MXPA06010254A - Compositions comprising drospirenone molecularly dispersed - Google Patents

Abstract

The present invention relates to pharmaceutical composition comprising steroidal drugs, such as drospirenone, in molecularly dispersed form. Preferably, the compositions are provided as solid, semi-solid or liquid forms, which in turn preferably are adapted for oral administration and preferably to be absorbed from the gastro-intestinal tract. Such compositions are found to have high bioavailability, good chemical stability, and fast in--vitro dissolution release and can be produced under conditions, which do not require costly equipment or safety guards.

Description

COMPOSITIONS THAT INCLUDE DISPERSED DROSPIRENONE AT THE MOLECULAR LEVEL FIELD OF THE INVENTION The present invention relates to the field of the science of the pharmaceutical formulation, in particular to methods for improving the solubility and bioavailability of li-pofilic compounds, such as, for example, steroid molecules, in particular drospirenone. The specific formulation technique of the present invention relates to the general principle of providing drospirenone in a dispersed form at the molecular level.

BACKGROUND OF THE INVENTION The unformulated drospirenone is not well absorbed in the gastrointestinal tract, in part due to its poor solubility in water and its low rate of dissolution in water. Furthermore, drospirenone has little chemical stability in acidic environments that include conditions in gastric fluid in the stomach. In fact, almost 50% of the drospirenone degrades in its therapeutically inactive isomer within 30 minutes when it contacts a solution of hydrochloric acid at a pH of about 1.0. As a consequence of this, enteric coatings can be suggested. It is considered that due to its nature as a steroid molecule, drospirenone must be absorbed in the upper part of the gastrointestinal tract (GI tract), as for example by the gastric mucosa and / or the mucous membrane of the duodenum, which would require that the drospirenone is completely dissolved already at the beginning of the Gl tract. It has been found that when drospirenone is provided in micronized form, the in vitro solution is high. For example, at least 70% of the drospirenone dissolves 30 minutes after the start of the dissolution test. However, the micronization technique requires special equipment that is expensive and can be difficult to manipulate. Alternative formulations of those that include drospirenone in micronized form may be necessary. Various formulation techniques are well known for the preparation of pharmaceutical compositions wherein the active component forms a mixture with a liquid, semi-solid or solid excipient. However, the objective of such techniques is only to obtain very fine particles of the active substance dispersed uniformly in excipients and not to obtain the active compound dispersed in excipients at the molecular level. In addition, said formulation techniques do not include a process for making a composition wherein the active compound dissolves in an initially critical step in the vehicle which then forms the final composition or at least a portion thereof. WO0245693 describes suitable dosage forms of active substances that are applied - whenever taste masking is desirable or damage to the coatings is to be expected. The dosage forms comprise the active substance as uniformly dispersed or dissolved in a matrix which is selected from the group consisting of paraffin, triglycerides of fatty alcohols, partial glycerides and fatty esters. WO0245693 is not related to molecularly dispersed compounds. US 5,789,442 relates to the formulation of the active compounds to form a mixture with conventional excipients, such as, for example, liquid, semiliquid, organic or inorganic solids, for parenteral or enteral administration. US 5,569,652 relates to the formulation of active compounds by treatment of the active compound with carriers and diluents. US 5,656,622 relates to new estradiol derivatives, which in combination with drospirenone can be provided as a capsule or tablet. EP 1 260 225 relates to compositions comprising an estrogen. WO 2004/041289 discloses drospirenone in a tablet pharmaceutical preparation which is prepared using conventional fluid bed technology. WO 2004/0222065 refers to compositions comprising a testosterone derivative and optionally a progestin (drospirenone is mentioned), wherein the drug is in an aqueous suspension or oil.

Still other techniques suggest using the active compound in micronized form to improve bioavailability by achieving rapid dissolution of the active compound in water. WO 01/52857 mentions compositions comprising drospirenan where the drospirenone is dissolved in a suitable solvent, for example methanol or ethyl acetate, before spraying it onto the inert carrier. Despite the fact that previous efforts have already provided some improvements in the bioavailability of drospirenone administered perorally, such efforts have not eliminated the initial step of dissolving drospirenone in gastrointestinal fluids before it can occur. absorption of the drug.

