WO2006119779A2 - A pharmaceutical composition comprising an aldosterone antagonist in form of solid solution - Google Patents

A pharmaceutical composition comprising an aldosterone antagonist in form of solid solution Download PDF

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Publication number
WO2006119779A2
WO2006119779A2 PCT/DK2006/050019 DK2006050019W WO2006119779A2 WO 2006119779 A2 WO2006119779 A2 WO 2006119779A2 DK 2006050019 W DK2006050019 W DK 2006050019W WO 2006119779 A2 WO2006119779 A2 WO 2006119779A2
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composition according
pharmaceutical composition
micrometer
active compound
tablet
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PCT/DK2006/050019
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French (fr)
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WO2006119779A3 (en
Inventor
Per Holm
Tomas Norling
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Lifecycle Pharma A/S
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Publication of WO2006119779A2 publication Critical patent/WO2006119779A2/en
Publication of WO2006119779A3 publication Critical patent/WO2006119779A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • a pharmaceutical composition comprising an aldosterone antagonist
  • the present invention relates to pharmaceutical compositions comprising a solid solution of an aldosterone antagonist and a method of preparation thereof. More specifically, the pharmaceutical composition comprises spironolactone or eplerenone dissolved in a solid polar lipid carrier.
  • the invention further relates to combinations of an aldosterone antagonist with other antihypertensives such as, for example, beta-blockers.
  • Aldosterone antagonists are inhibitors of the mineral corticosteroid aldosterone. Both spironolactone and eplerenone are competitive antagonist of aldosterone. They are equally effective but eplerenone are much more selective and binds to androgen and eplerenone receptors to a much lesser extend than spironolactone and hence do not cause significant sexual alterations.
  • Aldosterone antagonists are used therapeutically and prophylatically in both men and women for different purposes. At present, aldosterone antagonist are prescribed for example for hyper aldosteroism, for hypertension and for prevention of myocardial infarct. It is contemplated that aldosterone antagonists may also be useful therapeutically or prophylactically for cardiac hypertrophy, iscemic diseases in general, myocardial fibrosis and vascular fibrosis.
  • aldosterone antagonists are commercially available in oral, and parenteral dosage forms, for example under the trade names (depending on country and local regulations) Spirix, Aldactone (spironolactone); lnspra (eplerenone).
  • Spironolactone has the structural formula:
  • spironolactone sold under the name Aldactone.TM.
  • spironolactone contain 25, 50 or 100 mg doses of spironolactone in a matrix comprising, among other carrier materials, calcium sulfate dihydrate as a diluent, maize starch as a disintegrant, povidone K- 30 as a binding agent, magnesium stearate as a lubricant, and flavor, colorant, and coating ingredients that include hydroxypropylmethylcellulose and polyethylene glycol 400.
  • Eplerenone has the structural formula:
  • the recommended daily dosage of Spironolactone is between 25 and 600 mg. based on single or multiple dosing.
  • the recommended daily dosage of Eplerenone is from 25 to 150 mg.
  • US 6,495,165 discloses particulate Eplerenone in the form of micronized Eplerenone in pharmaceutical products resulting in immediate products with a Tmax within 1.8h and Cmax of at least 1500 ng/ml.
  • Wetting agents are suggested including sodium lauryl sulfate.
  • the bioavailability in dogs were increased by reducing the particle size from less than about 212 to 36 microns.
  • Co-therapy methods for treating a cardiovascular such as heart failure and hypertension with an angiotensin converting enzyme inhibitor and eplerenone optionally together with diuretics and digoxin is known from the prior art (US 6,747,020 and 6,410,524)
  • an aldosterone antagonist for example eplerenone
  • the object of the present invention is to provide means for an improved, cost effective manufacturing process with good physical stability and bioavailability especially of Eplerenone and/or decreased variability in pharmacokinetic parameters including plasma level after oral administration to a subject in need thereof.
  • microparticles or the nanoparticles is then used in the formulation with various pharmaceutical excipients for the preparation of the final product.
  • the conventional size-reducing step to micro- or nanoparticels as well as any de-aggregation step are made superfluous by preparing solid dispersions in vehicles which by virtue of their solubilizing properties in relation to the active compound, fully or partly dissolve the active ingredient and prevents agglomeration. Accordingly, the vehicles also have dispersing properties and is suitable for further processing by well known pharmaceutical processes.
  • a solid dispersion is a homogeneous mixture of one or more active ingredients in a pharmacologically inert matrix in the solid state.
  • Various classes of solid dispersion can be produced according to the number of phases, physical state of the phase or phases and according to the physical state of the active ingredient in the mixture.
  • Two phase systems include eutectic mixture where two (or more) crystalline phases are present and the amorphous suspension where the amorphous drug is suspended in either a crystalline or amorphous solid.
  • One phase systems include glass solution where the physical state is amorphous or and a second one phase system is the solid solution where the physical state of the phase is crystalline (solid).
  • a solid solution may based on the extent of miscibility between the active compound and the vehicle be called complete to the extend that the two components are soluble at solid state in all proportions, however, this is seldom the case.
  • there is only a limited solubility of the solute in the solvent Exceeding this limitation of solubility, in the present context, the solubility of the active compound in the vehicle, will result in the presence of a fraction of the active compound not being on a molecular level in the solid. According to the compositions of the present invention, such fraction will however be dispersed in the solid.
  • Analytical methods for determination of a solid dispersion or solid solution include x- ray powder diffraction, differential scanning calorimetry (DSC),thermogravimetric analysis, microcalorimetry, infrared spectros copy, Raman spectroscopy, and dissolution kinetics.
  • the solid solutions according to the present invention still have the advantages of maximal reduced “particle size" to the molecular level and also the possibility of an intimate presence of a carrier system which can increase the wetting of the active as will as increase the solubility of the active in any diffusion layer surrounding the active in order to prevent local precipitation in the drug delivery system, a function which also increase the dissolution if drug in crystal form is also present in the solid.
  • an eplerenone pharmaceutical product may be improved by administering eplerenone in the form of a pharmaceutical preparation comprising at least a part of eplerenone in solid solution and wherein the eplerenone is dispersed in a vehicle.
  • the improved property may include a higher amount of eplerenone absorbed (increased AUC) or decreased variability in any measurable pharmacokinetic parameter including AUC between or within subjects compared with a similar formulation not comprising eplerenone in solid solution or in micronized form.
  • such a preparation may result in variability as mentioned above at least comparable with InspraTM or other products comprising eplerenone and where this is present in micronized form of a particle size between 25 and 400 micron. This is done by a simple and easy method, which does not involve any time- consuming grinding or milling.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically, prophylactically and/or diagnostically active compound selected from the group of aldosterone antagonists, wherein at least about 10% w/w% of the active compound is present as a solid solution and/or a solid dispersion, optionally in combination with at least one further therapeutically, prophylactically and/or diagnostically active compound.
  • the invention provides a method for preparing the pharmaceutical composition of the invention, the method comprising the step of dissolving and/or dispersing the active compound in a polar lipid solid carrier, optionally followed by a step of contacting or mixing the solution with one or more release modifying agents and/or one or more pharmaceutically acceptable excipients.
  • the present invention relates to the use of the composition of the invention for the preparation of a medicament, for example in immediate release solid dosage form, in a controlled release solid dosage form, in a sublingual dosage form, in oral dosage form.
  • compositions of the present invention provide eplerenone in a form, which is freely accessible for absorption into the systemic circulation upon oral, and is ready for incorporation in the pharmaceutical compositions of the invention, for example a tablet for immediately or delayed release.
  • eplerenone dosage levels may be reduced.
  • a lower dose and/or lower variability likely results in a beneficial reduction in dose-related side effects as unexpected high peaks or plasma concentrations may be decreased.
  • the identification of such improved side effect profile will normally require extensive blinded clinical studies and the decreased variability in may directly be regarded as an increased safety of use as also inferior efficacy is avoided due to reduction in episodes of unexpected low bioavailability.
  • An important aspect of the invention is to make it possible to manufacture eplerenone products such as tablets easier and more cost efficient, without compromising bioavailability.
  • the resulting final product may also have excellent storage stability.
  • geometric weight mean diameter means the mean diameter of the log normal volume-size distribution.
  • solid dispersion is a homogeneous dispersion of the active compound such as eplerenone in a pharmacologically inert vehicle, matrix or carrier in a solid state and includes fine solid particles dispersed in a solid vehicle, matrix or carrier, the particles being at a non-molecular level as well as at a molecular level, however the latter is referred to as a solid solution.
  • solid solution of eplerenone denotes a homogeneous dispersion of the active compound such as eplerenone in a pharmacologically inert vehicle, matrix or carrier in a solid state where the eplerenone is present in a molecular level, or at lest close to monomolecular level. Close to monomolecular level includes absence or disappearance of crystals of the active compound as measured by well known techniques applied in the art.
  • the solid vehicle, matrix or carrier is used as the solid solvent for the active compound.
  • the solid vehicle, matrix or carrier may be comprised of pure components or mixtures of components including liquids, semi-solids and solids.
  • the solid vehicle, matrix or carrier further include melted or otherwise liquefied substances which is solidified by cooling, by mixing with or absorption to solid material in order to obtain a material which is solid at room temperature (for instance at any temperature between 18° and 25°C).
  • polar lipid carrier is intended to denote a carrier that is both hydrophilic and hydrophobic and, accordingly, can be admixed with eplerenone and water. It should be noted that the term “polar lipid” can be used interchangeable with amphiphilic and surfactant.
  • W denotes the time to reach the maximal plasma concentration (c max ) after administration; AUCo-infinity denotes the area under the plasma concentration versus time curve from time 0 to infinity; AUC 0-t denotes the area under the plasma concentration versus time curve from time 0 to time t; W 50 denotes the time where the plasma concentration is 50% or more of C max ; W 75 denotes the time where the plasma concentration is 75% or more of C max ; and MRT denotes mean residence time for eplerenone.
  • controlled release and "modified release” In the present context the terms
  • controlled release and modified release are intended to be equivalent terms covering any type of release of active compound or ingredient from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject.
  • a person skilled in the art knows how controlled release/modified release differs from the release of plain tablets or capsules, which may exhibit immediate release of the active compound after administration.
  • release in a controlled manner or “release in a modified manner” has the same meaning as stated above.
  • controlled release/modified release include slow release (that results in a lower C max and later U ax .
  • pharmaceutically acceptable excipient are intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical, cosmetic and/or foodstuff composition, which have acceptable technical properties.
  • the present invention relates, in its various embodiments, to:
  • a pharmaceutical composition comprising a therapeutically or prophylactically active compound selected from the group of aldosterone antagonists, wherein at least about 10 w/w% of the active compound is present as a solid solution, preferable at least 15%, more preferred at least 20% and more preferred at least 25% or such as 25 to 50% being in solid solution.
  • a pharmaceutical composition of the invention having at least about 50 w/w% of the active compound present as a solid solution such as from 50% to 75% being in solid solution.
  • a pharmaceutical composition of the invention having at least about 75%, such as at least about 85%, such as at least 90%, or about 99 w/w% of the active compound present as a solid solution.
  • a pharmaceutical composition wherein the active compound is present in an amount corresponding to the solubility of the active compound in the amount of carrier present in the composition. This result in a composition with a substantial part in dissolved form. Futher, when the active compound is present in an amount exceeding the solubility of the active compound in the amount of carrier present in the composition, the preparation is for a composition where only a smaller part of the active compound is present in the dissolved form. For a substantially 100% solid solution the active compound is present in an amount below the solubility of the active compound in the amount of carrier present in the composition e.
  • the pharmaceutical composition may be one wherein the solubility of the active compound in the carrier is at least 1%, such as at least 2%, more preferred at least 5%, such as at least 7% more preferred at least 15% measured at the melting point of the carrier and as w/w. In a further embodiement wherein the solubility of the active compound in the carrier is at least 17% such as at least 20%, more preferred at least 25%, such as at least 30%, and still more preferred at least 40% measured at the melting point of the carrier and as w/w.
  • the amount of active compound in the composition is at least about 1w/w%, preferably at least about 3w/w%, more preferably at least about 5w/w%, most preferably at least about 10w/w%, especially at least about 15w/w%.
  • the compositoon according to the invention may further comprise a second active compound present in crystalline form or in amorphous form or the second active compound is present partly in amorphous form and partly in crystalline form.
  • the second active compound is preferable a diuretic.
  • a further aspect of the invention is a final dosage form comprising the composition according to the invention I the form of a tablet such as a tablet selected from an effervescent tablet, a chewable tablet, an immediate release tablet, a delayed release tablet, an extended release tablet, a coated tablet, a sugar coated tablet, a film coated tablet, a film coated extended release tablet a multilayer tablet, a multilayer extended release tablet, a orally disintegrating tablet, or in the form of a troche or a wafer.
  • a capsule such as an coated capsule, a film coated capsule, a gelatin coated capsule, a capsule for delayed delayed or extended release.
  • a final dosage form in the form of a granule, an effervescent granule, a delayed release granule, a granule for solution, a granule for suspension including extended release suspension, a chewing gum, in the form of a powder or pellet, e.g for the preparation of a solution or suspension.
  • the final dosage form comprises one or more active compounds in a part of the dosage form which is physical distinctive from the part of the dosage form comprising the composition.
  • the dosage form is a multilayer tablet, preferably comprising, a diuretic in one layer of the tablet and eplerenone in a different layer of the tablet.
