FIELD OF THE INVENTION
The present invention describes novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally with one or more pharmaceutically acceptable excipient(s) wherein the said composition comprises the said active agent in a dispersed or dissolved state. Preferably the compositions are in the liquid state, semisolid state or solid state at room temperature. The present invention also provides process of preparing such novel compositions and therapeutic methods of using them.
BACKGROUND OF THE INVENTION
Hypertension or high blood pressure is a medical condition where the blood pressure in the arteries is chronically elevated. Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Patients with primary hypertension (a form with no identifiable underlying cause) are generally treated with active agents that reduce blood volume (which reduces central venous pressure and cardiac output), reduce systemic vascular resistance, or reduce cardiac output by depressing heart rate and stroke volume. Patients with secondary hypertension (a form caused by an identifiable underlying condition such as renal artery disease, thyroid disease, primary hyperaldosteronism, pregnancy, etc.) are best treated by controlling or removing the underlying disease or pathology, although they may still require antihypertensive active agents.
Many antihypertensive active agents have their primary action on systemic vascular resistance. Some of these active agents produce vasodilation by interfering with sympathetic adrenergic vascular tone (sympatholytics) or by blocking the formation of angiotensin II or its vascular receptors. Other active agents are direct arterial dilators, and some are mixed arterial and venous dilators. Although less commonly used because of a high incidence of side effects, there are active agents that act on regions in the brain that control sympathetic autonomic outflow. By reducing sympathetic efferent activity, centrally acting active agents decrease arterial pressure by decreasing systemic vascular resistance and cardiac output. Some antihypertensive active agents, most notably beta-blockers, depress heart rate and contractility (this decreases stroke volume) by blocking the influence of sympathetic nerves on the heart. Calcium-channel blockers, especially those that are more cardioselective, also reduce cardiac output by decreasing heart rate and contractility. Some calcium-channel blockers are more selective for the systemic vasculature and therefore reduce systemic vascular resistance.
Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-,γ-lactone, methyl ester, (7a,lla,17a)-. Its empirical formula is C24H30O6 and it has a molecular weight of 414.50. Eplerenone is an odorless, white to off- white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH independent. It is soluble in DCM and Acetonitrile. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0. Eplerenone is marketed under the tradename Inspra® in the US and is available only in the tablet form. Inspra® for oral administration contains 25 mg or 50 mg of eplerenone alongwith other inactive ingredients.
Eplerenone is indicated in congestive heart failure post-myocardial infarction and in hypertension. Inspra® is indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. The recommended dose of Inspra® is 50 mg once daily. Inspra® is also indicated for the treatment of hypertension.
Eplerenone is well absorbed following oral administration, with a bioavailability of approximately 98% and reaching a peak plasma concentration in about 1.5 hours. Food does not affect its absorption. Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half- life of 4 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone is unknown. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg. The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells. Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma. Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half- life of eplerenone is approximately 4 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.
Eplerenone was first reported in Grob et al., US Patent No. 4,559,332 that describes and claims a class of 9,11-epoxy steroid compounds and their salts alongwith the processes for the preparation of such compounds. These 9,11-epoxy steroid compounds are described as aldosterone antagonists that can be administered in a therapeutically effective amount to treat pathological
conditions associated with hyperaldosteronism such as hypertension, cardiac insufficiency and cirrhosis of the liver. The said patent discloses conventional formulations for the administration of these 9,11- epoxy steroid compounds such as in the form of tablets and hard gelatin capsules, wherein the active agent in present in a solid state.
Several patents/publications exist in the art such as US Patent Nos. 6410054, 6534093, 6558707, 6863902 and 7157101 relating to pharmaceutical compositions comprising eplerenone having specific particle size such as D.sub.90 particle size of about 25 to about 400 microns and/or dose such as 10-1000 mg, and/or in-vitro dissolution profile in different medias. PCT Publication bearing no. WO2007012960 describes pharmaceutical compositions comprising eplerenone particles having a D90 particle size of less than 25 microns and greater than 15 microns.
Various attempts to enhance the dissolution rate of eplerenone have been made in the prior art. WO00142272 describes crystalline forms of eplerenone having enhanced dissolution rate. WO00141770 discloses nanoparticulate compositions of eplerenone. WO03080181 discloses liquid formulations of eplerenone suitable for parenteral use wherein the drug is solubilised using cyclodextrin derivatives. WO00033847 discloses oral compositions comprising micronized eplerenone and process for their preparations. However, no formulation has been described in the art which comprises eplerenone in a dissolved or dispersed state and is intended for oral administration.
