MXPA06001172A - Pharmaceutical composition comprising drospirenone and ethynylestradiol - Google Patents

Abstract

A pharmaceutical composition that comprises drospirenone and ethynylestradiol with an improved dissolution rate. A method of preparation of a pharmaceutical formulation that comprises drospirenone and ethynylestradiol in order to improve its dissolution profile. Said formulation can be used to produce an anovulatory effect when administered correctly in humans.

Description

PHARMACEUTICAL COMPOSITION COMPRISING DROSPIRENONE AND ETINILESTRADIOL FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition containing drospirenone and ethinylestradiol with improved dissolution rate. Furthermore, the invention relates to a method for preparing a pharmaceutical formulation containing Drospirenone and Ethinylestradiol in order to improve its dissolution profile. This formulation can be used to produce an anovulatory effect when properly administered in humans.

BACKGROUND OF THE INVENTION It is known that estrogen and progestagen sex hormones are practically insoluble in water or are so slowly soluble that their biopharmaceutical properties are directly affected by this behavior or characteristics. Particularly, the synthetic progestogen Drospirenone or 6β, 7β, 15β, 16β-dimethylene-3-oxo-17a-pregn-4-en-21, 17-carbolactone, known from the DE3022337 and DE2652761 patents, in its crystalline state has a form of "spatulas" as shown in the microphotographs of Figure 1 with 200X magnification with sizes no smaller than 50 microns. The rate of dissolution of this crystal in oral pharmaceutical forms such as tablets, shows a very slow rate of dissolution as shown in Figure 17 here (see lots LP01, LP02 and LP03). The published application EP1216712A1 discloses the preparation of inclusion complexes between cyclodextrin and drospirenone for the purpose of increasing the water solubility of drospirenone. The bioavailability of a drug may be limited by poor dissolution of the same in aqueous body fluids, particularly gastric fluids, immediately after administration. The rate of dissolution can then be critical for the rapid achievement of therapeutically effective levels of the drug or additionally, as in the case of drospirenone, it can be influenced by a degradation of the active ingredient due to prolonged contact with the gastric fluids of pH very low, as disclosed in PCT application WO 01/15701 (from the patent family of EP121407B1). This behavior is demonstrated in vitro, in an acid medium (0.1 N HCl), for drospirenone samples with different particle sizes (see Figure 16 herein). It is observed that the presence of drug in the acidic medium decays rapidly, after an initial dissolution, independently of the particle size. Therefore the bioavailability of drospirenone is doubly affected by the low dissolution rate in aqueous medium and by the rapid degradation due to prolonged contact with gastric fluids of very low pH. The published patent EP1214076B1 discloses a pharmaceutical composition containing drospirenone and ethinylestradiol where the drospirenone is in micronized form, so that the particles of the active substance have a surface area of more than 10,000 cm2 / g, and a particle size distribution determined under the microscope, where no more than two particles in a given batch have a diameter of more than 30 μm, and preferably 20 particles or less have a diameter of between 10 μm and 30 μm, so as to increase their dissolution rate and in particular for use in oral contraception. Additionally, it is read in the last part of section [0017] of EP1214076B1"Instead of providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, for example methanol or ethyl acetate, and spray it on the surface of particles of an inert carrier followed by the incorporation of particles containing drospirenone on its surface to the composition. " However, this section appears isolated in the description of EP121407B1. All the preparation examples plus the independent main claims are referred to the micronized form.

SUMMARY OF THE INVENTION The problem to be solved by the present invention is to provide a pharmaceutical composition of drospirenone and ethinylestradiol with improved dissolution rate in water and body fluids and improved bioavailability.