  • the amount of the aldosterone antagonist when it is eplerenone present in the final dosage form is in an amount of from 5mg to 200mg such as in 5mg, 10mg, 12.5mg, 20mg, 25mg, 30mg, 35mg, 37.5mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg or 200mg.
  • a pharmaceutical composition of the invention having the active compound is dissolved in a polar lipid carrier.
  • a pharmaceutical composition of the invention having the polar lipid carrier selected from the group consisting of polyethylene glycols and polyoxyethylenes having a melting point of at least 20 0 C, esters and ethers of fatty acids such as acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof.
  • a pharmaceutical composition of the invention comprising one or more pharmaceutically acceptable excipients, for example selected from the group consisting of fillers, disintegrants, binders and lubricants.
  • a pharmaceutical composition of the invention which composition upon oral administration to a mammal in need thereof releases the active compound in a controlled manner and exhibits a relative AUC/AUCcont r oi value of at least about 1.0, the AUC values being determined under similar conditions; for example wherein the relative AUC/AUC CO nt r oi value is at least about 1.1 , preferably at least about 1.2, more preferably at least about 1.3, more preferably at least about 1.5, more preferably at least about 2.0 or more, the AUC values being determined under similar conditions.
  • the pharmaceutical composition of the invention comprising one or more release modifying agents, for example a polymer or a mixture of polymers, for example selected from the group consisting of cellulose derivatives such as hydroxyl propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose; poloxamers, polyethylene glycols, polyoxyethylene stearates, poly- epsilon-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA (Kollidon VA64), poly-methacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), polyvinyl alcohol (PVA) and poly(ethylene oxide) (PEO).
  • cellulose derivatives such as hydroxyl propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),
  • the pharmaceutical composition of the invention comprising a polymer having variable solubility in water in dependence of pH and, further, is selected from the group consisting of polyacrylamides; phthalate derivatives, preferably acid phthalates, of carbohydrates, including amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate, cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HMPCP), methylcellulose phthalate, methyl cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate; polyvinyl acetate phthalate (PVAP); cellulose derivatives including hydroxy hydroxy
  • composition of the invention in particulate form wherein the particles have a geometric weight mean diameter d gw of at least 10 micrometer, preferably at least 20 micrometer, more preferably between from about 20 micrometer to about 2000 micrometer, more preferably between from about 30 micrometer to about 2000 micrometer, more preferably between from about 50 micrometer to about 2000 micrometer, more preferably between from about 60 micrometer to about 2000 micrometer, more preferably between from about 75 micrometer to about 2000 micrometer, more preferably between from about 100 micrometer to about 1500 micrometer, more preferably between from about 100 micrometer to about 1000 micrometer, more preferably between or from about 100 micrometer to about 700 micrometer, especially between from about 50 micrometer to about 400 micrometer, more especially from about 50 micrometer to about 350 micrometer, even more especially from between about 50 micrometer to about 300 micrometer, in particular from between 100 micrometer to about 300 micrometer.
  • a method for the preparation of a pharmaceutical composition of the invention comprising the step of dissolving or dispersing an aldosterone antagonist in a polar lipid solid carrier to obtain a solid solution, optionally further comprising the step of contacting the solid solution with a release modifying agent, optionally in admixture with one or more pharmaceutically acceptable excipients, optionally wherein the solid solution in liquidized form is spraying onto the release modifying agent.
  • composition of the invention for the preparation of a medicament in an immediate release solid dosage form, or for the preparation of a medicament in a controlled release solid dosage form, or for the preparation of a medicament in a sublingual dosage form, or for the preparation of a medicament in an oral dosage form.
  • compositions of the invention for the preparation of a medicament in a final dosage form comprising loading the composition in liquid state to a porous material for incorporation into a capsule or for loading of a porous tablet.
  • Suitable methods and porous tablets is disclosed in PCT publication WO 2006/000229 A2 published 5 January 2006 which is hereby incorporated by reference.
  • a solid solution for pharmaceutical use comprising eplerenone dissolved in a polar lipid carrier or vehicle, wherein the amount or concentration of eplerenone in the carrier is less than 40% w/w, preferably less than 30w/w%, preferably less than 25w/w%, more preferably less than 20w/w%, even more preferably less than 15w/w%, most preferably less than 10w/w%, especially less than 5w/w%, more especially less than 2w/w%.
  • the amount of eplerenone in the solid solution of the invention is preferably at least 0.01w/w%, preferably at least 0.05w/w%, more preferably at least 0.1w/w%, most preferably at least 0.5w/w%, especially at least 1w/w%.
  • the solid carrier should be present in from 60 to 98% w/w of the solid solution.
  • the concentration of eplerenone in the polar lipid carrier is at the most 40% w/w such as, e.g., at the most 35% w/w, at the most 30% w/w, at the most 25% w/w, at the most 20% w/w, at the most 10% w/w or at the most 5% w/w.
  • the concentration of eplerenone in the solid carrier ensures that the eplenerone is rapidly dissolved upon ingestion and, furthermore, the solid carrier may aid in releasing eplerenone in a suitable manner.
  • the concentration of eplerenone in the polar lipid carrier is at least about 0.1% w/w such as, e.g., at least about 0.5% w/w, at least about 1.0% w/w, at least about 5.0% w/w
  • eplerenone may be used in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates including the hydrate, anhydrate, complexes thereof etc.).
  • the polar lipid carrier or vehicle is selected from the group consisting of polyethylene glycols and polyoxyethylenes having a melting point of at least 20 0 C, esters and ethers of fatty acids such as acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof.
  • esters and ethers of fatty acids such as acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof.
  • polar lipids are lipid type substances which forms structured aggregates with water at temperatures up to 100 degrees.
  • polar lipids examples include esters and ethers of fatty acids like acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof.
  • Polymers like POE and PEG are considered to be waxes.
  • fatty acids alone are considered to belong to polar lipids.
  • the polar lipid carriers that can be used in the solid solution according to the invention is a monoglycerider like glyceryl monooleate, glyceryl mono laurate, glyceryl mono caprate,
  • the polar lipid carrier for use in a solid solution according to the invention is e.g. polyglycolised glycerides including Gelucire 50/13, or other Gelucire types such as, e.g., Gelucire 44/14 etc., Gelucire 50/10, Gelucire 62/05.
  • the present invention relates to a composition, preferably a pharmaceutical composition, in particulate form comprising eplerenone together with one or more pharmaceutically acceptable excipients, wherein the composition upon oral administration to a mammal in need thereof exhibits an AUC/AUC C ⁇ ntro i value of at least about 1.0, the AUC values being determined under similar conditions.
  • the composition used as a control is given in the same dosage and is a commercially available Eplerenone composition intended for oral administration. In the present context, it should be understood that the control composition is Inspra ® 50 mg tablets.
  • the bioavailability obtained after administration of a composition according to the invention may be improved.
  • the AUC/AUCcontroi value of the inventive composition is at least about 1.0 such as about 1.1 or more, about 1.2 or more, about 1.3 or more, about 1.5 or more, about 2.0, the AUC values being determined under similar conditions.
  • composition of the invention may further comprise a second or even a third therapeutically, diagnostically or prophylactically active compound selected from the group consisting of beta-blockers such as metoprolol, bisabolol, carved ilol, pindolol, propranolol, nadolol, atenolol, esmolol, acetobutolol, labetalol, timolol; diuretics such as acetazolamide, dichlorphenamide, methazolamide (i.e.
  • beta-blockers such as metoprolol, bisabolol, carved ilol, pindolol, propranolol, nadolol, atenolol, esmolol, acetobutolol, labetalol, timolol
  • diuretics such as acetazolamide, dichlorphenamide, methazolamide (i.e.
  • loop diuretics such furosemide, bumetamide, ethacrynic acid, torsemide, azosemide, muzolimine, piretanide, tripamide
  • thiazide and thiazide-like diuretics such as bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone
  • angiotensin Il receptor antagonists such as candesartan, cilexetil, irbesartan, losartan, telmisartan, valsa tartan eprosartan
  • ACE inhibitors such as captopril, enalapril, enalaprilat, fosinopril sodium, lisinopril,
  • the solid solution according to the invention may be prepared according to methods known by a person skilled in the art such as, e.g. by dissolution of the two components (Eplerenone and the polar lipid carrier) in a suitable solvent followed by evaporation of the solvent or it may be prepared by heating one or both of the components to accelerate dissolution of Eplerenone in the carrier or to melt the carrier together with Eplerenone, or simply disperse the finely divided particles in the melted carrier.
  • Solid solutions can be prepared by dissolving a physical mixture of the active compound Eplerenone and the carrier in a common organic solvent, followed by evaporation of the solvent.
  • the carrier is a hydrophilic polymer.
  • Suitable organic solvents include pharmaceutical acceptable solvents in which the active compound is soluble such as methanol, ethanol, methylene chloride, chloroform, ethylacetate, acetone or mixtures thereof.
  • Suitable water soluble carriers include polar lipid carriers mentioned above.
  • diethylene monoglycol ether is used as the carrier either alone or in combination with one or more other carriers mentioned above.
  • the solubility of eplerenone in Trancutol P is10% w/w when heated to 80 0 C. Upon spontaneous cooling of the warm solution to room temperature, partial precipitation of eplerenone gradually takes place. However this precipitation is decreased with crystal inhibitors.
  • various crystal inhibitors according to the present invention nclude polyvinylpyrrolidone in various molecular weights K12, K25, K30 and K90, polysorbate, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol, maltodextrines, sugars etc.
  • the stabilibizing effect of crystal inhibitors may involve fast solidification arresting the active in the dispersed state where every single crystallite of the drug is intimately encircled by the carrier composition and or a solubility factor and/or an increased solubility.
  • the solid state is favorable in the sense of stabilizing the physical state of dissolved eplerenone in a otherwise liquid like Transcuol P upon cooling, in the sense of reducing potential chemical degradation and in the sense of providing the formulation with better tablet technological properties.
  • an improved compatibility to hard capsule shells of various material gelatine, HPMC, polysaccharide
  • a formulation containing Transcutol P in the solid state due to a decreased interaction potential from Transcutol P being otherwise described as incompatible with hard capsules.
  • composition according to the present invention may comprise a carrier or carrier system which comprises different substances which may be completely miscible wherein the solubility of the active may be higher than in the individual components.
  • the active compound may be soluble in one or more of the components. In the present context this is also considered a solid solution according to the invention.
  • the solid solution is preferably formed by spray drying techniques, controlled agglomeration, freeze-drying or coating on carrier particles or any other solvent removal process.
  • the dried product contains the active compound present in the form of a solid solution.
  • an especially suitable method is by dissolving Eplerenone in the carrier and then spraying this solution on a powder or powder mixture using a controlled agglomeration method described in WO 03/004001 (by the same Applicant). Stabilizing agents etc. may be added in order to ensure the stability of the solid solution. Details concerning the controlled agglomeration method are given in the above-identified publication, which is hereby incorporated by reference as well as in the Examples herein.
  • the invention provide a process for preparing a particulate pharmaceutical material comprising Eplerenone which method comprises spraying a first composition in liquid form, said composition preferably being a solid solution of Eplerenone into a second composition comprising a support, said second composition e.g. being in the fluidised state and having a temperature less than the melting point of the carrier.
  • the active compound may be present in the carrier composition and/or in the second composition.
  • the particulate material of a pharmaceutical composition has a geometric weight mean diameter d gw of ⁇ 10 ⁇ m such as, e.g. ⁇ 20 ⁇ m, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g.
  • the solid material obtained by the above-mentioned method is in particulate form that has suitable properties with respect to flowability and/or compressibility and is therefore suitable for further processing into pharmaceutical dosage forms.
  • compositions for immediate release It is an advantage of a solid solution according to the invention that it provides a system that can be used in the preparation of several dosage forms and due to the fact that Eplerenone is present in solid solution and thereby readily releasable it is a suitable system both for immediate release compositions as well as for controlled release compositions.
  • the immediate release compositions may be the solid solution as such or, more preferred, in the form of an oral dosage form wherein the solid solution is present in admixture with pharmaceutically acceptable excipients that do no intend to significally delay the release of Eplerenone from the composition.
  • An immediate release composition normally release at least about 50% of the Eplerenone contained in the composition within at the most about 2 hours, as determined by a suitable dissolution test such as, e.g., described in Ph. Eur.
  • the invention provides a pharmaceutical composition or a solid dosage form that releases Eplerenone relatively fast so as to enable a relatively fast onset of therapeutic effect.
  • at least about 50% w/w of Eplerenone contained in the composition is released within at the most about 1.5 hours such as, e.g., within at the most about 1 hour, within at the most about 0.75 hours or within at the most about 0.5 hours employing a suitable dissolution method.
  • At least about 55% w/w such as, e.g., at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w or at least about 85% w/w of Eplerenone is release within at the most about 1.5 hours such as, e.g., within at the most about 1 hour, within at the most about 0.75 hours or within at the most about 0.5 hours employing a suitable dissolution method.
  • an immediate release composition normally has a disintegration time of at the most 60 min such as, e.g., at the most about 45 min, at the most about 30 min, at the most about 15 min or at the most about 10 min when tested according to Ph. Eur.
  • a controlled release composition typically comprises the solid solution in admixture with one or more release modifying agents and, optionally, further one or more pharmaceutically acceptable excipients.
