US6242003 describes color stable sustained release tablet wherein the granules comprises fluvastatin and HPMC with the mean particle size of granules less than 200 microns; and the HPMC is present in an amount from 15 to 50 weight percent having upto 12 percent hydroxypropyl functionality. The fine granular size according to this invention reduces the mottling problem of the formulation.
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WO2000021525 claims use of non-ionic polymers like hydroxyethyl cellulose, hydroxypropyl cellulose and poly (ethylene oxide) along with HPMC to prepare the sustained release composition of statins.
WO2005097194 describes a sustained release formulation comprising a solid dispersant including the HMG-CoA reductase inhibitor, a solubilizing agent, and a stabilizing agent; a sustained release composite carrier; and a gel hydration accelerator.
US6531507 describes buffering substance or basifying substance in a finely distributed form obtained by co-crystallization and/or co-precipitation of HMG-CoA reductase inhibitor and the buffering substance or basifying substance.
WO2004010980 claims sustained release composition comprising HMG-CoA reductase inhibitor or a pharmaceutical acceptable salt thereof wherein the composition comprises an inner phase (internal) and an outer phase (external), wherein at least the outer phase comprises at least one matrix former. The stabilizer used in the formulation is magnesium aluminium metasilicate at about 1-15 weight % of the composition.
WO2003074034 claims medicament containing at least one active ingredient which lowers the cholesterol level in the blood, comprising a means for releasing the active ingredient wherein the active ingredient is released with at least two different release rates, with a first release rate in a first period and with a second release rate, which is higher than the first release rate, in a subsequent second period, where the second period starts 2 to 12 hours after administration of the medicament, and where the means for releasing does not exclusively comprise an enteric coating.
WO2005115380 claims a delayed burst release oral formulation for localized release of a statin in the gastrointestinal tract, comprising core of statin, its metabolite, ester or salt and at least one burst controlling agent; and an outer coating over the core, comprising a water insoluble hydrophobic carrier and a water insoluble hydrophilic particular matter, the water insoluble hydrophilic particulate matter allowing entry of liquid into said core.
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Fluvastatin exhibits photodegradation. The discoloration problem is further aggravated if HPMC is used which forms gel matrix by hydration leading to uneven mottled appearance. Lescol XL is marketed by Novartis comprising 80 mg of fluvastatin. To make the formulation color stable the manufacturer has reduced the mean granular size to less than 200 micron; used hydroxypropyl methyl cellulose at 15-50 weight percent of the weight of composition with hydroxypropyl content of upto 12%. Reducing the granule size involve tedious steps which makes the manufacturing process complex. So there is the need to prepare a formulation of HMG CoA reductase inhibitor, which is sustained release in nature and color stable on prolonged storage; and employ simple manufacturing process.
Objects of the Invention
The prime object of the present invention is to formulate a sustained release orally administrable solid dosage form comprising HMG CoA reductase inhibitor and pharmaceutically acceptable salt thereof.
Another object of the invention is to formulate sustained release solid oral dosage formulation of HMG-CoA reductase inhibitor, preferably fluvastatin or pharmaceutically acceptable salt thereof.
Sustained release formulation of fluvastatin or pharmaceutically acceptable salt thereof having effective plasma drug concentration over a prolonged period of time causing a sustained drug release is another object of the invention.
Still a further object of the invention is to formulate a sustained release solid oral dosage form of fluvastatin or its pharmaceutical acceptable salt which can be used by a patient once a day or twice a day, more preferably once a day.
It is a further object of this invention to provide a relatively simple process for the preparation of orally administrable sustained release solid oral formulation comprising fluvastatin or its pharmaceutically acceptable salt.
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Summary of the Invention
The inventors of the present invention have prepared a sustained release formulation of HMG-CoA reductase inhibitors preferably fluvastatin. This formulation is relatively free of discoloration problem upon prolonged storage. The sustained release formulation of the present invention is prepared by using polymers like sodium alginate, kollidon SR, HPMC and the likes. These polymers are either used alone or in combination. HPMC if used in the formulation of the present invention is preferably at an amount less than 15% of the weight of composition to avoid formation of hydrated gel pockets which may lead to discoloration. Sodium alginate when used alone or in combination with polymers other than HPMC or in combination with HPMC has surprisingly shown sustained release effect with color stability on prolonged storage in the present invention.
The solid oral dosage formulation of the present invention is prepared by technology known in the art. Protection from moisture is an important parameter in formulating a color stable dosage form. So the formulation of the present invention is formulated either by dry granulation method or slugging / compaction method or wet granulation method or direct compression method. The prepared tablet is then coated or formulated as tablet in tablet formulation or filled inside capsule. All the processes are carried out at low relative humidity atmosphere and the finished dosage form can finally be packed in triple laminated blister pack or HDPE container.