The present inventors have found that by means of a pharmaceutical composition of drospirenone and ethinylestradiol in an amorphous form, without the presence of a crystalline state, it is possible to improve the dissolution profiles of both active compounds, thus increasing their bioavailability. Also, the present inventors have demonstrated that the use of the volatile solvent, methylene chloride, and in particular, the use of the combination of a mixture of the methylene chloride and methanol solvents gives better results with respect to the dissolution rate than with the use of methanol only. For more details, refer, for example, to Table 2 of Example 4 and Table 3 of Example 5 herein. The use of methanol is only theoretically suggested in the prior art document EP1214076B1 (see above). As explained herein, the volatile solvent methylene chloride is used to dissolve the drugs. In the subsequent granulation step, it is dried until very low residual levels of solvent are reached (see Example 1). However, although such levels are low, the skilled person knows that it is still possible to measure small amounts of the volatile solvent of interest in the final pharmaceutical composition. The skilled person knows that this can be done, for example, by the use of gas chromatography (GC) and mass spectrometry (MS). Therefore, a first aspect of the present invention relates to a pharmaceutical composition containing drospirenone and ethinylestradiol in an amorphous form, adsorbed on a therapeutically inert solid support, in combination with pharmaceutically acceptable excipients, characterized in that the composition comprises of the volatile solvent methylene chloride. As mentioned above, in the present invention it is preferred to use a mixture of the methylene chloride and methanol solvents. Accordingly, in a preferred embodiment the composition of the first aspect is characterized in that the composition comprises measurable amounts of both volatile solvents: methylene chloride and methanol. The dissolution speed of drospirenone and ethinylestradiol is increased by introducing changes in its crystalline structure, in such a way that the energy needed to dissolve the drug is lower. In this case, the rate of dissolution will increase considerably, thus achieving an increase in the speed of absorption of drugs. In this way, the contact time of the drugs with the gastric medium is reduced where the pH is too low, thus avoiding the possible reactions of degradation by hydrolysis of the sensitive drugs, as mentioned above. It is therefore an object of the present invention to provide a pharmaceutical composition containing drospirenone and ethinylestradiol in an amorphous form, without the presence of crystalline state, preferably starting from non-micronized drug and using in its preparation suitable dissolving / granulating solvents. Surprisingly, it has been found that the highest dissolution rate is obtained by solubilization of drospirenone and ethinylestradiol in the appropriate combination of a mixture of the methylene chloride and methanol solvents and subsequent adsorption on inert pharmaceutically suitable excipients. It has been observed that the use of another solvent, such as ethanol, even with the use of heat, despite dissolving the drug, does not allow the application on pharmaceutically suitable excipients. Additionally, the use of methylene chloride and in particular the use of the appropriate combination of a mixture of the methylene chloride and methanol solvents gives improved results with respect to the use of methanol alone. The new pharmaceutical composition of the invention is designed to provide a rapid dissolution of drospirenone and ethinylestradiol in water as a reference solvent. More particularly, the invention provides a solid particulate composition comprising drospirenone and ethinylestradiol in an amorphous state adsorbed on a therapeutically inert support, with some water-soluble components and other water-insoluble components, which aid in rapid disintegration of the pharmaceutical formulation. Even more particularly, it is a further object of the invention a pharmaceutical composition that provides improved dissolution of drospirenone and ethinylestradiol, which comprises a solid particulate formulation of an adsorbate consisting of drospirenone and ethinylestradiol in an amorphous state adsorbed on a solid, therapeutically inert support, in combination with pharmaceutically acceptable excipients. In a preferred embodiment, the solid particulate composition comprises particles of the following suitable materials or mixtures of them: corn starch, pregelatinized starch, lactose, Croscarmellose sodium, yellow iron oxide and Povidone coated with drospirenone and ethinylestradiol in the amorphous state. In addition, another object of the present invention is a method of preparing a pharmaceutical composition of drospirenone and ethinylestradiol, wherein said active compounds are in an amorphous state and free of crystalline forms. Accordingly, a second relevant object of the present invention is a method for the preparation of a new pharmaceutical composition of drospirenone and ethinylestradiol comprising i) dissolving Drospirenone and ethinylestradiol in a volatile solvent or mixture of volatile solvents, ii) optionally adding a water soluble polymer, iii) mixing until dissolution, iv) applying the resulting solution on a solid, therapeutically inert support, and v) drying the obtained adsorbate.