There still exists a need to develop pharmaceutical compositions comprising eplerenone exhibiting superior performance with respect to improved and/or less variable bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, as well as other improved pharmacokinetic, chemical and/or physical properties. Such compositions should be easy to formulate, cost-effective and reproducible i.e. they should be devoid of any substantial batch-to-batch variability or variation in content uniformity of each dosage form.
The inventors of the present invention have done extensive research and conducted several experiments to alleviate the drawbacks existing in prior art to develop compositions comprising eplerenone that preferably possess improved and/or less variable bioavailability, are substantially easy to formulate, cost-effective and reproducible, and can be formulated by using different conventional excipients, thus demonstrating a significant advancement over the prior art.
SUMMARY OF INVENTION
It is an objective of the present invention to provide novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof,
optionally with one or more pharmaceutically acceptable excipient(s) wherein the said composition comprises the said active agent in a dispersed or dissolved state.
It is an objective of the present invention to provide novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof in an amount of from 0.1% w/w to 90% w/w; at least one carrier material(s) comprising hydrophilic phase and/or lipophilic phase and/or surfactant(s) present in an amount of from 0.1% w/w to 80% w/w; optionally one or more pharmaceutically acceptable solvent(s) present in an amount of from 0% w/w to 99% w/w; and optionally one or more other pharmaceutically acceptable excipient(s) present in an amount of from 0% w/w to 99.8% w/w of the composition; wherein the said composition comprises the said active agent in a dispersed or dissolved state.
It is also an objective of the present invention to provide composition which comprises eplerenone in the dissolved state in the hydrophilic phase and/or lipophilic phase and/or surfactant, or which is in the form of solid lipid nanoparticles wherein eplerenone is present in the dissolved state in the lipid phase.
It is another objective of the present invention to provide novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally with one or more pharmaceutically acceptable excipient(s) in the form of a soft gelatin capsule, wherein the said capsule comprises the said active agent in a dispersed or dissolved state.
It is also an objective of the present invention to provide process for the preparation of novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally with one or more pharmaceutically acceptable excipient(s) wherein the said composition comprises the said active agent in a dispersed or dissolved state.
It is also an objective of the present invention to provide process for preparing a composition according to the present invention, wherein the said process comprises of the following steps: i) treating eplerenone with at least one carrier material(s) and optionally with solvent(s), ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iii) formulating the material of step (ii) into a suitable dosage form.
It is also an objective of the present invention to provide use of the novel pharmaceutical compositions for the management of congestive heart failure post-myocardial infarction and/or hypertension which comprises administrating to a subject in need thereof, a pharmaceutically effective amount of the composition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally with one or more pharmaceutically acceptable excipient(s) wherein the said composition comprises the said active agent in a dispersed or dissolved state. Preferably the composition of the present invention is in the form of a soft gelatin capsule intended for oral administration.
In an embodiment, the present invention provides novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof in an amount of from 0.1% w/w to 90% w/w; at least one carrier material(s) comprising hydrophilic phase and/or lipophilic phase and/or surfactant(s) present in an amount of from 0.1% w/w to 80% w/w; optionally one or more pharmaceutically acceptable solvent(s) present in an amount of from 0% w/w to 99% w/w; and optionally one or more other pharmaceutically acceptable excipient(s) present in an amount of from 0% w/w to 99.8% w/w of the composition; wherein the said composition comprises the said active agent in a dispersed or dissolved state.
According to an aspect of the present invention, the pharmaceutical compositions comprising dissolved eplerenone in a pharmaceutically acceptable carrier material can effectively deliver a therapeutically preferred amount of the active agent to the subject. In addition, the combination of carrier material(s) with the dissolved eplerenone has been found to provide better solubilization characteristics of the active agent.
Eplerenone is a poorly soluble substance. The effective administration of eplerenone to a subject is complicated by its low solubility and poor physico-chemical properties such as compressibility. The inventors of the present invention have surprisingly found out composition wherein the drug is present in dissolved or dispersed state in a pharmaceutically acceptable state in a pharmaceutically acceptable carrier medium. It has also been discovered that the pharmaceutical compositions comprising dissolved eplerenone as the active agent intended for oral administration in a daily dosage amount of about 10 mg to about 200 mg along with a
pharmaceutically acceptable carrier material(s) are unique compositions exhibiting superior performance with respect to improved and/or less variable bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, as well as other improved pharmacokinetic, chemical and/or physical properties.
The pharmaceutical compositions of the present invention are useful for oral administration where administration of an aldosterone receptor blocker such as eplerenone is indicated. It has been found that these compositions are particularly effective in the treatment of cardiovascular diseases such as heart failure; hypertension (especially the management of mild to moderate hypertension); edema associated with liver insufficiency; post-myocardial infarction; cirrhosis of the liver; stroke prevention; and reduction of heart rate for subjects exhibiting an accelerated heart rate.