Detailed Description of the Invention
The sustained release formulation of the present invention comprises granules prepared by wet granulation or dry granulation method, or pellets prepared by extrusion and spheronization method. The granules or pellets are optionally coated and then compressed into tablet or filled inside the capsule. Tablets prepared by dry granulation or slugging / compaction or wet granulation or direct compression methods are either coated or formulated as tablet in tablet formulation or as core mini tablets filled capsule formulation.
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The active pharmaceutical ingredient of the present invention is an HMG-CoA reductase inhibitors like lovastatin, atorvastatin, simvastatin, pravastatin, rosuvastatin and fluvastatin. The preferred active ingredient is fluvastatin. The active pharmaceutical ingredient is present in an amount from 15 to 30 % of the weight of the composition.
The stabilizing agent used in the formulation is selected from alkali or alkaline earth metal salts like carbonates, bicarbonates, oxides, hydroxides, silicates, aluminates and salt of glycine and the likes. These are used either alone or in combination. The preferred stabilizing agent is calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium silicate, and magnesium aluminate or aluminium magnesium hydroxide. The stabilizing agent is present in an amount from 0.5 to 10 % of the weight of the composition.
The polymer to impart sustained release effect in the formulation of the present invention is hydroxylpropyl methyl cellulose, kollidon SR, sodium alginate and the likes. These polymers may also be used in combination with other polymers like ethyl cellulose, carboxy methyl cellulose sodium, copolymer of polyvinyl acetates and wax and the likes. HPMC used in the formulation is of various grades like METHOCEL K 100 LV, K4MCR, and K15MCR. The amount of HPMC in the present invention is between 0.5 to 15 % of the weight of the composition more preferably less than 15% of the weight of the composition.
Binder can be selected from the group comprising of but not limited to polyvinylpyrollidone, starch, modified starch, methyl cellulose, ethyl cellulose, polyethylene glycol, polyvinyl alcohol, hydroxypropyl cellulose and the likes. Binder is present in amount from 0.5 to 15 % of the weight of the composition.
Diluent can be selected from the group comprising of but not limited to lactose, sucrose, mannitol, sorbitol, inositol, kaolin, starch, bentonite, microcrystalline cellulose, calcium phosphates, calcium sulfate and the likes. It is present in amount from 10 to 80 % of the weight of the composition.
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Lubricant can be selected from the group comprising of but not limited to magnesium stearate, stearic acid, talc, calcium stearate, sodium stearyl fumerate and the likes. The amount of lubricant is 0.1 to 5 % of the weight of the composition.
Film coating solution comprises of known colours like readymade opadry yellow, or transparent coating solution comprising of hydroxy propyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrollidone, poly ethylene glycol or methacrylic acid copolymer type-A, type-B, and type-C, polyvinyl acetate phthalate, hydroxylpropyl methyl cellulose phthalate, and the likes.
Process for preparation of the dosage form:
In the present invention the granules are prepared either by dry granulation method or compaction method or wet granulation method and the pellets are prepared by extrusion and speronization process. These granules and pellets are optionally coated and compressed to form core tablet or are filled inside the capsule. The core tablet is either coated or formulated into tablet in tablet preparation or the mini core tablets are filled inside capsule at low relative humidity atmosphere. The tablet in tablet formulation can optionally be coated with suitable coating solution.
The process of preparation is summarized as below:
A. Preparation of Core tablet: It involves the following steps:-
1. Active pharmaceutical ingredient, alkalizing agent, diluent, binders and release controlling polymer either alone or in combination with other polymers are dry mixed to get a uniform blend.
2. The blend is wet granulated by the granulating agent like purified water.
3. The prepared granules are dried, lubricated and then compressed to form core tablet.
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OR
3. The uniform dry blend of step 1 is lubricated and compressed to form the core tablet.
4. The core tablet as per step 3 is formulated as tablet in tablet form by employing process known to person skilled in the art.
OR
4. Optionally the core tablet prepared in step 3 is film coated with transparent coating solution or colour coating solution.
The tablet in tablet formulation may optionally be coated by transparent coating or color coating solution comprising known colours.
The transparent coating solution comprises hydroxy propyl ethyl cellulose, polyvinyl alcohol, polyvinyl pyrollidone or poly ethylene glycol and the colour coating solution comprises of known colours.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of the appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.
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The above said invention can be illustrated by but not limited to following example(s):
Exam pie-1
Core tablet comprising sodium alginate as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Sodium Alginate 12.00
8 Purified water Qs
9 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6 and 7 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 9 and finally compressed to form the core tablet.
