FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL PATENT SPECIFICATION
[See section 10; rule 13]
TITLE "MODIFIED RELEASE DOSAGE FORM OF FLUVASTATIN SODIUM"
TORRENT PHARMACEUTICALS LTD., a company incorporated under the Companies Act, 1956, of Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India
23 JAN 2004

The following specification particularly describes the invention, the nature of this invention (and the manner in which it is to be performed):


MODIFIED RELEASE DOSAGE FORM OF FLUVASTATIN SODIUM
FIELD OF INVENTION
This invention relates to a modified release dosage form comprising highly soluble salt of pharmaceutical active ingredient e.g. HMG-CoA reductase inhibitor such as fluvastatin, which utilizes dual retard technique; a process for preparing the dosage form. Also the active ingredient can be low solubility active ingredient.
BACKGROUND OF THE INVENTION
The statins are used to reduce blood cholesterol levels in patients in need of such treatment. The site of action of the statins is liver. Lovastatin, pravstatin, simvastatin, mevastatin, atrovastatin, fluvastatin and cervastatin derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and used as anti-hypercholesterolemic agents.
The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to aspergillus, monascus, nocardia amycolatopsis, Mucor or Penicillium genus. Some are obtained by treating the fermentation products using the methods of chemical synthesis like simvastatin or they are the products of total chemical synthesis like fluvastatin, atrovastatin and cervastatin.
Fluvastatin sodium 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 a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol and its chemical name is [R, S - (E)]-(±) 7- [3-(4-fluorophenyl)-1-(1-methylethylO-lH-indol-2-yl]-3,5-dihydroxy-6-heptonic acid, monosodium salt. The empirical formula is C24H25FNO4 .Na, its molecular weight is 433.46.
Fluvastatin is a competitive inhibitor of HMG-CoA reductase, which is responsible for 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 there by increases the

uptake of LDL particles. The end result of these biochemical processes is reduction of the plasma cholesterol concentration.
Conventional rapid release forms of statins e.g. which release the statin within about 2 hours have mild side effects associated with systemic delivery of the statin. The statins appear to enter systemic circulation because of the relatively high concentration of statin entering the liver in a relatively short time tends to flood the liver such that some of the statin is not metabolized on the first pass.
Sustained release formulations have been suggested in patent EP 0375156 as a means of preventing or ameliorating the side effects associated with systematic entry of the statins- lovastatin, simvastatin and pravastatin.
There are a number of different modified release dosage forms available commercially. Many of these modified delivery systems utilize hydrophilic, polymeric matrices that provide useful levels of control to the delivery of sparingly soluble drugs. For soluble drugs, however, and particularly for highly soluble drugs, such matrices do not provide adequate control over the release rate, instead resulting in a release that approximates first-order kinetics and may have a problem of dose dumping or burst release.
The various techniques to make modified release dosage form of drugs as described in prior art are as follows-
Use certain excipients in matrix, which modify the release of an active agent dispersed within said matrix. Hydroxypropyl methyl cellulose (HPMC) polymers have been suggested as release-modifying excipients, either alone or in combination with other materials, in sustained release formulations for use with a wide variety of active agents including the HMG-CoA reductase inhibitors, see for example US patent 4369172, 4357469, 4226849, 4389393 and WO 02/28181 Al.
EP 0948 320 Bl discloses sustained release tablet formulations of HMG-CoA reductase inhibitors said composition selected from the group consisting of matrix formulations, diffusion-controlled membrane coated formulations and combinations thereof. The eroding and non-eroding matrix formulations can be based on hydrophilic and/or hydrophobic matrix forming excipients. The matrix and membrane coated formulations may be monolithic, such as tablets, or in the form of multiple units administered in a

