TW200840587A - Molecular dispersions of drospirenone - Google Patents

Abstract

The present invention relates to liquid pharmaceutical compositions comprising steroidal drugs, such as drospirenone, in molecularly dispersed form. The compositions 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

200840587 IX. INSTRUCTIONS: [Technical field to which the invention pertains] The present invention relates to the field of δ ^ table allocation science, and in particular to the improvement of pro-involution a substance (for example, steroid _ & k knife, special疋5 is related to the solubility and bioavailability of snail _) v ^ method. The particular formulation technique of the present invention is based on the general principle that k is provided as a sub-dispersed form of snail. [Prior Art] Unblended drospirenone is not sufficiently absorbed in the gastrointestinal tract, in part because of its poor solubility in water and its low dissolution rate in its water. In addition, the snail/ketone has poor chemical stability in an acidic environment including the conditions provided in the gastric juice of the stomach. In fact, within 3Q minutes of exposure to a hydrochloric acid solution having a pH of about U, almost spirulina degraded into its therapeutically non-rotating isomer. As a result, it is recommended to use an enteric coating. We hypothesize that drospirenone, which is in the natural state of steroid molecules, should be absorbed in the upper half of the gastrointestinal tract (eg, gi), for example, from the gastric mucosa and/or duodenal mucosa, which requires that drospirenone should be completely dissolved in 〇1 The beginning. We have found that when the micronized form of drospirenone is provided, its solubility in vitro is higher. For example, as long as 3 minutes after the start of the dissolution test, at least 7% of the snails have dissolved. However, micronization technology requires special equipment, is costly and may not be easy to operate. This may require alternative formulations of such drospirenone formulations including micronized forms. Different formulation techniques for preparing a Baile composition having an active ingredient in admixture with a liquid, semi-solid or solid excipient are well known. However, the technique of the technique of 132010.doc 200840587 and the like is only to prepare fine particles of the active material uniformly dispersed with the excipient, instead of preparing the activated a substance dispersed at the molecular level with the excipient. Moreover, such formulation techniques do not include a method of preparing a composition in which the active compound in the initial critical step is dissolved in a carrier and then the resuscending agent constitutes the final composition or at least a portion thereof.

WO 0245693 describes active dosage forms suitable for use, whether it is necessary to mask the taste or to destroy the coating. These dosage forms comprise an active material which is uniformly dispersed or dissolved in a matrix selected from the group consisting of paraffin waxes, fatty alcohols, triglycerides, partial glycerides and fatty acid esters. U. US 5,569,652 relates to active compound formulations which are processed by the use of vehicles and diluents together with active compounds. US 5,656,622 is a novel derivative of estradiol which is used in combination with snail to act as a sac or a squirt. EP 1 260 225 relates to compositions comprising estrogen. WO 2004/041289 describes snails in pharmaceutical drug formulations prepared by the use of conventional fluidized bed techniques. WO 2004/0222 G65 relates to a composition comprising a testosterone derivative and optionally a progesterone (referring to snail (4), wherein the drug is an aqueous or an oily suspension." His technique is still active in micronized form. The compound improves the bioavailability by effecting rapid dissolution of the active compound in water. 132010.doc 200840587 WO 01/52857 mentions a composition comprising drospirenone because the drospirenone is sprayed onto an inert carrier. It has previously been dissolved in a suitable solvent such as methanol or ethyl acetate. Although previous results have produced some improvements in the bioavailability of drospirenone administered orally, these results have not been eliminated. The present invention provides a pharmaceutical composition comprising at least one steroid drug in a molecularly dispersed form, such as a luteinizing hormone (eg, drospirenone, Progesterone, eplerenone, etprenene (et〇n〇gestrel) and/or estrogen (estritol and its scorpion). The drug comprises a steroid drug, preferably drospirenone, which is present in the composition in a non-particulate form. In the presence of a molecularly dispersed form, it is desirable that the drug be present in the vehicle in a dissolved state. When the unit disintegrates immediately, the drug will be released very rapidly. In a pharmaceutical composition in which the drug is in a molecularly dispersed form, the disintegration time is actually the step of the drug release rate. It means that the present invention can significantly improve bioavailability. The compositions are preferably provided as solid, semi-solid or liquid forms, all of which are preferably suitable for oral administration and preferably in contact with gastric juice. And then absorbed from the gastrointestinal tract. We have found that these compositions have high bioavailability, good chemical stability and rapid dissolution in vitro and can be produced without the need for costly equipment or safety equipment. 132010.doc 200840587 Preparation methods and uses for pharmaceutical compositions, and also for such compositions. The compositions of the present invention are The method comprising the steps of: a) providing drospirenone and one or more carriers; and b) completely dissolving the drospirenone in the or the carrier; and c) drying step b as appropriate The mixture obtained in the above. We have found that the pharmaceutical group containing the molecularly dispersed form of the snail shoulder does not have excellent manufacturing methods, physical or chemical stability, in vitro permeability of intestinal cells in vitro, and in vivo bioavailability. Efficacy.,,, ° In the first aspect, the present invention provides a composition comprising a snail comprising a molecule dispersed in a carrier of the medicinal wind. The carrier contains a dissolution solution: (4) = , mouth ', ,, the composition is a solid, semi-solid or liquid form === the same characteristic is that the snail is dissolved in the carrier at the molecular level. And has the property of dissolution. Generally, "...before, instead of s knowing the solution of snail solution, X-ray diffraction analysis or other appropriate means such as microtechnology, electron microscopy or dissolution = dissolution 1 in = solution form, ie molecular dispersion When the form exists, the characteristic: long: occurs immediately when the early disintegration occurs. Therefore, the common disintegration time of the dosage form and the disintegration time of the comparative formulation of the field occur simultaneously with the error range associated with the η analysis method at the time of dissolution. And a solution comprising a body or a liquid composition in a pharmaceutically acceptable carrier, whether the composition is solid or semisolid, and the common feature of the composition is snail, Molecular grade, commercially available extracts have properties of medium and/or dissolved drospirenone properties J32010.doc 200840587 rather than conventional drospirenone solutions. The compositions of the present invention advantageously exhibit rapid dissolution of the snail web in vitro. 'Money speed dissolution is defined as at least 7% drospirenone in the composition dissolves 30 minutes after the onset of the in vitro solubility test, in particular, at least 8% by weight of drospirenone after the in vitro solubility test is started 2 〇 Dissolved in minutes, more preferably at least 85% by weight of snails are dissolved at η minutes after the onset of the in vitro solubility test. Let us 7. (: _ ml water is used as the dissolution medium and the XXVm blade device 2 is used as a dissolution test device for testing, and the device is operated at 5 〇〇 rpm, for example 50 or 75 rpm. As mentioned above, Higher bioavailability can be achieved with micronized drugs. However, this technique has certain disadvantages because micronized drugs have a tendency to flocculate during production and their operators are susceptible to dust from the micronized music. The production method of the present invention can avoid such disadvantages' = a small number of production steps of the guide material, a reduction in the formation of dust during the manufacturing process, a higher level of volume, a higher level of environment and occupational safety, manufacturing: The composition of the present invention is preferably in a solid, semi-solid or liquid form. The solid composition according to the present invention may be referred to as a solid solution. The semi-solid and liquid compositions are meant to be defined as dissolved form = 屈 solution - wherein the solvent has the viscosity and/or melting point of whether the composition is a semi-solid or liquid composition. "Molecular dispersion" or "molecular dispersant" is used to describe any solid, solid and liquid system 'where component A (eg drospirenone) is at the molecular level 132〇1〇·ς|〇〇200840587 In another component B (such as a solvent or a polymer), it is impossible to detect component A of the crystalline form by X-ray diffraction analysis, and it is impossible to detect the particle form by using micro-technology. Component A, whether crystalline or amorphous, is understood to mean that the term "molecular dispersant" is dissolved in component B regardless of the nature of component B. The term "molecular dispersion" is interchangeable with the term "molecular dissolution".