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Example-2
Core tablet comprising mixture of sodium alginate, carboxy methyl cellulose sodium and ethyl cellulose as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Sodium Alginate 4.00
8 Carboxy methyl cellulose Sodium 4.00
9 ethyl cellulose 4.00
10 Purified water Qs
11 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6, 7 8 and 9 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 11 and finally compressed to form the core tablet.
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Example-3
Core tablet comprising mixture of sodium alginate and hydroxyl propyl methyl cellulose as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Sodium Alginate 6.00
8 Hydroxyl propyl methyl cellulose K 100 LV 6.00
9 Purified water Qs
10 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6, 7 and 8 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 10 and finally compressed to form the core tablet.
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Example-4
Core tablet comprising mixture of carboxy methyl cellulose Sodium and hydroxyl propyl methyl cellulose as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Carboxy methyl cellulose Sodium 6.00
8 Hydroxyl propyl methyl cellulose K 100 LV 6.00
9 Purified water Qs
10 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6, 7 and 8 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 10 and finally compressed to form the core tablet.
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Example-5
Core tablet comprising hydroxy propyl methyl cellulose K 4 MCR as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Hydroxyl propyl methyl cellulose K4MCR 12.00
8 Purified water Qs
9 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6 and 7 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 9 and finally compressed to form the core tablet.
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Example-6
Core tablet comprising combination of different grades of hydroxy propyl methyl cellulose as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Hydroxyl propyl methyl cellulose K 4 MCR 8.00
8 Hydroxyl propyl methyl cellulose K15MCR 4.00
9 Purified water Qs
10 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6, 7 and 8 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 10 and finally compressed to form the core tablet.
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ExampIe-7
Core tablet comprising combination of Ethyl cellulose and hydroxy propyl methyl cellulose as SR polymer:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 16.85
2 Potassium Bicarbonate 2.60
3 Calcium Carbonate 5.20
4 Microcrystalline cellulose 57.90
5 Povidone 1.50
6 Klucel HXF 3.25
7 Ethyl cellulose 6.00
8 Hydroxyl propyl methyl cellulose K 4 MCR 6.00
9 Purified water Qs
10 Magnesium Stearate 0.70
The ingredients 1, 2, 3, 4, 5, 6, 7 and 8 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 10 and finally compressed to form the core tablet.
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Example-8
Core tablet comprising hydroxy propyl methyl cellulose K 100 LV as SR polymer using wet granulation method:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 25.92
2 Potassium Bicarbonate 2.59
3 Microcrystalline cellulose 34.23
4 Povidone 1.50
5 Klucel HXF 5.00
6 Methocel K 100 LV 30.00
7 Purified water Qs
8 Magnesium Stearate 0.75
The ingredients 1, 2, 3, 4, 5 and 6 are dry mixed to get a uniform blend. The blend is wet granulated with purified water. The granules are then dried and lubricated with ingredient 8 and finally compressed to form the core tablet.
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Example-9
Core tablet comprising hydroxy propyl methyl cellulose K 100 LV as SR polymer using dry granulation method:

Sr. No. Ingredients %of formulation
1 Fluvastatin Sodium 25.92
2 Potassium Bicarbonate 2.59
3 Microcrystalline cellulose 34.23
4 Povidone 1.50
5 Klucel HXF 5.00
6 Methocel K 100 LV 30.00
7 Magnesium Stearate 0.75
The ingredients 1, 2, 3, 4, 5 and 6 are dry mixed to get a uniform blend. The blend is then lubricated with ingredient 7 and finally compressed to form the core tablet.
Example-10
Composition of Outer tablet to prepare the tablet in tablet formulation

Sr. No. Ingredients % range
1 Microcrystalline cellulose 101 10-90
2 Povidone 0.5-15
3 Croscarmellose Sodium 0.1-15
4 Magnesium Stearate 0.1-5
The core tablets prepared as per the examples 1 -9 can be formulated as tablet in tablet composition with the outer tablet blend preparation of example-10 employing process known to person skilled in the art.
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The tablet in tablet formulation prepared may be coated by suitable coating solution comprising of opadry yellow or transparent coating solution of example-11.
The core tablet prepared may also directly be coated by the opadry yellow solution or, the transparent coating solution of example-11.
Example-11
Film coating solution

Sr. No. Ingredients % Range
1 Hydroxy propyl methyl cellulose 10-95
2 Poly ethylene glycol 400 1-15
Dated this 26 th day of October 2006.

Signature:
Ketana Laljibhai Babaria For and on behalf of the applicant
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We hereby assent to the action already taken by the said person in the above matter.
Dated this 26tn day of October, 2006.
Signature:________________
Name: Jayanta Kumar Mandal Director Astron Research Limited
To,
The Controller of patent The Patent Office at Mumbai