In a preferred embodiment, the pharmaceutical compositions of the present invention comprise dissolved eplerenone in association with one or more non-toxic, pharmaceutically-acceptable carrier(s), excipients and/or adjuvants (collectively referred to herein as "carrier materials"). The carrier materials useful according to the present invention are compatible with the active agent and other ingredients of the composition, and are not deleterious to the recipient. The pharmaceutical compositions of the present invention can be adapted for administration preferably by oral route by selection of appropriate carrier materials and a dosage of eplerenone effective for the treatment intended. Accordingly, the carrier material(s) employed can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit dose composition, for example, a capsule, which can contain from about 1% to about 95%, preferably about 10% to about 80%, more preferably about 20% to about 60%, and still more preferably about 20% to about 40%, by weight of eplerenone. Such pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components. The said carrier material is composed of pharmaceutically acceptable materials comprising hydrophilic phase and/or lipophilic phase and/or surfactants. The compositions of the present invention may be in the form of self emulsifying drug delivery system (SEDDS) or self micro-emulsifying drug delivery system (SMEDDS) or self nano-emulsifying drug delivery system (SNEDDS). The compositions may be in the form of a suspension, or a solubilized system such as an emulsion, or a colloidal dispersion.
For oral administration, the pharmaceutical composition can contain a desired amount of dissolved or dispersed eplerenone and be in the form of, for example, a hard or soft shell capsule, an elixir, a liquid, or any other form reasonably adapted for oral administration. Such a pharmaceutical composition is preferably made in the form of a discrete dosage unit containing a predetermined amount of eplerenone, such as capsules in hard or soft gelatin or vegetable
capsules or the like. Such oral dosage forms can further comprise, for example, buffering agents and/or anti-oxidants and or preservatives. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, syrups, and elixirs containing one or more inert diluents commonly used in the art.
In another embodiment, the composition of the present invention can be in the form of solid lipid nanoparticles wherein the drug is in the dissolved state in the lipid phase. In yet another embodiment, the composition of the present invention comprises eplerenone in the dissolved state in the hydrophilic phase, lipophilic phase or surfactant, or the combination of these.
In a preferred embodiment, the compositions of the present invention comprising eplerenone as active agent may be in the form of an emulsion, microemulsion, nanoemulsion, emulsion pre-concentrate, microemulsion pre-concentrate or submicron emulsions.
In an embodiment, the compositions of the present invention comprise a hydrophilic phase wherein the said hydrophilic phase comprises one or more hydrophilic material selected from but not limited to a group comprising glycols e.g. polyalkylene glycols, propylene glycol, polypropylene glycol etc.; lower alkanols e.g. ethanol; dimethyl isosorbide; propylene carbonate; glycofurol; transcutol; carboxylic acid esters of polyols e.g. glyceryl triacetate; and the like or mixtures thereof.
In an embodiment, the compositions of the present invention comprise a lipophilic phase wherein the said lipophilic phase comprises one or more lipophilic material such as pharmaceutically acceptable solvents. Especially suitable materials for use as lipophilic phase components are selected from but not limited to a group comprising saturated or unsaturated fatty acids e.g. oleic acid, linoleic acid, linolenic acid, etc.; fatty acid mono-, di-, or triglycerides preferably medium chain fatty acid triglycerides; natural vegetable oils such as coconut oil, olive oil, arachis oil, cottonseed oil, mustard oil, etc; glycerol triacetate or (l,2,3)-triacetin; dibutyl sebacate; triethyl citrate; neutral oils e.g. neutral plant oils, in particular fractionated coconut oils such as known and commercially available under the trade name MIGLYOL® e.g. MIGLYOL® 810, MIGLYOL® 812, MIGLYOL® 818 and the like or mixtures thereof. Also suitable are caprylic-capric acid triglycerides such as known and commercially available under the trade name MYRITOL® e.g. MYRITOL® 813. Fŵrther suitable products of this class are monoglyceride/diglyceride mixtures (e.g. CAPMUL®), medium-chain triglycerides (e.g. CAPTEX® 300, CAPTEX® 800 and NEOBEE® M5), and glycerol and polyglycerol esters (e.g. MAZOL® 165C and MAZOL® 300K).