'Surgical 5" "solid dispersant" refers to a state in which drospirenone is in a substantially non-particulate form and is dispersed in a polymer matrix. This state is also referred to as solid, enthalpy. The drospirenone is in a crystalline form and is dispersed in the polymeric basal such that the crystallization is so fine that it cannot be resolved by X-rays, and then to the crystallization. As used herein, the term, substantially "Particulate form" means a state in which more than 9 Å is in a non-particulate form. , or alternatively, microscopic techniques such as crystallization and non-crystalline particles can be used to study the absence of mass. As used herein, the term "substantially non-particulate form" is used in this state, and when analyzed using a microscopic device, drospirenone in excess of 90°/〇 is in a non-particulate form. "Used to describe any solid system in which - components are dispersed in another component at the molecular level. In the special form, the solid solution is characterized by having drospirenone (or other active ingredient) having a molecule dispersed in a solvent which is adsorbed on a solid carrier capable of adsorbing the solution while remaining solid. That is, the snail is completely :: in the solvent present on the surface of the carrier. The solvent is transferred to 132〇1〇 by completely dissolving the drospirenone in the solvent and then by adding the force and the solid carrier attached to the solvent: (J〇q -11-200840587: the mouthpiece is kept at the same time) The solid form of the snails is dissolved in the form of the snails, and the solid solution is said to contain drospirenone in which the molecules are dispersed in the composition, and the phlegm of the body is dispersed in a solvent. The term "solution" is used to describe any semi-solid and liquid system in which - the component is dispersed in the other component on a molecular level. Thus, 'we understand that the composition of the present invention comprises a non-particulate form of a ketone such as The snails are not present in the composition in the form of micronized particles or in the form of particles within the nanometer range. Thus the term "molecular partitioning does not substantially include particles of drospirenone which are very fine (e.g., micronized) Particles or nano-sized particles) and pharmaceutically acceptable ingredients or carriers; compositions for dry mixing or compositions in which the final composition still comprises snails in the form of granules. The term "supersaturated solution" Used for drawing A solution containing a concentration of a drug to a saturation concentration determined at room temperature. That is, the powder is not detected by powder x-ray diffraction analysis. Crystalline form of the drug. It is expected that the supersaturated solution is substantially thermodynamically unstable, which will lead to solution saturation and drug recrystallization. The term "stabilized supersaturated solution" is used to describe a supersaturated solution in which X-ray diffraction analysis is used to detect Less than any recrystallization drug. For example, the addition of a crystallization inhibitor can achieve stability. The term "microemulsion" is used to describe a colloidal dispersant that is slightly opaque, milky white, transparent and substantially transparent, when The dispersant spontaneously or substantially spontaneously forms upon contact with the aqueous medium. The microemulsion is thermodynamically stable and contains droplets or liquids, nanosized particles having an average diameter of less than about 2 μηη 132010.doc -12-200840587. In general, 'lipophilic drugs incorporated into microemulsions are present in dissolved form in the small droplets or liquids" nanosized "size particles mentioned. The term "microemulsion preconcentrate" refers to a composition that spontaneously forms a microscopic formation in gastric juice after dilution or oral administration in an aqueous medium (e.g., in water) at a ratio of 1:1 to 1:10, such as 1:10. In one embodiment of the invention, the composition is in liquid form. Thus, the composition comprises a pharmaceutically acceptable solvent which is Φ liquid at room temperature and/or has less than 4 Å. The melting point. These solvents may be selected from the list shown in the following h) to U). In another embodiment, the pharmaceutically acceptable solvent is half solid at room temperature and/or has less than 4 (TC) The melting point. The solvents may be selected from the list shown below... to U). In general, the solvent used in the liquid or semi-solid composition of the present invention and which is liquid or semi-solid at room temperature includes ( But not limited to) · ethanol, isopropanol, glycerol, propylene glycol, transcutol® (diethylene glycol monoethyl ether), more than 10 alcohols, citric acid esters, monoglycerides, diglycerides Classes, vegetable oils, vegetable fats, partially synthesized triglycerides (eg Chain triglycerides (MCT), such as miglyo®), synthetic triglycerides, mixtures of glycerol fatty acid esters such as Imwitor®, fatty alcohols, fatty alcohol ethers, fatty acids, fatty acid esters, waxes Classes, stone soil, pure water and mixtures thereof. In addition, surfactants and cosolvents can be used. It is recognized by those skilled in the art that a number of solvent melting points mentioned above depend, for example, on the length and degree of substitution of the hydrocarbon chain. Thus, those skilled in the art will be able to readily select a suitable solvent to produce a liquid or semi-solid composition. 132010.doc -13· 200840587 Preferably, the solvents are selected from the group consisting of ethanol, propylene glycol, partially synthesized triglycerides or vegetable oils. Examples of the polyhydric alcohols are generally glycerin, propylene glycol, sorbitol, mannitol, inositol, pentaerythritol, maltitol, lactitol. Examples of the phthalic acid esters are generally tributyl citrate, triethyl citrate, aCetyl_tributylcitrat, and citric acid citrate. Examples of φ monoglycerides are typically glyceryl monostearate, glycerol monopalmitate, glycerol monooleate, glycerol monolinoleate. An example of a glycerin self-oxime is generally glyceryl dibehenate and glycerol distearate. Examples of vegetable oils are generally eucalyptus oil, peanut oil, and castor oil. Examples of fats are generally lard. Examples of synthetic and partially synthesized triglycerides are generally neutral oil, softisan®, witepsol(g), supp〇cire8. • Examples of glycerin fatty acid vinegars are generally glycerol monocaprylate, glyceryl dodecanoate, caprylic/capric glyceride, glyceryl stearate. Examples of fatty alcohols are generally octanol, decyl alcohol, dodecanol, tetradecanol, hexadecanol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, ricinoleol. Examples of fatty alcohol ethers are generally oleic acid oleate, cetyl palmitate, and ethyl oleate. Examples of fatty acids are generally capric acid, caprylic acid, dodecanoic acid, palmitic acid, hexadecanolic acid, octadecanoic acid, oleic acid, and linoleic acid. Examples of fatty acid esters are typically dodecanoate, caprylate, phthalate, 132010.doc -14-200840587 stearate. - Examples of fiber types are generally white bee stings and bee stings. Suitable surfactants include, but are not limited to: a) printing grease b) block copolymers of ethylene oxide and propylene oxide such as Pluronic® and Poloxamer® grade c) glycerol and polyoxyethylene Glycerin 1 and its mixtures such as Gelucire®, Labrafil® and Labrasol® grades d) Propylene glycol vinegars such as Lauroglycol® and Capryol® grade e) Severe sugar fatty acid esters such as 811 (^0 € 31613® f) sorbitol fatty acids Esters and polyoxyethylene sorbitol fatty acid esters and mixtures thereof such as Span and Tween® grade g) polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers and polyoxyethylene monoacids, diacids and triglycerides And mixtures thereof such as Cremophor® grade. In an embodiment of the present invention of the present invention, the liquid or semi-solid composition of the present invention comprises the following solvents: h) medium chain triglyceride i) castor oil j) Imwitor® 308 (glycerol monooctanoate)