Preferably, at least one of the volatile solvents of step (i) is methylene chloride. Preferably, a water soluble polymer is added in step (ii). The active compounds drospirenone and ethinylestradiol, used in preparation of the pharmaceutical composition of the invention are preferably in the form of non-micronized particles, more preferably with an average diameter of not less than 50 μm and a specific surface area of less than about 5000 cm2 / g measured by the BET Technique. Advantageously, the use of non-micronized forms decreases the environmental drawbacks associated with an additional step in the manipulation of hormones, such as the micronization process. A third aspect of the invention relates to a pharmaceutical preparation comprising a number of dosage units for daily oral administration over a period of at least 21 consecutive days, wherein said dosage units comprise approximately from 1 to 4 mg of drospirenone and about 0.01 to 0.05 mg of ethinylestradiol, wherein said drospirenone and ethinylestradiol are in amorphous form, adsorbed on a therapeutically inert solid support, of the first aspect of the invention or embodiments thereof as described herein, in combination with pharmaceutically acceptable excipients. A fourth aspect of the invention relates to the use of drospirenone combined with ethinylestradiol to prepare a pharmaceutical composition, of the first aspect of the invention or embodiments thereof as described herein, for the anovulation of a mammal, in particular a human, the composition comprising an amount of drospirenone corresponding to a daily dosage, upon administration of the composition, of from about 1 mg to 4 mg, and comprising an amount of ethinylestradiol corresponding to a daily dosage, upon administration of the composition, of from 0.01. at 0.05 mg. The fourth aspect can alternatively be formulated as a method for the anovulation of a mammal, in particular a human, consisting of administering a pharmaceutical composition, of the first aspect of the invention or embodiments thereof as described herein, made from of a number of dosage units for oral administration, wherein said dosage units consist of about 1 mg to 4 mg of drospirenone and about 0.01 to 0.05 mg of ethinylestradiol, in which the drospirenone and the ethinylestradiol are in a amorphous form, adsorbed on a solid, therapeutically inert support, in combination with pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows microphotographs of drospirenone in its crystalline state (200X magnification) Figure 2A shows a microphotograph of a lactose particle; Figure 2B shows a microphotograph of a population of lactose particles; Figure 2C shows a microphotograph of a particle of corn starch; Figure 2D shows a microphotograph of a population of corn starch particles; Figure 2E shows a microphotograph of a particle of pregelatinized starch; Figure 2F shows a microphotograph of a population of pregelatinized starch particles; Figure 2G shows a microphotograph of a particle of Croscarmellose sodium; Figure 2H shows a microphotograph of a population of Croscarmellose sodium particles; Figure 21 shows a microphotograph of a yellow iron oxide particle; Figure 2J shows a microphotograph of a population of yellow herr oxide particles; Figure 2K shows a photomicrograph of a Povidone particle; Figure 2L shows a microphotograph of a population of Povidone particles; Figure 3 shows a microphotograph of the physical mixture of the different components of the adsorbate; Figures 4A and 4B show microphotographs of the adsorbate of drospirenone and ethinyl estradiol on the components suitable for obtaining tablets, in two approaches. Figure 5 shows a graph of the differential calorimetric scan of lactose alone; Figure 6 shows a graph of the differential calorimetric sweep of drospirenone; Figure 7 shows a graph of the differential calorimetric scavenging of magnesium stearate; Figure 8 shows a graph of the differential calorimetric sweeping of corn starch; Figure 9 shows a graph of the differential calorimetric scan of pregelatinized starch; Figure 10 shows a graph of the differential calorimetric yellow iron oxide scan. Figure 11 shows a graph of the differential calorimetric scan of Croscarmellose sodium (Ac-Di-Sol). Figure 12 shows a graph of the differential calorimetric scan of Povidone; Figure 13 shows a graph of the differential calorimetric sweep of the placebo (mixture of excipient components with the absence of ethinylestradiol and drospirenone). Figure 14 shows a graph of the differential calorimetric sweep of the simple mixture of the adsorbate components. Figure 15 shows a graph of the differential calorimetric scan of the granulate of Example 1 containing drospirenone and ethinylestradiol adsorbed on the inert excipients. Figure 16 shows dissolution profiles of drospirenone tablets in an aqueous medium strongly acid 0.1 N HCl. Figure 17 shows dissolution profiles of tablets of the invention containing amorphous drospirenone adsorbed on inert excipients, as compared to dissolution profiles. of compositions containing crystalline drospirenone with various particle sizes.

Figure 18 shows dissolution profiles of tablets of the invention containing amorphous ethinylestradiol adsorbed on inert excipients, as compared to the dissolution profiles of compositions containing crystalline ethinylestradiol with various particle sizes.