In another embodiment, the compositions of the present invention may further comprise at least one pharmaceutically acceptable 'surfactant(s). The surfactant component may comprise
hydrophilic and/or lipophilic surfactants, or mixtures thereof. The surfactant(s) may be selected from a group comprising anionic, cationic and non-ionic surfactants, or suitable mixtures thereof. Especially preferred are non-ionic hydrophilic and non-ionic lipophilic surfactants.
Examples of suitable hydrophilic surfactants include but are not limited to a group comprising reaction products of natural or hydrogenated vegetable oils and (poly)ethylene glycol i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils for example polyoxyethylene glycolated natural or hydrogenated castor oils such as those commercialized under the trade names Cremophor® RH40, Cremophor® RH60. Cremophor® EL and Nikkol®; polyoxyethylene sorbitan fatty acid esters e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters e.g. products under the trade name Tween®, which includes polyoxyethylene (20) sorbitan mono-laurate (Tween® 20), polyoxyethylene (20) sorbitan mono-palmitate (Tween® 40), polyoxyethylene (20) sorbitan mono-oleate (Tween® 80), etc. depending on the kind of fatty acid; polyoxyethylene fatty acid esters for example, polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj® as well as polyoxyethylene fatty acid esters known and commercially available under the trade name Cetiol® HE; polyoxyethylene-polyoxypropylene co-polymers e.g. of the type known and commercially available under the trade names Pluronic® and Emkalyx®; polyoxyethylene-polyoxypropylene block co-polymers e.g. of the type known and commercially available under the trade name Poloxamer®; dioctylsuccinate; dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]-succinate; sodium lauryl sulfate; cetyltrimethylammonium bromide (CTAB); bile salts such as alkali metal salts e.g. sodium taurocholate; sucrose esters e.g. sucrose acetate isobutyrate; and the like, or mixtures thereof.
Examples of suitable lipophilic surfactants according to the present invention is selected from but not limited to a group comprising phospholipids, in particular lecithins especially, soybean lecithin; trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols such as trans-esterification products of various natural (e.g. non-hydrogenated) vegetable oils for example, maize oil, kernel oil, almond oil, ground nut oil, olive oil and palm oil and mixtures thereof with polyethylene glycols, for example LABRAFIL® (such as LABRAFIL® M 1944 CS, LABRAFIL® M 2130 CS, etc.) and LABRASOL®; mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol such as caprylic/capric acid mono- and di-glycerides e.g. IMWITOR® (such as IMWITOR® 742); sorbitan fatty acid esters e.g. of the type known and commercially available under the trade name SPAN®, for example including sorbitan-monolauryl, -monopalmityl, -monostearyl, -tristearyl, -monooleyl and -trioleyl esters; pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example pentaerythrite- -dioleate, -distearate, -monolaurate, -polyglycol ether and mionostearate; pentaerythrite fatty acid esters; monoglycerides, e.g. glycerol monooleate, glycerol monopalmitate and glycerol monostearate, for example as known and commercially available under the trade names
MYVATEX®, MYVAPLEX® and MYVEROL® and acetyiated, e.g. mono- and di-acetylated monoglycerides, for example as known and commercially available under the trade name MYVACET®; fatty acid mono-, and di-esters of propylene glycol e.g. propylene glycol laurate commercially available under the trade names LAUROGLYCOL® and LABRAFAC® PG; sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols, e.g. products comprising sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, for example soya sterols and derivatives thereof, such as known under the trade name GENEROL® e.g. GENEROL® 122, 122 E5, 122 E10, and 122 E25; and the like or mixtures thereof.
In an embodiment, the compositions of the present invention may additionally comprise a co-surfactant chosen from but not limited to mixture of mono- and diglycerides of oleic acid (Peceol®), propylene glycol monolaurate (Lauroglycol® 129), polyethylene glycol monocaprylate (Capryol® 90), glyceryl monolinoleate (Maisine® 35-1), Glyceryl Stearate (Imwitor® 900), Glyceryl Cocoate (Imwitor® 928), Glyceryl Stearate SE (Imwitor® 960K), Caprylic/Capric Glycerides (Imwitor® 988), or the like, or mixtures thereof. It might be understood that any of the compounds disclosed herein as surfactant or co-surfactant can function alternatively as either a surfactant or a co-surfactant.
In an embodiment, the compositions of the present invention comprise either a single surfactant or mixture of surfactants, e.g. comprising a first surfactant and one or more co-surfactants. Surfactant and co-surfactant combinations may be selected, e.g. from any of the surfactant types indicated above, or any such other compound known to the art. When the surfactant comprises an effective solvent for the eplerenone active agent, as in the case e.g. of surfactants or mixtures of surfactants described herein before, it may be incorporated into compositions as defined not only as surfactant, but in excess as an additional carrier or co-solvent phase, i.e. as part of the hydrophilic or lipophilic phase.