  • release modifying agents are typically selected from the group consisting polymers, water-miscible and water immiscible polymers and, in a specific embodiment the resulting mixture is a solid mixture.
  • a polymer for use as a release modifying agent is a cellulose derivative selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose; poloxamers, polyoxyethylene stearates, poly- ⁇ -caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA
  • the release modifying agent is a cellulose derivative like e.g. hydroxypropyl methylcellulose. Pectinates, alginates galactomannans, xanthan gums.
  • the polymer for use as a release modifying agent is a polymer that has a pH-dependant water-solubility and the polymer is selected from the group consisting of polyacrylamides; phthalate derivatives such as acid phthalates of carbohydrates including amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HMPCP), methylcellulose phthalate, methyl cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate; phthalates of other compounds including polyvinyl phthalate,
  • the release modifying agent is a water-insoluble polymer that is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose nitrate, and the like.
  • a solid solution according to the present invention serves as a suitable basic material to provide pharmaceutical compositions and solid dosage forms for improved treatment of conditions that respond to Eplerenone treatment, especially to oral and sublingual.
  • the release may be pH dependant, i.e. the release predominantly takes place after passage of the stomach.
  • a pH dependent release is mainly provided by means of enteric coating material as described herein (polymers that have pH-dependant solubility).
  • the release may also be pH independent, e.g. by providing the composition with a controlled release coating such as, e.g. a cellulose based coating like e.g. ethylcellulose or by providing the composition in the form of a matrix composition such as, e.g., a hydrophilic cellulose polymer matrix type e.g. based on HPMC.
  • a combination may of course also be employed.
  • the change in bio-availability and/or the changes in other bio-availability related parameters are normally determined by in vivo studies in a suitable animal model testing the compositions in question together with e.g. Inspra® or a similar commercially available Eplerenone- or Eplerenone-containing product.
  • Inspra® a similar commercially available Eplerenone- or Eplerenone-containing product.
  • Eplerenone- or Eplerenone-containing product e.g.
  • the use of a dog model for establishing evidence of the bioavailability of certain formulations is general practice in the pharmaceutical industry.
  • the studies relevant for Eplerenone/Eplerenone are non-radomized, cross-over studies, where each dog is its own control. Four dogs and four treatments are normally applied. As no intraveneous injections are given, the bio-availabilities obtained are relative.
  • the pharmaceutical compositions according to the invention provide significant higher bioavailability of Eplerenone, which may reduce the daily dosage. Furthermore, the compositions provide a more reproducible plasma profile and AUC.
  • Eplerenone compositions As mentioned above, one of the major challenges with respect to formulation of Eplerenone compositions is the low and highly variable absorption of an orally administered dosage owing to the poor water solubility of Eplerenone/Eplerenone.
  • a further advantage of a composition of the present invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to traditional oral treatment. Accordingly, upon oral administration to a mammal in need thereof a pharmaceutical composition according to the invention releases Eplerenone in such a state, that a larger fraction of the drug is absorbed and absorbed more reproducible than Inspra® or a similar commercially available Eplerenone-containing product.
  • the products are substantially bioequivalent.
  • Parameters often used in bioequivalence studies are t maXj c ma ⁇ , AU Co-infinity, AUCn-t- Other relevant parameters may be W 50 , W 75 and/or MRT. Accordingly, at least one of these parameters may be applied when determining whether bioequivalence is present. Furthermore, in the present context, two compositions are regarded as bioequivalent if value of the parameter used is within 80-125% of that of Inspra® or a similar commercially available Eplerenone-containing product used in the test.
  • Delayed release is mainly brought about by some kind of enteric coating. Whereas semipermeable coating will show some kind of delayed release, it does not provide an adequate or sufficient delay of the release profile. Additionally it requires a certain amount of time to release the content.
  • the coating sought for this invention is a pH dependant coating. This type of coating is very resistant to release of drug until a certain pH is reached. Within a very small increment of pH (1/10), the film alters properties and becomes permeable. Examples of pH-sensitive polymers are mentioned hereinbefore.
  • pH-sensitive polymers of specific interest include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropyl methylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers.
  • the release of the active compound from a composition having a delayed release coating could also be an enzymatic reaction, if for example Zein or mono/di-glyceride mixtures are employed as coating material.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Eplerenone together with one or more pharmaceutically acceptable excipient, wherein the composition upon oral administration to a mammal in need thereof in a controlled manner releases at least about 80% w/w within 0.75 hours or more, such as, e.g., at least about 50% w/w of the total amount of Eplerenone within about 24 hours, such as, e.g., within about 22 hours, within about 20 hours, within about 18 hours, within about 15 hours or within about 12 hours.
  • Eplerenone is released 15 hours after oral administration to a mammal of a composition according to the invention or, alternatively, when tested in a suitable in vitro dissolution test, 15 hours after start of such a test.
  • composition according to the invention releases at least about 50% w/w of the total amount of Eplerenone and/or an analogue thereof within about 10 hours such as, e.g., within about 8 hours, within about 6 hours, within about 4 hours or within about 3 hours.
  • a pharmaceutical composition according to the invention upon oral administration to a mammal in need thereof, releases at least 80% w/w Eplerenone after about 0.5 hours or more such as, e.g., after about 0.75 hours or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more or about 5 hours or more; or alternatively, when tested in a suitable in vitro dissolution test releases at least 80% w/w after about 0.5 hours or more such as, e.g., after about 0.75 hours or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more or about 5 hours or more after start of the test.
  • Suitable conditions for the in vitro dissolution test are employing USP dissolution test (paddle method) and a buffer pH 7.5 containing 2.5% SDS and 1g/ml_ of pancreatin as dissolution medium.
  • the following conditions are fulfilled with respect to in vitro dissolution test: i) at least about 50% w/w of the total amount of Eplerenone is released within about 10 hours such as, e.g., within about 8 hours, within about 6 hours, within about 4 hours, within about 3 hours, within about 2 hours, within about 1 hour, within about 45 min, within about 30 min or within about 15 min, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5 ii) at least about 50% w/w of the total amount of Eplerenone is released within about 1.5 hours such as, e.g., within about 1 hour, within about 0.75 hours, within about 0.5 hours or within about 20 minutes, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5.
  • iii) at least about 55% w/w such as, e.g., about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more or about 80% w/w or more of the total amount of Eplerenone is released within about 15 hours such as, e.g., within about 12 hours, within about 10 hours, within 8 hours or within about 6 hours, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5 iv) at least about 55% w/w such as, e.g., about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more or about 80% w/w or more of the total amount of Eplerenone is released within about 5 hours such as, e.g., within about 4 hours, within about 3 hours, within about 2 hours, within about 1 hours or within
  • the composition is designed to have a delayed release of Eplerenone. Therefore, the invention also includes a pharmaceutical composition in particulate form comprising Eplerenone together with one or more pharmaceutically acceptable excipient, wherein the composition upon oral administration to a mammal in need thereof has a delayed release of Eplerenone so that at the most 10% w/w such as, e.g., at the most about 7.5% w/w or at the most about 5% w/w of the total amount of Eplerenone is released within the first two hours such as, e.g., within the first hour after administration.
  • a pharmaceutical composition in particulate form comprising Eplerenone together with one or more pharmaceutically acceptable excipient
  • the composition is designed to release the Eplerenone within a few minutes. This is the case when sublingual formulations are used.
  • the following conditions are fulfilled with respect to in vitro dissolution test performed under acidic conditions: i) at the most about 30% w/w such as, e.g., at the most about 25% w/w, at the most about 20% w/w, at the most about 15% w/w or at the most about 10% w/w of the Eplerenone is released within 2 hours in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 5 such as, e.g.
  • the most about 40% w/w such as, e.g., at the most about 30% w/w, at the most about 25% w/w or at the most about 20% w/w of the Eplerenone is released within 6 hours when tested in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 4.5 such as, e.g.
  • the most about 30% w/w such as, e.g., at the most about 25% w/w, at the most about 20% w/w or at the most about 15% w/w of the Eplerenone is released within 4 hours when tested in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 4.5 such as, e.g. at the most about 4.0, at the most about 3.5, at the most about 3, at the most about 2 or at the most about 1.5, and/or
  • composition of the invention may also comprise a further therapeutically, prophylactical and/or diagnostically active compound.
  • a further therapeutically, prophylactical and/or diagnostically active compound may also comprise a further therapeutically, prophylactical and/or diagnostically active compound.
  • any combination of Eplerenone and other aldosterone antagonist is contemplated.
  • a solid solution according to the invention is especially suitable for processing into oral dosage from, e.g. involving a step of spraying the solid solution onto one or more suitable pharmaceutically acceptable excipients (optionally in admixture with other substances like e.g. other therapeutically active compounds etc).
  • suitable pharmaceutically acceptable excipients optionally in admixture with other substances like e.g. other therapeutically active compounds etc.
  • dosage forms for oral administration are of interest e.g. tablets, sachets, capsules etc.
  • a person skilled in the art know how to produce suitable dosage form e.g. with reference to Remington's Pharmaceutical Science.
  • excipients for use in a composition or solid dosage form according to the invention include fillers, diluents, disintegrants, binders, lubricants or mixtures thereof.
  • the choice of excipients is normally made taken such different uses into considerations.
  • Other pharmaceutically acceptable excipients for suitable use are e.g. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, humectants, sweetening agents, wetting agents etc.
  • suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, ⁇ -lactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g.
  • lactose e.g. spray-dried lactose, ⁇ -lactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®
  • microcrystalline cellulose variant grades of
  • methylcellulose polymers such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbon
  • diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
  • disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.
  • binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
  • Glidants and lubricants may also be included in the composition.
  • examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
  • excipients which may be included in a composition or solid dosage form of the invention are e.g. flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc.
  • additives in a composition or a solid dosage form according to the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butyl ated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc.
  • the carrier composition may also contain e.g. stabilising agents.
  • the concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.
  • a composition or solid dosage form according to the invention may also include one or more surfactants or substances having surface-active properties. It is contemplated that such substances are involved in the wetting of the slightly soluble active compound and thus, contributes to improved solubility characteristics of the active compound.
  • Suitable excipients for use in a composition or a solid dosage form according to the invention are surfactants such as, e.g., amphiphillic surfactants as those disclosed in WO 00/50007 in the name of Lipocine, Inc.
  • suitable surfactants are i) polyethoxylated fatty acids such as, e.g. fatty acid mono- or diesters of polyethylene glycol or mixtures thereof such as, e.g.
  • mono - or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, and the polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30,
  • esters like the above-mentioned but in the form of glyceryl esters of the individual fatty acids; iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters with e.g. vegetable oils like e.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like, iv) polyglycerized fatty acids like e.g.
  • vegetable oils like e.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like
  • polyglycerized fatty acids like e.g.
  • glyceryl monooleate glyceryl dioleae, glyceryl mono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.
  • sterol and sterol derivatives viii) polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG with the various molecular weights indicated above, and the various Tween ® series
  • polyethylene glycol alkyl ethers such as, e.g. PEG oleyl ether and PEG lauryl ether
  • sugar esters like e.g.
  • sucrose monopalmitate and sucrose monolaurate xi) polyethylene glycol alkyl phenols like e.g. the Triton® X or N series; xii) polyoxyethylene-polyoxypropylene block copolymers such as, e.g., the Pluronic® series, the Synperonic® series, Emkalyx®, Lutrol®, Supronic® etc.
  • polymers The generic term for these polymers is "poloxamers" and relevant examples in the present context are Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407; xiii) sorbitan fatty acid esters like the Span® series or Ariacel® series such as, e.g.
  • the concentration of the surfactant(s) is normally in a range of from about 0,1 - 80% w/w such as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w, or alternatively, from about 0.10 to about 80% w/w such as, e.g. from about 10 to about 70% w/w, from about 20 to about 60% w/w or from about 30 to about 50% w/w.
  • At least one of the pharmaceutically acceptable excipients may be selected from the group consisting of silica acid or a derivative or salt thereof including silicates, silicon dioxide and polymers thereof; magnesium aluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite.
  • Such materials are is especially useful as a sorption material for liquid material.
  • the material is used as a sorption material for the polar lipids.
  • the material that has the ability to function as a sorption material for the polar lipids are also denoted "sorption material".
  • the pharmaceutically acceptable excipient may comprise a silica acid or a derivative or salt thereof such as, e.g., silicon dioxide or a polymer thereof as a pharmaceutically acceptable excipient.
  • Dependent on the quality employed a silicon dioxide may be a lubricant or it may be an sorption material. Qualities fulfilling the latter function seem to be most important.
  • a composition or solid dosage form according to invention comprises a pharmaceutically acceptable excipient that is a silicon dioxide product that has properties corresponding to Aeroperl® 300, (available from Degussa, Frankfurt, Germany). As it appears from the examples herein, very suitable materials are Aeroperl® 300 and Nuesellin and including materials with properties like or corresponding to those of them.
  • compositions or dosage forms according to the invention are very advantageous for the preparation of pharmaceuticals, wherein the composition comprises a polar lipid.
  • One of the advantages is that is it possible to incorporate a relatively large amount of low melting polar lipids e.g. at room temperature and still have a solid granulate.
  • a sorption material according to the invention it is possible to prepare solid compositions with a relatively high load of low melting materials by use of a sorption material according to the invention.