SUMMARY OF THE INVENTION A pharmaceutical composition comprising at least one steroid drug such as a progestin (e.g., drospirenone, progesterone, eplerenone, etonogestrel) and / or an estrogen (estradiol and esters thereof) in dispersed form is now provided. molecular. That is, the composition comprises a steroid drug, preferably drospirenone, which is present in the composition in a non-particulate form. The intention that the drug be pre-satiated in a dispersed form at the molecular level, is that it is present in the excipient in a dissolved state. The dispersed drug at the molecular level will be released very quickly as the dissolution occurs instantaneously when the dosage unit disintegrates. In a pharmaceutical composition wherein the drug is dispersed at the molecular level, the disintegration time is effectively the rate determining step for the release of the drug, which means that the bioavailability can be significantly improved by the present invention. Preferably, the compositions are provided as a solid, a semisolid or in liquid form, all forms in turn are preferably adapted for oral administration and are preferably contacted with the gastric fluid and then absorbed in the gastrointestinal tract. It is found that said compositions have a high bioavailability, good chemical stability and rapid dissolution by in vitro release and can be produced under conditions that do not require expensive equipment or safety precautions. The present invention relates not only to pharmaceutical compositions, but also to methods for the preparation and use of the compositions. The compositions of the invention are provided by a process comprising the steps of: a) providing drospirenone and one or more carrier (s); and b) dissolving the drospirenone completely in said one or more vehicle (s); and c) optionally, drying the mixture obtained in step b). DETAILED DESCRIPTION OF THE INVENTION It has been found that pharmaceutical compositions comprising drospirenone in a dispersed form at the molecular level show superior performance with respect to the manufacturing process, physical or chemical stability, in vitro dissolution, in vitro permeation of human colon cells, and bioavailability in vivo. . In a first aspect, the invention provides a composition comprising drospirenone dispersed at the molecular level in a vehicle acceptable for pharmaceutical use. Alternatively, the invention encompasses a composition comprising drospirenone in dissolved form in a carrier acceptable for pharmaceutical use, whether the composition is solid, semi-solid or if it is in liquid form. A common feature of all compositions is that drospirenone dissolves at a molecular level in a pharmaceutically acceptable vehicle and behaves like dissolved drospirenone without being a conventional drospirenone solution. Typically, drospirenone can not be detected by X-ray diffraction analysis or other suitable methods such as optical microscopy, electron microscopy or dissolution. As the drug is already present in a dissolved formDispersing at the molecular level, dissolution will happen instantaneously when the disintegration of the dosage unit has happened. Therefore, a common characteristic of a dosage form is that when the disintegration time of the dosage form is compared with the dissolution time, they will occur simultaneously within the errors associated with the methods of analysis. In alternative terms, the invention encompasses a composition comprising drospirenone in dissolved form in a vehicle acceptable for pharmaceutical use whether the composition is in solid, semi-solid or liquid form. A common feature of all the compositions is that dróspyrenone dissolves at a molecular level in a pharmaceutically acceptable carrier and behaves as dissolved drospirenone without being a conventional drospirenone solution. Advantageously, the compositions of the invention show a rapid dissolution of drospirenone in vi tro. A rapid dissolution is defined as the dissolution of at least 70% of drospirenone from the compositions at the time point of 30 minutes after the start of the in vitro dissolution test, in particular at least 80% by weight of the drospirenone. pyrenone at the time point of 20 minutes after the start of the in vitro dissolution test, even more preferably at least 85% by weight of the drospirenone at the 15 minute time point after the start of the dissolution test in vitro The test was carried out using 900 ml of water at 37 ° C as a dissolution medium and a USP XXVIII 2 paddle apparatus operated at 50-100 rpm, such as 50 or 75 rpm, as a dissolution test apparatus. As mentioned, a high bioavailability can be achieved using micronized drug. But this technology has some disadvantages because the micronized drug tends to flocculate during production and easily the personnel handling it can be exposed to the dust coming from it. Said disadvantages can be avoided with the production process of the present, leading to a lower number of production steps, less dust formation during manufacturing, higher level of containment, higher level of environmental and occupational safety, reduction of the costs of manufacturing, better mixing uniformity and better dose uniformity. Compositions of the invention preferably have the form of a solid, a semi-solid or a liquid. The solid compositions according to the present invention can be referred to as solid solutions. The semi-solid and liquid compositions according to the present invention define solutions with drospirenone in dissolved form, wherein the solvent has a viscosity and / or melting point which determines whether the composition is a semi-solid or liquid composition. The term "dispersed at the molecular level" or "molecular dispersion" is used to describe any solid, semi-solid and liquid system where one component A (such as drospirenone) is dispersed at the molecular level within another component B (such as A solvent or a polymer), such that component A can not be detected in crystalline form by X-ray diffraction analysis, nor detected as a particulate form, whether in crystalline form or in amorphous form, by any microscopy technique. By the term "molecular dispersion" it should also be understood that drospirenone is dissolved in component B independently of the nature of B. That is to say that the term "dispersed at the molecular level" can be used as a synonym for the term "dissolved at the molecular level". " The term "solid dispersion" refers to the condition where the drospirenone is in a substantially non-particulate form and is dispersed in a polymer matrix. Said condition can also be called "solid solution". Alternatively, the drospirenone is in crystalline form and is dispersed in a polymer matrix such that the crystals are so fine that they can not be detected by X-ray diffraction analysis. As used herein, the term "substantially non-particulate" refers to the condition where more than 90% of the drospirenone is in non-particulate form. Alternatively, the absence of particulate matter such as crystals and amorphous particles can be investigated by microscopy. As used herein, the term "substantially non-particulate" refers to a condition where more than 90% of the drospirenone is in non-particulate form when analyzed by microscopy. The term "solid solution" is used to describe any solid system where one component is dispersed at the molecular level within another. In a particular form, a solid solution is characterized by having drospirenone (or other active ingredient) dispersed at the molecular level in a solvent that is absorbed onto a solid carrier capable of adsorbing the solvent while remaining solid. That is, the drospirenone is completely dissolved in the solvent present on the surface of the vehicle. These solid solutions are formed by completely dissolving the drospirenone in a solvent and then transforming the solvent into a solid by adding a solid vehicle that absorbs the solvent, while maintaining the drospirenone in dissolved form. It is said that a solid solution contains drospirenone dispersed at the molecular level within the composition, more specifically within the solvent. The term "solution" is used to describe any semisolid and liquid system where one component is dispersed at a molecular level within another. Therefore, it should be understood that the compositions of the invention comprise drospirenone in a non-particulate form, for example where the drospirenone is not present in the composition in the form of micronized particles or particles within the nanometer-sized ranges. . Therefore, the term "dispersed at the molecular level" essentially excludes compositions where very fine drospirenone particles, such as micronized particles or nanoparticles, have been mixed dry with ingredients or vehicles acceptable for pharmaceutical use or where the composition final still comprises drospirenone in the form of particles. The term "supersaturated solution" is used to describe a solution that contains a concentration of dro-ga that is greater than its saturation concentration when determined at room temperature. In other words, despite the higher content of drospirenone, no crystalline drug can be detected by X-ray diffraction analysis. Basically, supersaturated solutions are expected to be thermodynamically unstable leading to a saturated solution and recrystallized drug. The term "stabilized supersaturated solution" is used to describe a supersaturated solution where recrystallized drug can not be detected by X-ray fraction analysis. For example, stabilization can be achieved by adding a crystallization inhibiting agent.

The term "microemulsion" is used to describe a slightly opaque, opalescent, non-opaque or substantially non-opaque colloidal dispersion that is formed spontaneously or substantially spontaneously when its components are contacted with an aqueous medium. A microemulsion is thermodynamically stable and contains droplets or "nano" liquid particles with an average diameter of less than approximately 2 μm. Typically, a lipophilic drug that is incorporated into a microemulsion will be present in dissolved form within the droplets or "nano" liquid particles mentioned. The term "microemulsion preconcentrate" refers to a composition that spontaneously forms a microemulsion in an aqueous medium, for example, in water, eg by diluting it to between 1: 1 and 1:10 for example 1:10 or in the gastric juice after oral application. In an embodiment of the invention, the composition is in the form of a liquid. Therefore, the composition comprises a solvent acceptable for pharmaceutical use, which is a liquid at room temperature and / or has a melting point of less than 40 ° C. Said solvents can be selected from list h) to u) shown below. In another embodiment, the solvent acceptable for pharmaceutical use is a semi-solid at room temperature and / or has a melting point of less than 40 ° C. Said solvents can be selected from list h) to u) shown below. Generally speaking, solvents for use in liquid compositions of the invention and which are either a liquid or a semi-solid at room temperature include but are not limited to: ethanol, isopropanol, glycerol, propylene glycol, Transcu tol® (ethylene glycol monoethyl ether), polyols, esters of citric acid, mono.glycerides, diglycerides, vegetable oils, vegetable fats, partially synthetic triglycerides p. ex. medium chain triglycerides (MCT) such as Miglyol®, synthetic triglycerides, mixtures of fatty acid esters and glycerol such as, for example, Imwitor®, fatty alcohols, fatty alcohol ethers, fatty acids, fatty acid esters, waxes, paraffin, purified water and mixtures thereof. In addition, surfactants and cosolvents can be used. Those skilled in the art will recognize that the melting point of several of the solvents mentioned above depends for example on the length of the hydrocarbon chains and the degree of substitution. Therefore, the skilled person will be easily able to select the correct solvent to produce a liquid or semi-solid composition. Preferably, the solvents are selected from the group comprising ethanol; propylene glycol; partially synthetic triglycerides; or vegetable oils. Typically, examples of polyols are glycerol, propylene glycol, sorbitol, mannitol, inositol, pentaerythritol, maltitol, lactitol. Typically examples of citric acid esters are tributyl citrate, triethyl citrate, acetyl tributyl citrate, glyceryl citrate stearate. Typically, examples of monoglycerides are glycerol monostearate, glycerol monopalmitate, glycerol monooleate, glycerol monolinoleate. Typically, the diglyceride examples are glycerol dibehenate, glycerol distearate. Typically, examples of vegetable oils are olive oil, peanut oil, castor oil. Typically, the examples of fats are lard. Typically, the examples of synthetic and partially synthetic triglycerides are neutral oil, Softisan®, Witepsol®, Suppocire®. Typically, examples of fatty acid esters with glycerol are glycerol onocaprylate, glyceryl laurate, caprylic / capric glycerides, glyceryl stearate. Typically, the examples of fatty alcohols are octanol, decanol, dodecanol, tetradecanol, hexadecanol, octadecanol, oleyl alcohol, linalool, ricinol. Typically, examples of fatty alcohol ethers are the oleyl ether, cetylpalmitic, ethyloleic, Typically, the examples of Fatty acids are capric acid, caprylic acid, lauric acid, palmitic acid, cetyl acid, stearyl acid, oleic acid, linoleic acid. Typically, examples of fatty acid esters are esters of lauric acid, caprylic acid, capric acid, stearic acid. Typically, examples of waxes are alba wax, beeswax.