tablet, capsule or sachets. The matrix material is selected from the group consisting of polyethylene oxide, hydroxypropyl methyl cellulose, xanthane, polyvinyl chloride and paraffin. The material for film formation is selected from the group consisting of ethyl cellulose, hydroxypropylmethyl cellulose and hydorxypropyl cellulose.
US patent 6242003 and 6432447 B2 disclose oral dosage form comprising fluvastatin and hydroxypropylmethyl cellulose, which is oral dosage form is color-stable upon prolonged periods of storage.
WO 00/21525 discloses pharmaceutical composition containing a pharmaceutically active agent, hydroxypropyl methyl cellulose and a non-ionic, hydrophilic polymer selected from the group consisting of hydroxyethyl cellulose having a number average molecular weight ranging from 90,000 to 1,300,000, hydroxypropyl cellulose having a number average molecular weight of 370,000 to 1,500,000 and poly (ethylene oxide) having a number average molecular weight ranging from 100,000 to 500,000
U.S.Patent 5,356,896 discloses fluvastatin sodium is stabilized against pH-related degradation by an alkaline stabilizing medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition.
WO 01/78680 discloses Pharmaceutical compositions comprising Fluvastatin, HPMC and optionally other pharmaceutical excipients, which are, colour stable upon prolonged periods of storage.
Another method of prolonging the release of a highly water-soluble drug is disclosed PCT Patent application no. W099/47128. A biphasic controlled release delivery system for metformin hydrochloride, which has prolonged gastric residence and that swells following hydration. The cited example teaches use of combination of at least one hydrophilic polymer and which is an essential part for swelling. Non swellable or nonerodeble formulations are not included in the invention.
Similarly US patent no. 6340475 B2 assigned to Depomed Inc. describes monolithic controlled release formulation of highly water soluble drugs. The formulation swells when ingested thus prolongs its residence time in the stomach. The formulations are made of hydrophilic polymers, which result in swellable and erodible matrix.
Kim et al. In United States patent number 6337091 describes a matrix based controlled release formulation for highly

soluble drugs over long periods of time. The release controlling agent is a swellable gum which encapsulates or make granules of drug, which is then disposed in more swellable erodible polymers such as HPMC or poly(ethylene oxide).
Whilst these systems can provide for modified release for selected active ingredients like active ingredients with low dose or low water solubility. When a highly soluble active ingredient is used, most of these systems have the disadvantages such as comparatively low payload of active ingredient thus making dosage form bulky and expensive or use of complex manufacturing procedure and/or equipment.
There exists a need for compositions and process for making orally deliverable dosage form of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin as modified release that overcomes the problems discussed above. This invention addresses the need.
Therefore, it would be of considerable commercial benefit to design a dosage form with high pay load of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin.
Therefore an objective of the present invention is to develop a modified release dosage form of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin.
Accordingly, an object of the present invention is to have a dosage form, which uses dual retard technique to control the release of the highly soluble salt of HMG-CoA reductase inhibitor fluvastatin and significantly reduce the amount of release controlling agents which are otherwise required in very high quantity.
Another objective of the present invention is to have also a dosage form, which uses dual retard technique to control the release of the highly soluble active ingredients with dose less then 100 mg and significantly reduce the amount of release controlling agents, which are otherwise required in very high quantity.
A further objective of the present invention is to have a dosage form, which gives accurate dosing and is prepared by conventional and simple processes.
A further objective of the present invention is to have a dosage form, which can be given twice a day or more preferably can be given once a day.