  • the sorption material for use in the processing into solid compositions normally absorbs about 5% w/w or more, such as, e.g., about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 55% w/w or more, about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more, about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more of a polar lipid and is still a solid material.
  • the tablets prepared in the Examples herein were subject to at test for tablet hardness employing Schleuniger Model 6D apparatus and performed in accordance with the general instructions for the apparatus.
  • geometric weight mean diameter d gw The geometric weight mean diameter was determined by employment of a method of laser diffraction dispersing the particulate material obtained (or the starting material) in air.
  • the measurements were performed at 1.5 bar dispersive pressure in Malvern equipment, which records the distribution of the equivalent spherical diameter. This distribution is fitted to a log normal volume-size distribution.
  • the dissolution rate was determined by employment of USP paddle dissolution method at 37 0 C.
  • WO 03/004001 For the preparation of a pharmaceutical composition in solid form according to the invention the method described in WO 03/004001 (by the present inventors) has been employed.
  • the method ensures a controlled agglomeration process, i.e. a strict control of the growth in particle size while at the same time it is possible to use a relatively large amount of a low melting polar lipid or other low melting surfactants.
  • HPMC refers to Metolose 90 SH (type 2208) or Metolose 60 SH (type 2910) from ShinEtsu, available in different degree of polymerisation (viscosity, 3-100.000 cP). Tablets, capsules or granules might be enteric coated with different types of polymers such as hydroxypropylmethylcellulose acetate succinate (Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulose phtalate HPMCP or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100/S, Eudragit 100/L.
  • Aqoat hydroxypropylmethylcellulose acetate succinate
  • CAP cellulose acetate phthalate CAP
  • HPMCP hydroxypropylmethylcellulose phtalate HPMCP
  • methacrylic acid copolymers such as Eudragit L30D, Eudragit 100/S, Eudragit 100/L.
  • Eplerenone may be mixed/dissolved in a mixture of Glyceryl mono caprate and Glyceryl mono laurate (60:40 w/w ratios) at 70 0 C.
  • the solution is sprayed on 250 g lactose in a fluid bed Strea-1.
  • the granular product is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
  • the mixture may be compressed into 11 mm tablets with strength of 100 mg (693) mg tablet with compound cup shaped. Desired mean disintegration time: 20 min, desired hardness: 45 N
  • Modified release matrix tablet based on lipophilic matrix of glyceryl monolaurate Substance % Mg
  • Eplerenone may be mixed/dissolved in Glyceryl monostearate at 70 0 C.
  • the solution is sprayed on 250 g lactose in a fluid bed Strea-1.
  • the granular product is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
  • the mixture may be compressed into 8 mm tablets with a strength of 100 mg (750 mg tablet) with compound cup shape. Desired mean disintegration time: 20 min, Hardness: 45 N
  • the tablets may be subjected to dissolution testing without further coating, as descriped below.
  • Eplerenone may be mixed/dissolved in Gelucire at 70 0 C.
  • the solution is sprayed on 250 g lactose in a fluid bed Strea-1.
  • the granular product is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
  • the mixture may be compressed into 13 mm tablets with strength of 100 mg (700 mg tablet) with compound cup shape. Desired mean disintegration time: 20 min, Desired hardness: 45 N
  • These tablets may be coated with a "delayed" release coating.
  • a composition of the coating is shown in the table below.
  • Triethyl acethylcitrate, antifoam emulsion and purified water are mixed by Ultra Turrax at 9500 rpm for 30 min. After 1 min talcum is added. The mixture is strained through sieve 300 and stirred by magnet. Eudragit is strained through sieve 300 and added the mixture. Stirring for 5 min. The coating is stirred throughout the coating process.
  • the process condition of the coating process is shown in the following table.
  • the film coated tablets is cured for 48 hours at 30 0 C before dissolution testing.
  • Standard dissolution USP is used.
  • Eplerenone is quantified by HPLC.
  • Desired dissolution profile for example 5 Tablets of Eplerenone

Abstract

A pharmaceutical composition comprising a therapeutically or prophylactically active compound selected from the group of aldosterone antagonists, wherein the active compound is present as a solid solution.

Description

A pharmaceutical composition comprising an aldosterone antagonist
Field of the invention The present invention relates to pharmaceutical compositions comprising a solid solution of an aldosterone antagonist and a method of preparation thereof. More specifically, the pharmaceutical composition comprises spironolactone or eplerenone dissolved in a solid polar lipid carrier. The invention further relates to combinations of an aldosterone antagonist with other antihypertensives such as, for example, beta-blockers.
Background of the invention
Aldosterone antagonists are inhibitors of the mineral corticosteroid aldosterone. Both spironolactone and eplerenone are competitive antagonist of aldosterone. They are equally effective but eplerenone are much more selective and binds to androgen and eplerenone receptors to a much lesser extend than spironolactone and hence do not cause significant sexual alterations.
Aldosterone antagonists are used therapeutically and prophylatically in both men and women for different purposes. At present, aldosterone antagonist are prescribed for example for hyper aldosteroism, for hypertension and for prevention of myocardial infarct. It is contemplated that aldosterone antagonists may also be useful therapeutically or prophylactically for cardiac hypertrophy, iscemic diseases in general, myocardial fibrosis and vascular fibrosis.
At present, aldosterone antagonists are commercially available in oral, and parenteral dosage forms, for example under the trade names (depending on country and local regulations) Spirix, Aldactone (spironolactone); lnspra (eplerenone). Spironolactone has the structural formula:
Figure imgf000002_0001
Molecular weight: 416.58; practically insoluble in water and practically independent of pH; melting point around 1340C. Commercial formulations of spironolactone (sold under the name Aldactone.TM.) contain 25, 50 or 100 mg doses of spironolactone in a matrix comprising, among other carrier materials, calcium sulfate dihydrate as a diluent, maize starch as a disintegrant, povidone K- 30 as a binding agent, magnesium stearate as a lubricant, and flavor, colorant, and coating ingredients that include hydroxypropylmethylcellulose and polyethylene glycol 400. Eplerenone has the structural formula:
Figure imgf000003_0001
Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy- 17-hydroxy-3-oxo-, gamma-lactone, methyl ester, (7alpha,11alpha,17alpha)-. Its empirical formula is C24H30O6 and it has a molecular weight of 414.50. Log P = 7.1 The recommended daily dosage of Spironolactone is between 25 and 600 mg. based on single or multiple dosing. The recommended daily dosage of Eplerenone is from 25 to 150 mg.
Both Spironolactone and Eplerenone are metabolized through CYP 3A4. They both have a relative long half-life, and any delay of the release would only serve as a mean to avoid the upper Gl tract metabolism.
Due to the poor water solubility several attempts for the preparation of improved products has been disclosed in the prior art.
US 6,495,165 discloses particulate Eplerenone in the form of micronized Eplerenone in pharmaceutical products resulting in immediate products with a Tmax within 1.8h and Cmax of at least 1500 ng/ml. Wetting agents are suggested including sodium lauryl sulfate. The bioavailability in dogs were increased by reducing the particle size from less than about 212 to 36 microns.
The US patents 6,410,054; 6,534,093; 6,558,707 and 6,863,902 relate to immediate release procucts with micronized Eplerenone. WO 01/41770 A2 discloses the compositions and manufacture of "nano particulate eplerenone". The nano-sized drug compound is obtained by simple mechanical grinding
Co-therapy methods for treating a cardiovascular such as heart failure and hypertension with an angiotensin converting enzyme inhibitor and eplerenone optionally together with diuretics and digoxin is known from the prior art (US 6,747,020 and 6,410,524) However, there is still a need for novel pharmaceutical compositions comprising an aldosterone antagonist, for example eplerenone, having improved properties resulting in an increased bioavailability and a decreased variability compared to Inspra™, as well as a simple and cost effective manufacturing process. The object of the present invention is to provide means for an improved, cost effective manufacturing process with good physical stability and bioavailability especially of Eplerenone and/or decreased variability in pharmacokinetic parameters including plasma level after oral administration to a subject in need thereof.
Summary of the invention
Increase in surface area by producing smaller drug particles is a well known technology for increasing the bioavailability of poorly soluble drugs. The microparticles or the nanoparticles is then used in the formulation with various pharmaceutical excipients for the preparation of the final product.
However, handling and processing with the nano and microparticles involve a number of problems as the small particles very easily form aggregates which reduce the surface area for wetting and dissolution. The effect of the reduced particle size may be lost if specific procedures are not employed in order to reduce the aggregates to primary particles either during the processing or directly on the micro- or nanoparticle before processing. The agglomerates of active compound otherwise formed may differ in size, density, flowability etc, which again complicates the control of processes involved in the preparation of a well defined final formulation with respect to dissolution characteristics, uniformity and content of active compound. According to one aspect of the present invention, the conventional size-reducing step to micro- or nanoparticels as well as any de-aggregation step are made superfluous by preparing solid dispersions in vehicles which by virtue of their solubilizing properties in relation to the active compound, fully or partly dissolve the active ingredient and prevents agglomeration. Accordingly, the vehicles also have dispersing properties and is suitable for further processing by well known pharmaceutical processes.
A solid dispersion is a homogeneous mixture of one or more active ingredients in a pharmacologically inert matrix in the solid state. Various classes of solid dispersion can be produced according to the number of phases, physical state of the phase or phases and according to the physical state of the active ingredient in the mixture. Two phase systems include eutectic mixture where two (or more) crystalline phases are present and the amorphous suspension where the amorphous drug is suspended in either a crystalline or amorphous solid. One phase systems include glass solution where the physical state is amorphous or and a second one phase system is the solid solution where the physical state of the phase is crystalline (solid).
A solid solution may based on the extent of miscibility between the active compound and the vehicle be called complete to the extend that the two components are soluble at solid state in all proportions, however, this is seldom the case. Generally, as is also the situation of the present invention, there is only a limited solubility of the solute in the solvent. Exceeding this limitation of solubility, in the present context, the solubility of the active compound in the vehicle, will result in the presence of a fraction of the active compound not being on a molecular level in the solid. According to the compositions of the present invention, such fraction will however be dispersed in the solid.
Analytical methods for determination of a solid dispersion or solid solution include x- ray powder diffraction, differential scanning calorimetry (DSC),thermogravimetric analysis, microcalorimetry, infrared spectros copy, Raman spectroscopy, and dissolution kinetics.
In the determination of a solid solution it is generally the absence of crystals which is relevant. A single Tg temperature (DSC) within the Tg values of the drug and excipients alone is indicative of an amorphous solution; X-ray powder diffraction (XRPD) where the absence of sharp peaks in the diffractogram is indicative for a amorphous material etc. The quantitative determination of mixtures of amorphous material and crystals may require several technologies to give the full picture, however it is general considered that solid solutions below 5% can be detected.
The solid solutions according to the present invention still have the advantages of maximal reduced "particle size" to the molecular level and also the possibility of an intimate presence of a carrier system which can increase the wetting of the active as will as increase the solubility of the active in any diffusion layer surrounding the active in order to prevent local precipitation in the drug delivery system, a function which also increase the dissolution if drug in crystal form is also present in the solid.
Accordingly, the inventors have found that the pharmacokinetic properties of an eplerenone pharmaceutical product may be improved by administering eplerenone in the form of a pharmaceutical preparation comprising at least a part of eplerenone in solid solution and wherein the eplerenone is dispersed in a vehicle. The improved property may include a higher amount of eplerenone absorbed (increased AUC) or decreased variability in any measurable pharmacokinetic parameter including AUC between or within subjects compared with a similar formulation not comprising eplerenone in solid solution or in micronized form. Further, it is also contemplated that such a preparation may result in variability as mentioned above at least comparable with Inspra™ or other products comprising eplerenone and where this is present in micronized form of a particle size between 25 and 400 micron. This is done by a simple and easy method, which does not involve any time- consuming grinding or milling.
Accordingly, in a first aspect the present invention relates to a pharmaceutical composition comprising a therapeutically, prophylactically and/or diagnostically active compound selected from the group of aldosterone antagonists, wherein at least about 10% w/w% of the active compound is present as a solid solution and/or a solid dispersion, optionally in combination with at least one further therapeutically, prophylactically and/or diagnostically active compound.
In a second aspect, the invention provides a method for preparing the pharmaceutical composition of the invention, the method comprising the step of dissolving and/or dispersing the active compound in a polar lipid solid carrier, optionally followed by a step of contacting or mixing the solution with one or more release modifying agents and/or one or more pharmaceutically acceptable excipients.
Further, the present invention relates to the use of the composition of the invention for the preparation of a medicament, for example in immediate release solid dosage form, in a controlled release solid dosage form, in a sublingual dosage form, in oral dosage form.
Thus, the compositions of the present invention provide eplerenone in a form, which is freely accessible for absorption into the systemic circulation upon oral, and is ready for incorporation in the pharmaceutical compositions of the invention, for example a tablet for immediately or delayed release.
By providing a pharmaceutical eplerenone preparation having good bioavailability and low variation in plasma level, eplerenone dosage levels may be reduced. A lower dose and/or lower variability likely results in a beneficial reduction in dose-related side effects as unexpected high peaks or plasma concentrations may be decreased. However, the identification of such improved side effect profile will normally require extensive blinded clinical studies and the decreased variability in may directly be regarded as an increased safety of use as also inferior efficacy is avoided due to reduction in episodes of unexpected low bioavailability.