DETAILED DESCRIPTION OF THE INVENTION A PHARMACEUTICAL COMPOSITION COMPRISING: DRQSPIRENQNA AND ETINGLESTRADIOL AND AN EARTH TO REPAIR According to a first aspect, the present invention provides a solid particulate formulation consisting of drospirenone and ethinylestradiol in an amorphous state adsorbed on a pharmaceutically acceptable and therapeutically inert carrier. The term "adsorbed on a therapeutically inert solid support" may in the present also be expressed as "adsorbed on a therapeutically inert solid base" and the expressions herein may be used interchangeably. Preferably, the solid particulate formulation comprises particles of pharmaceutically acceptable excipients coated with drospirenone and ethinylestradiol in an amorphous state and ready to be compressed to their final pharmaceutical formulation.

The composition of the invention can be obtained according to the steps of: i) dissolving drospirenone and ethinylestradiol in a volatile solvent mixture, ii) adding a water soluble polymer and / or in the volatile solvent or volatile solvent mixture, iii) mix until dissolution, iv) apply the resulting solution on a support of solid, pharmaceutically acceptable and therapeutically inert particles, v) dry the obtained adsorbate. The volatile solvent can be methanol. However, preferably, the volatile solvent is methylene chloride and even more preferably it is a mixture of methylene chloride and methanol, which is acceptable for use in drug manufacturing processes. Preferably, the volatile solvent is a mixture of methylene chloride / methanol [9 to 4]: [3 to 0.5] v / v. Within the range of blends it is preferred that the volatile solvent be a 6: 1 v / v methylene chloride / methanol mixture or a 5: 2 v / v methylene chloride mixture. The drospirenone can be prepared according to as described in for example US 4,129,564. The drospirenone drug used in the preparation of the pharmaceutical composition of the invention is preferably in the form of non-micronized particles with a mean diameter of not less than 50 μm and a specific surface area of less than about 5000 cm2 / g, obtained by the technique of BET. The estrogen ethinylestradiol can be prepared according to the methods described in GB 516,444, US 2,243,887, US 2,251,939, US 2,265,976 and US 2,267,257. The drug ethinylestradiol used in the preparation of the pharmaceutical composition of the invention is preferably in the form of non-micronized particles with an average diameter of not less than 50 μm and a specific surface area of about 5000 cm2 / g, obtained by the BET technique . Water-soluble polymers suitable for preparing the binder solution are preferably selected from the polyvinyl pyrrolidones, with Povidone K 30 polyvinylpyrrolidone being preferred in the method of the invention (such as that provided by BASF or ISP). Examples of other suitable water-soluble polymers include a polymer selected from the group consisting of: alginic acid, carbomer, sodium carboxymethylcellulose, carrageenan, dextrin, hydroxypropylmethylcellulose, polyethylene glycol, polymethacrylates, polyvinyl alcohol and povidone K90. The resulting solution is applied on a solid, pharmaceutically acceptable, therapeutically inert support. The application is preferably carried out by means of a mixer-granulator type Pony mixer. However, it can also be carried out by other techniques, such as spraying in the form of a fluid bed spray. Suitable particulate materials for preparing the support of the invention are selected from starch, pregelatinized starch, lactose, croscarmellose sodium, yellow iron oxide and mixtures thereof. The lactose used is preferably lactose monohydrate, commonly used as an excipient and diluent in the pharmaceutical industry. This Lactose can be supplied by manufacturers such as MEGGLE, QUEST International, BORCULO Whey Products The starch can be corn or potatoes, commonly used as a diluent in the pharmaceutical industry. The starch can be provided by: COLORCON, OAVEBE, CERESTAR INT.