Suitable surfactants include, by way of example: a) Lecithin b) Block copolymers of ethylene oxide and propylene oxide, such as the Pluronic® and Poloxamer® grades c) Glycerol esters, and polyoxyethylene glycerol esters, and mixtures thereof the same as, for example, grades Gelucire®, Labrafil® and Labrasol® d) Propylene glycol esters, such as Lauroglycol® and Capryol® grades e) Esters of sucrose and fatty acids such as, for example, Sweeteners® f) Sorbitan esters and fatty acids, and esters of polyoxyethylene sorbitan and fatty acids, and mixtures thereof such as, for example, Span® and Tween® grades g) Polyoxyethylene esters and fatty acids, polyoxyethylene ethers and fatty alcohols, and mono-esters , di- and triglycerides of polyoxyethylene, and mixtures thereof, such as for example Cremophor® grades. In presently interesting embodiments of the invention, the liquid or semisolid compositions of the invention comprise as solvent: h) medium chain triglycerides i) castor oil j) Imwitor® 308 (glyceryl monocaprylate) k) Cremophor® EL 1 ) Cremophor® RH 40 @ Polyoxyethylene-40-hydroxystearate Glycerol)) polyethylene glycol 400 n) transcutol® P @ (ethylenediglycol monoethyl ether) o) triethyl citrate p) a mixture of 7% by weight of glycerol and 93% by weight of polyethylene glycol 400 q) a mixture of 50% by weight of I witor 308 and 50% by weight of polyethylene glycol 400 r) a mixture of 50% by weight of castor oil and 50% by weight of tributyl citrate s) a mixture of 50% by weight of castor oil and 50% by weight of polyethylene glycol 400 t) a mixture of 75% by weight of I witor 742, and 25% by weight of polyethylene glycol 400 u) a mixture of 75% by weight of Imwitor 742, % by weight of polyethylene glycol 400 and 10% by weight of ethanol or mixtures of any solvent h) a or) . Therefore, in some embodiments of the invention, the at least one vehicle acceptable for pharmaceutical use is selected from the group consisting of medium chain triglycerides, castor oil, glycerol monocaprylate (Imwitor® 308) , caprylic / capric glycerides (Im-witor 742®), glycerol polyoxyethylene-35-tri-ricinoleate (Cremophor EL®), polyoxyethylene-glyceral-40-hydroxystearate (Cremophor® RH 40), polyethylene glycol 400, monoethyl ether of ethylene diglycol (Transcutol® P), triethyl citrate and mixtures thereof. In particular, a mixture of glycerol and polyethylene glycol 400, a mixture of glycerol monocaprylate (Im-witor® 308) and polyethylene glycol 400, a mixture of castor oil and tributyl citrate, a mixture of castor oil and polyethylene glycol 400, a a mixture of caprylic / capric glycerides (Imwitor® 742) and polyethylene glycol 400, a mixture of caprylic / capric glycerides (Imwitor® 742) and polyethylene glycol 400 and ethanol. In general, the amount of drospirenone in 2g of said liquid or semi-solid compositions is within the range comprised between lmg and 30mg, preferably 8mg. All said liquid compositions can be encapsulated, for example in soft gelatine capsules. In further embodiments of the invention, the composition is in the form of a pre-concentrate of a microemulsion. Said embodiments generally comprise the liquid and semisolid as mentioned above, but may further comprise at least one emulsifier. Suitable emulsifiers of the invention are polyoxyethylene-35-glycerol tri-ricinoleate (Cremophor® EL), polyoxyethylene-40-glycerol hydroxystearate (Cremophor® RH40), polyoxyethylene-400 mono-ricinoleate, fatty acid esters and polyoxyethylene glycerol (Gelucire®, Labrafil®, Labrasol®) and others. The emulsifier can be mixed with suitable co-emulsifiers and / or co-solvent, such as, for example, ethylene glycol mono-ethyl ether (Transcutol® P), glycerol monocaprylate (Imwitor 308), and propylene glycol esters (Lauro-glycol®, Capryol®) . In still other embodiments of the invention, the composition is in the form of a solid. In one embodiment thereof, the composition comprises a pharmaceutically acceptable carrier that is solid at room temperature and / or has a melting point greater than 40 ° C, such as within the range between 40-80. ° C. Suitable solid carriers include solid polyethylene glycols, such as polyethylene glycol 6000, vegetable oils and fats, partially synthetic triglycerides, synthetic triglycerides, mixtures of fatty acid esters and glycerol, such as, for example, Imwitor®, mono-, di- and triglycerides, fatty acid esters and polyoxyethylene glycerol such as eg Gelucire®, fatty acids, fatty acid esters, waxes, paraffin, or mixtures thereof. In some embodiments thereof, the molecular dispersion comprises drospirenone dispersed substantially uniformly in a matrix composed of a mixture comprising at least one fatty alcohol and at least one solid paraffin. In other embodiments, the matrix comprises at least one triglyceride and at least one solid paraffin or at least one partial glyceride and at least one solid paraffin or at least one fatty acid ester and at least one paraffin solid In said preparations, the preparation preferably comprises microspheres.