An important aspect of the invention is to make it possible to manufacture eplerenone products such as tablets easier and more cost efficient, without compromising bioavailability. The resulting final product may also have excellent storage stability.
Description of the invention DEFINITIONS When used herein, "geometric weight mean diameter" means the mean diameter of the log normal volume-size distribution. The term "solid dispersion" is a homogeneous dispersion of the active compound such as eplerenone in a pharmacologically inert vehicle, matrix or carrier in a solid state and includes fine solid particles dispersed in a solid vehicle, matrix or carrier, the particles being at a non-molecular level as well as at a molecular level, however the latter is referred to as a solid solution.
In the present context, the term "solid solution" of eplerenone denotes a homogeneous dispersion of the active compound such as eplerenone in a pharmacologically inert vehicle, matrix or carrier in a solid state where the eplerenone is present in a molecular level, or at lest close to monomolecular level. Close to monomolecular level includes absence or disappearance of crystals of the active compound as measured by well known techniques applied in the art.
In the present context, the solid vehicle, matrix or carrier is used as the solid solvent for the active compound. The solid vehicle, matrix or carrier may be comprised of pure components or mixtures of components including liquids, semi-solids and solids. The solid vehicle, matrix or carrier further include melted or otherwise liquefied substances which is solidified by cooling, by mixing with or absorption to solid material in order to obtain a material which is solid at room temperature (for instance at any temperature between 18° and 25°C).
In the present context, the term "polar lipid carrier" is intended to denote a carrier that is both hydrophilic and hydrophobic and, accordingly, can be admixed with eplerenone and water. It should be noted that the term "polar lipid" can be used interchangeable with amphiphilic and surfactant.
In the present context "W denotes the time to reach the maximal plasma concentration (cmax) after administration; AUCo-infinity denotes the area under the plasma concentration versus time curve from time 0 to infinity; AUC0-t denotes the area under the plasma concentration versus time curve from time 0 to time t; W50 denotes the time where the plasma concentration is 50% or more of Cmax; W75 denotes the time where the plasma concentration is 75% or more of Cmax; and MRT denotes mean residence time for eplerenone. The terms "controlled release" and "modified release" In the present context the terms
"controlled release" and "modified release" are intended to be equivalent terms covering any type of release of active compound or ingredient from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject. A person skilled in the art knows how controlled release/modified release differs from the release of plain tablets or capsules, which may exhibit immediate release of the active compound after administration. The terms "release in a controlled manner" or "release in a modified manner" has the same meaning as stated above. The terms controlled release/modified release include slow release (that results in a lower Cmax and later Uax. but t/2 is unchanged), extended release (that results in a lower Cmax, later tmax, but apparent t% is longer); delayed release (that result in an unchanged Cmax, but lag time and, accordingly, tmax is delayed, and t% is unchanged) as well as pulsatile release, burst release, sustained release, prolonged release, chrono-optimized release, fast release (to obtain an enhanced onset of action) etc. Included in the terms is also e.g. utilization of specific conditions within the body e.g. different enzymes or pH changes in order to control the release of the drug substance.
In the present context the terms "pharmaceutically acceptable excipient" are intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical, cosmetic and/or foodstuff composition, which have acceptable technical properties.
The present invention relates, in its various embodiments, to:
a. A pharmaceutical composition comprising a therapeutically or prophylactically active compound selected from the group of aldosterone antagonists, wherein at least about 10 w/w% of the active compound is present as a solid solution, preferable at least 15%, more preferred at least 20% and more preferred at least 25% or such as 25 to 50% being in solid solution.
b. A pharmaceutical composition of the invention having at least about 50 w/w% of the active compound present as a solid solution such as from 50% to 75% being in solid solution.
c. A pharmaceutical composition of the invention having at least about 75%, such as at least about 85%, such as at least 90%, or about 99 w/w% of the active compound present as a solid solution.
d. A pharmaceutical composition wherein the active compound is present in an amount corresponding to the solubility of the active compound in the amount of carrier present in the composition. This result in a composition with a substantial part in dissolved form. Futher, when the active compound is present in an amount exceeding the solubility of the active compound in the amount of carrier present in the composition, the preparation is for a composition where only a smaller part of the active compound is present in the dissolved form. For a substantially 100% solid solution the active compound is present in an amount below the solubility of the active compound in the amount of carrier present in the composition e. The pharmaceutical composition may be one wherein the solubility of the active compound in the carrier is at least 1%, such as at least 2%, more preferred at least 5%, such as at least 7% more preferred at least 15% measured at the melting point of the carrier and as w/w. In a further embodiement wherein the solubility of the active compound in the carrier is at least 17% such as at least 20%, more preferred at least 25%, such as at least 30%, and still more preferred at least 40% measured at the melting point of the carrier and as w/w. It may also be wherein the amount of active compound in the composition is at least about 1w/w%, preferably at least about 3w/w%, more preferably at least about 5w/w%, most preferably at least about 10w/w%, especially at least about 15w/w%.
f. The compositoon according to the invention may further comprise a second active compound present in crystalline form or in amorphous form or the second active compound is present partly in amorphous form and partly in crystalline form. The second active compound is preferable a diuretic.
g. A further aspect of the invention is a final dosage form comprising the composition according to the invention I the form of a tablet such as a tablet selected from an effervescent tablet, a chewable tablet, an immediate release tablet, a delayed release tablet, an extended release tablet, a coated tablet, a sugar coated tablet, a film coated tablet, a film coated extended release tablet a multilayer tablet, a multilayer extended release tablet, a orally disintegrating tablet, or in the form of a troche or a wafer. Alternatively, in the form of a capsule, such as an coated capsule, a film coated capsule, a gelatin coated capsule, a capsule for delayed delayed or extended release. In a futher alternative, a final dosage form in the form of a granule, an effervescent granule, a delayed release granule, a granule for solution, a granule for suspension including extended release suspension, a chewing gum, in the form of a powder or pellet, e.g for the preparation of a solution or suspension. In one aspect the final dosage form comprises one or more active compounds in a part of the dosage form which is physical distinctive from the part of the dosage form comprising the composition. In a still further aspect the dosage form is a multilayer tablet, preferably comprising, a diuretic in one layer of the tablet and eplerenone in a different layer of the tablet. The amount of the aldosterone antagonist when it is eplerenone present in the final dosage form is in an amount of from 5mg to 200mg such as in 5mg, 10mg, 12.5mg, 20mg, 25mg, 30mg, 35mg, 37.5mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg or 200mg.
h. A pharmaceutical composition of the invention having the active compound is dissolved in a polar lipid carrier. i. A pharmaceutical composition of the invention having the polar lipid carrier selected from the group consisting of polyethylene glycols and polyoxyethylenes having a melting point of at least 200C, esters and ethers of fatty acids such as acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof.
j. A pharmaceutical composition of the invention comprising one or more pharmaceutically acceptable excipients, for example selected from the group consisting of fillers, disintegrants, binders and lubricants.
k. A pharmaceutical composition of the invention, which composition upon oral administration to a mammal in need thereof releases the active compound in a controlled manner and exhibits a relative AUC/AUCcontroi value of at least about 1.0, the AUC values being determined under similar conditions; for example wherein the relative AUC/AUCCOntroi value is at least about 1.1 , preferably at least about 1.2, more preferably at least about 1.3, more preferably at least about 1.5, more preferably at least about 2.0 or more, the AUC values being determined under similar conditions.
I. The pharmaceutical composition of the invention in powder form.
m. The pharmaceutical composition of the invention comprising one or more release modifying agents, for example a polymer or a mixture of polymers, for example selected from the group consisting of cellulose derivatives such as hydroxyl propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose; poloxamers, polyethylene glycols, polyoxyethylene stearates, poly- epsilon-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA (Kollidon VA64), poly-methacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), polyvinyl alcohol (PVA) and poly(ethylene oxide) (PEO).
n. The pharmaceutical composition of the invention comprising a polymer having variable solubility in water in dependence of pH and, further, is selected from the group consisting of polyacrylamides; phthalate derivatives, preferably acid phthalates, of carbohydrates, including amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate, cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HMPCP), methylcellulose phthalate, methyl cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate; polyvinyl acetate phthalate (PVAP); cellulose derivatives including hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose, cellulose acetate trimellitate; alginates; carbomers; polyacrylic acid derivatives including acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, methacrylic acid copolymer (Eudragit L, Eudragit S); styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers; shellac, starch glycolate; polacrylin; and vinyl acetate and crotonic acid copolymers. The polymer may be selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose nitrate and mixtures thereof.
o. The composition of the invention in particulate form, wherein the particles have a geometric weight mean diameter dgw of at least 10 micrometer, preferably at least 20 micrometer, more preferably between from about 20 micrometer to about 2000 micrometer, more preferably between from about 30 micrometer to about 2000 micrometer, more preferably between from about 50 micrometer to about 2000 micrometer, more preferably between from about 60 micrometer to about 2000 micrometer, more preferably between from about 75 micrometer to about 2000 micrometer, more preferably between from about 100 micrometer to about 1500 micrometer, more preferably between from about 100 micrometer to about 1000 micrometer, more preferably between or from about 100 micrometer to about 700 micrometer, especially between from about 50 micrometer to about 400 micrometer, more especially from about 50 micrometer to about 350 micrometer, even more especially from between about 50 micrometer to about 300 micrometer, in particular from between 100 micrometer to about 300 micrometer.
p. A method for the preparation of a pharmaceutical composition of the invention, the method comprising the step of dissolving or dispersing an aldosterone antagonist in a polar lipid solid carrier to obtain a solid solution, optionally further comprising the step of contacting the solid solution with a release modifying agent, optionally in admixture with one or more pharmaceutically acceptable excipients, optionally wherein the solid solution in liquidized form is spraying onto the release modifying agent.
q. Use of the pharmaceutical composition of the invention for the preparation of a medicament in an immediate release solid dosage form, or for the preparation of a medicament in a controlled release solid dosage form, or for the preparation of a medicament in a sublingual dosage form, or for the preparation of a medicament in an oral dosage form.
r. Use of the pharmaceutical composition of the invention for the preparation of a medicament in a final dosage form comprising loading the composition in liquid state to a porous material for incorporation into a capsule or for loading of a porous tablet. Suitable methods and porous tablets is disclosed in PCT publication WO 2006/000229 A2 published 5 January 2006 which is hereby incorporated by reference.
In a first embodiment of the invention, there is provided a solid solution for pharmaceutical use comprising eplerenone dissolved in a polar lipid carrier or vehicle, wherein the amount or concentration of eplerenone in the carrier is less than 40% w/w, preferably less than 30w/w%, preferably less than 25w/w%, more preferably less than 20w/w%, even more preferably less than 15w/w%, most preferably less than 10w/w%, especially less than 5w/w%, more especially less than 2w/w%.
On the other hand, the amount of eplerenone in the solid solution of the invention is preferably at least 0.01w/w%, preferably at least 0.05w/w%, more preferably at least 0.1w/w%, most preferably at least 0.5w/w%, especially at least 1w/w%.
Accordingly, the solid carrier should be present in from 60 to 98% w/w of the solid solution. Thus, the concentration of eplerenone in the polar lipid carrier is at the most 40% w/w such as, e.g., at the most 35% w/w, at the most 30% w/w, at the most 25% w/w, at the most 20% w/w, at the most 10% w/w or at the most 5% w/w. The concentration of eplerenone in the solid carrier ensures that the eplenerone is rapidly dissolved upon ingestion and, furthermore, the solid carrier may aid in releasing eplerenone in a suitable manner. In order to obtain a suitable amount in the final composition there is a lower limit for the concentration of eplerenone in the composition. Thus, in a further aspect of the invention, the concentration of eplerenone in the polar lipid carrier is at least about 0.1% w/w such as, e.g., at least about 0.5% w/w, at least about 1.0% w/w, at least about 5.0% w/w
It is contemplated that any derivative or active metabolite of eplerenone is useful in the present invention.
Within the scope of the present invention, eplerenone may be used in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates including the hydrate, anhydrate, complexes thereof etc.).
The polar lipid carrier or vehicle is selected from the group consisting of polyethylene glycols and polyoxyethylenes having a melting point of at least 20 0C, esters and ethers of fatty acids such as acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof. Basically, polar lipids are lipid type substances which forms structured aggregates with water at temperatures up to 100 degrees.
Examples of useful polar lipids are esters and ethers of fatty acids like acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof. Polymers like POE and PEG are considered to be waxes. Also fatty acids alone are considered to belong to polar lipids.
In a preferred embodiment, the polar lipid carriers that can be used in the solid solution according to the invention is a monoglycerider like glyceryl monooleate, glyceryl mono laurate, glyceryl mono caprate, In yet another embodiment, the polar lipid carrier for use in a solid solution according to the invention is e.g. polyglycolised glycerides including Gelucire 50/13, or other Gelucire types such as, e.g., Gelucire 44/14 etc., Gelucire 50/10, Gelucire 62/05.
In another aspect, the present invention relates to a composition, preferably a pharmaceutical composition, in particulate form comprising eplerenone together with one or more pharmaceutically acceptable excipients, wherein the composition upon oral administration to a mammal in need thereof exhibits an AUC/AUCCθntroi value of at least about 1.0, the AUC values being determined under similar conditions. The composition used as a control is given in the same dosage and is a commercially available Eplerenone composition intended for oral administration. In the present context, it should be understood that the control composition is Inspra® 50 mg tablets.