BRIEF DESCRIPTION OF THE INVENTION
This invention relates to a modified release dosage form comprising highly soluble salt of pharmaceutical active ingredient e.g. HMG-CoA reductase inhibitor such as fluvastatin, which utilizes dual retard technique; a process for preparing the dosage form. Also the active ingredient can be low solubility active ingredient.
The above objects are realized by a dosage form, which comprises of a) Micro matrix particles containing highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, one or more hydrophobic release controlling agent and optionally one or more commonly used pharmaceutically excipients , b) Coating of Micro matrix particles with one or more hydrophobic release controlling agents, c) Blending of coated micro matrix particles with one or more pharmaceutically acceptable lubricants and d) Compression of lubricated blend into tablet. The tablets so obtained can optionally be coated with pharmaceutically acceptable fast dissolving film forming agents.
The present invention also teaches the use of dual retard technique to effectively control the release rate of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin by using small quantity of release controlling agents. This dual retard technique thus sufficiently reduces the size of the dosage form, which is convenient for swallowing.
The present invention also provides a novel process for preparing the novel formulations of the invention.
The present invention further provides a method of treating an mammal, particularly a human in need of treatment utilizing highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, comprising administering a therapeutically effective amount of composition or solid oral dosage form according to the invention to provide administration of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin.
The present invention also teaches to use dual retard technique for highly soluble active ingredients with dose less then 100 mg.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a modified release dosage form comprising of a highly soluble salt of HMG-CoA reductase inhibitor fluvastatin prepared by using dual retard technique to control the release of the highly soluble salt

of HMG-CoA reductase inhibitor fluvastatin and to increase the payload.
The terra "modified release" as used herein in relation to the composition according to the invention or a rate controlling polymer or used in any other context means release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release. The term "modified release dosage form" as used herein can be described as dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products (as per US FDA guideline for 'SUPAC-MR: Modified Release Solid Oral Dosage Forms').
The term "dosage form" denotes any form of the formulation that contains an amount sufficient to achieve a therapeutic effect with a single administration.
The term "high solubility" as used herein in relation to active agent means that from less than 1 part to 3 0 parts of the water will require dissolving 1 part of highly soluble salt of HMG-CoA reductase inhibitor for example fluvastatin.
The term "low solubility" as used herein relation to modified release means that more than 30 parts of solvent is required to dissolve 1 part of active ingredient.
The term "active ingredient" refers to an agent, active ingredient compound or other substance, or compositions and mixture thereof that provide some pharmacological, often beneficial, effect. Reference to a specific active ingredient shall include where appropriate the active ingredient and it's pharmaceutically acceptable salts.
The active ingredient can be selected from the group comprises of the following therapeutic classes but not limited to antidiabetics, anti-histamines, anti¬depressants, anti-viral agents, anesthetics, antacids, anti-arthritis, antibiotics, anti-psychotics, anti¬spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, respiratory stimulants, vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics, anti-cholesterolemics, anti¬convulsants, anti-depressants, anti-diarrhea preparations,

anti-infective, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants, cerebral dilators, chelating agents, cholecystokinin antagonists, cognition activators, deodorants, dermatological agents, diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal preparations, vaso-constrictors, vertigo agents, biguanides, sulphonylurease, meglitinides, PPAR gama agonist [insulin sensitisers (thiazolidinedione)], alpha-glucosidase inhibitors
The high solubility active ingredients with dosage less than 100 mg. are comprises of the following therapeutic classes but not limited to antidiabetics, anti-histamines, anti-depressants, anti-viral agents, anesthetics, antacids, anti-arthritis, antibiotics, anti-psychotics, anti¬spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, respiratory stimulants, vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics, anti-cholesterolemics, anti¬convulsants, anti-depressants, anti-diarrhea preparations, anti-infective, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants, cerebral dilators, chelating agents, cholecystokinin antagonists, cognition activators, deodorants, dermatological agents, diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal preparations, vaso-constrictors, vertigo agents, biguanides, sulphonylurease, meglitinides, PPAR gama agonist [insulin sensitisers (thiazolidinedione)], alpha-glucosidase inhibitors.
The invention provides a novel modified release dosage form of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, which utilizes dual retard technique to effectively reduce the quantity of release controlling agents; a process for preparing the dosage form.
The dosage form comprises of a) Micro matrix particles containing highly soluble salt of HMG-CoA reductase