In another embodiment, the compositions of the present invention comprise one or more pharmaceutically acceptable solvent(s) selected from but not limited to a group comprising alcohol such as ethanol or isopropanol or butanol, acetone, acetonitrile, dimethyl sulfoxide, pentane, hexane, heptane, petroleum ether, chloroform, dichloromethane, dichloroethane, ethyl acetate, ethyl methyl ketone, dimethylacetamide, dimethyl sulfosuccinate, N-methyl pyrrolidone, polyoxyl 40 hydrogenated castor oil (Cremophor® RH40), polyoxyl 60 hydrogenated castor oil (Cremophor® RH60), polyoxyl 35 castor oil (Cremophor® EL), polyoxyethylene (20) sorbitan mono-oleate (Tween® 80). oleic acid, propylene glycol, propylene glycol monolaurate, polyethylene glycol (PEG) such as PEG 400, and the like, or suitable mixtures thereof.
In yet another embodiment, the compositions of the present invention comprise at least one complexing agent such as a cyclodextrin selected from a group comprising but not limited to alpha-cyclodextrin, beta-cyclodextrin, betahydroxy-cyclodextrin, gamma-cyclodextrin, hydroxypropyl cyclodextrin and the like, or mixtures thereof, or any other complexing agent known to the art.
In yet another embodiment, compositions of the present invention may also comprise a resin material such as anionic, cationic or non-ionic ion exchange resin. In an embodiment, the ion exchange resin(s) of the present invention is selected from a group comprising cross-linked polyacrylic copolymer resins such as Indion® 204, Indion® 214, Indion® 224, Indion® 234; Amberlite resins such as IRP-64®, Polacrilin potassium and the like, or mixtures thereof. In still further embodiment, the compositions additionally comprise a sustaining material for controlling the release of the active agent selected from but not limited to a group comprising cellulose and cellulose derivatives, waxes, carbomers, polyalkylene polyols, polycarbophils, methacrylate derivatives, gelatins, gums, polyethylene oxides and the like, or mixtures thereof.
In accordance with the present invention, the compositions may also include one or more anti-oxidants selected from but not limited to a group comprising ascorbyl palmitate, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), propyl gallate, tocopherols e.g. alpha-tocopherol (vitamin E) and the like, or mixtures thereof.
Other pharmaceutically acceptable excipients useful in the composition of the present invention are selected from but not limited to a group of excipients generally known to persons skilled in the art such as diluents; fillers; colorants; preservatives; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents such as glycerin, various grades of polyethylene oxides, transcutol and glycofurol; tonicity adjusting agents; pH adjusting agents; osmotic agents; chelating agents; viscosifying agents; wetting agents; emulsifying agents; acids; sugar alcohols; reducing sugars; non-reducing sugars; bulking agents; organic acid(s) and the like, used either alone or in combination thereof e.g. diluents such as lactose, mannitol, sorbitol, starch, microcrystalline cellulose, xylitol, fructose, sucrose, dextrose, dicalcium phosphate, calcium sulphate are useful. The vehicles suitable for use in the present invention can be selected from but not limited to a group comprising dimethylacetamide, dimethylformamide, dimethylsulphoxide, N-methyl pyrrolidone, benzyl benzoate, benzyl alcohol, ethyl oleate, polyoxyethylene glycolated castor oils (Cremophor® EL), polyethylene glycol MW 200 to 6000, propylene glycol, hexylene glycols, butylene glycols and glycol derivatives such as polyethylene glycol 660 hydroxy stearate (commercially available as
Solutrol® HS15). In another embodiment of the present invention, the compositions may additionally comprise an antimicrobial preservative such as methyl paraben, propyl paraben or benzyl alcohol, or mixtures thereof. The stabilizers useful in the present invention may include acid stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid as well as basic stabilizers such as potassium hydrogen phosphate, glycine, lysine, arginine or tris(hydroxymethyl)aminomethane.
It will be appreciated that certain excipient(s) used in the present composition can serve more than one purpose, for example a co-surfactant can function as a vehicle or carrier material also.
In another embodiment, the composition of the present invention can be formulated into a dosage form selected from the group consisting capsules, liquid dispersions, oral suspensions, fast melt formulations, sustained release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and a combination of immediate release and controlled release portions in single unit dose formulations.
In still another embodiment, the present invention provides a process for the preparation of novel pharmaceutical compositions for oral administration comprising eplerenone as an active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally with one or more pharmaceutical ly acceptable excipient(s) wherein the said composition comprises the said active agent in a dispersed or dissolved state.