k) Cremophor8EL l) Cremophor8RH 40 (polyoxyethylene-40-glycerol-hydroxystearate) m) polyethylene glycol 400 n) transcutol® P (diethylene glycol monoethyl hydrazine) 132010.doc -15- 200840587 〇) citric acid triethyl hydrazine ρ) a mixture of 7% by weight of glycerin and 93% by weight of polyethylene glycol 4 q q) a mixture of 50% by weight of iImwitor 308 and 50% by weight of polyethylene glycol 4 r ) 50 weight. / Mixture of castor oil with 50 weight d/❾ of tributyl citrate s) 50% by weight of castor oil with 50% by weight. /. a mixture of polyethylene glycol 4 t t) 75 wt% 2 lmwitor® 742 and 25% by weight of polyethylene glycol 400 mixture 1 〇 75% by weight of Imwitor 8742, 15 weight 0 / 〇 polyethylene glycol 400 and a mixture of 10% by weight ethanol, or a mixture of h) to u) any solvent. Accordingly, in certain embodiments of the invention, the at least one pharmaceutically acceptable carrier is selected from the group consisting of medium chain triglycerides, castor oil, glycerol monocaprylate (Imwitor® 308), caprylic/capric acid Glycerol Cool (Imwitor 742®), Polyoxyethylene-3 5-Glycerol-Triricinoleic Acid _((1^111〇卩11〇1:£1^), Polyoxyethylene-40-glycerol-hydroxystearate a group of esters (Cremophor® RH 40), polyethylene glycol 400, diethylene glycol monoethyl ether (transcutol® P), triethyl citrate and mixtures thereof. In particular, glycerol and polyethylene glycol a mixture of 400, a mixture of glycerol monocaprylate (Imwitor® 308) and polyethylene glycol 400, a mixture of castor oil and tributyl citrate, a mixture of castor oil and polyethylene glycol 400, octanoic acid/capric acid glycerol Mixture of ester (Imwitor® 742) with polyethylene glycol 400, octanoic acid/capric acid glyceride (Imwitor® 742) and a mixture of polyethylene glycol 400 and ethanol. Included in 2 g of these liquid or semi-solid compositions The amount of snail is generally in the range of 1 mg to 30 mg, preferably 8 mg. 132010.doc •16- 200840587 All liquids such as hydrazine can be used. The capsule is enclosed, for example, in a soft gelatin capsule. In other embodiments of the invention, the composition is in the form of a microemulsion preconcentrate. These examples generally comprise a liquid and a half as mentioned above. a solid solvent, but may additionally comprise at least one emulsifier. Suitable emulsifiers for the present invention are related to polyoxyethylene _35_glycerol-sodium ruthenium oleate (Cremophor® EL), polyoxyethylene "Ο-glycerol-hydroxyl hard" Acid ester (Cremophor® RH40), polyoxyethylene 4〇〇_monoricinoleate, polyoxyethylene fatty acid glyceride (Gelueire8, Labrafil®, Labras〇18) and its hydrazine. The co-emulsifier and/or the co-solvent are mixed, such as monoethyl ketone (Transcut® 18p), glycerol monocaprylate (Imwitor® 308) and propylene glycol ester (Lauroglycol®, Capryol®). In still other embodiments, the composition is in solid form. In one embodiment, the composition comprises a pharmaceutically acceptable carrier, the carrier being in solid form at room temperature and/or having a higher than 4 〇溶c melting point, for example at 40-80 ° C As a suitable solid carrier, mention may be made of solid polyethylene glycol (for example polyethylene glycol 6000), vegetable oils and fats, partially synthesized diglycerides, synthetic diglycerides, such as Imwitor®. Mixtures of glycerol fatty acid esters, monoacids, mixtures of diacids and triglycerides, polyoxyethylidene fatty acid vinegars (eg Gelucire®), fatty acids, fatty acid esters, waxes, paraffins or mixtures thereof. In some of these embodiments, the molecular dispersing agent comprises drospirenone substantially uniformly dispersed in a matrix comprising a mixture comprising at least one fatty alcohol and at least one paraffin wax. In other embodiments, the substrate 132010.doc 200840587 comprises at least one triglyceride and at least one solid paraffin or at least one partial glycerol and at least one solid dendrobium or at least one fatty acid vinegar and at least one solid paraffin wax. Among these preparations, preparations containing microspheres are preferred. In a solid composition of another form of the invention, the pharmaceutically acceptable carrier is a polymer. The polymer is preferably a hydrophilic polymer containing a free hydrophilic group, such as a polymer having a functional group in a side chain, such as having a φ 'transferred hydrophilic s energy group such as a slow group, a δ group, A benzyl group, an amine group, an acid amine group, a thiol group or a decyl group. Typical examples of 亲水/gluten-water hydrophilic polymers include, but are not limited to, polyvinylpyrrolidone (Povidone 8, Kollidon 8), polyvinyl acetate, polyvinyl alcohol, polyvinyl phthalate, Polyethylene glycol (PEG), polyethylene oxide, gelatin, carbomer, methacrylic acid copolymer, ammonium methacrylate copolymer, cellulose, carboxymethyl cellulose, methyl cellulose, ethyl Cellulose, (tetra)methylcellulose • (HPMC), propyl cellulose (HPC), cellulose acetate phthalate and 'propyl propyl methyl cellulose phthalate or copolymers thereof mixture. The hydrophilic polymer may also be a water-insoluble polymer including, but not limited to, crosslinked polyalkylene fluorene, transacetin and crosslinked stearyl cellulose. The polymer is preferably selected from the group consisting of The polyethylene bitumen is a group of 8, K〇lHd〇_ and polyethylene glycol (PEG) and is particularly preferably a poly(b) ketone. When a water-insoluble polymer is used, it is preferably a cross. Polyalkenyl ketone ketone. 1320I0.doc -18 - 200840587 All of the foregoing polymers are well known in the art. Polyvinylpyrrolidone is a polymer of 1-vinyl-2-pyrrolidinone. Commercially available as Povidone or Kollidon having an average molecular weight in the range of from about 2,000 to about 1,500, 〇〇〇. The polyvinylpyrrolidone used typically has from about 7, from about 5 to about 54,000. The average molecular weight in the range is preferably in the range of from about 28,0 Torr to about 54,000. Crosslinking of the cross-linked povidone-based N-ethyl fluoren-2-pyrrolidone The crosslinked polyethylidene typically has a particle size of from about 2 μm to about 25 μm, and is preferably about 5 μm See, for example, from about 25〇 Kollidon (Kollidon), produced by the B ASF for the polyvinyl pyrrolidone, the pharmaceutical industry). The ratio of drospirenone to polymer is preferably from about 丨: 丨 to about 丨: 丨, more preferably from about 1:2 to about 1:20, and most preferably from about 1:5 to about 1:1〇 . When the molecular dispersant of the present invention is prepared by dissolving drospirenone and a polymer in a mixture of an organic solvent or an organic solvent, suitable organic solvents include, but are not limited to, di-methane, methanol, ethanol, and Propanol, acetone, tetrahydrofuran or a mixture thereof. The solvent can be removed by conventional means: e.g., evaporation of the solution J under a mask using a double-turn 5 dry* dander or spray dryer or supercritical fluid extraction method. It is to be understood that the present compositions can also be applied to other drug molecules other than drospirenone and to combinations of two or more types of drug molecules. Accordingly, the compositions of the present invention also comprise any compound which is lipophilic and has poor solubility in water of 25. In general, the compound has a water in 25t ^ 132010.doc -19- 200840587

