FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)


COMPLETE SPECIFICATION
(SECTION 10)
PHARMACEUTICAL COMPOSITION USING MICRONIZED
EPLERENONE"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
Glenmark Pharmaceuticals Limited, Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East),
Mumbai - 400 099, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION: AND THE MANNER IN,
WHICH IT IS TO BE PERFORME
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PHARMACEUTICAL COMPOSITION USING MICRONIZED EPLERENONE
PRIORITY
This application claims the benefit under provisional application filed on July 29, 2005 and complete specification filed for the same invention which is converted into a provisional application on 29th July, 20O6. This complete specification is merging these two applications.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to a pharmaceutical composition containing at least
micronized particles of one or more aldosterone antagonists and a process for its
preparation.
2. Description of the Related Art
Aldosterone antagonists are known to be useful in treatment of hypertension and associated cardiac disease or insufficiency. For example, the compound methyl hydrogen 9,11 a-epoxy-17a-hydroxy-3-oxopregn-4-ene-7a, 21 -dicarboxyl ate, y-lactone (referred to herein as eplerenone) was first reported in U.S. Patent No. 4,559,332 ("the '332 patent") which discloses a class of 9,11-epoxy steroid compounds and their salts together with processes for the preparation of such compounds. Eplerenone is an aldosterone receptor antagonist that can be administered in a therapeutically effective amount where use of an aldosterone receptor antagonist is indicated for treatment of, for example, pathological conditions associated with hyperaldosteronism such as hypertension, heart failure including cardiac insufficiency and cirrhosis of the liver. The '332 patent further discloses formulations such as tablets and capsules for oral administration of the 9,11-epoxy steroid compounds including eplerenone.
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Eplerenone can be represented by the structure of Formula I
o

Eplerenone is marketed under the tradename Inspra . Inspra is indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction less than or equal to 40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. Inspra® is also indicated for the treatment of hypertension. See, e.g., Physician's Desk Reference, "Inspra", 60th Edition, pp. 2520-2524 (2005).
Spironolactone, also known as (7a,17a)-7-(acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid y-lactone, a 20-spiroxane steroid compound having activity as an aldosterone receptor antagonist and can be represented by the structure of Formula II.

Spironolactone is marketed under the tradename Aldactone®. Spironolactone, however, exhibits antiandrogenic activity that can result in gynecomastia and impotenance in men, and weak progestational activity that produces menstrual irregularities in women. Commercial formulations sold under the name Aldactone® provide 25, 50 and 100 mg unit doses of spironolactone. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1562, monograph 8839.
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WO 00/33847 discloses pharmaceutical compositions useful as aldosterone receptor blockers containing micronized eplerenone as the active ingredient in a daily dosage amount of about 10 mg to about 1000 mg. WO 00/33847 further discloses the micronized eplerenone having a D90 particle size of 25 to 400 microns. Problems associated with the use of such micronized particles of eplerenone include poor dissolution and erratic bioavailability.
WO 01/41770 discloses pharmaceutical composition using eplerenone particles wherein 90% of the particles are smaller than about 15 microns.
It would be desirable to provide alternative pharmaceutical compositions containing micronized particles of one or more aldosterone antagonists such as micronized eplerenone that eliminate and reduce the drawbacks of the prior art in a convenient and cost efficient manner for efficient, commercial scale production.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, aldosterone antagonist particles having a D90 particle size of less than 25 microns and greater than 15 microns is provided.
In accordance with a second embodiment of the present invention, aldosterone antagonist particles having a D90 particle size of less than about 20 microns and greater than 15 microns is provided.
In accordance with a third embodiment of the present invention, eplerenone particles having a D% particle size of less than 25 microns and greater than 15 microns is provided.
In accordance with a fourth embodiment of the present invention, eplerenone particles having a D90 particle size of less than about 20 microns and greater than 15 microns is provided.
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In accordance with a fifth embodiment of the present invention, a pharmaceutical composition is provided comprising aldosterone antagonist particles having a D90 particle size of less than 25 microns and greater than 15 microns.