In another embodiment is provided a process for the preparation of novel low dose composition
of eplerenone, wherein the said process comprises of the following steps:
i) treating eplerenone with at least one carrier material(s) and optionally with solvent(s),
ii) optionally adding one or more other pharmaceutical ly acceptable excipient(s), and
iii) formulating the material of step (ii) into a suitable dosage form.
In a further embodiment of the present invention, the pharmaceutical compositions can be prepared by well known methods in the art, e.g. by mixing the active agent eplerenone along with one or more pharmaceutical excipient(s) optionally with another active agent(s). For semi-solid or liquid preparations comprising eplerenone in a dissolved or dispersed state, in additional to a solid excipient(s), liquid and/or semi-solid excipient(s) known to the art are used.
In an embodiment, the present invention provides an orally deliverable pharmaceutical composition comprising a solvent liquid and eplerenone, wherein at least a substantial portion of the eplerenone is in dissolved and/or solubilized form in the solvent liquid, and wherein the
solvent liquid is hydrophilic or lipophilic, aqueous or non-aqueous, but preferably not solely water. In another embodiment, the compositions according to the present invention are substantially devoid of water such that they are better suited for encapsulation in soft or hard gelatin capsules. In a further embodiment, if water is present, the compositions of the present invention contain less than about 10% w/w of water, preferably less than about 5% w/w of water.
In another embodiment of the invention, the active agent eplerenone is in the form of a solid solution such that it forms a molecular dispersion with pharmaceutical carrier(s). The carrier(s) useful in the present invention include polyols such as mannitol, maltitol, xylitol, or the like; lactose; sucrose; polyvinyl pyrrolidone; polyethylene glycol, or the like, or suitable mixtures thereof. The said molecular dispersions in accordance with the present invention are particularly suitable for filling in capsules. Such capsules can be in the form of immediate release capsules, or can contain a controlled release or delayed release formulation.
In accordance with the present invention, the selection and combination of carrier material(s) used in the pharmaceutical compositions of the present invention provide compositions exhibiting improved performance with respect to, among other properties, at least one property such as bioavailability, reduced variability, stability, compatibility of eplerenone and carrier material(s), dissolution profile, and/or other pharmacokinetic, chemical and/or physical properties, and/or toxicity profile of the active agent.
In yet another embodiment, the present invention provides use of the novel pharmaceutical compositions for the management of congestive heart failure post-myocardial infarction and/or hypertension which comprises administrating to a subject in need thereof, a pharmaceutically effective amount of the composition.
For the treatment of heart failure, the pharmaceutical composition in accordance with the present invention provides a daily dose of eplerenone in the amount of about 10 mg to about 200 mg, preferably about 25 mg to about 75 mg, and more preferably about 50 mg.
For the treatment of hypertension, the pharmaceutical composition provides a daily dose of eplerenone in an amount of about 50 mg to about 300 mg, preferably about 50 mg to about 150 mg, and more preferably about 100 mg. A daily dose of about 0.67 to 4.00 mg/kg body weight, preferably between about 0.67 and about 2.00 mg/kg body weight and most preferably about 1.33 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day, preferably one dose per day.
For the treatment of edema associated with liver insufficiency, the pharmaceutical composition in accordance with the present invention preferably provides a daily dose of eplerenone in an amount of about 50 mg to about 500 mg, more preferably about 100 mg to about 400 mg, and more preferably about 300 mg. A daily dose of about 0.67 to about 6.67 mg/kg body weight, preferably between about 1.33 and about 5.33 mg/kg body weight and more preferably about 4.00 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day, preferably one dose per day.
The following examples are only intended to further illustrate different embodiments of the invention, and are therefore not deemed to restrict the scope of the invention in any manner whatsoever.
EXAMPLES
Example-1:
S. No. Ingredient Quantity/capsule (mg)
1. Eplerenone 25
2. Polyethylene glycol 108
3. Poly oxyl 40 hydrogenated castor oil (Cremophor® RH 40) 10
4. Propylene glycol monolaurate 130
Procedure:
i) Polyethylene glycol was mixed with Cremophor® RH 40 and heated upto 50 to 60°C, and
Eplerenone was dispersed in the resultant mixture with stirring, ii) Propylene glycol monolaurate was then added to the bulk mixture of step (i) and mixed.
The resultant mixture was then filtered, iii) The mixture of step (ii) was filled into hard gelatin capsules and sealed.