As it appears from the Examples herein the bioavailability obtained after administration of a composition according to the invention may be improved. Thus, in specific embodiments of the invention, the AUC/AUCcontroi value of the inventive composition is at least about 1.0 such as about 1.1 or more, about 1.2 or more, about 1.3 or more, about 1.5 or more, about 2.0, the AUC values being determined under similar conditions.
The composition of the invention may further comprise a second or even a third therapeutically, diagnostically or prophylactically active compound selected from the group consisting of beta-blockers such as metoprolol, bisabolol, carved ilol, pindolol, propranolol, nadolol, atenolol, esmolol, acetobutolol, labetalol, timolol; diuretics such as acetazolamide, dichlorphenamide, methazolamide (i.e. carbonic anhydrase inhibitors); loop diuretics such furosemide, bumetamide, ethacrynic acid, torsemide, azosemide, muzolimine, piretanide, tripamide; thiazide and thiazide-like diuretics such as bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone; angiotensin Il receptor antagonists such as candesartan, cilexetil, irbesartan, losartan, telmisartan, valsa tartan eprosartan; ACE inhibitors such as captopril, enalapril, enalaprilat, fosinopril sodium, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, lercanidipine, nimodipine, nisoldipine, verapamil.
Preparation of a solid solution The solid solution according to the invention may be prepared according to methods known by a person skilled in the art such as, e.g. by dissolution of the two components (Eplerenone and the polar lipid carrier) in a suitable solvent followed by evaporation of the solvent or it may be prepared by heating one or both of the components to accelerate dissolution of Eplerenone in the carrier or to melt the carrier together with Eplerenone, or simply disperse the finely divided particles in the melted carrier.
Solid solutions (solvent method) can be prepared by dissolving a physical mixture of the active compound Eplerenone and the carrier in a common organic solvent, followed by evaporation of the solvent. In this case, the carrier is a hydrophilic polymer. Suitable organic solvents include pharmaceutical acceptable solvents in which the active compound is soluble such as methanol, ethanol, methylene chloride, chloroform, ethylacetate, acetone or mixtures thereof.
Suitable water soluble carriers include polar lipid carriers mentioned above.
In a further embodiment diethylene monoglycol ether, Transcutol P, is used as the carrier either alone or in combination with one or more other carriers mentioned above. The solubility of eplerenone in Trancutol P is10% w/w when heated to 80 0C. Upon spontaneous cooling of the warm solution to room temperature, partial precipitation of eplerenone gradually takes place. However this precipitation is decreased with crystal inhibitors. The use of various crystal inhibitors according to the present invention nclude polyvinylpyrrolidone in various molecular weights K12, K25, K30 and K90, polysorbate, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol, maltodextrines, sugars etc. wihich inhibit the recrystallisation of eplerenone. The same can be obtained with other amphiphilic agents e.g. phospholipids, cholesterol which is a steroid alcohol and esters thereof. Furthermore, cholesterol (solubility parameter 9.55) is miscible with Transcutol P in concentrations up to 20 % enabling the creation of a solid mass of transcutol (containing the drug substance in the dissolved state ) and cholesterol upon cooling of a solution containing dissolved eplerenone from 800C to RT. The stabilibizing effect of crystal inhibitors may involve fast solidification arresting the active in the dispersed state where every single crystallite of the drug is intimately encircled by the carrier composition and or a solubility factor and/or an increased solubility. The solid state is favorable in the sense of stabilizing the physical state of dissolved eplerenone in a otherwise liquid like Transcuol P upon cooling, in the sense of reducing potential chemical degradation and in the sense of providing the formulation with better tablet technological properties. Furthermore, an improved compatibility to hard capsule shells of various material (gelatine, HPMC, polysaccharide) is obtainable by the use of a formulation containing Transcutol P in the solid state due to a decreased interaction potential from Transcutol P being otherwise described as incompatible with hard capsules. It should also be considered, that the composition according to the present invention may comprise a carrier or carrier system which comprises different substances which may be completely miscible wherein the solubility of the active may be higher than in the individual components. In addition, if not completely miscible, the active compound may be soluble in one or more of the components. In the present context this is also considered a solid solution according to the invention.
Furthermore, by the melt agglomeration technology enabling the transformation of Transcutol P from being in the liquid state to being in the solid state in a granular form (with or without presence of crystal inhibitor) an improved compatibility to hard capsule shells could be obtained. The solid solution is preferably formed by spray drying techniques, controlled agglomeration, freeze-drying or coating on carrier particles or any other solvent removal process. The dried product contains the active compound present in the form of a solid solution.
An especially suitable method is by dissolving Eplerenone in the carrier and then spraying this solution on a powder or powder mixture using a controlled agglomeration method described in WO 03/004001 (by the same Applicant). Stabilizing agents etc. may be added in order to ensure the stability of the solid solution. Details concerning the controlled agglomeration method are given in the above-identified publication, which is hereby incorporated by reference as well as in the Examples herein. In short, the invention provide a process for preparing a particulate pharmaceutical material comprising Eplerenone which method comprises spraying a first composition in liquid form, said composition preferably being a solid solution of Eplerenone into a second composition comprising a support, said second composition e.g. being in the fluidised state and having a temperature less than the melting point of the carrier. In principle the active compound may be present in the carrier composition and/or in the second composition.
An advantage of using the controlled agglomeration method described in WO 03/004001 is that it is possible to apply a relatively large amount of a melt to a particulate material without having an undesirable growth in particle size. Accordingly, in one embodiment of the invention, the particulate material of a pharmaceutical composition has a geometric weight mean diameter dgw of ≥ 10 μm such as, e.g. ≥ 20 μm, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g. from about 100 to about 1500 μm, from about 100 to about 1000 μm or from about 100 to about 700 μm, or at the most about 400 μm or at the most 300 μm such as, e.g., from about 50 to about 400 μm such as, e.g., from about 50 to about 350 μm, from about 50 to about 300 μm, from about 50 to about 250 μm or from about 100 to about 300 μm. The solid material obtained by the above-mentioned method is in particulate form that has suitable properties with respect to flowability and/or compressibility and is therefore suitable for further processing into pharmaceutical dosage forms.
Pharmaceutical compositions for immediate release It is an advantage of a solid solution according to the invention that it provides a system that can be used in the preparation of several dosage forms and due to the fact that Eplerenone is present in solid solution and thereby readily releasable it is a suitable system both for immediate release compositions as well as for controlled release compositions. The immediate release compositions may be the solid solution as such or, more preferred, in the form of an oral dosage form wherein the solid solution is present in admixture with pharmaceutically acceptable excipients that do no intend to significally delay the release of Eplerenone from the composition.
An immediate release composition normally release at least about 50% of the Eplerenone contained in the composition within at the most about 2 hours, as determined by a suitable dissolution test such as, e.g., described in Ph. Eur. In a specific aspect, the invention provides a pharmaceutical composition or a solid dosage form that releases Eplerenone relatively fast so as to enable a relatively fast onset of therapeutic effect. Within the meaning of immediate release is also understood, that at least about 50% w/w of Eplerenone contained in the composition is released within at the most about 1.5 hours such as, e.g., within at the most about 1 hour, within at the most about 0.75 hours or within at the most about 0.5 hours employing a suitable dissolution method. Further examples include that at least about 55% w/w, such as, e.g., at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w or at least about 85% w/w of Eplerenone is release within at the most about 1.5 hours such as, e.g., within at the most about 1 hour, within at the most about 0.75 hours or within at the most about 0.5 hours employing a suitable dissolution method.
In those cases where the composition is in the form of tablets, an immediate release composition normally has a disintegration time of at the most 60 min such as, e.g., at the most about 45 min, at the most about 30 min, at the most about 15 min or at the most about 10 min when tested according to Ph. Eur.
Release modifying agents A controlled release composition typically comprises the solid solution in admixture with one or more release modifying agents and, optionally, further one or more pharmaceutically acceptable excipients. Such release modifying agents are typically selected from the group consisting polymers, water-miscible and water immiscible polymers and, in a specific embodiment the resulting mixture is a solid mixture.
Typically a polymer for use as a release modifying agent according to the invention is a cellulose derivative selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose; poloxamers, polyoxyethylene stearates, poly-ε-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA
(Kollidon VA64), poly-methacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), polyvinyl alcohol (PVA), poly(ethylene oxide) (PEO) and the like. In interesting embodiments, the release modifying agent is a cellulose derivative like e.g. hydroxypropyl methylcellulose. Pectinates, alginates galactomannans, xanthan gums. In another embodiment of the invention, the polymer for use as a release modifying agent is a polymer that has a pH-dependant water-solubility and the polymer is selected from the group consisting of polyacrylamides; phthalate derivatives such as acid phthalates of carbohydrates including amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HMPCP), methylcellulose phthalate, methyl cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate; phthalates of other compounds including polyvinyl acetate phthalate (PVAP); other cellulose derivatives including hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose, cellulose acetate trimellitate; alginates; carbomers; polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, methacrylic acid copolymer (Eudragit L, Eudragit S); styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers; shellac, starch glycolate; polacrylin; vinyl acetate and crotonic acid copolymers and the like. Typically these types of polymers delay the release so that no release or only a small amount of Eplerenone is released under conditions corresponding to an acidic pH, i.e. in the stomach; while the release takes place once the composition (or parts thereof) has passed the stomach and entered into the intestines. In yet another embodiment, the release modifying agent is a water-insoluble polymer that is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose nitrate, and the like.
Modified release pharmaceutical compositions
There is a need for developing pharmaceutical Eplerenone-containing compositions notably for oral use that lead to an improved treatment of conditions with Eplerenone, cf. above.
Use of a solid solution according to the present invention serves as a suitable basic material to provide pharmaceutical compositions and solid dosage forms for improved treatment of conditions that respond to Eplerenone treatment, especially to oral and sublingual.
In one aspect the release may be pH dependant, i.e. the release predominantly takes place after passage of the stomach. Such a pH dependent release is mainly provided by means of enteric coating material as described herein (polymers that have pH-dependant solubility). The release may also be pH independent, e.g. by providing the composition with a controlled release coating such as, e.g. a cellulose based coating like e.g. ethylcellulose or by providing the composition in the form of a matrix composition such as, e.g., a hydrophilic cellulose polymer matrix type e.g. based on HPMC. A combination may of course also be employed.
In general, the change in bio-availability and/or the changes in other bio-availability related parameters are normally determined by in vivo studies in a suitable animal model testing the compositions in question together with e.g. Inspra® or a similar commercially available Eplerenone- or Eplerenone-containing product. The use of a dog model for establishing evidence of the bioavailability of certain formulations is general practice in the pharmaceutical industry.
The studies relevant for Eplerenone/Eplerenone are non-radomized, cross-over studies, where each dog is its own control. Four dogs and four treatments are normally applied. As no intraveneous injections are given, the bio-availabilities obtained are relative. Thus, the pharmaceutical compositions according to the invention provide significant higher bioavailability of Eplerenone, which may reduce the daily dosage. Furthermore, the compositions provide a more reproducible plasma profile and AUC.
As mentioned above, one of the major challenges with respect to formulation of Eplerenone compositions is the low and highly variable absorption of an orally administered dosage owing to the poor water solubility of Eplerenone/Eplerenone.
This highly variable absorption does give rise to a number of adverse event reactions as well as lack of effect in some cases. A further advantage of a composition of the present invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to traditional oral treatment. Accordingly, upon oral administration to a mammal in need thereof a pharmaceutical composition according to the invention releases Eplerenone in such a state, that a larger fraction of the drug is absorbed and absorbed more reproducible than Inspra® or a similar commercially available Eplerenone-containing product. When administered in a dose that is at the about most about 85% w/w such as, e.g., at the most about 80% w/w, at the most about 75%, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of Eplerenone or Eplerenone administered in the form of Inspra® or a similar commercially available Eplerenone-containing product, the products are substantially bioequivalent.
Parameters often used in bioequivalence studies are tmaXj cmaκ, AU Co-infinity, AUCn-t- Other relevant parameters may be W50, W75 and/or MRT. Accordingly, at least one of these parameters may be applied when determining whether bioequivalence is present. Furthermore, in the present context, two compositions are regarded as bioequivalent if value of the parameter used is within 80-125% of that of Inspra® or a similar commercially available Eplerenone-containing product used in the test.
Increasing the bioavailability, the Area Under the Curve, will normally reduce the intra- and inter- variability related to absorption of a drug substance. This is particularly true; whenever the low and impaired bioavailability is a consequence of poor water solubility. It is contemplated that compositions according to the invention will provide CVs (CV = coefficient of variation) on Area under Curve data that are significantly smaller than with Prometrium® and like products.
Delayed release is mainly brought about by some kind of enteric coating. Whereas semipermeable coating will show some kind of delayed release, it does not provide an adequate or sufficient delay of the release profile. Additionally it requires a certain amount of time to release the content. The coating sought for this invention, is a pH dependant coating. This type of coating is very resistant to release of drug until a certain pH is reached. Within a very small increment of pH (1/10), the film alters properties and becomes permeable. Examples of pH-sensitive polymers are mentioned hereinbefore. However, pH-sensitive polymers of specific interest include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropyl methylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers. The release of the active compound from a composition having a delayed release coating could also be an enzymatic reaction, if for example Zein or mono/di-glyceride mixtures are employed as coating material. Further, the invention relates to a pharmaceutical composition comprising Eplerenone together with one or more pharmaceutically acceptable excipient, wherein the composition upon oral administration to a mammal in need thereof in a controlled manner releases at least about 80% w/w within 0.75 hours or more, such as, e.g., at least about 50% w/w of the total amount of Eplerenone within about 24 hours, such as, e.g., within about 22 hours, within about 20 hours, within about 18 hours, within about 15 hours or within about 12 hours.