In accordance with a sixth embodiment of the present invention, a pharmaceutical composition is provided comprising aldosterone antagonist particles having a D90 particle size of less than about 20 microns and greater than 15 microns.
In accordance with a seventh embodiment of the present invention, a pharmaceutical composition having improved solubility is provided comprising epierenone particles having a D90 particle size of less than 25 microns and greater than 15 microns.
In accordance with an eighth embodiment of the present invention, a pharmaceutical composition having improved' solubility is provided comprising epierenone particles having a D90 particle size of less than about 20 microns and greater than 15 microns.
In accordance with a ninth embodiment of the present invention, a tablet dosage form is provided comprising aldosterone antagonist particles having a D90 particle size of less than 25 microns and greater than 15 microns.
In accordance with a tenth embodiment of the present invention, a tablet dosage form is provided comprising aldosterone antagonist particles having a D90 particle size of less than about 20 microns and greater than 15 microns.
In accordance with an eleventh embodiment of the present invention, a tablet dosage form is provided comprising epierenone particles having a D$0 particle size of less than 25 microns and greater than 15 microns.
In accordance with a twelfth embodiment of the present invention, a tablet dosage form is provided comprising epierenone particles having a D90 particle size of less than about 20 microns and greater than 15 microns.
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In accordance with a thirteenth embodiment of the present invention, a pharmaceutical composition is provided comprising eplerenone particles having a D90 particle size of less than 25 microns and greater than 15 microns, wherein the dissolution profile includes releasing about 25 to about 40% of the eplerenone in 5 minutes, about 60 to about 85% of the eplerenone in 10 minutes and about 90% of the eplerenone in 30 minutes as determined using USP Apparatus II at 50 rpm in 1000 ml of 0.1N HC1 medium at 37°C.
In accordance with a fourteenth embodiment of the present invention, a therapeutic method is provided comprising administering aldosterone antagonist particles having a D90 particle size of less than 25 microns and greater than 15 microns to a subject having an aldosterone-mediated condition or disorder.
The use of a smaller particle size of an aldosterone antagonist such as eplerenone may result in an increase in the effective exposed surface to the dissolving media, aid in solubility and increase the bioavailability of the pharmaceutical dosage form. Furthermore, the aldosterone antagonist particles having a smaller aspect ratio can facilitate processing during the production of pharmaceutical dosage forms of an aldosterone antagonist such as eplerenone. Moreover, as an aldosterone antagonist such as eplerenone has poor solubility in water, and solubility is directly proportional to the surface area, by reducing the particle size of an aldosterone antagonist such as eplerenone, the solubilization of the active principle in a pharmaceutical dosage form can be improved, which in turn helps to improve the erratic bioavailability of eplerenone pharmaceutical solid dosage forms. Thus, it is believed that the compositions of the present invention can be a bioequivalent to Inspra®
DEFINITIONS
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
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The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
When needed, other binders may also be included in the present invention. Exemplary binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly(propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
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The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "glidant" as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "lubricant" as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "disintegrant" as used herein is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides),
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gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g.,
TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide,
phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethyl cellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy! propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.
Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to aldosterone antagonist particles having a D90 particle size of less than 25 microns and greater than 15 microns (see Figure 1) and their use in pharmaceutical compositions. In another embodiment, the present invention is directed to pharmaceutical compositions containing at least aldosterone antagonist particles having a D90 particle size of less than about 20 microns and greater than 15 microns. The term 'particle size" as used herein is an average diameter upon conversion of the volume of the particles into a sphere. The particle size of the aldosterone antagonist such as epierenone was measured using a Malvern I Mastersizer. The aldosterone antagonists for use herein can be any aldosterone antagonists include, but are not limited to, spironolactone, epierenone and the like with epierenone being preferred. The aldosterone antagonists such
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as spironolactone and eplerenone can be prepared by processes well known in the art. See, e.g., U.S. Patent Nos. 4,559,332 and 7,038,040.