A solubility below 1 mg/ml, such as less than 0.5, 0.1, 0.05 or 0·01 mg/ml. The chelate is typically a steroid molecule and/or is typically a hormone/anti-hormone. A wide range of other active pharmaceutical ingredients may benefit from this technology, such as albendazole, aminogluthethimide, aminosalicylic acid (3-, 4- or 5-amino sulphate) Acid), amiodarone, astemizole, azathioprine, beclamide, benorylate, benzene british ( Benperidol), bezafibrate, biotin, bromocriptine, bromocriptine mesylate, bumetanide, busulphan , cabergoline, carbamazepine, cefixime, chenodeoxycholic acid, chlorambucil, chloroquine, magnesite (chlorpropamide), chlorprothixene, chlorthalidone, cinnarizine, cinoxacin, clobazam, clofazimine, Clofibrate, chlorite shaws (clonazepam), cyclopentthiazide, cyclosporin 、, dapsone, demeclocycline, diazoxide, diflunis Diflunisal, digitalis poison (by name: 〇\丨11), digoxin, disulfiram, domperidone, droperidol, enoxa Enoxacin, epothilone, ethionamide, etretin 132010.doc -20- 200840587

(etretinate), felodipine, fenbufen, fexofenadine, flumazenii, folic acid, furosemide, glipizide ), gliquidone, griseofulvin, haloperidol, hydrochlorothiazide, hydroflumethiazide, ibuprofen, ilo Iproprost, indomethacin, isocarboxazid, isosorbide dinitrate, isotretinoin, isradipine, istraconazole Itraconazole), ketazolam, ketoconazol, ketoprofen, lansoprazole, liothyronine sodium, lisuride Loperamide, loratadine, lorazepam, lovastatin, toluene. Mebendazole, medazepam, mefenamic acid, menadione, mequitazine, methotrexate, misoprostol (misoprostol), morphine, niclosamide, nifedipine, nimodipine, nitrazepam, omeprazole, Oxacy Oxa (oxazepam), oxytetracycline, pantoprazole, perphenazine, phenylbutazone, pimozide, pindolol , probenecid, probucol, pyrantel embonate, 132010.doc -21 - 200840587

Pyrimethamine, retinol, riboflavin, simvastatin, stilboestrol, sulindac, sulindip Sulphadiazine), sulphamethoxazole, sulphasalazine, sulpiride, tamoxifen, temazepam, 17 phenylene Thiabendazole, thioguanine, tocopherol, tolbutamide, tretinoin, triamteren, triazolam, armor Trimethoprim and zopiclone As described above, the compounds of the invention are generally steroid molecules or otherwise may be mentioned: • Androgens, such as testosterone and its esters (heptanoic acid sterolone, hydrazine-acid sterolone, testosterone cypionate, propionate sterolone • estrogens/antiestrogens such as estradiol and its esters (estradiol valerate, Acid estradiol, estradiol cyclopentanoate, estradiol undecylate, estriol, estrone, co-estrogens, equilin, ethinyl Glycol 〇 1:1^1171 € 81:1^(11〇1), fenestrel, mestranol, nylestriol, fast female &| (quinestrol), Clomifen (clomifene), estrogen receptor alpha agonist, estrogen receptor alpha antagonist, estrogen receptor beta agonist, estrogen receptor beta antagonist, estrogen receptor downregulator. Types of solids, such as cortisones and glucocorticoids 132010.doc -22- 200840587, such as beclomethasone dipropionate, betamethasone, betamethasone valerate , budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, dexamethasone, fluorinated acetate Fludrocortisone acetate, prednisolone, prednis One) 〇