SALES, GRAIN PROCESSING CORP., PARTICLE DYNAMICs INC., GLUTAL, etc. The pregelatinized starch can be corn or potatoes, commonly used as a diluent and binder in the pharmaceutical industry. The pregelatinized starch can be provided by: COLORCON, OAVEBE, CERESTAR INT. YOU GO OUT, GRAIN PROCESSING CORP., PARTICLE DYNAMICS INC., GLUTAL, Croscarmellose sodium, commonly used as a superdisintegrant in the pharmaceutical industry can be provided by: COLORCON, ALLCHEM INTERNATIONAL, METSA SPECIALITY CHEMICAL LTD, AVEBE, etc. Yellow iron oxide, commonly used as a coloring material in the pharmaceutical industry, can be provided by COLORCON. Magnesium stearate, commonly used as a lubricant in the pharmaceutical industry, may be provided by LE STAR QUÍMICA. The drying of the obtained granulate can be carried out by any drying method known in the art, preferably according to a particular embodiment, the drying is carried out in static bed stove. Drying is conducted until obtaining a granulate with residual levels of solvent 100 times below that admitted by the International Conference on Harmonization of technical requirements for the registration of pharmaceutical products for use in humans, in its Q3C guide. When the granulate is subjected to drying, the presence of polyvinylpyrrolidone in the solution of drospirenone and ethinylestradiol acts through the formation of a three-dimensional polymer network, preventing the crystalline growth of drospirenone and ethinylestradiol, so that the drugs are deposited on the particles of excipients in an amorphous state. Then, this mixture should only be lubricated to be able to compress it and obtain the pharmaceutical form that constitutes the dosage unit. A separate aspect of the invention relates to a pharmaceutical composition comprising drospirenone and ethinylestradiol in amorphous form, adsorbed on a therapeutically inert solid support, in combination with pharmaceutically acceptable excipients obtained by a method for the preparation of a pharmaceutical composition of the second aspect of the invention and embodiments thereof as described herein. Particular examples of embodiment are provided below, which have a merely illustrative intention without, however, limiting the scope of the invention, which is determined by the claims.

Preferably, the pharmaceutical preparation of the third aspect of the invention is characterized in that it comprises drospirenone and ethinylestradiol in amorphous form, adsorbed on solid bases chosen from particles selected from the group consisting of corn starch, pregelatinized starch, lactose, croscarmellose sodium, yellow iron oxide, polyvinylpyrrolidone or mixtures of one or more of them, in combination with pharmaceutically acceptable excipients. Additionally, the pharmaceutical preparation is preferably characterized in that at least 80% of the drospirenone is dissolved from said dosage units within 20 minutes, in an assay carried out in a dissolution apparatus according to the American Pharmacopoeia Edition N ° 27, Apparatus 2, in 900 ml of distilled water thermostated at 37 ° C and stirred at 50 rpm. In a further embodiment the pharmaceutical preparation is preferably characterized in that at least 80% of the ethinylestradiol is dissolved from said dose units within 20 minutes, in an assay carried out in a dissolution apparatus according to the American Pharmacopoeia Edition N ° 27, Apparatus 2, in 900 ml of distilled water thermostated at 37 ° C and stirred at 50 rpm. Compositions particularly suitable for oral administration are unit dosage formulations such as tablets, capsules, pills, powders presented in sachet, etc. Such dosage units will normally contain an at of drospirenone in the range of from about 1 mg to about 4 mg, more preferably 3 mg and an at of ethinylestradiol in the range of from about 0.01 to about 0.05 mg, more preferably from 0.02 to 0.03 mg.

A METHOD FOR ANOVOTION IN A MAMMERIAN This fourth aspect can be alternatively formulated as a method for the anovulation of a mammal, particularly a human, which consists of administering a pharmaceutical composition of the first aspect of the invention or embodiments thereof as described herein, performed as a number of dosage units for daily oral delivery, wherein said dosage units comprise about 1 mg to 4 mg of drospirenone and about 0.01 to 0.05 mg of ethinylestradiol, wherein said drospirenone and ethinylestradiol they are in amorphous form, adsorbed on a therapeutically inert solid support, in combination with pharmaceutically acceptable excipients. With respect to the method for the anovulation of a mammal, in particular a human, of the fourth aspect of the invention, daily oral administration is preferably for a period of at least 21 consecutive days. Additionally, there may be 7 or less of said dosage units that do not contain active agent.

Alternatively, it is possible to include, in the dosing regimen, a period of 7 days or less during which dosing units are not ingested. In suitable embodiments, the number of dosage units comprising the combination of drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the number of daily dosage units that do not contain active agent may accordingly be 7, 6, 5 or 4, depending on the case. Alternatively, the pharmaceutical composition, of the first aspect of the invention or embodiments thereof as described herein, can be used for hormone replacement therapy (HRT). The skilled person knows how to optimize dosages and administration with respect to hormone replacement therapy.

PHARMACEUTICALLY ACCEPTABLE EXCIPIENT "Pharmaceutically acceptable excipient" shall be understood as any conventional pharmaceutically acceptable carrier including binders, tablet disintegrants, diluents, lubricants, tablet glidants, capsule and / or tablet opacifiers, colorants, sweeteners, flavors, antioxidants, buffering agents, etc.