In another form of a solid composition of the invention, the vehicle acceptable for pharmaceutical use is a polymer. The polymer is preferably a hydrophilic polymer comprising free hydrophilic groups, such as polymers with functional groups on the side chains, such as, for example, free hydrophilic functional groups, such as, for example, carboxylic-, ester-, hydroxy-, amino-, amide, halogen- or sulfo-. Typical examples of hydrophilic polymers that are soluble in water include, but are not limited to: polyvinylpyrrolidone (Povidone®, Kollidon®); polyvinyl acetate; polyvinyl alcohol; polyvinyl alcohol phthalate; polyethylene glycol (PEG); polyethylene oxide; jelly; Carbomer; methacrylic acid copolymer; ammonium methacrylate copolymer; cellulose, carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropylmethylcellulose (HPMC), idroxy-pro-pilcelulose (HPC); cellulose acetate phthalate; and hydroxypropylmethylcellulose phthalate; or copolymers or mixtures thereof. The hydrophilic polymer can also be a water insoluble polymer including, but not limited to crospovidone; Sodium starch glycolate; and croscarmellose. Preferably, the polymer is selected from the group comprising polyvinylpyrrolidone (Povidone®, Kollidon®) and polyethylene glycol (PEG), and polyvinylpyrrolidone is particularly preferred. When a water-insoluble polymer is employed, crospovidone is preferred. All of the above polymers are well known in the art. The polyvinylpyrrolidone represents polymers of 1-vinyl-2-pyrrolidone. It can be obtained commercially as Povidone or Kollidon with an average weight in the range between approximately 2,000 and approximately 1,500,000. In general, the polyvinyl pyrrolidone used has an average weight in the range between about 7000 and about 54,000, with between about 28,000 and about 54,000 being preferred. Crospovidone represents synthetic crosslinked homopolymers of water insoluble N-vinyl-2-pyrrolidone. In general, crospovidone has a particle size between about 20μm and about 250μm, and preferably between about 50μm and about 250μm (see, for example, Kollidon, polyvinylpyrrolidone for the pharmaceutical industry, from BASF). Preferably, the ratio of the drospirenone to polystyrene is between about 1: 1 and about 1: 100, more preferably between about 1: 2 and about 1:20, and even more preferably between about 1: 5 and about 1:10 . When the molecular dispersion of the present invention is prepared by dissolving drospirenone and the polymer in an organic solvent or mixture of organic solvents, suitable organic solvents include, but are not limited to: methylene chloride, methanol, ethanol, isopropanol, acetone, tetrahydrofuran , or mixtures thereof. The solvent can be removed using conventional means: eg, evaporating the solvent under hood; using a double drum dryer or spray drying or a supercritical fluid extraction process. It should be understood that the composition of the present dispersed at the molecular level can also be applied to other drug molecules other than drospirenone and to combinations of two or more types of drug molecules. Therefore, the compositions of the invention can comprise any compound that is lipophilic and has a poor solubility in water at 25 ° C. In general, the compound should have a solubility less than Img / ml in water at 25 ° C, such as, for example, less than 0.5, 0.1, 0.05 or 0.01 mg / ml. Typically, the compound will generally be a steroid molecule and / or a hormone / antihormone. A wide range of other active pharmaceutical ingredients can benefit from the present technology, such as, for example, albendazole, aminoglutethimide, aminosalicylic acids (3-4- or 5-aminosalicylic acids) amiodarone, astemizole, azathioprine, beclamide, benorilat-o, benperidol, bezafibrate, biotin, bromocriptine, bromocriptine mesylate, bumetanide, busulfan, cabergoline, carbamazepine, cefixime, chenodeoxycholic acid, chlorambucil, chloroquine, chlorpropamide, chlorprothixene, chlorthalidone, cinnarazine, cinoxacin, clobazam, clofazimine, clofibrate, clonazepam, cyclopentiazide, cyclosporin A, dapsone, demeclocycline, diazoxide, diflunisai, digitoxin, digoxin, disulfiram, domperidone, droperi-dol, enoxacin, epothilone, ethionamide, etretinate, felodipine, fenbufen, fexofenadine , flumazenil, folic acid, furosemide, glipizide, gliquidone, griseofulvin, haloperidol, hydroclo-rotiazide, hydroflumethiazide, ibuprofen, iloprost, indomethacin, isocarboxazide, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketazolam, ketoconazole, ketoprofen, lansoprazole, sodium liothyronine , lisuride, lopera ida, loratadine, lorazepam, lovastatin, mebendazole, medazepam, mefenamic acid, menadione, mequitazine, methotrexate, misoprostol, morphine, ida niclosa, nifedipine, nimodipine, nitrazepam, omeprazole, oxazepa, oxytetracycline, pantoprazole, perphenazine, phenylbutazone, pimozide, pindolol, probenecid, probucol, pyrantel embonate, pyrimetha ina, retinol, riboflavin, simvastatin, stilbestrol, sulindac, sulfadiazine, sulfame-toxazole, sulfasalazine, sulpiride, tamoxifen, temazepam, thiabendazole, thioguanine, tocopherol, tolbutamide, tretinoin, triamteren, triazolam, trimethoprim, zopiclone. As said, a compound of the invention can be a steroid molecule or otherwise a hormone, of which there can be mentioned; • androgens, such as eg testosterone and testosterone esters (testosterone enanthate, testosterone undecanoate, testosterone cypionate, testosterone propionate) • estrogens / antiestrogens, such as estradiol and esters thereof (estradiol valerate) , estradiol enanthate, estradiol cypionate, estradiol undecylate), estriol, estrone, conjugated estrogens, equilin, ethinyl estradiol, fenestrel, mestranol, nilestriol, quinestrol, clomiphene, estrogen alpha receptor agonists, receptor antagonists estrogen alpha, beta-estrogen receptor agonists, beta-estrogen receptor antagonists, estrogen receptor desensitizers. Corticosteroids, such as eg cortisones and glucocorticoids, for example beclomethasone dipropionate, betamethasone, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, dexamethasone, fludrocortisone acetate, prednisolone, prednisone. • progestins / antiandrogens, eg cyproterone, etonogestrel, desogestrel, gestodene, levonorgestrel, nortisoterones, norgestimate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestrel, edrogestoin, medroxyprogesterone acetate, progesterone, specific ligands of progesterone A receptor, progesterone B receptor specific ligands, mesoprogestins, antiprogestins, asoprisnil, asoprisnil ecamate • aldosterone antagonists, such as spironolactones, eplerenone, canrenoate, canrenone, dicirenone, mexenoioate, prorenoate , epostane, mespirenone, oxprenoate, spirorenone, spiroxasone, prorenone. • Vitamin D hormones, such as, for example, alfacalcidol, calcifediol, calciferol, calcitriol. It should be understood that the compositions of the invention may comprise more than one drug active substance, e.g. ex. a combination of two or more drug substances. For example, a composition of the invention may comprise an effective dose for therapeutic use of the drospirenone and an effective dose for therapeutic use of an estrogen. Form of pharmaceutical formulation Optionally, the composition comprising the molecular dispersion may further comprise one or more additional active ingredients and / or excipients which are selected from the group comprising: disintegrants, lubricants, glidants, artificial sweeteners, bulking agents, dyes and one or more flavorings. The composition comprising the molecular dispersion can be produced in solid dosage forms. Solid dosage forms include tablets, film coated tablets, granules, pellets, pills, capsules and powders including for example any form of modified release of said dosage forms such as dosage forms with re-delayed release coatings. , sustained release coatings, enteric coatings, immediate release formulations, effervescent dosage forms and chewable forms. Capsules include, for example, soft gelatin capsules, hard gelatin capsules, hydroxypropylmethylcellulose (HPMC) capsules, and carrageenan capsules. In some embodiments, the compositions may be formulated in an appropriate manner for buccal or sublingual administration. For example in the form of tablets comprising drospirenone in a molecular dispersion of a flavored base or in the form of tablets in an inert base of gelatin, glycerin, sucrose or acacia. The solid solutions of the drospirenone in polymer films can also be placed directly on the buccal mucosa without any additional process. The liquid compositions may be suitable for buccal or sublingual spraying. All dosage forms can be produced using methods well known in the art. Typically, the amount of drospirenone varies within the range between about 1 and about 50% by weight in the dispersed compositions at the molecular level, preferably between about 5 and about 50% by weight.; and is present within the range between about 0.1 and about 5.0% by weight of the pharmaceutical dosage form, such as for example tablets, granules, pellets or powders, preferably between about 1.0 and about 5.0% by weight. weight. That is to say that the dispersed composition at the molecular level is typically present within the range between about 5 and 100% by weight of the pharmaceutical dosage form, preferably between about 10 and about 50% by weight. Bxcipients As noted above, the compositions of the invention comprise several additional excipients in addition to polymer, solvent, surfactant and crystallization inhibitor required. Suitable disintegrants are selected from the group consisting of: croscarmellose sodium (a cross-linked polymer of sodium carboxymethylcellulose), crospovidone, NF starch; sodium or potassium polyacrylline and sodium starch glycolate. Those skilled in the art will appreciate that it is desirable that compressible tablets disintegrate within 30 minutes, more desirable within 10 minutes, more desirable within 5 minutes; therefore, the disintegrant that is preferably used causes the disintegration of the tablet within 30 minutes, more preferably within 10 minutes, more preferably within 5 minutes. Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and so on. Preferably, magnesium stearate is used. Suitable glidants include pyrogenic silica, talc, and the like.