• Progesterone/antiandrogen, such as cyproterone, etonogestrel, desogestrel, gestodene, levonorgestrel , norethisterones, norgestimate, norethindrone, norethisterone acetate, norethynodrel, norgestimate, methyl acetylenketone (11 〇1^681: 1), medrogestone, mederate progesterone acetate, progesterone, progesterone receptor A-specific ligand, progesterone receptor Body B-specific ligands, mesoprogestins, antiprogestins, asoprisnil, asoprisnil ecamate ° • ketone antagonists, such as spironolactones, eplerenone , canrenoate, canrenone, dicirenone, mexrenoate, prorenoate, epostane, snail Ketone (mespirenone), oxprenoate, snail Spironone, spiroxasone, prorenone. 132010.doc 23· 200840587 • Vitamin D hormones such as afaractin (he is 丨^.1), diol (four) cifedid), liquefied alcohol (on gamma 1), calcitriol (four) also (four) . It will be appreciated that the compositions of the present invention may comprise more than one active drug, such as a combination of two or more drugs. For example, the compositions of the present invention may comprise, administer an effective amount of drospirenone and a therapeutically effective amount of estrogen. The form of the pharmaceutical formulation may include a plurality of molecular dispersing agents.

Further, the active ingredient and/or excipient' is selected from the group consisting of a disintegrant, a lubricant, a glidant, an artificial sweetener, a bulking agent' colorant, and one or more flavorants. < A composition containing a molecular dispersant can be produced in a solid dosage form. The solid dosage form comprises a troche, a film-coated lozenge, granules, pellets, nine doses, capsules, and administrations, for example, and includes any modified release form of such dosage forms, such as a delayed release coating, a sustained release coating Enteric coated dosage form, immediate release formulation, effervescent dosage form and _ form. (d) including gelatin capsules, hard gelatin capsules, propylmethylcellulose (Hp and guacamole capsules. ^ = In some embodiments, the composition may be suitably formulated for use in sublingual or sublingual administration. For example, in the molecular dispersing agent of the flavoring base, it is in the form of a tablet or a tablet in the form of a gelatin, a sucrose or an arsenone: a base. The snail snail is directly placed on the cheek mucosa without any other treatment. The liquid group can be applied to the cheek or sublingual spray application.,,, hunting, all dosage forms can be prepared by methods well known in the art. 13201〇.d〇c -24 - 200840587 Similarly, the amount of drospirenone in the molecularly dispersed composition ranges from about i to about 5 ounces by weight, preferably from about 5 to about 50% by weight. And the amount thereof in a pharmaceutical dosage form such as a granule: granule, pellet or powder is in the range of from about 10 to about 5% by weight, preferably from about 1 Torr to about 5% by weight. The amount of the dispersion composition in the pharmaceutical dosage form is generally in the range of from about 5 to 10% by weight, preferably about 1 Torr. Up to about 5% by weight. Excipients

As noted above, the compositions of the present invention comprise several other excipients in addition to the desired polymers, solvents, surfactants, and crystallization inhibitors. Suitable disintegrants are selected from & cross-linked stearyl cellulose (a cross-linked polymer of slow methylcellulose sodium), cross-linked povidone, starch nf, posacine sodium Or a group consisting of potassium and sodium starch glycolate. Those skilled in the art should understand that we need a compressible tablet to disintegrate in 3 minutes. It is more necessary to disintegrate within 10 minutes, and it is most necessary to disintegrate within 5 minutes; therefore, the disintegrant used is more Preferably, the tablet disintegrates in 3 () minutes, more preferably disintegrates in 10 minutes, and most preferably disintegrates in 5 minutes. Suitable lubricants include talc, stearic acid, stearic acid, stearic acid, hydrogenated vegetable oils, and the like. Magnesium stearate is preferably used. Suitable glidants include pyrogenic ceria, talc, and the like. Suitable builders include xylitol, mannitol, compressible sugars, lactose, calcium phosphate and microcrystalline cellulose. Suitable artificial sweeteners include saccharin, sikaram and aspartame. Known flavorants and known ships can be used if necessary. A colorant is added to the composition. I32010.doc 25 200840587 Method for preparing drospirenone molecular dispersing agent 1. Composition according to the invention by the method comprising the following (4): a) providing drospirenone and one or more seeding agents; and b) Completely dissolved in - or a plurality of carriers; and c) a mixture obtained as in the case of 'drying step b'. The step of dissolving drospirenone in the step 'in step b) is preferably carried out by a method selected from the group consisting of heating, ultrasonic treatment, and pressing. Mixing, batching and/or smelting extrusion The mixture produced by drying step b may include spray drying or other methods known in the art. It is to be understood that the method can be carried out using the pharmaceutically acceptable carrier mentioned above and the active compounds mentioned above. Methods and compositions for preparing microemulsion preconcentrates are described in Examples 1 through 6. Under the condition of ensuring that the snail is completely dissolved in the liquid/semi-solid solvent, for example, operating at 5 (TC using an ultrasonic bath, by including a method of mixing a liquid or semi-solid solvent or a mixture thereof with drospirenone) A microemulsion preconcentrate is prepared. For example, 'for liquid/semisolid solvents, see the solvents listed above, especially h) to u). The resulting preconcentrate may contain drospirenone: from every 15 〇 0 mg concentrate containing i to each _ concentrated concentrate! The mg snail shoulders preferably contain i mg of drospirenone per gram of concentrated concentrate, for example, i mg drospirenone per 75 yoke or 25 〇mg concentrate. . It is also possible to add at least one of the emulsifiers as mentioned above to the liquid/semi-solid solvent. 132010.doc -26- 200840587 Once water is added to the preconcentrate, ^, then a ready-to-feed milky white microemulsion can be formed spontaneously. The amount of water added - slaves, is typically 2 ml to (10) per 1 g of the concentrate, for example hm is added per 1 § of the condensate, for example 5 ml to 70 mi per 1 g of the concentrate. The resulting microemulsion did not show any precipitation or crystallization and centrifugation (6_u' H) min for at least three days and did not cause any sedimentation or crystallization. Example 7 describes the preparation of a liquid combination containing molecularly divided drospirenone