Micronization of the aldosterone antagonist particles may be carried out using, for example, a ball mill, colloid mill, grinding mill, air jet mill, roller mill, impact mill, etc. An air jet mill is particularly suited as the majority of the milling in an air jet mill occurs through particle-particle collision rather than collision of the particles with the metal surfaces of the equipment. Thus, there can be a limited generation of heat during micronization that may lead to degradation of the aldosterone antagonist. The process of micronization in an air jet mill involves at least exposing the particles to streams of compressed air or gas creating a fluidized bed of the particles; and accelerating the particles towards the center of the mill such that collision of the particles with each other can be achieved. The impact of the particles colliding with each other will break the particles into smaller micron size particles by balancing airflow force and centrifugal force.
The micronized aldosterone antagonist particles such as eplerenone thus obtained may then be formulated into a pharmaceutical composition or dosage form. Such compositions and dosage forms include, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals either orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracistemally, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray. For example, the active ingredient of the invention, or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
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Capsule dosages will contain the micronized aldosterone antagonist particles of the present invention within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Actual dosage levels of the micronized aldosterone antagonist particles such as eplerenone in the compositions of the invention may be varied to obtain an amount of micronized aldosterone antagonist that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The compositions of the present invention in the form of individual dosage units contain the micronized aldosterone antagonist particles in an amount of about 10 mg to about 1000 mg, preferably from about 20 mg to about 400 mg, more preferably from about 25 mg to about 200 mg and still more preferably from about 25 mg to about 150 mg. The selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of
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the compounds of this invention administered to a host in single or divided dose and can vary widely depending upon a variety of factors including, for example, the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc. In one embodiment, the daily dose can be administered in one to four doses per day. The present compositions may provide a therapeutic effect as aldosterone receptor blockers over a period of about 12 hours to about 24 hours after oral administration.
The pharmaceutical compositions of the present invention can also contain one or more pharmaceutically inert carrier. The term "pharmaceutically inert carrier" as used herein refers to a substance that is physiologically acceptable, and compatible with the micronized aldosterone antagonist particles and other excipients in the formulation, while having a capacity to absorb the micronized aldosterone antagonist on its surface. The use of a carrier may also prevent the reagglomeration of the micronized aldosterone antagonist particles and assist in wetting the micronized aldosterone antagonist particles by the uptake of water via capillary action thereby enhancing dissolution.
The pharmaceutical compositions of the present invention can also contain one or more pharmaceutically acceptable inert excipients. Such pharmaceutically acceptable inert excipients include, but are not limited to, one or more binders, diluents, surfactants, disintegrants, lubricants/glidants, coloring agents, and the like and mixtures thereof. The pharmaceutically acceptable inert excipients may be used intragranularly and/or extragranularly.
Suitable binders include, but are not limited to, one or more methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, kagacanth, sodium alginate, propylene glycol, and the like and mixtures thereof.
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Suitable diluents include, but are not limited to, one or more of calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
Suitable lubricants/glidants include, but are not limited to, one or more colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of a fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
The pharmaceutical compositions of the present invention can be obtained by at least sifting the micronized particles with a diluent/filler followed by granulation in, for example, a high shear mixer using a binder solution, e.g., hydroxypropyl methyl cellulose in water. The granulation can be carried out in a Rapid Mixer Granulator (RMG) and the granules are wet milled, and the wet granules are dried and then lubricated. The lubricated blend can then be compressed into minitablets and the tablets are optionally coated with a film coating composition.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
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EXAMPLE 1
Eplerenone was prepared using the process described in product patent US4559332. The micronization process is achieved by particle-particle attrition inside the jet mill by applying compressed atmospheric air using the following parameters. Parameters
1. Compressed air pressure in main supply line to the jet mill should be 4 to 5 kg/cm2.
2. Feed rate of the powder to jet mill using the screw feeder is about 500gm/hr.
Eplerenone is micronised using MALVERN particle size analyzer using spiral jet mill ( model no - JM 200 ). The D% of the eplerenone particles was 15.17 microns.
EXAMPLE 2
The ingredients and the percent w/w formula of the composition of this example of the present invention are set forth in Table 1.