Example-2:
5. No. Ingredient Quantity/capsule (mg)
'Fill material' composition
1. Eplerenone 50
2. Propylene glycol 120
3. Cremophor® RH60 55
4. Propylene glycol monolaurate 120
5. Oleic acid 25
Capsule 'shell' composition
6. Gelatin 200
7. Glycerin 15
8. Methyl paraben 0.060
9. Propyl paraben 0.024
10. Purified water 180
11. Colorant 0.08
Procedure:
i) Ingredients 2-5 were mixed together with continuous stirring.
ii) To the mixture of step (i), Eplerenone was added and mixed to obtain a homogeneous
dispersion which is the 'fill' material, iii) Gelatin was soaked in about half the quantity of Purified water for about 30-45 minutes
under slow stirring, iv) To the remaining amount of Purified water, Colorant followed by Glycerin and, then
Propyl paraben and Methyl paraben, were added and dispersed with continuous stirring, v) The entire material of step (iv) was added with stirring to the material of step (iii), and the
mixture was cooked under heat and vacuum to obtain the gelatin mass of desired consistency, vi) The fill material of step (ii) was encapsulated using the Gelatin mass of step (v) in a
suitable Soft Gelatin Encapsulating machine to obtain soft gelatin capsules.
Example-3:
S. No. Ingredient Quantity/capsule (mg)
1. Eplerenone 12.5
2. Propylene glycol 85.0
3. Cremophor®EL 10.0
4. Propylene glycol monolaurate 107.0
5. Propylene glycol dicaprylate/dicaprate 5.0
6. Triacetin 1.5
Procedure:
i) Propylene glycol was mixed with Cremophor® EL and heated upto 55 to 60°C, and
Eplerenone was dispersed in the resultant mixture.
ii) Propylene glycol monolaurate was then added to the bulk mixture of step (i) and mixed, iii) Propylene glycol dicaprylate/dicaprate followed by Triacetin was added to the mixture of
step (ii). The resultant mixture was then filtered, iv) The mixture of step (iii) was filled into soft gelatin capsules.
Example-4:
S. No. Ingredient Quantity (mg/5 ml)
1. Eplerenone 50.0
2. Citric acid monohydrate 1.5
3. Hydroxyethyl cellulose 20.0
4. Sorbitol solution (70% w/v) 50.0
5. Saccharin sodium 0.5
6. Sodium benzoate 1.0
7. Raspberry flavor q.s.
8. Purified water q.s. to 5ml
Procedure:
i) Eplerenone and Hydroxyethyl cellulose were sifted through #40 sieve and were blended together, ii) Citric acid monohydrate, Saccharin sodium, Sodium benzoate, Raspberry flavor and Sorbitol
solution were dispersed together in Purified water, iii) The material of step (i) was added with continuous stirring to the material of step (ii) and a
homogeneous suspension was obtained.
Example-5:
S. No. Ingredient Quantity/capsule (mg)
1. Eplerenone 50
2. Dichloromethane q.s. (lost in processing)

2. Maisine®35-l 150
3. Labrafil®M2125 150
4. Span® 80 50
Procedure:
i) Eplerenone was dissolved in Dichloromethane with stirring.
ii) Maisine® 35-1 and Labrafil® M 2125 were mixed together and heated upto 50 to 60°C.
iii) Span® 80 was added to the material of step (ii) under continuous stirring.
iv) The material of step (i) was added with stirring to the material of step (iii) maintained at
above 50°C. The bulk was then brought to about 37-40°C. v) The material of step (iv) was made into soft gelatin capsules.
Example-6:
5. No. Ingredient Quantity/capsule (mg)
1. Eplerenone 100
2. Propylene glycol 130
3. Polyethylene glycol 100
4. Tween® 80 40
5. Oleic acid 27
6. Triacetin 2.93
7. Tocopheryl acetate 0.07
Procedure:
i) Propylene glycol and Polyethylene glycol were mixed with Tween® 80 and heated upto
about 50 to 60°C.
ii) Eplerenone was dispersed in the resultant mixture obtained in step (i). iii) Oleic acid was then added to the bulk mixture of step (ii) and mixed, iv) To the material of step (iii) was added Triacetin and Tocopheryl acetate, and the resultant
mixture was then filtered, v) The liquid material of step (iv) was made into soft gelatin capsules.
Example-7:
S. No. Ingredient Quantity/capsule (% w/w)
1. Eplerenone 15
2. Maisine®35-l 50
3. Imwitor® 742 30
4. Acetonitrile 5
Procedure:
i) Eplerenone was dissolved in Acetonitrile with stirring.
ii) Maisine® 35-1 and Imwitor® 742 were mixed together with continuous stirring, iii) The material of step (i) was added to the material of step (ii) with continuous stirring to yield a solution for filling into a soft gelatin capsule.