Method and preferred composition. A liquid composition containing a molecularly dispersed dextrosane is obtained by dissolving - (quantitative) (4) _ in (5) generations by dissolving in a solvent towel, the solvent being liquid π-like IS at room temperature and which is as above As defined. The amount of snail _ is generally 8 mg per 2 g of the liquid applied to 3 〇. Examples of suitable solvents are generally mentioned above, especially the solvents as listed in h) to u) above. The composition according to the examples can be enclosed in a capsule. It is substantially preferred to incorporate the composition according to Examples 1-6 into a hard gelatin capsule and to seal it after filling; and preferably the composition according to Example 7 is filled into a soft gelatin capsule. Shell Example 8 shows that the choice of solvent and interface/tongue agent in the liquid and semi-solid compositions of the present invention does not alter the dissolution rate and permeability of drospirenone, which is rapidly absorbed from all of the formulations studied. However, it was surprisingly found that the formulation according to Example 2 provided a lower degree of degradation of drospirenone. Examples 9 to 13 and 24 describe a method of preparing a solid solution and a preferred formulation: There are basically two methods of preparing a solid solution. In one embodiment (Examples 12, 13 and 24), the active is mixed with a dry powdered polymer or polymer mixture and optionally an additive, such as 132〇l〇.doc -27- 200840587 Sucr_er surfactant. The mixture is continuously extruded at a rotation rate in the range of 10 to i 0 〇 r p m using a single-screw extruder or a twin-screw extruder or the like. Optionally, the temperature of the extruder is controlled by heating and cooling, respectively, such that the process temperature is within the range of, for example, 4 〇 15 Torr. In this exercise, the entire mixture is liquefied at the final pressure and temperature, so that the active material is dissolved in the polymer towel. The resulting resolidified leak is cut or broken into pieces which are ground and sieved for further processing. See Table 25 for the in vitro dissolution data obtained. In another embodiment (Examples 10 and u), a solid solution can be prepared from the solution by spray drying, wherein the solution comprises the active compound and the polymer and optionally an additive such as a surfactant in dissolved form. Those skilled in the art understand that spray drying conditions must be adapted to the equipment used. The spray dried product is further dried in a dry box or via a drier stored in a desiccant such as phosphorus pentoxide. As mentioned previously, the polymer is preferably a hydrophilic polymer comprising a free hydrophilic group, such as a polymer having a functional group in the side chain, wherein the functional groups may, for example, be free hydrophilic functional groups, such as an enradyl group. , g-based, succinyl, aramidyl, halo or a reductive acid group. Typical examples of water-soluble hydrophilic polymers include, but are not limited to, polyvinylpyrrolidone (P〇vid〇ne8, Kollidon®), polyvinyl acetate, polyvinyl alcohol, polyvinyl alcohol ortho-benzene Dicaprate, polyethylene glycol (PEG), polyethylene oxide, gelatin, carbomer, mercaptopropionic acid copolymer, ammonium thiol acrylate copolymer, cellulose, methyl cellulose, A Cellulose, ethyl cellulose, cellulose acetate (HPMC), hydroxypropyl cellulose (HPC), phthalic acid acetate 132010.doc •28- 200840587 Vitamin and hydroxypropyl Mercapto cellulose phthalate or a copolymer or mixture thereof. The hydrophilic polymer may also be a water insoluble polymer including, but not limited to, crosslinked polyvinylpyrrolidone, sodium starch glycolate, and crosslinked carboxyindole cellulose. Preferably, the polymer is selected from the group consisting of polyvinylpyrrolidone (Povidone 8, Kollidon®) and polyethylene glycol (PEG), and particularly preferably polyvinylpyrrolidone. When a water-insoluble polymer is used, it is preferably a crosslinked polyene σ specific ketone.

Shell Example 14 17 4 Field describes the method of incorporating a solid solution into an oral dosage form such as a rotatory agent. It is not difficult to imagine a person skilled in the art to fill a similar formulation into a hard gelatin capsule. Preferred formulations essentially comprise a hydrophilic polymer as mentioned above to promote isolation of the drug from intestinal fluid. Example 18 describes a method of preparing a solid solution in a polymer film. The solution or suspension of the active and polymer as described above and the additive of the condition are generally pulled up in a film stretcher of the doctor blade in the range of (4) (iv): a film. The obtained film is dried in a dry box and cut into a prescribed soap level. The length of the type composition can be administered orally (Example 20) and can also be applied through the cheek mucosa and under the tongue. I卩兮t丨旦', technology (example 19). The latter mentions that: (4) can be easily adapted to the individual needs of each patient. See Table 26 for the in vitro dissolution data obtained. Examples 21-23 describe another method of face-to-sublingual administration, the basin providing a low viscosity to the "viscosity solution" of the straight-receiving portion...., Example 1 1320I0.doc -29- 200840587 by 18.9 g Crem〇 Ph〇r® RH 40 and 2,1 g Transcut® 1® and 9.0 g of medium-bond diglyceride were mixed at 50 ° C to prepare a microemulsion pre-concentrate. Then, 40 mg of snail was added and used The ultrasonic bath was mixed for 10 minutes. The 750 mg of the obtained microemulsion preconcentrate contained 1 mg of snail. When 100 mL of water was added, the milky white microemulsion spontaneously formed. The obtained microemulsion did not show any sedimentation or crystallization within at least three days. The effect (6 〇〇〇U, 10 min) did not cause any sedimentation or crystallization. The same observation was carried out immediately after adding 200 00 mL of water. Example 2 Preparation according to Example 1 using 12 〇mg instead of 4 〇mg drospirenone The formulation has the same characteristics, but the 250 mg of the resulting microemulsion pre-concentrate contains } mg drospirenone. Example 3 Fine-grained 18·9 g Cremophor® EL and 2.1 g Transcutol® P and 9·0 g medium chain Triglyceride was mixed at 50 ° C to prepare a microemulsion preconcentrate. After adding '40 mg of drospirenone and mixing for 5 minutes at 5 ° C using an ultrasonic bath. 750 mg of the resulting microemulsion preconcentrate contains ! mg drospirenone. When added to 100 mL of water, spontaneous formation A slightly opaque microemulsion. The resulting microemulsion did not show any sedimentation or crystallization within at least two days. Centrifugation (6000 U, 10 min) did not cause any sedimentation or crystallization. The same observation was carried out immediately after adding 2000 mL of water. 4 The composition prepared according to Example 3 using 120 mg instead of 40 mg snail was having the same characteristics as 132010.doc • 30- 200840587, but the 250 mg of the obtained microemulsion preconcentrate contained i mg snail _. Example 5 A microemulsion preconcentrate was prepared by mixing 18·9 g of Cremophor® EL and 2.1 g of TranScutol®® & 9 g of castor oil at 50° C. Then, 40 mg of drospirenone was added and an ultrasonic bath was used. The mixture was mixed for 5 minutes under 5 。. The microemulsion pre-concentrate obtained at 75 〇mg contained 1 mg of snail. When the 100 mL of water was added, the milky white microemulsion spontaneously formed. The obtained microemulsion did not show any sedimentation for at least three days. Or crystallization. Centrifugation (6〇〇 〇u, 10 min) did not produce any sedimentation or crystallization. The same observation was carried out immediately after adding 2000 mL of water. Example 6 The formulation prepared according to Example 5 using 120 mg instead of 40 mg drospirenone had the same characteristics, but 250 The microemulsion pre-concentrate obtained in mg contains! Mg 螺 酉 酉. Example 7 Preparation of a molecularly dispersed yield by dissolving 1% to 30 mg (preferably 8 mg) of drospirenone in 1,992 g of any of the following liquids by stirring at 25-40 ° C Liquid composition of spirone: h) medium chain triglyceride i) sesame oil j) glycerol monooctanoic acid g (eg Imwit〇r® 308) k) incoming gas _35-glycerol-two sesame oleate ( For example, Cremophor® EL) l) Incompetent Ethylene-40-glycerol·Hydroxyphoric Acid I (Cremophor® RH 40) 132010.doc -31 - 200840587