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TABLE 1

STEP INGREDIENTS TYPE OF EXCIPIENT AMOUNT(mg/tablet) for 25 me. AMOUNT(mg/tablet) for 50 mg Wt. % for 25 mg)
A. CORE TABLET
1 Eplerenone Active Drug 25.340* 50.68* 30.902
Lactose Monohydrate Diluent 35.360 70.72 43.122
Microcrystalline Cellulose (AvicelPH 101) Binder/Disintegra nt 6.380 12.76 7.780
Croscarmellose Sodium Disintegrant 2.130 4.26 2.598
II Purified Water Vehicle q.s. q.s. -
Hydroxy propyl methyl cellulose 3 cps Binding agent 2.550 5.10 3.110
III Microcrystalline Cellulose (AvicelPH 101) Lubricant 4.000 8.00 4.878
Sodium Lauryl Sulphate Wetting agent 0.850 1.7 1.037
Croscarmellose Sodium Disintegrant 2.120 4.24 2.585
Talc Lubricant 0.850 1.7 1.037
Magnesium Stearate Lubricant 0.420 0.84 0.512
Core Weight 80.0 mg 160mg
B. COATING
Hydroxypropyl methylcellulose 15 cps Polymer 1.150 2.30 1.402
Dibutyl Phthalate Plastisizer 0.015 0.03 0.018
Polyethylene Glycol 6000 Plastisizer 0.048 0.096 0.059
Talc Glidant 0.480 0.96 0.585
Titanium Dioxide Opacifier 0.290 0.58 0.354
Yellow Oxide of Iron Coloring agent 0.009 0.018 0.011
Red Oxide of Iron Coloring agent 0.008 0.016 0.010
Isopropyl Alcohol Vehicle q.s. q.s. -
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Dichloromethane (Methylene Chloride) Vehicle q.s. q.s. -
2.0 mg/tablet 4.0 mg/tablet 100.00
* Quantity of eplerenone based on a potency of 98.90% (on dried basis) and loss of drying of 0.23%.
The composition of this example was prepared as follows:
I. Sifting and Dry Mixing
Eplerenone of Example 1 having a particle size D90 less than 25 microns and greater than 15 microns, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were sifted through a 60 # sieve and mixed for 10 minutes.
II. Preparation of granulating agent
A binder solution was prepared with hydroxy propyl methylcellulose 3 Cps and purified water.
III. Wet mixing
The binder solution of step II was added to the dry mixture of step I and mixed for 15 minutes in a rapid mixer granulator. The rapid mixer granulator was run at a slow speed for 3-5 minutes and then at a fast speed for 10 minutes to get the desired wet granule consistency.
IV. Wet sifting
The wet material of step III was sifted through a 10 # sieve.
V. Drying
The sifted wet material of step IV was dried in a Rapid Dryer at a temperature of 60°C for 30 minutes.
VI. Diminution
The dried material of step V was sifted through a 18 # sieve and the fines were collected through a 40 # sieve.
VII. Lubrication
The fines collected in step VI were lubricated with Avicel PH 101, sodium lauryl sulphate , croscarmellose sodium, talc and magnesium stearate.
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Dissolution tests of two different batches of the eplerenone tablets of Table 1 were carried out. The dissolution of the eplerenone tablets was determined as directed in the U.S. Pharmacopoeia (USP) in 1000 ml of 0.1 N HC1 at 37°C (± 0.5°C) using an USP Dissolution Apparatus Type II at an agitation of 50 rotations per minute (rpm). The dissolution profile of the eplerenone tablets is in the range of about 25 to about 40% in 5 minutes, about 60 to about 85% in 10 minutes and not less than about 70% in 30 minutes. The dissolution profile of the eplerenone tablets are set forth below in Table 2. The dissolved eplerenone is expressed in cumulative percent of drug dissolved over an elapsed time period in minutes.