In a further embodiment at the most about 60% w/w such as, e.g., at the most 62% w/w, at the most about 65% w/w or at the most about 70% w/w Eplerenone is released 15 hours after oral administration to a mammal of a composition according to the invention or, alternatively, when tested in a suitable in vitro dissolution test, 15 hours after start of such a test.
More specifically, upon oral administration to a mammal in need thereof a composition according to the invention releases at least about 50% w/w of the total amount of Eplerenone and/or an analogue thereof within about 10 hours such as, e.g., within about 8 hours, within about 6 hours, within about 4 hours or within about 3 hours.
In another embodiment, upon oral administration to a mammal in need thereof, a pharmaceutical composition according to the invention releases at least 80% w/w Eplerenone after about 0.5 hours or more such as, e.g., after about 0.75 hours or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more or about 5 hours or more; or alternatively, when tested in a suitable in vitro dissolution test releases at least 80% w/w after about 0.5 hours or more such as, e.g., after about 0.75 hours or more, about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more or about 5 hours or more after start of the test.
Suitable conditions for the in vitro dissolution test are employing USP dissolution test (paddle method) and a buffer pH 7.5 containing 2.5% SDS and 1g/ml_ of pancreatin as dissolution medium.
In other embodiments, the following conditions are fulfilled with respect to in vitro dissolution test: i) at least about 50% w/w of the total amount of Eplerenone is released within about 10 hours such as, e.g., within about 8 hours, within about 6 hours, within about 4 hours, within about 3 hours, within about 2 hours, within about 1 hour, within about 45 min, within about 30 min or within about 15 min, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5 ii) at least about 50% w/w of the total amount of Eplerenone is released within about 1.5 hours such as, e.g., within about 1 hour, within about 0.75 hours, within about 0.5 hours or within about 20 minutes, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5. iii) at least about 55% w/w such as, e.g., about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more or about 80% w/w or more of the total amount of Eplerenone is released within about 15 hours such as, e.g., within about 12 hours, within about 10 hours, within 8 hours or within about 6 hours, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5 iv) at least about 55% w/w such as, e.g., about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more or about 80% w/w or more of the total amount of Eplerenone is released within about 5 hours such as, e.g., within about 4 hours, within about 3 hours, within about 2 hours, within about 1 hours or within about 30 minutes, when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5, and/or v) at least about 20% w/w such as, e.g., at least about 25% w/w, at least about 30% w/w, at least about 35% w/w or at least about 40% w/w of the total amount of Eplerenone is released within the first 3 hours such as, e.g., within the first 2 hours or within the first hour when tested in an in vitro dissolution test and employing a dissolution medium comprising a buffer having pH 7.5.
In an interesting embodiment, the composition is designed to have a delayed release of Eplerenone. Therefore, the invention also includes a pharmaceutical composition in particulate form comprising Eplerenone together with one or more pharmaceutically acceptable excipient, wherein the composition upon oral administration to a mammal in need thereof has a delayed release of Eplerenone so that at the most 10% w/w such as, e.g., at the most about 7.5% w/w or at the most about 5% w/w of the total amount of Eplerenone is released within the first two hours such as, e.g., within the first hour after administration.
In another embodiment of the invention, the composition is designed to release the Eplerenone within a few minutes. This is the case when sublingual formulations are used.
In other embodiments, the following conditions are fulfilled with respect to in vitro dissolution test performed under acidic conditions: i) at the most about 30% w/w such as, e.g., at the most about 25% w/w, at the most about 20% w/w, at the most about 15% w/w or at the most about 10% w/w of the Eplerenone is released within 2 hours in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 5 such as, e.g. at the most about 4.5, at the most about 4, at the most about 3.5, at the most about 3, at the most about 2 or at the most about 1.5, ii) at the most about 10% w/w such as, e.g., at the most about 7.5% w/w, at the most about 5% w/w or at the most about 2.5% w/w of the Eplerenone is released within 2 hours in an in vitro dissolution test employing a dissolution medium having a pH of at the most about
5 such as, e.g. at the most about 4.5, at the most about 4, at the most about 3.5, at the most about 3, at the most about 2 or at the most about 1.5 iii) at the most about 60% w/w such as, e.g., at the most about 50% w/w, at the most about 40% w/w or at the most about 30% w/w of the Eplerenone is released within 15 hours such as, e.g., within about 12 hours, when tested in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 4.5 such as, e.g. at the most about 4.0, at the most about 3.5, at the most about 3, at the most about 2 or at the most about 1.5 iv) at the most about 40% w/w such as, e.g., at the most about 30% w/w, at the most about 25% w/w or at the most about 20% w/w of the Eplerenone is released within 6 hours when tested in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 4.5 such as, e.g. at the most about 4.0, at the most about 3.5, at the most about 3, at the most about 2 or at the most about 1.5, v) at the most about 30% w/w such as, e.g., at the most about 25% w/w, at the most about 20% w/w or at the most about 15% w/w of the Eplerenone is released within 4 hours when tested in an in vitro dissolution test employing a dissolution medium having a pH of at the most about 4.5 such as, e.g. at the most about 4.0, at the most about 3.5, at the most about 3, at the most about 2 or at the most about 1.5, and/or
Apart from Eplerenone, the composition of the invention may also comprise a further therapeutically, prophylactical and/or diagnostically active compound. Notably, any combination of Eplerenone and other aldosterone antagonist is contemplated.
Pharmaceutically acceptable excipients
As mentioned before, a solid solution according to the invention is especially suitable for processing into oral dosage from, e.g. involving a step of spraying the solid solution onto one or more suitable pharmaceutically acceptable excipients (optionally in admixture with other substances like e.g. other therapeutically active compounds etc). Especially dosage forms for oral administration are of interest e.g. tablets, sachets, capsules etc. A person skilled in the art know how to produce suitable dosage form e.g. with reference to Remington's Pharmaceutical Science.
Examples of suitable excipients for use in a composition or solid dosage form according to the invention include fillers, diluents, disintegrants, binders, lubricants or mixtures thereof. As the composition or solid dosage form according to the invention may be used for different purposes, the choice of excipients is normally made taken such different uses into considerations. Other pharmaceutically acceptable excipients for suitable use are e.g. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, humectants, sweetening agents, wetting agents etc.
Examples of suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc.
Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
Specific examples of disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.
Specific examples of binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
Glidants and lubricants may also be included in the composition. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
Other excipients which may be included in a composition or solid dosage form of the invention are e.g. flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc.
Other additives in a composition or a solid dosage form according to the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butyl ated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier composition may also contain e.g. stabilising agents. The concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.
A composition or solid dosage form according to the invention may also include one or more surfactants or substances having surface-active properties. It is contemplated that such substances are involved in the wetting of the slightly soluble active compound and thus, contributes to improved solubility characteristics of the active compound.
Examples on surfactants are given in the following.
Suitable excipients for use in a composition or a solid dosage form according to the invention are surfactants such as, e.g., amphiphillic surfactants as those disclosed in WO 00/50007 in the name of Lipocine, Inc. Examples on suitable surfactants are i) polyethoxylated fatty acids such as, e.g. fatty acid mono- or diesters of polyethylene glycol or mixtures thereof such as, e.g. mono - or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, and the polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30,
PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000, ii) polyethylene glycol glycerol fatty acid esters, i.e. esters like the above-mentioned but in the form of glyceryl esters of the individual fatty acids; iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters with e.g. vegetable oils like e.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like, iv) polyglycerized fatty acids like e.g. polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate, v) propylene glycol fatty acid esters such as, e.g. propylene glycol monolaurate, propylene glycol ricinoleate and the like, vi) mono- and diglycerides like e.g. glyceryl monooleate, glyceryl dioleae, glyceryl mono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.; vii) sterol and sterol derivatives; viii) polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG with the various molecular weights indicated above, and the various Tween ® series; ix) polyethylene glycol alkyl ethers such as, e.g. PEG oleyl ether and PEG lauryl ether; x) sugar esters like e.g. sucrose monopalmitate and sucrose monolaurate; xi) polyethylene glycol alkyl phenols like e.g. the Triton® X or N series; xii) polyoxyethylene-polyoxypropylene block copolymers such as, e.g., the Pluronic® series, the Synperonic® series, Emkalyx®, Lutrol®, Supronic® etc. The generic term for these polymers is "poloxamers" and relevant examples in the present context are Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407; xiii) sorbitan fatty acid esters like the Span® series or Ariacel® series such as, e.g. sorbinan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate etc.; xiv) lower alcohol fatty acid esters like e.g. oleate, isopropyl myristate, isopropyl palmitate etc.; xv) ionic surfactants including cationic, anionic and zwitterionic surfactants such as, e.g. fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates and sulfonates etc.
When a surfactant or a mixture of surfactants is present in a composition or a solid dosage form of the invention, the concentration of the surfactant(s) is normally in a range of from about 0,1 - 80% w/w such as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w, or alternatively, from about 0.10 to about 80% w/w such as, e.g. from about 10 to about 70% w/w, from about 20 to about 60% w/w or from about 30 to about 50% w/w.
In a specific aspect of the invention, at least one of the pharmaceutically acceptable excipients may be selected from the group consisting of silica acid or a derivative or salt thereof including silicates, silicon dioxide and polymers thereof; magnesium aluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite.
Such materials are is especially useful as a sorption material for liquid material. In a specific embodiment, the material is used as a sorption material for the polar lipids. The material that has the ability to function as a sorption material for the polar lipids are also denoted "sorption material". Notably, the pharmaceutically acceptable excipient may comprise a silica acid or a derivative or salt thereof such as, e.g., silicon dioxide or a polymer thereof as a pharmaceutically acceptable excipient. Dependent on the quality employed a silicon dioxide may be a lubricant or it may be an sorption material. Qualities fulfilling the latter function seem to be most important.
In a specific embodiment, a composition or solid dosage form according to invention comprises a pharmaceutically acceptable excipient that is a silicon dioxide product that has properties corresponding to Aeroperl® 300, (available from Degussa, Frankfurt, Germany). As it appears from the examples herein, very suitable materials are Aeroperl® 300 and Nuesellin and including materials with properties like or corresponding to those of them.
Use of a sorption material in compositions or dosage forms according to the invention is very advantageous for the preparation of pharmaceuticals, wherein the composition comprises a polar lipid. One of the advantages is that is it possible to incorporate a relatively large amount of low melting polar lipids e.g. at room temperature and still have a solid granulate. Thus, it is possible to prepare solid compositions with a relatively high load of low melting materials by use of a sorption material according to the invention. Within the pharmaceutical field it is an advantage to be able to incorporate a relatively large amount of a polar lipid in a solid composition especially in those situation where the active compound does not have suitable properties with respect to water solubility (e.g. poor water solubility), stability in aqueous medium (i.e. degradation occurs in aqueous medium), oral bioavailability (e.g. low bioavailability) etc., or in those situations where it is desired to modify the release of an active compound from a composition in order to obtain a controlled, delayed, sustained and/or pulsed delivery of the active compound. Thus, in a specific embodiment it is used in the preparation of pharmaceutical compositions. The sorption material for use in the processing into solid compositions normally absorbs about 5% w/w or more, such as, e.g., about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 55% w/w or more, about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more, about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more of a polar lipid and is still a solid material.
The invention is further illustrated in the following non-limiting examples.
Materials and methods Determination of weight variation
The tablets prepared in the Examples herein were subjected to a weight variation test performed in accordance with the latest edition of Ph. Eur. (2003)
Determination of average tablet hardness
The tablets prepared in the Examples herein were subject to at test for tablet hardness employing Schleuniger Model 6D apparatus and performed in accordance with the general instructions for the apparatus.
Determination of disintegration time
The time for a tablet to disintegrate, i.e. to decompose into particles or agglomerates, was determined in accordance with Ph. Eur.
Determinations of geometric weight mean diameter dgw The geometric weight mean diameter was determined by employment of a method of laser diffraction dispersing the particulate material obtained (or the starting material) in air.
The measurements were performed at 1.5 bar dispersive pressure in Malvern equipment, which records the distribution of the equivalent spherical diameter. This distribution is fitted to a log normal volume-size distribution.
Determination of dissolution rate
The dissolution rate was determined by employment of USP paddle dissolution method at 37 0C.
Prior Art Example
Pharmacokinetics of different particle size of Eplerenone as disclosed in US
6,495,165 (dog study 200mg capsules):
Pharmacokinetic Parameter Value
Pharmacokinetic D90 = 212 D90 = 86 D90 = 36
Parameter microns microns microns
Cmax (μg/mL) 3.98 7.02 7.39
Tmax (hours) 1.50 1.75 2.25
AUC [(μg/mL)hr] 26.6 49.2 53.1
Relative 53.25 100 107.9
Bioavailability % EXAMPLES
For the preparation of a pharmaceutical composition in solid form according to the invention the method described in WO 03/004001 (by the present inventors) has been employed. The method ensures a controlled agglomeration process, i.e. a strict control of the growth in particle size while at the same time it is possible to use a relatively large amount of a low melting polar lipid or other low melting surfactants.