m) polyethylene glycol 400 - n) transcutol P ^ 〇) triethyl citrate p) mixture of 7% glycerol and 93% polyethylene glycol 400 q) 50% glycerol monocaprylate (eg Imwitor® 308) Mixture with 50% polyethylene glycol 400 r) Mixture of 50% castor oil and 50% tributyl citrate s) Mixture of 50% castor oil and 50% polyethylene glycol 400® t) 75% caprylic acid/癸Mixture of glycerides (eg Imwitor® 742) with 25% polyethylene glycol 400 u) 75% caprylic/capric glyceride (eg Imwitor® 742), 15% polyethylene glycol 400 and 10% ethanol. In the case of preparation using 8 mg of drospirenone, 250 mg of the resulting microemulsion preconcentrate contained 1 mg of drospirenone. All such compositions and mixtures thereof can be enclosed in capsules, such as soft gelatin capsules.例 Example 8 A composition containing the molecularly dispersed form of drospirenone according to Examples 2, 4, 6 and 7 was studied in a combined in vitro solubility-in vitro permeability test. Each 250 mg of drospirenone was dispersed in 250 mL of isotonic buffered saline. 1 mL of the resulting liquid was tested in a Caco-2 permeability study for 120 minutes. The principles of the Caco-2 study are described in detail in the following literature, for example, Haltner E, Schmitz S? Gindorf C. In vitro Permeabilitatsuntersuchungen als Ersatz fur Tier- und Humanstudien - welche 132010.doc -32- 200840587

Voraussetzungen miissen erfullt 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 of ECVAM workshop 46. ATLA Alternatives to Laboratory Animals. 29 (2001): 649-668 〇 essentially measures the permeability of a compound through a single layer of human colon cancer cells. In addition, studies have been conducted on the intestinal metabolism and chemical stability of drospirenone converted to its atropisomer. The device was operated at 37 ° C using 900 mL of water as the dissolution medium and USP XXVIII blade device 2 as the dissolution test device to determine in vitro solubility at 50 rpm. The apparent permeability of drospirenone from all compositions through human colon cells was in the range between 200 and 350 nm/s, which showed no significant difference in high permeability. However, differences in the degree of degradation due to isomerization of drospirenone were detected. Measure the degradation of drospirenone at the beginning (after preparation of the composition), - after dissolution, before the start of the permeability study - and at the end of the final permeability study (ie after 120 minutes of contact with colon cells) That is, converted to a non-rotating isomer):

The initial difference in the composition of the % degradation of DRSP was based on Example 2 (RH40, Transcutol®, MCT) 2·0 3.1 + 1.1 according to Example 4 (EL, Transcuto1®, MCT) 3.8 4.7 + 0.9 according to the example EL (EL, Transcutol®, Ricrims) 4.8 5.4 + 0.6 according to Example 7) (Imwitor® 308) 6.5 7.5 + 1.0 132010.doc •33- 200840587 4.9 5.7 + 0.8 4.5 5.1 + 0.6 3.4 3.9 + 0.5 7.6 7.9 + 0.3 3.8 5.3 + 1.5 5.8 6.4 + 0.6 According to Example 7k (EL) according to Example 71 (RH40) according to Example 7 m (PEG 400) according to Example 7n (Transcutol®) according to Example 7 (triethyl citrate) according to Example 7q (PEG 400, Imwitor® 308) 9

Dissolving the phloem shown in the range of 1 11 ^ to 30 mg in 1·05 g white beeswax and 2 g medium chain triglyceride and 0·07 g by melting all the components at about 100 ° C and stirring. A semi-solid composition containing the molecularly dispersed form of drospirenone is prepared in a mixture of phospholipids. The composition can be enclosed in a soft or hard capsule. Example 1 0 Preparation of a solid solution of drospirenone by drying: g sucroester WE15; 1 g of snail, I, 8 g of Kollidon® K30 and 1 were mixed in 300 mL of pure water. The dispersion was heated to 6 Torr and continuously stirred until all the excipients were dissolved. The resulting solution was spray dried using a small spray dryer (Mid Spray yer) Buchi 190 (inlet temperature of 12 3£3 (:, outlet temperature of 8 generations, flow rate of 4 g/min). The spray dried product Stored in a desiccator using ruthenium pentoxide as a desiccant for at least 24 h. Example 11 Preparation of solid solution of snail snail by spray drying: 1 g of snail, 8 of the snail, vinylpyrrolidone-acetic acid Ethylene vinegar copolymer (Koliidon® VA 64, β ι ) and 1 g Gelucire® 44/14 were stirred and dispersed in 3〇〇1320I0.doc -34- 200840587 mL pure water. The dispersion was heated to 60 ° C and continuously stirred. Until all the excipients were dissolved. The resulting solution was spray dried using a small spray dryer Biichi 19 (inlet temperature 12 〇 C, outlet temperature 80 ° C, flow rate 4 g / min). The product was stored in a desiccator using phosphorus pentoxide as a desiccant for at least 24 h. Example 12 Preparation of a solid solution of drospirenone by melt extrusion: mixing 10% drospirenone, 50% polyvinylpyrrolidone And 5 % sucrose monooleate. Continuously extruded at 60 t: and 5 rpm using a single screw extruder Example 13 Preparation of solid solution of drospirenone by melt extrusion · Mixing 30% drospirenone, 30% polyethylene glycol 6 〇〇〇 and 4% sucrose monooleate. Using a single screw The extruder was continuously extruded at 6 Torr & 5 rpm. Example 14 The compositions according to Examples 10-12 were processed into troches. To achieve this, 300 g of each composition was combined with 49 〇g. The microcrystalline cellulose was blended, then 10 g of magnesium stearate was added and the mixture was blended again for a few minutes. The resulting material was directly tableted to yield a tablet having a tablet weight of 8 〇 mg. Each single tablet contained 3 Mg snail _. " Example 1 5 The composition according to Example UM2 can be processed into a tablet. To achieve this, 3 〇〇g of each composition is blended with 49 〇 乳糖 lactose, and then added (7) § 132010. Doc 200840587 Magnesium stearate and the mixture was blended again for 1 minute. The resulting material was directly tableted to yield a tablet with a tablet weight of 80 mg. Each tablet contained 3 mg drospirenone.