TABLE 2

Time Intervals Eplerenone Tablets 50 mg Batch 1 Eplerenone Tablets 50 mg Batch 2
Time in minutes Drug Release (% in average) Drug Release (% in average)
5 37.0% 45.2%
10 73.9% 82.4%
15 92.9% 92.0%
20 96.3% 95.2%
30 97.3% 97.3%
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
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WHAT IS CLAIMED IS:
1. Eplerenone having a D90 particle size of less than 25 microns and greater than 15 microns.
2. Eplerenone having a D90 particle size of less than about 20 microns and greater than 15 microns.
3. The aldosterone antagonist particles of Claims I and 2, wherein the Eplerenone is an aldosterone antagonist.
4. A pharmaceutical composition comprising a therapeutically effective amount of the Eplerenone particles of Claims 1-3.
5. The pharmaceutical composition of Claim 3, wherein the Eplerenone particles
are present in an amount of about 10 mg to about 1000 mg.
6. The pharmaceutical composition of Claim 3, wherein the Eplerenone as
aldosterone antagonist particles are present in an amount of about 25 mg to about 150 mg.
7. The pharmaceutical composition of Claims 4-6, farther comprising one or more
pharmaceuticaily acceptable excipients.
8. The pharmaceutical composition of Claim 7, wherein the one or more
pharmaceuticaily acceptable excipients is selected from the group consisting of a binder,
diluent, filler, glidant, lubricant, disintegrant, wetting agent and mixtures thereof.
9. The pharmaceutical composition of Claims 4-8, in the form of a tablet or capsule.
10. The pharmaceutical composition of Claims 4-9, wherein the dissolution profile of the composition includes releasing about 25 to about 40% of the aldosterone antagonist
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particles in 5 minutes as determined using USP Apparatus II at 50 rpm in 1000 ml of 0.1 N HCI medium at 37°C.
11. The pharmaceutical composition of Claims 4-10, wherein the dissolution profile of the composition includes releasing about 60 to about 85% of the aldosterone antagonist particles in 10 minutes as determined using USP Apparatus II at 50 rpm in 1000 ml of 0.1N HCI medium at 37°C.
12. The pharmaceutical composition of Claims 4-11, wherein the dissolution profile of the composition includes releasing about 90% of the aldosterone antagonist particles in 30 minutes as determined using USP Apparatus II at 50 rpm in 1000 ml of 0.1N HCI medium at 37°C.
13. A therapeutic method comprising administering the Eplerenone as aldosterone
antagonist particles of Claims 1-3 to a subject having an aldosterone-mediated condition
or disorder.
14. The method of Claiml3 wherein the Eplerenone as aldosterone antagonist
particles are administered in an amount of about 10 mg to about 1000 mg.
15. The method of Claims 13 and 14, wherein the condition or disorder is selected
from the group consisting of heart failure, hypertension, edema associated with liver
insufficiency, post-myocardial infarction, cirrhosis of the liver and accelerated heart rate.
16. The method of Claims 13-15, wherein the Eplerenone as aldosterone
antagonist particles are formulated with one or more pharmaceutically acceptable
excipients in an orally deliverable composition.
17. A therapeutic method comprising administering the pharmaceutical
composition of Claims 4-12 to a subject having an aldosterone-mediated condition or
disorder.
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18. The method of Claim 17, wherein the Eplerenone as aldosterone antagonist particles are present in the composition in an amount of about 10 mg to about 1000 mg.
19. The method of Claims 17 and 18, wherein the condition or disorder is selected from the group consisting of heart failure, hypertension, edema associated with liver insufficiency, post-myocardial infarction, cirrhosis of the liver and accelerated heart rate.
20. A method of use of Eplerenone as aldosterone antagonist particles having a
D90 particle size of less than 25 microns and greater than 15 microns in the manufacture of
a medicament for treatment or prophylaxis of an aldosterone-mediated condition or
disorder.
Dated this Twenty Ninth (29th) day of July, 2006
Taranpreet Lamba. (Sr. Manager-IPM)
Glen mark Pharmaceuticals Limited
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ABSTRACT
An aldosterone antagonist such as eplerenone having a particle size of less than about 25 microns and greater than 15 micron is provided. Also provided a process for preparing same pharmaceutical composition for the same.

Dated this Twenty Fourth ( 29th) day of July, 2006

Taranpreet Lamba. (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited
2 4 JUL 2006