Appropriate volume-increasing agents include xylitol, mannitol, compressible sugars, lactose, calcium phosphate and microcrystalline celluloses. Suitable artificial sweeteners include saccharin, cyclamate and aspartame. If desired, known flavors and known FD &C dyes can be added to the composition. Process for preparing drospirenone molecular dispersions 1. Compositions of the invention that can be prepared by a process comprising the steps of: a) providing drospirenone and one or more carrier (s); and b) dissolving the drospirenone completely in said one or more vehicle (s); and c) optionally, drying the mixture which was obtained in step b). In the process described above, the step of dissolving drospirenone in step b) is preferably carried out by a means which is selected from heating, ultrasonic treatment, vigorous mixing, stirring and / or melt extrusion. The drying of the mixture obtained from step b may include spray drying or other methods known in the art. It should be understood that the process can be carried out using the acceptable vehicles for pharmaceutical use mentioned above and the active compounds mentioned above. Examples 1 to 6 describe a process and compositions for preparing microemulsion preconcentrates. In general, a microemulsion preconcentrate is prepared by a process comprising mixing a liquid solvent or a semi-solid or a mixture thereof and drospirenone under conditions which ensure the complete dissolution of the drospirenone in the liquid / semi-solid solvent, such as, for example, by using an ultrasonic bath operated at 50 ° C. For examples of liquid solvents or semi-solids, see above, in particular the solvents listed h) to u). The obtained preconcentrate can contain between drospirenone Img each 1500mg of concentrate and lmg each lOOmg of concentration, preferably between lmg of drospirenone each lOOOmg of concentrate and lmg each 150mg of concentrate, as for example dmg of drospirenone every 750mg or 250mg of concentrate. Optionally, at least one additional agent as mentioned above is also added to the liquid / semi-solid. Adding water to the pre-concentrate spontaneously forms an opalescent microemulsion ready to be administered. Typically, the amount of water added is between 2ml and 100ml each lg of the concentrate, such as between 4ml and 80ml each lg of the concentrate, such as between 5ml and 70ml each lg of the concentrate.

The obtained microemulsion does not show any sedimentation or crystallization for at least three days and the centrifugation (6000U, 10 min) does not cause any sedimentation or crystallization. Example 7 describes a preferred process and compositions for preparing liquid compositions containing dispersed drospirenone at the molecular level. Liquid compositions containing drospirenone dispersed at the molecular level are prepared by dissolving an amount of drospirenone in a solvent by stirring at 25-40 ° C, where the solvent is a liquid at room temperature and defined above. Typically, the drospirenone is applied in an amount between lmg and 30mg, preferably 8mg every 2g of the liquid. Typically, examples of suitable solvents were mentioned above, in particular the solvents listed above from h) to u).

The compositions according to examples 1-7 can be encapsulated in capsules. Basically, the compositions according to Examples 1-6 are preferably encapsulated in hard gelatin capsules which are sealed after filling them; and compositions according to examples 7 are preferably encapsulated in soft gelatin capsules. Example 8 shows that the selection of solvents and surfactants in liquid and semi-solid compositions of the invention does not alter the rate of dissolution and the permeability of the drospirenone.; Drospirenone is rapidly absorbed from all the formulations that were investigated. However, it was surprisingly found that the formulation according to Example 2 provides a lower degree of degradation of drospirenone. Examples 9 to 13 and 24 describe the process for pre-stopping solid solutions and preferred formulations: Basically, there are two methods for preparing solid solutions. In one embodiment (examples 12, 13 and 24) the active substance was mixed with a dry pulverized polymer or a mixture of polymers and optionally an additive such as, for example, a surfactant such as, for example, a sucrose ester. This mixture was continuously extruded using a single screw extruder or twin screw extruder or similar equipment extruder with a rotation speed in the range between 10 and lOOrpm. Optionally the temperature of the extruder can be controlled by heating and cooling, respectively, in such a way that the process temperature is for example within the range between 40-150 ° C. During said process the complete mixture is liquefied under the pressure and temperature obtained by thus dissolving the active substance in the polymer. The obtained resolidified extrudate can be cut or broken into pieces, grind and sift for further processing. The resulting in vitro dissolution data can be seen in example 25. In another embodiment (examples 10 and 11) the solid solution was prepared by spray drying from a solution containing the active substance and the polymer and optionally an additive such as, for example, a surfactant in dissolved form. Those skilled in the art know that spray drying conditions must be adjusted to the equipment used. The spray-dried product is further dried in a drying cabinet or by storage in a desiccator using a drying agent such as, for example, phosphorus pentoxide.