As used herein, the term "binder" refers to substances used to cause adhesion of the powder particles in the tablet granules, and include, by way of example and without limitation, alginic acid, sodium carboxymethylcellulose, polyvinylpyrrolidone, sugars, ethylcellulose, gelatin, guar gum, polyethylene glycol, polyethylene oxide or combinations thereof and the like known to those with common knowledge in the art. As used herein, the term "tablet disintegrant" refers to a compound used in solid dosage forms to promote breakdown of the solid mass into small particles. Examples of disintegrants include, but are not limited to, starches, pre-gelatinized starches, bentonite, microcrystalline cellulose and their ethers and salts, calcium or sodium carboxymethylcellulose and its modifications, alginates, cross-linked povidone, gums such as guar, agar, pectin and the like. for those with common knowledge in art. As used herein, the term "diluent or tablet loading" refers to inert substances used as fillers to create the desired mass, in the preparation of tablets and capsules, and include, by way of example and without limitation, dibasic phosphate of calcium, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, sorbitol, starch and similar sugars (mono and polysaccharides) known to those of ordinary skill in the art. As used herein, the term "lubricant" refers to substances that are used in tablet formulations to reduce friction during compression of the tablets, including by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, 1-Leucine, sodium Tri-Hethenate, zinc stearate, talc and the like known to those with common knowledge in the art. As used herein, the term "tablet glider" designates agents employed in the formulations of capsules and tablets to promote granulation fluidity, including, but not limited to, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, and the like known to those with common knowledge in the art. As used herein, the term "opacifiers of capsules or tablets" refers to a compound used to coat a tablet or capsule with an opaque coating combined or not with a colorant, and includes, by way of example, non-limiting, titanium dioxide , magnesium carbonate, calcium carbonate and the like known to those with common knowledge in the art. As used herein, the term "dye" refers to a compound used to color the pharmaceutical compositions, such as, for example, and without limitation, caramel, ferric oxide, grape skin extract, beta-carotene, carmine, turmeric, bases dyes and their lacquers (eg, bright blue, punched red, sunset yellow, quinoline yellow, etc.) and other materials known to those with common knowledge in the art. As used herein, the term "sweetening agent" designates a compound used to impart a preparation with a sweet taste, and includes by way of example without being limiting, sucrose, dextrose, aspartame, mannitol, sodium saccharin, sorbitol and the like known to those with common knowledge in art. As used herein, the term "flavoring" refers to a compound used to impart a pleasant flavor and / or aroma to a pharmaceutical preparation. Examples of flavoring agents include, but are not limited to flavoring oils and aromatic synthetic flavors and / or natural oils, and extracts of plants, leaves, flowers, fruits and other combinations thereof.

As used herein, the term "antioxidant" designates an agent that inhibits oxidation and therefore deterioration of the active agent and other components by oxidative processes, and includes by way of example without being limiting, ascorbic acid, palmitate ascorbyl, sodium bisulfite and the like known to those with common knowledge in the art. As used herein, the term "buffering agent" designates a compound employed to resist pH change when there is dissolution or addition of acids or alkalis in the composition, and include by way of example without being limiting, potassium metaphosphate, potassium phosphate, sodium monobasic acetate, sodium citrate and the like known to those with common knowledge in the art. It should be understood that the compounds used in the art of pharmaceutical formulation generally serve a variety of functions and purposes, the agents mentioned for a certain function, therefore, not being limited to said function.