Example-8:
5. No. Ingredient Quantity/capsule (mg)
1. Eplerenone 50
2. Miglyol®812 100
3. Myverol® 18-92 100
4. Cremophor® RH 40 50
Procedure:
All the ingredients 1-4 were intimately admixed in the indicated proportions in conventional manner and the obtained mixture filled into soft or hard gelatin capsules each containing 50 mg eplerenone.

We Claim:
1. A novel pharmaceutical composition for oral administration comprising eplerenone as an
active agent or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates,
analogues, enantiomers, tautomeric forms or mixtures thereof in an amount of from 0.1%
w/w to 90% w/w; at least one carrier material(s) comprising hydrophilic phase and/or
lipophilic phase and/or surfactant(s) present in an amount of from 0.1% w/w to 80% w/w;
optionally one or more pharmaceutically acceptable solvent(s) present in an amount of
from 0% w/w to 99% vv/w; and optionally one or more other pharmaceutically acceptable
excipient(s) present in an amount of from 0% w/w to 99.8% w/w of composition; wherein
the said composition comprises the said active agent in a dispersed or dissolved state.
2. A composition according to claim 1, which comprises eplerenone in the dissolved state in
the hydrophilic phase and/or lipophilic phase and/or surfactant, or which is in the form of
solid lipid nanoparticles wherein eplerenone is present in the dissolved state in the lipid
phase.
3. A composition according to claim 1, wherein the hydrophilic phase comprises one or more
hydrophilic material selected from a group comprising glycols; lower alkanols; dimethyl
isosorbide; propylene carbonate; glycofurol; transcutol; carboxylic acid esters of polyols;
and the like or mixtures thereof.
4. A composition according to claim 1, wherein the lipophilic phase comprises one or more
lipophilic material selected from a group comprising saturated or unsaturated fatty acids;
fatty acid mono-, di-, or triglycerides; natural vegetable oils; glycerol triacetate; dibutyl
sebacate; triethyl citrate; neutral oils; caprytic-capric acid triglycerides;
monoglyceride/diglyceride mixtures; medium chain triglycerides; glycerol and
polyglycerol esters, and the like, or mixtures thereof.
5. A composition according to claim 1, wherein the surfactant(s) is a hydrophilic surfactant
selected from a group comprising reaction products of natural or hydrogenated vegetable
oils and (poly)ethylene glycol; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene
fatty acid esters; polyoxyethylene-polyoxypropylene co-polymers; sodium lauryl sulfate;
cetyltrimethylammonium bromide; bile salts; sucrose esters and the like, or mixtures
thereof.
6. A composition according to claim 1, wherein the surfactant(s) is a lipophilic surfactant
selected from a group comprising phospholipids; trans-esterification products of natural
vegetable oil triglycerides and polyalkylene polyols; sorbitan fatty acid esters;
pentaerythritol fatty acid esters; polyalkylene glycol ethers; monoglycerides; acetylated
monoglycerides; fatty acid mono-, and di-esters of propylene glycol; sterols and
derivatives, and the like, or mixtures thereof.
7. A composition according to claim 1, wherein the solvent(s) is selected from a group
comprising alcohol, acetone, acetonitrile, dimethyl sulfoxide, pentane, hexane, heptane,
petroleum ether, chloroform, dichloromethane, dichloroethane, ethyl acetate, ethyl methyl
ketone, dimethylacetamide, dimethyl sulfosuccinate, N-methyl pyrrolidone, polyoxyl 40
hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 35 castor oil,
polyoxyethylene (20) sorbitan mono-oleate, oleic acid, propylene glycol, propylene glycol
monolaurate, polyethylene glycol and the like, or suitable mixtures thereof.
8. A composition according to claim 1, wherein the pharmaceutically acceptable excipient(s)
are selected from a group comprising diluents, fillers, colorants, preservatives, chelating
agents, vehicles, bulking agents, stabilizers, preservatives, hydrophilic polymers, solubility
enhancing agents, tonicity adjusting agents, pH adjusting agents, osmotic agents, chelating
agents, viscosifying agents, wetting agents, emulsifying agents, acids, sugar alcohols,
reducing sugars, non-reducing sugars, bulking agents, organic acid(s) and the like, used
either alone or in combination thereof.
9. A process for preparing a composition according to claim 1 wherein the said process
comprises of the following steps:
i) treating eplerenone with at least one carrier material(s) and optionally with solvent(s), ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and iii) formulating the material of step (ii) into a suitable dosage form.
10. The novel pharmaceutical compositions comprising eplerenone in the dissolved or
dispersed state and processes thereof substantially as herein described and illustrated by the
examples.