As mentioned above, the polymer is preferably a hydrophilic polymer, comprising free hydrophilic groups, such as, for example, polymers with functional groups in the side chains, such as, for example, free hydrophilic functional groups, eg carboxylic groups, ester-, hydroxy-, amino-, amide, halogen- or sulfo-. Typical examples of hydrophilic polymers that are soluble in water include, but are not limited to: polyvinylpyrrolidone (Povidone®, Kolli-don®); polyvinyl acetate; polyvinyl alcohol; polyvinyl alcohol phthalate; polyethylene glycol (PEG); polyethylene oxide; jelly; Carbomer; methacrylic acid copolymer; ammonium methacrylate copolymer; cellulose, carboxymethylcellulose; methylcellulose; hydroxy ethyl cellulose; hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC); cellulose acetate phthalate; and hydroxypropyl methylcellulose phthalate; or copolymers or mixtures thereof. The hydrophilic polymer can also be a water insoluble polymer including, but not limited to, crospovidone; Sodium starch glycolate; and croscarmellose. Preferably, the polymer is selected from the group comprising polyvinylpyrrolidone (Povidone®, Kollidon®) and polyethylene glycol (PEG), and in particular polyvinylpyrrolidone is preferred. When a water-insoluble polymer is employed, crospovidone is preferred. Examples 14 to 17 describe a process for incorporating solid solutions into oral dosage forms such as tablets. An experienced person will easily imagine that similar formulations can also be used to fill hard gelatine capsules. Preferred formulations basically include hydrophilic polymers as mentioned above to accelerate the partition of the drug into the intestinal fluid. In Example 18, a process for preparing solid solutions in thin films of polymer is described. Basically, a solution or suspension of active agent and polymers as described above and optional additives are stretched to give a thin film in a film stretching machine using a blade in the range 100-1000m. The film obtained is dried in a drying cabinet and cut into defined units. This kind of composition can be administered perorally (example 20) and also in the buccal and sublingual mucosa (example 19). The latter provides the advantage that the dosage can be easily adapted to the individual needs of each patient. The in vitro dissolution data obtained can be seen in example 26. Another method of buccal and sublingual administration is described in examples 21-23 which provide a solution of low to medium viscosity which is sprayed directly on the site. of absorption. Example 1 A microemulsion preconcentrate was prepared by mixing 18.9 g of Cremophor® RH 40 and 2, lg of Transcutol® P and 9.0 g of medium chain triglycerides at 50 ° C. Then, 40mg of drospirenone was added and mixed using an ultrasonic bath for 10 minutes at 50 ° C. The 750 mg of the microemulsion preconcentrate that was obtained contained Img of drospirenone. When lOOml of water was added, an opalescent microemulsion was spontaneously formed. The microemulsion that was obtained showed no sedimentation or crystallization for at least three days. Centrifugation (6000U, 10 min) did not cause any sedimentation or crystallization. The same was observed when adding 2000ml of water. Example 2 A formulation prepared according to Example 1 using 120mg of drospirenone instead of 40mg had the same properties, but 250mg of the microemulsion preconcentrate that was obtained contained lmg of drospirenone. Example 3 A microemulsion preconcentrate was prepared by mixing 18, 9g of Cremophor® EL and 2, lg of Transcutol® P and 9, Og of medium chain tri-glycerides at 50 ° C. Then, 40mg of drospirenone was added and mixed using an ultrasonic bath for 15 minutes at 50 ° C. 750 mg of the microemulsion preconcentrate that was obtained contained lmg of drospirenone. When lOOml of water was added, a slightly opaque microemulsion was formed spontaneously. The microemulsion that was obtained showed no sedimentation or crystallization for at least three days. Centrifugation (6000U, 10 min) did not cause any sedimentation or crystallization. The same was observed when adding 2000ml of water. Example 4 A composition prepared according to Example 3 using 120mg of drospirenone instead of 40mg had the same properties, but 250mg of the microemulsion preconcentrate that was obtained contained 1mg of drospirenone. Example 5 A microemulsion preconcentrate was prepared by mixing 18.9g of Cremophor® EL and 2, lg of Transcutol® P and 9.0g of castor oil at 50 ° C. Then, 40mg of drospirenone was added and mixed using an ultrasonic bath for 5 minutes at 50 ° C. 750 mg of the microemulsion preconcentrate that was obtained contained lmg of drospirenone. When water lOOml was added, an opalescent microemulsion was spontaneously formed. The microemulsion that was obtained showed no sedimentation or crystallization for at least three days. The centrifugation (6000U, 10 min.) Did not cause any sedimentation or crystallization. The same was observed when adding 2000ml of water. Example 6 A composition prepared according to Example 15 using 120mg of drospirenone instead of 40mg had the same properties, but 250mg of the microemulsion preconcentrate that was obtained contained Img of drospirenone. Example 7 Liquid compositions containing dispersed dros-pirenone were prepared at the molecular level by dissolving an amount of the drospirenone within the range between lmg and 30mg, preferably 8mg, in 1.992g of one of the following liquids by agitation at 25-40 ° C. h) Medium chain triglycerides i) Castor oil j) Glyceryl monocaprylate (eg Imwitor® 308) k) Polyoxyethylene-35-glyceryl tri-ricinoleate (eg Cremophor® EL) 1) Polyoxyethylene-40-hydroxystearate glycerol (Cremophor® 'RH 40) m) polyethylene glycol 400 n) Transcutol P o) triethyl citrate p) a mixture of 7% glycerol and 93% polyethylene glycol 400 q) a mixture of 50% glyceryl monocaprylate (for example Imwitor ® 308) and 50% polyethylene glycol 400 r) a mixture of 50% castor oil and 50% tributyl citrate s) a mixture of 50% castor oil and 50% polyethylene glycol 400 t) a mixture of 75 % of caprylic / capric glycerides (for example Imwitor® 742), and 25% polyethylene glycol 400 u) a mixture of 75% caprylic / capric glycerides (for example Imwitor® 742), 15% polyethylene glycol 400 and 10% ethanol When the preparation was carried out using 8mg of drospirenone, 250mg of the microemulsion preconcentrate that was obtained contained lmg of drospirenone. All such compositions as well as mixtures thereof can be encapsulated, for example in soft gelatin capsules. Example 8 Drospirenone-containing compositions were investigated in dispersed form at the molecular level according to examples 2, 4, 6, and 7 in the combined in vitro dissolution-in vitro permeation test. 250mg of each composition was dispersed in 250ml buffered saline isotonic saline solution. Lml was tested for the liquid obtained in a Caco-2 permeation study for 120 minutes. The principle of Caco-2 studies is well described in the literature, for example in Haltner E, Schmitz S, Gindorf C. In vitro Permeabilitatsun-tersuchungen ais Ersatz für Tier- and Humanstudien - welche Voraussetzungen müssen erfüllt sein? ALTEX 18 (2001): 81-87; and Le Ferrec E, Chesne C, Artursson P, Brayden D, Fabre G, Gires P, Guillou F, Rousset M, Rubas W. In vitro models of the intestinal barrier: The report and recommendations in ECVAM workshop 46. ATLA Alternatives to Laboratory Animáis. 