inhibitor fluvastatin, one or more hydrophobic release controlling agent and optionally one or more commonly used pharmaceutically excipients, b) Coating of Micro matrix particles with one or more hydrophobic release controlling agents, c) Blending of coated micro matrix particles with one or more pharmaceutically acceptable lubricants and d) Compression of lubricated blend into tablet. The tablets so obtained can optionally be coated with pharmaceutically acceptable fast dissolving film forming agents. The release of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin is controlled through dual retard technique. The dual retard technique is a combination of matrix formulations and reservoir formulations. First the micro matrix particles of highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, one or more commonly used pharmaceutically excipients and one or more hydrophobic release controlling agents are formed and then these are further coated with one or more hydrophobic release controlling agents. Thus the dual retard release technique presents the double barriers and effectively controls the release of the highly soluble salt of HMG-CoA reductase inhibitor fluvastatin from the present invention in predictable manner and also significantly reduces the amount of release controlling agents which are otherwise required in very high quantity and make the dosage form very bulky. The other advantages of the present invention are such as it reduces the chances of dose dumping, unnecessary burst effects and failure of the system.
The highly soluble salt of HMG-CoA reductase inhibitor
fluvastatin can be present in the form of pharmaceutically
acceptable salts. Pharmaceutically acceptable salts forming
part of this invention are intended to define but not
limited to salts of the carboxylic acid moiety such as
alkali metal salts like Li, Na and K salts; alkaline earth
metal salts like Ca and Mg salts; salts of organic bases
such as lysine, arginine, guanidine, diethanolamine,
choline, and the like; ammonium or substituted ammonium
salts and aluminum salts. Salts may be acid addition
salts which defines but not limited to sulfates, nitrates,
phosphates, perchlorates, borates, hydrohalides, acetates,
tartrates, maleates, citrates, succinates, palmoates,
methanesulfonates, benzoates, salicylates,
hydroxynaphthoates, benzensulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
Further, highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, may be present either in the form of one

substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof.
As indicated above the present invention may comprise pharmaceutically acceptable excipients such as lubricants, diluents, fast dissolving film forming agents and such like. As will be appreciated by those skilled in the art, the exact choice of excipient and their relative amounts will depend to some extent on the final oral dosage form.
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, Mannitol and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as those sold under the Trade Mark Avicel PH 101, Avicel PH 102, Avicel PH 112, Avicel PH 200, Avicel PH301 and Avicel PH 3 02; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose DCL21 (Pharmatose is a Trade Mark), including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress (Emcompress is a Trade Mark); mannitol; Pearlitol SD 200 (Pearlitol SD 200 is a trade mark); starch; sorbitol; sucrose; and glucose.
Suitable binders include for example starch, povidone, hydroxypropylmethylcellulose, pregelatinised starch, hydroxypropylcellulose and/or mixtures of the foregoing.
Suitable fast dissolving film forming agents include for example hydroxypropylmethylcellulose, povidone, hydroxypropylcellulose and/or mixtures of the foregoing.
Suitable lubricants, including agents that act on the flowability of the powder to be compressed are, for example, colloidal slilcon dioxide; talc; stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate.
In micro matrix particles, highly soluble salt of HMG-CoA reductase inhibitor fluvastatin and one or more hydrophobic release controlling agents are preferably present in a ratio of from 100:1 to 100:75.
Micro matrix particles and coating of one or more hydrophobic release controlling agents are preferably present in a ratio of from 100:0.5 to 100:75.According to one embodiment the release controlling agents are pharmaceutically excipients, which are hydrophobic in nature.