HPMC refers to Metolose 90 SH (type 2208) or Metolose 60 SH (type 2910) from ShinEtsu, available in different degree of polymerisation (viscosity, 3-100.000 cP). Tablets, capsules or granules might be enteric coated with different types of polymers such as hydroxypropylmethylcellulose acetate succinate (Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulose phtalate HPMCP or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100/S, Eudragit 100/L.
Example 1
Example of an improved immediate release tablet
Substances % Mg
Eplerenone 14.4 100.0
Lactose 200 mesh 49,1 340.0
Glyceryl mono caprate 21.6 150.0
Glyceryl mono laurate 14.4 100.0
Magnesium stearate 0.5 3.0
Total 100.00 693.0
Eplerenone may be mixed/dissolved in a mixture of Glyceryl mono caprate and Glyceryl mono laurate (60:40 w/w ratios) at 70 0C. The solution is sprayed on 250 g lactose in a fluid bed Strea-1. The granular product is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
The mixture may be compressed into 11 mm tablets with strength of 100 mg (693) mg tablet with compound cup shaped. Desired mean disintegration time: 20 min, desired hardness: 45 N
Example 4
Modified release matrix tablet based on lipophilic matrix of glyceryl monolaurate Substance % Mg
Eplerenone 13.3 100.00
Lactose 200 mesh 39.9 300.00
Glyceryl monolaurate 46.5 350.00
Magnesium stearate 0.3 2.50
100.00 752.5
Eplerenone may be mixed/dissolved in Glyceryl monostearate at 70 0C. The solution is sprayed on 250 g lactose in a fluid bed Strea-1. The granular product is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
The mixture may be compressed into 8 mm tablets with a strength of 100 mg (750 mg tablet) with compound cup shape. Desired mean disintegration time: 20 min, Hardness: 45 N
The tablets may be subjected to dissolution testing without further coating, as descriped below.
Desired dissolution profile for Example 4 tablets of Eplerenone pH 6.8
Figure imgf000029_0001
Example 5
Delayed release tablets based on lipophilic matrix of gelucire 44/14
Substance % mg
Eplerenone 14.2 100.0
Aeroperl 300 42.7 300.0
Gelucire 44/14 42.7 300.0
Magnesium stearate 0.4 3.0
100.0 700.0 Eplerenone may be mixed/dissolved in Gelucire at 70 0C. The solution is sprayed on 250 g lactose in a fluid bed Strea-1. The granular product is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
The mixture may be compressed into 13 mm tablets with strength of 100 mg (700 mg tablet) with compound cup shape. Desired mean disintegration time: 20 min, Desired hardness: 45 N
These tablets may be coated with a "delayed" release coating.
A composition of the coating is shown in the table below.
Figure imgf000030_0001
Preparation of coating suspension:
Triethyl acethylcitrate, antifoam emulsion and purified water are mixed by Ultra Turrax at 9500 rpm for 30 min. After 1 min talcum is added. The mixture is strained through sieve 300 and stirred by magnet. Eudragit is strained through sieve 300 and added the mixture. Stirring for 5 min. The coating is stirred throughout the coating process.
The process condition of the coating process is shown in the following table.
Figure imgf000030_0002
Approx. 400 g of tablets is coated
The film coated tablets is cured for 48 hours at 30 0C before dissolution testing. Standard dissolution USP is used. Paddle speed 50 rpm 900 ml dissolution media
Phosphate buffer pH 2.0 and pH 6.8
The 2 first hours are pH 2 then the media is changed to pH 6.8
Eplerenone is quantified by HPLC.
Desired dissolution profile for example 5 Tablets of Eplerenone
Time (hours) % Released
00.0 0
01.0 0
02.0 0
03.0 25
04.0 42
06.0 78
08.0 94
12.0 102

Claims

Claims
1. A pharmaceutical composition comprising a therapeutically or prophylactically active compound selected from the group of aldosterone antagonists and a carrier, wherein at least about 10 w/w% of the active compound is present as a solid solution in the composition.
2. A pharmaceutical composition according to claim 1 , wherein at least about 15 w/w% of the active compound is present as a solid solution.
3. A pharmaceutical composition according to claim 1 , wherein at least about 20 w/w% of the active compound is present as a solid solution.
4. A pharmaceutical composition according to claim 1, wherein at least about 25 w/w% of the active compound is present as a solid solution.
5. A pharmaceutical composition according to claim 1, wherein at least about 50 w/w% of the active compound is present as a solid solution
6. A pharmaceutical composition according to claim 1 , wherein at least about 70 w/w% of the active compound is present as a solid solution.
7. A pharmaceutical composition according to claim 1 , wherein at least about 90 w/w% of the active compound is present as a solid solution.
8. A pharmaceutical composition according to claim 1 , wherein at least about 99 w/w% of the active compound is present as a solid solution.
9. A pharmaceutical composition according to any of claims 1-8, wherein the aldosterone antagonist is eplerenone.
10. A pharmaceutical composition according to claim 1 , wherein the active compound is present in an amount corresponding to the solubility of the active compound in the amount of carrier present in the composition.
11. A pharmaceutical composition according to claim 1 , wherein the active compound is present in an amount exceeding the solubility of the active compound in the amount of carrier present in the composition
12. A pharmaceutical composition according to claim 1 , wherein the active compound is present in an amount below the solubility of the active compound in the amount of carrier present in the composition
13. The pharmaceutical composition according to claim 1 , wherein the solubility of the active compound in the carrier is at least 1%, such as at least 2%, more preferred at least 5%, such as at least 7% more preferred at least 15% measured at the melting point of the carrier and as w/w.
14. The pharmaceutical composition according to claim 1 , wherein the solubility of the active compound in the carrier is at least 17% such as at least 20%, more preferred at least 25%, such as at least 30%, and still more preferred at least 40% measured at the melting point of the carrier and as w/w.
15. The pharmaceutical composition according to claim 1, wherein the amount of active compound in the composition is at least about 1w/w%, preferably at least about 3w/w%, more preferably at least about 5w/w%, most preferably at least about 10w/w%, especially at least about 15w/w%.
16. A pharmaceutical composition according to any of claim 15, wherein the carrier is a polar lipid carrier.
17. A pharmaceutical composition according to claim 16, wherein the polar lipid carrier is selected from the group consisting of polyethylene glycols and polyoxyethylenes having a melting point of at least 200C, esters and ethers of fatty acids such as acylglycerols, glycerol ethers, phospholipids, diol lipids, glycosides, waxes, glycospingolipids, glycosylglycerides, and mixtures thereof.
18. A pharmaceutical composition according to any of claim 1-17, which further comprises a crystal growth inhibitor.
19. The composition according to any of claims 1-18, further comprising one or more pharmaceutically acceptable excipient(s) selected from the group consisting of fillers, disintegrants, binders and lubricants.
20. A pharmaceutical composition according to any of the preceding claims , wherein the composition upon oral administration to a mammal in need thereof exhibits a relative AUC/AUCcontroi value of at least about 1.0, the AUC values being determined under similar conditions compared with a composition not comprising a solid solution of the active compound.
21. A pharmaceutical composition according to claim 20, wherein the relative AUC/AUCCOntroi value is at least about 1.1, preferably at least about 1.2, more preferably at least about 1.3, more preferably at least about 1.5, more preferably at least about 2.0 or more, the AUC values being determined under similar conditions.
22. The pharmaceutical composition according to any of the preceding claims in a solid particulate form or in powder form.
23. The pharmaceutical composition according to any of the preceding claims, which further comprises one or more release modifying agents.
24. The pharmaceutical composition according to claim 23, wherein the release modifying agent is a polymer or a mixture of polymers.
25. The pharmaceutical composition according to claim 24, wherein the polymer is selected from the group consisting of cellulose derivatives such as hydroxyl propyl methyl cellulose
(HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose; poloxamers, polyethylene glycols, polyoxyethylene stearates, poly- epsilon-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA (Kollidon VA64), poly-methacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), polyvinyl alcohol (PVA) and poly(ethylene oxide) (PEO).
26. The pharmaceutical composition according to claim 24, wherein the polymer has a variable solubility in water in dependence of pH and, further, is selected from the group consisting of polyacrylamides; phthalate derivatives, preferably acid phthalates, of carbohydrates, including amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate, cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HMPCP), methylcellulose phthalate, methyl cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate; polyvinyl acetate phthalate (PVAP); cellulose derivatives including hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose, cellulose acetate trimellitate; alginates; carbomers; polyacrylic acid derivatives including acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, methacrylic acid copolymer (Eudragit L, Eudragit S); styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers; shellac, starch glycolate; polacrylin; and vinyl acetate and crotonic acid copolymers.
27. The composition according to claim 24, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose nitrate and mixtures thereof.
28. The composition according to claim 22 in particulate form, wherein the particles have a geometric weight mean diameter dgw of at least 10 micrometer, preferably at least 20 micrometer, more preferably between from about 20 micrometer to about 2000 micrometer, more preferably between from about 30 micrometer to about 2000 micrometer, more preferably between from about 50 micrometer to about 2000 micrometer, more preferably between from about 60 micrometer to about 2000 micrometer, more preferably between from about 75 micrometer to about 2000 micrometer, more preferably between from about 100 micrometer to about 1500 micrometer, more preferably between from about 100 micrometer to about 1000 micrometer, more preferably between or from about 100 micrometer to about 700 micrometer, especially between from about 50 micrometer to about 400 micrometer, more especially from about 50 micrometer to about 350 micrometer, even more especially from between about 50 micrometer to about 300 micrometer, in particular from between 100 micrometer to about 300 micrometer.
29. A pharmaceutical composition according to any of the previous claims wherein the aldosterone antagonist is eplerenone and is present in an amount of from 5mg to 200mg.
30. Wherein the amount is selected from 5mg, 10mg, 12.5mg, 20mg, 25mg, 30mg, 35mg, 37.5mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg and 200mg.
31. A composition according to any of the preceding claims further comprising a second active compound
32. A composition according to claim 31 wherein the second active compound is present in crystalline form or in amorphous form or the second active compound is present partly in amorphous form and partly in crystalline form.
33. A composition according to any of claims 31-32 wherein the second active compound is a diuretic.
34. A final dosage form comprising the composition according to any of claims 1-33 in the form of a tablet such as a tablet selected from an effervescent tablet, a chewable tablet, an immediate release tablet, a delayed release tablet, an extended release tablet, a coated tablet, a sugar coated tablet, a film coated tablet, a film coated extended release tablet a multilayer tablet, a multilayer extended release tablet, a orally disintegrating tablet, or in the form of a troche or a wafer.
35. A final dosage form according to any of claims 1-33 in the form of a capsule, such as an coated capsule, a film coated capsule, a gelatin coated capsule, a capsule for delayed delayed or extended release.
36. A final dosage form according to any of claims 1-33 in the form of a granule, an effervescent granule, a delayed release granule, a granule for solution, a granule for suspension including extended release suspension.
37. A final dosage form according to claims 1-33 in the form of a chewing gum.
38. A final dosage form according to any of claims 1-33 in the form of a powder or pellet.
39. A final dosage form according to claim 38 wherein the powder or pellet is for the preparation of a solution or suspension.
40. A final dosage form according to any of claims 34-39 comprising one or more active compounds in a part of the dosage form which is physical distinctive from the part of the dosage form comprising the composition according to any of claims 1-33.
41. A final dosage form according to claim 40 in the form a multilayer tablet.
42. A final dosage form according to claim 41 comprising a diuretic in one layer of the tablet and eplerenone in a different layer of the tablet.
43. A method for the preparation of the pharmaceutical composition according to any of claimsi to 33, the method comprising the step of dissolving or dispersing an aldosterone antagonist in the carrier to obtain a solid solution.
44. A method according to claim 43 wherin the carrier is a polar lipid.
45. A method according to any of claims 43-44, which further comprises the step of contacting the solid solution with a solid carrier.
46. A method according to any of claims 43 to 45 wherein the solid solution is contacted with a porous tablet for absorption by the porous tablet to form a solid dosage form.
47. A method according to any of claims 43 to 46, which further comprises the step of contacting the solid solution with a release modifying agent, optionally in admixture with one or more pharmaceutically acceptable excipients.
48. The method according to claim 47, wherein the solid solution in liquidized form is sprayed onto the release modifying agent.
49. Use of the pharmaceutical composition according to any of claim 1 to 22 and 28 to 33 for the preparation of a medicament in an immediate release solid dosage form.
50. Use of the pharmaceutical composition according to any of claim 1 to 33 for the preparation of a medicament in a controlled release solid dosage form.
51. Method for treating cardiovascular disease including hypertension by administering to a patient in need thereof a pharmaceutically active amount of an aldosterone antagonist in a pharmaceutical composition according to any of claims 1 to 33.
52. Method for treating cardiovascular disease including hypertension by administering to a patient in need thereof a pharmaceutically active amount of an aldosterone antagonist in a final dosage form according to any of claims 34 to 42.
PCT/DK2006/050019 2005-05-10 2006-05-10 A pharmaceutical composition comprising an aldosterone antagonist in form of solid solution WO2006119779A2 (en)

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