29 (2001): 649-668. Basically, the permeation of the compound is measured through a monolayer of human colon carcinoma cells. In addition, intestinal metabolism and chemical stability are investigated with respect to the transformation of drospirenone into its inactive isomer. The in vitro dissolution is determined using 900ml of water at 37 ° C as dissolution medium and as a dissolution test apparatus a USP XXVIII 2 apparatus of blades operated at 50rpm. The apparent permeability of drospirenone through human colon cells from all the compositions that were investigated was within the range between 200 and 350nm / s indicating a high permeability with no significant differences. However, differences were detected with respect to the extent of degradation by isomerization of dros-pirenone. Degradation of drospirenone (ie transformation in the inactive isomer) was measured initially (after preparing the compositions), - after dissolution, before the beginning of the permeation study - and finally at the end of the permeation study, ie after 120 i-ñutos in contact with colon cells: Composition% DRSP degraded Initial Final Difference According to Example 2 2.0 3.1 + 1.1 (RH40, Transcutol®, MCT) According to Example 4 3.8 4.7 + 0.9 (EL, Transcutol®, MCT) According to Example 6 4.8 5.4 + 0.6 (EL, Transcutol®, Castor) According to Example 7j-6.5 7.5 + 1.0 (Imwitor® 308 ) According to the example 7k 4.9 5.7 + 0.8 (EL) According to example 71 4.5 5.1 + 0.6 (RH40) According to the example 7m 3.4 3, 9 + 0.5 (PEG 400) According to the example 7n 7.6 7.9 + 0.3 (Transcutol®) According to the example 7o 3.8 5.3 + 1.5 (triethyl citrate) According to the example 7q 5.8 6.4 + 0.6 (PEG 400, Imwitor® 308) EXAMPLE 9 Semisolid compositions containing drospirenone dispersed at the molecular level were prepared by dissolving an amount of the drospirenone within the range between lmg and 30mg in a mixture of 0.05g of alba wax and 2g of medium chain triglycerides and 0.07g of melting lecithin. all components at approximately 100 ° C and agitation. Said composition can be encapsulated in soft gelatin capsules or in hard gelatin capsules. Example 10 Solid drospirenone solution prepared by spray drying: Drospirenone Ig, 8g Kollidon® K30 and lg of WE15 sucrose ester were dispersed in 300ml of purified water by shaking. The dispersion was heated to 60 ° C and stirred continuously until all the excipients dissolved. The solution obtained was spray-dried using a Büchi 190 Mini Spray Dryer (intake temperature 120 ° C, outlet temperature 80 ° C, flow 4 g / min). The spray-dried product was maintained for at least 24 h in a desiccator using phosphorus pentoxide as a drying agent. EXAMPLE 11 Solid solution of drospirenone prepared by spray drying: - Drospirenone Ig, 8 g of a copolymer of vinyl pyrrolidone-vinyl acetate (Kollidon® VA 64) and Gelucire® 44/14 Ig in 300 ml were dispersed by agitation. purified water. The dispersion was heated to 60 ° C and stirred continuously until all the excipients were dissolved. The solution obtained was spray-dried using a Büchi 190 Mini Spray Dryer (intake temperature 120 ° C, outlet temperature 80 ° C, flow 4 g / min). The spray-dried product was maintained for at least 24 h in a desiccator using phosphorus pentoxide as a drying agent. Example 12 Solid drospirenone solution prepared by melt extrusion: 10% drospirenone, 50% polyvinyl pyrrolidone and 50% sucrose monooleate were mixed. The mixture was extruded continuously using a single screw extruder at 60 ° C and 50 rpm. Example 13 Solid drospirenone solution prepared by melt extrusion: 30% drospirenone, 30% polyethylene glycol 6000 and 40% sucrose monooleate were mixed. The mixture was extruded continuously using a single screw extruder at 60 ° C and 50 rpm. Example 14 The compositions according to examples 10-12 can be processed into tablets. For this purpose, 300g of the respective compositions were mixed with 490g of microcrystalline cellulose, then 10g of magnesium stearate was added and the mixture was mixed again for 1 minute. The mass obtained was directly compressed into 80 mg tablets. Each individual tablet contained 3mg of drospirenone. Example 15 The compositions according to examples 10-12 can be processed into tablets. For this purpose, 300g of the respective compositions were mixed with 490g of lactose, then 10g of magnesium stearate was added and the mixture was mixed again for 1 minute. The mass obtained was directly compressed into 80 mg tablets. Each individual tablet contained 3mg of drospirenone. Example 16 The compositions according to examples 10-12 can be processed into tablets. For this purpose, 300g of the respective compositions were mixed with 490g of microcrystalline cellulose, then 10Og of pyrogenic silica was added and the mixture was mixed again for 1 minute. The mass obtained was directly compressed into 80 mg tablets. Each individual tablet contained 3mg of drospirenone. Example 1 1OOg of the composition according to Example 13 was mixed with 395g of microcrystalline cellulose, then 5g of magnesium stearate was added and the mixture was mixed again for 1 minute. The mass that was obtained was directly compressed into tablets of 50mg of weight. Each individual tablet contained 3mg of drospirenone. Example 18 Drospirenone Ig and lg of polyoxyethylene-polyoxypropylene copolymer were dissolved by stirring in 94g of ethanol. In the solution obtained, one was homogeneously added. powder mixture of 17g of hydroxypropylcellulose and 17g of cellulose. The suspension that was obtained was stretched to give a thin film in an appropriate film stretching machine using a 500μm blade. After drying to dryness, a whitish film similar to a paper with a thickness of approximately 180μm was obtained. One unit of said film, ie a sheet of approximately 3cm2 contains 1mg of drospirenone. Example 19 The composition according to example 18 can be cut into pieces of between about 1 and about 15cm2 which are administered directly into the buccal mucosa, releasing between 0.33 and 5mg of drospirenone to the buccal mucosa. Example 20 The composition according to example 18 can be cut into pieces that are used to fill hard gelatin capsules for peroral application. Example 21 5 g of drospirenone, lg of tocopherol acetate and 5 drops of peppermint oil were brought to 100 ml with ethanol and dissolved by stirring. The solution obtained was used to fill lOml glass bottles that were covered with a pump with spray nozzle. One application released 0, lml of solution containing 0.5mg of drospirenone. EXAMPLE 22 5 g of drospirenone, 1 g of ascorbyl palmitate, 50 g of medium chain triglycerides, 300 g of Cremophor ® EL and 20 g of glycerol monoester were brought to 100 ml with ethanol and dissolved by stirring. The solution that was obtained was used to fill lOml glass bottles that were covered with a pump with a spray nozzle. One application released 0, lml of solution containing 0.5mg of drospirenone. Example 23 Solutions were administered according to Examples 21 and 22 individually as a sublingual spray, for example by spraying 6 times to release 3mg of drospirenone. The formulation according to Example 22 provides a prolonged residence time on the buccal mucosa. Example 24 Solid solution of drospirenone prepared by melt extrusion: 10% drospirenone, and 90% polyethylene glycol 6000 were mixed. The mixture was continuously extruded using a single screw extruder at 60 ° C and 50rpm. EXAMPLE 25 30mg of the formulation according to Example 24 was analyzed in an in vitro dissolution test using 900ml of water at 37 ° C as a dissolution medium and a USP XXVIII 2 bladed apparatus as a dissolution test apparatus. at 50rpm. The drospirenone contained in the formulation dissolved completely within 10 minutes. Therefore, it should be understood that such a rapid solution occurs within the disintegration time of the dosage form. Therefore, the dissolution step is not the speed determining step for the release of drospirenone. It will therefore be understood that in the present example drospirenone is already present in a "dissolved form", as p. eg dispersed at the molecular level since otherwise a dissolution so rapid would not be obtained. Example 26 The composition according to example 18 cut into pieces of 9cm2 (containing 3mg of drospirenone) was subjected to an in vitro dissolution test using 900ml of water at 37 ° C as a dissolution medium and as a dissolution test apparatus. a USP XXVIxI 2 pallet unit operated at 50rpm. The following results were obtained: drospirenone released after 10 min: 95.0%, after 20 min: 97.1%, and after 30 min: 97.2%.