The polymers that can be used to form the rate-control ling membrane or micromatrix are described in greater detail herein below.
The hydrophobic release controlling agents are selected from but are not limited to Ammonio methacrylate copolymers type A and B as described in USP, methacrylic acid copolymer type A, B and C as described in USP, Polyacrylate dispersion 30% as described in Ph. Eur., Polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly (hexyl methacrylate) . Poly(isodecyl methacrylate) , poly (lauryl methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl actylate), poly (octadecyl acrylate), waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil.
According to an especially preferred embodiment the release controlling agents contains ammonio methacrylate co¬polymers and fatty acid esters as hereinafter described.
The suitable hydrophobic agents are polymers sold under the Trade Mark Eudragit RS (Ammonio Methacrylate Copolymer type B USP),Eudragit NE 30D (Polyacrylate dispersion 30% Ph., Eur.), Eudragit RL (Ammonio Methacrylate Copolymer type A USP) and Kollicoat SR 30 D and fatty acid esters such as glyceryl behenate, and hydrogenated castor oil. Eudragit polymers are polymeric lacquer substances based on acrylate and/or methacrylates.
The dosage form can also include a material that improves the processing of the release controlling agents. Such materials are generally referred to as "plasticisers" and include, for example, adipates, azelates, benzoates, citrates, isoebucaes, phthalates, sebacates, stearates, tartrates, polyhydric alcohols and glycols.
Representative plasticisers include acetylated monoglycerides; butyl phthalyl butyl gylcolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate,; ethyl

phthalyl ethyl glycolate; glycerin; ethylene glycol, propylene glycol; Triethyl citrate; triacetin; tripropinoin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylexyl phthalate, di-n-octyl phthalate, di-I-octyl phthalate, di-I-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylexyl trimellitate, di-2-ethylexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate, glycerol distearate and glyceryl monocaprate.
The amount of plasticiser to be used is from about 1% to 50%based on the weight of the dry release controlling agent(s).
The amount of release controlling agent(s) to be used in forming the outer portion will be determined based on various parameters such as the desired delivery properties, including the amount of active ingredient to be delivered, the active ingredient release rate desired, and the size of the micro matrix particles.
The novel modified release dosage form of the present invention can be manufactured by the following procedure: The micro matrix particles can be manufactured in accordance with usual techniques in which highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, one or more hydrophobic release controlling agent and optionally one or more commonly used pharmaceutically excipients are mixed and granulated by adding solvent in a low or high shear mixer or by fluidized bed granulator. The granulate is dried, preferably in a fluidized bed dryer. The dried granulate is sized. The sizing of the micromatrix particles can be done using oscillating granulator, comminuting mill or any other conventional method. The sieve used for the sizing can have openings from 0.25 mm to 5 mm. Alternatively the micro matrix particles can be made by extrusion, spheronization or by roller compaction. The micro matrix particles can be coated by a solution of one or more hydrophobic release controlling agents by any known method, including spray application. Spraying can be carried out using a fluidized bed coated (preferably Wurster coating), or in a pan coating system. Alternatively the coating of the micro matrix particles with one or more

rate controlling agents can be done by hot melt process using a granulator or fluidized bed coated (preferably Wurster coating), or in a pan coating system. The coated micromatrix particles are blended with lubricants in equipments like cone blenders, drum blenders, V-blenders etc. The compression of tablets is carried out on usual compression machines (e.g. machines of the Manesty, Cadmach or Kilian) . The tablets can be made of various sizes and shapes. The tablets can optionally be film coated using conventional coating machines or perforated coating pan machines or in fluid bed processors.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 (a) is a cross section of coated micro matrix particles prepared by spheronization and coating for the purpose of illustration only.
FIG. 1 (b) is a cross section of coated micro matrix particles prepared by granulation and coating for the purpose of illustration only.
FIG. 1 (a) and 1(b) show the cross section of the coated micro matrix particles 1 as described in the present invention and having 2 a high solubility active ingredient, 3 hydrophobic release controlling agent and 4 a coating of hydrophobic release controlling agent.
DIFFERENT MODES FOR PRACTICING THE INVENTION
The following examples further illustrate but by no means limit the present invention. The following examples can be carried out.
EXAMPLES
EXAMPLE 1
A) Micro matrix particles- 40 %w/w of fluvastatin or other
active ingredient referred above is mixed with 10 %w/w of
Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and
50% w/w lactose monohydrate. The mixture is granulated with
a solvent mixture of acetone and methylene chloride and
then dried. The granules are sized.
B) Coating of Micro matrix particles- 85 %w/w of micro
matrix particles is charged in fluidized bed processor. 15
%w/w of hydrogenated castor oil is dissolved in Methylene