Example 16 will be processed into a tablet according to the example 10-12 Japanese; L 12 composition. To achieve this, 300 g of each composition was blended with _g microcrystalline cellulose, then 10 g of pyrogenic cerium oxide was added and the mixture was again blended for 1 minute. Will

The material was directly tableted to yield a tablet having a tablet weight of 80 mg. Each single tablet contains 3 mg of drospirenone. Example 1 7 A composition of Example 13 was blended with 395 § microcrystalline cellulose, followed by the addition of 5 g of magnesium amicate and the mixture was blended again for a minute. The resulting material was directly bonded to give a lozenge weight of 5 nicknames. Each single vortex contains 3 mg of drospirenone. Example 1 8 1 § drospirenone and 1 g of a polyoxyethylene-polyoxypropylene copolymer were dissolved in 94 g of ethanol by mixing. A final mixture of 17 g of propylcellulose and i7 g of cellulose was added to the resulting solution. The suspended liquid which was applied was stretched into a film on a suitable film stretching machine using a 5 〇〇 doctor blade. After drying, a white (4)-like film having a thickness of about 18 Å μηη was obtained. __ Units This thin 臈 (meaning a sheet of about 3 c m 2) contains i m g 屈. Example 19 A composition according to Example 18 can be cut into pieces of about 丨 to about 15 cy, which can be directly administered to the face film, releasing G33W mg 屈罗朗 to I32010.doc -36- 200840587 cheek mucosa. - Example 20. The composition according to the shell example 18 can be cut into pieces which are filled in a hard capsule for oral administration. Example 21 5 g of snail _, i g tocopheryl acetate and $ peppermint oil were made into 1000 mL with ethanol and dissolved by stirring. The resulting solution is filled in an i〇 glass bottle and

Capsule spray _ cover. The mL solution containing 〇·5 mg drospirenone was released in one application. Example 22 5 g of drospirenone, 1 g of ascorbyl palmitate, 50 g of medium chain triglyceride, 300 g of Cremoph〇r8EL & 2 g g monoglyceride were made into 1 〇 (8) mL with ethanol and dissolved by stirring. The resulting solution was filled in a 1 〇 111] 1 glass vial and sprinkled with a pump. One dose of sputum containing 5 mg of snails was released. Example 23 Lu The solutions according to Examples 21 and 22 were separately administered as a sublingual spray, for example, 3 mg of drospirenone was released 6 times. The formulation according to Example 22 provides an extended residence time on the cheek mucosa. Example 24 A solid solution of drospirenone was prepared by melt extrusion: 10% snail and 90% polyethylene glycol 6000 were mixed. The mixture was continuously extruded at 60 ° C and 50 rpm using a single screw extruder. Example 25 132010.doc -37--200840587 'At 37 C' using 900 mL of water as the dissolution medium and using the Qingxvm blade device 2 as the dissolution test device in the in vitro solubility test according to Example 24 Operate the device under 5 。. The drospirenone contained in the formulation completely dissolved in ι〇 minutes. Therefore, we understand that rapid dissolution occurs during the disintegration time of the dosage form. Therefore, the dissolution step is not a step of releasing the rate limit. We should understand that, therefore, in the example of Qujing, the dissolved form "existence, such as molecularly dispersed form, would otherwise not achieve such rapid dissolution. Example 26 A composition according to Example 18 was cut into pieces of 9 cm 2 (containing 3 Mailroxone) using 900 machine water as a dissolution medium under m: and using XXV pottery device 2 as a dissolution test device to make the pieces Subject to in vitro solubility testing, the device was operated at 50 rpm. The results were found to be as follows (7) minutes after release of 95. snail _, after 2G minutes, release 97 1% _ and after 3 〇 minutes, 97.2% drospirenone was released.

132010.doc 38-

Claims (1)

200840587 X. Patent application scope: - A liquid composition suitable for oral administration comprising molecules dispersed in at least one pharmaceutically acceptable effect: <Drospirenone in the tincture 〇 The liquid composition of claim 1, wherein the at least one pharmaceutically acceptable carrier is selected from the group consisting of medium chain triglycerides, lotus oil, glycerol monocaprylate, caprylic acid/capric acid Glycerin vinegar, polyoxyethylene-35-glycerol-30,000 linoleic acid _, polyoxyethylene, 4 〇 glycerol, stearyl sulphate S 曰 乙 乙 乙 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 Ethyl ester and mixtures thereof. The liquid composition of claim 2, wherein the at least one pharmaceutically acceptable carrier is selected from the group consisting of glycerin and polyethylene glycol 400, glycerol monocaprylate and polyethylene glycol Mixture of 4〇〇, castor oil 14# mixture of dibutyl citrate, mixture of castor oil and polyethylene glycol 4〇〇 mixture of octanoic acid/capric glyceride and polyethylene glycol 400, octanoic acid/ A mixture of glyceryl phthalate and polyethylene glycol 4 hydrazine and ethanol. The liquid composition of any one of items 1 to 3, which further comprises at least one emulsifier. The liquid composition of any one of items 1 to 3, which is in the form of a microemulsion preconcentrate. The liquid composition according to any one of items 1 to 3, wherein the composition further comprises an estrogen. The liquid composition according to any one of items 1 to 3, which is filled in a capsule. 8. The liquid composition of claim 7, wherein the liquid composition is incorporated into a soft gelatin capsule of 132010.doc 200840587. 9. A method of preparing a liquid composition as defined in claim 1 comprising the steps of: a) providing drospirenone and one or more carriers; and b) completely dissolving the snail in the one or more carriers ketone. 10. The method of claim 9, wherein the step of dissolving drospirenone is carried out by a method selected from the group consisting of heating, ultrasonic treatment, thorough mixing, and agitation. 132010.doc 200840587 VII. Designation of representative figure: β (-) The representative figure of this case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the characteristics that can best show the invention. Chemical formula · (none) 132010.doc