Claims (20)

1. CLAIMS 1. A composition comprising drospirenone dispersed at molecular level in at least one vehicle acceptable for pharmaceutical use. The composition according to claim 1 in the form of a liquid or a semi-solid, wherein at least one of the vehicles acceptable for pharmaceutical use is selected from the group consisting of glycerol, propylene glycol, ethylene glycol monoethyl ether, polyols , esters of citric acid, monoglycerides, diglycerides, vegetable oils, vegetable fats, partially synthetic triglycerides, synthetic triglycerides, mixtures of fatty acid esters with glycerol, fatty alcohols, ethers of fatty alcohols, fatty acids, fatty acid esters, waxes, paraffin and mixtures thereof. 3. The composition according to claim 2, further comprising at least one emulsifier. The composition according to any of the preceding claims, wherein said at least one pharmaceutically acceptable carrier is selected from the group consisting of medium chain triglycerides, castor oil, glycerol monocaprylate, caprylic glycerides / capric, polyoxyethylene-35-tri-ricinoleate glycerol, polyoxyethylene-40-hydroxystearate glycerol, polyethylene glycol 400, diethylene glycol monoethyl ether, triethyl citrate and mixtures thereof. 5. The composition according to claim 4, wherein said at least one carrier acceptable for pharmaceutical use is selected from the group consisting of glycerol and polyethylene glycol 400, a mixture of glycerol monocaprylate and polyethylene glycol 400, a mixture of castor and tributyl citrate, a mixture of castor oil and polyethylene glycol 400, a mixture of caprylic / capric glycerides and polyethylene glycol 400, a mixture of caprylic / capric glycerides and polyethylene glycol 400 and ethanol. 6. The composition according to any of the preceding claims in the form of a microemulsion preconcentrate. The composition according to claim 1 in the form of a solid, wherein at least one of the vehicles acceptable for pharmaceutical use is solid at room temperature and / or has a melting point in the range between 40- 80 ° C and is selected from the group consisting of polyethylene glycol 6000 vegetable oils, vegetable fats, partially synthetic triglycerides, synthetic triglycerides, mixtures of fatty acid esters with glycerol, mixtures of mono-, di- and tri-glycerides, polyoxyethylene fatty acid esters with glycerol, fatty acids, fatty acid esters, waxes, paraffin, and mixtures thereof. The composition according to claim 1, wherein the acceptable carrier for pharmaceutical use is a polymer, preferably a hydrophilic polymer. 9. The composition according to claim 8, wherein the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone; polyvinyl acetate; polyvinyl alcohol; polyvinyl alcohol phthalate; polyethylene glycol; polyethylene oxide; jelly; Carbomer; methacrylic acid copolymer; ammonium methacrylate copolymer; cellulose, carboxymethylcellulose; methylcellulose; hydroxy ethyl cellulose; hydroxypropyl methylcellulose, hydroxypropylcellulose; cellulose acetate phthalate; and hydroxypropyl methylcellulose phthalate; crospovidone; Sodium starch glycolate; croscarmellose; and copolymers thereof, and mixtures thereof. 10. The composition according to any of claims 1-9, wherein the composition further comprises an estrogen. 11. A process for providing drospirenone dispersed at the molecular level in a vehicle acceptable for pharmaceutical use and comprising the steps of: a) providing drospirenone and one or more carrier (s); and b) dissolving the drospirenone completely in said one or more vehicle (s); and c) optionally, drying the mixture obtained in step b). 12. The process according to claim 11, wherein the step of dissolving drospirenone is carried out by a medium which is selected from the group consisting of heating, ultrasonic treatment, vigorous mixing, stirring and melt extrusion. The process according to any of claims 11 to 12, wherein the vehicle is in the form of a liquid or a semi-solid, wherein at least one of the vehicles acceptable for pharmaceutical use is selected from the group consisting of glycerol, propylene glycol, ethylene glycol monoethyl ether, polyols ,. esters of citric acid, monoglycerides, diglycerides, vegetable oils, vegetable fats, partially synthetic triglycerides, synthetic triglycerides, mixtures of fatty acid esters with glycerol, fatty alcohols, fatty alcohol ethers, fatty acids, fatty acid esters, waxes , paraffin and mixtures thereof. The process according to any of claims 11 to 13, wherein the vehicle further comprises at least one emulsifier. 15. The process according to any of claims 11 to 14, wherein said at least one vehicle acceptable for pharmaceutical use is selected from the group consisting of medium chain triglycerides, castor oil, glycerol monocaprylate. , caprylic / capric glycerides, glycerol polyoxyethylene-35-tri-ricinoleate, polyoxyethylene-glycerol-40-hydroxystearate, polyethylene-glycol 400, diethylene glycol monoethyl ether, triethyl citrate and mixtures thereof. 16. The process according to any of claims 11 to 14, wherein said at least one carrier acceptable for pharmaceutical use is selected from the group consisting of glycerol and polyethylene glycol 400, a mixture of glycerol monocaprylate and polyethylene glycol 400, a mixture of castor oil and tributyl citrate, a mixture of castor oil and polyethylene glycol 400, a mixture of caprylic / capric glycerides and polyethylene glycol 400, a mixture of caprylic / capric glycerides and polyethylene glycol 400 and ethanol. 17. The process according to any of claims 11 to 16, wherein the mixture obtained from step b) or c) is in the form of a microemulsion preconcentrate. The process according to claim any of claims 11 or 12, wherein at least one of the vehicles acceptable for pharmaceutical use is solid at room temperature and / or has a melting point in the range between 40- 80 ° C and is selected from the group consisting of polyethylene glycol 6000 vegetable oils, vegetable fats, partially synthetic triglycerides, synthetic triglycerides, mixtures of fatty acid esters with glycerol, mixtures of mono-, di- and tri-glycerides, polyoxyethylene esters of fatty acid with glycerol, fatty acids, fatty acid esters, waxes, paraffin, and mixtures of the misos. 19. The process according to any of claims 11 or 12, wherein the acceptable carrier for pharmaceutical use is a polymer, preferably a hydrophilic polymer. The process according to claim 19, wherein the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone; polyvinyl acetate; polyvinyl alcohol; polyvinyl alcohol phthalate; polyethylene glycol; polyethylene oxide; jelly; Carbomer; methacrylic acid copolymer; ammonium methacrylate copolymer; cellulose, carboxymethylcellulose; methylcellulose; hydroxy ethyl cellulose; hydroxypropyl methylcellulose, hydroxypropylcellulose; cellulose acetate phthalate; and hydroxypropyl methylcellulose phthalate; crospovidone; Sodium starch glycolate; croscarmellose; and copolymers thereof, and mixtures thereof.