chloride and this coating solution is sprayed to coat the micro matrix particles. The coated micro matrix particles are sieved.
C) Blending with lubricant- 99 % w/w coated micro matrix particles are mixed with 1 %w/w magnesium stearate.
D) Compression of tablets- Lubricated granules are pressed to tablet (equivalent to 80 mg fluvastatin) using suitable punches.
EXAMPLE 2
A) Micro matrix particles- 70 %w/w of fluvastatin or other
active ingredient referred above is mixed with 10 %w/w of
Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and
20% w/w mannitol. The mixture is granulated with a solvent
mixture of acetone and methylene chloride and then dried.
The granules are sized.
B) Coating of Micro matrix particles- 90 %w/w of micro matrix particles is charged in fluidized bed processor. 10 %w/w of hydrogenated castor oil is dissolved in Methylene chloride and this coating solution is sprayed to coat the micro matrix particles. The coated micro matrix particles are sieved.
C) Blending with lubricant- 99 % w/w coated micro matrix particles are mixed with 1 %w/w magnesium stearate.
D) Compression of tablets- Lubricated granules are pressed to tablet (equivalent to 80 mg fluvastatin) using suitable punches.

What is claimed is:
1. A modified release dosage form comprising of highly-soluble salt of HMG-CoA reductase inhibitor fluvastatin prepared by using dual retard technique to control the release of the highly soluble salt of HMG-CoA reductase inhibitor fluvastatin.
2. A dosage form according to claim 1, the dosage form comprises 1) micro matrix particles and 2) coating on micro matrix particles.
3. A dosage form according to claim 2, the micro matrix particles comprises one or more hydrophobic release controlling agents and optionally one or more pharmaceutically acceptable excipients.
4. A dosage form according to claim 3, the hydrophobic release controlling agents are selected from ammonio methacrylate co-polymers, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate.
5. A dosage form according to claim 4, the hydrophobic release controlling agents are selected from ammonio methacrylate co-polymers.
6. A dosage form according to claim 5, the hydrophobic release controlling agents are Eudragit RS (Ammonio Methacrylate Copolymer type B USP), Eudragit RL
(Ammonio Methacrylate Copolymer type A USP) and Eudragit NE3 0D (Polyacrylate dispersion 3 0% Ph. Eur.).
7. A dosage form according to claim 2, in micro matrix particles, highly soluble salt of HMG-CoA reductase inhibitor fluvastatin and one or more hydrophobic release controlling agents are preferably present in a ratio of from 100:1 to 100:75.
8. A dosage form according to claim 2, coating of micro matrix particles comprises one or more hydrophobic release controlling agents.

A dosage form according to claim 8, the hydrophobic release controlling agents are selected from waxes, fatty alcohols and fatty acid esters.
A dosage form according to claim 9, the hydrophobic release controlling agents is selected from fatty acid esters.
A dosage form according to claim 10, the hydrophobic release controlling agents are hydrogenated castor oil and glycerol distearase.
A dosage form according to claim 2, micro matrix particles and coating of one or more hydrophobic release controlling agents are preferably present in a ratio of from 100:0.5 to 100:75.
A dosage form according to claim 1, wherein the tablets are coated with fast dissolving film coating.
A process for the preparation of a modified release dosage form comprising of a highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, substantially as herein described, particularly with respect to examples.
A modified release dosage form comprising of a highly soluble salt of HMG-CoA reductase inhibitor fluvastatin, substantially as herein described, particularly with respect to examples.
For TORRENT PHARMACEUTICALS LIMITED Dr. Umesh Rewaji Zope Head - Patent Cell