SEPARATE SEPARATE ASPECTS OF THE INVENTION As explained herein and demonstrated in the preparation examples included herein (see, for example, Table 2 of Example 4 and Table 3 of Example 5), a pharmaceutical composition as described in the present it can be characterized as having a very good dissolution profile. More specifically, it can be characterized in that at least 80% of the drospirenone and the ethinylestradiol are dissolved from said composition within 20 minutes in an assay performed in a recognized standard dissolution apparatus. This is the first time that a pharmaceutical composition has been described with said preferred dissolution profile and constitutes a significant contribution to art. As explained herein, said pharmaceutical composition is preferably obtained by the use of methylene chloride as one of the volatile solvents. However, once the skilled person knows that such a pharmaceutical composition can be obtained, he could further investigate the subject and probably identify other solvents besides methylene chloride that could be used to make suitable pharmaceutical compositions. Accordingly, a separate aspect separate from the invention relates to a pharmaceutical composition comprising drospirenone and ethinylestradiol in amorphous form, adsorbed on a therapeutically inert solid support, in combination with pharmaceutically acceptable excipients, characterized in that at least 80% of the drospirenone and at least 80% of the ethinylestradiol are dissolved from said composition within 20 minutes in a test conducted in a dissolution apparatus according to the United States Pharmacopoeia [U.S. Pharmacopoeia), Issue number 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rpm. As discussed above, the pharmaceutical composition of this separate independent aspect of the invention can be made by the use of methylene chloride as the volatile solvent. However, it can also be done by using other volatile solvent (s) excluding methylene chloride. Consistent with this, another independent separate aspect of the invention relates to a method for the preparation of a pharmaceutical composition, of the above separate separate aspect of the invention comprising the following steps: i) Dissolving drospirenone and ethinylestradiol in a volatile solvent or in a mixture of volatile solvents, ii) Optionally, add a water-soluble polymer, iii) Mix until the solution, iv) Apply the resulting solution on a base of solid particles that are therapeutically inert, v) Dry the adsorbate granulate obtained. Preferably, a water soluble polymer is added in step ii). The preparation examples included herein provide guidance in order to identify other (not methylene chloride) suitable volatile solvents. For example, in comparative example 2B it is shown that 16 ml of methanol alone is not sufficient to completely dissolve 3.06 g of drospirenone. This can be used as a basis to identify suitable solvents. The dissolution protocol can be repeated, as described in Preparation Example 1 herein, but using a panel of other solvents that may be suitable. Those that are capable of completely dissolving drospirenone are the preferred solvents herein. Therefore, a preferred embodiment of the separate independent appearance method mentioned above, is when the volatile solvent or mixture of volatile solvents of step i) is / are solvent (s) capable / capable of completely dissolving drospirenone in the following test of dissolution: 16.0 ml of the volatile solvent or the mixture of volatile solvents are placed in a stainless steel agitation apparatus, then, 0.0306 g of ethinylestradiol (not micronized with a particle size of not less than 50 μm) under constant stirring; the mixture is stirred until it is completely dissolved, then 3.06 g of drospirenone (not micronized with a particle size of not less than 50 μm) are added under constant stirring until the drospirenone is completely dissolved. All of the embodiments described above with respect to the aspects of the above-mentioned invention are also preferred embodiments with respect to the separate independent aspects of the invention described in this section.

EXAMPLES Reference Example Dissolution profiles of crystalline drospirenone in acid medium The drospirenone dissolution profiles were obtained from tablets containing drospirenone in crystalline state with different particle sizes, by means of a dissolution apparatus designated in the American Pharmacopoeia Ed. N ° 27, Apparatus 2, at 50 rpm and 900 ml of 0.07% lauryl sulfate in strongly acidic medium 0.1 N HCl thermostated at 37 ° C. The results of the quantity of drug dissolved at different times are summarized in the following table: Table 1 Samples: LPOl: Lot of tablets with crystalline Drospirenone not micronized with average particle size > 100 μm LP02: Lot of tablets with crystalline Drospirenone non-micronized with average particle size = 100 μm LP04: Lot of tablets with micronized crystalline Drospirenone with average particle size = 10 μm For a better interpretation of the results shown in Table 1, they are represented in Figure 16.

The instability of drospirenone in an acid medium, regardless of the particle size, is observed from said figure. EXAMPLE 1 Amount needed to make 1000 tablets: Granules: Drospirenone (+ 2% excess due to losses in the process) 3,0600 g Ethinylestradiol (+ 2% excess due to losses in the process) 0.0306 g Corn starch 12.7800 g Pregelatinized starch 15.4400 g Lactose monohydrate 44.0000 g Croscarmellose sodium 0.4000 g Yellow Iron Oxide 0.0900 g Povidona 3.4000 g Methylene Chloride / Methanol (6: 1) 16.0000 mi Lubrication and final mixture: Croscarmellose sodium 0.4000 g Magnesium stearate 0.4000 g Coating: Colorless aqueous lacquer 5% 0.0060 g (OPADRY YS-1-7006 at 5%) II. PREPARATION TECHNIQUE II. 1 . Dissolution of the active ingredients and Binder In a stainless steel container equipped with a stirrer, 16.00 ml of Dichloromethane / Methanol solution were placed in a 6: 1 ratio. Then, under constant agitation, 0.0306 g of ethinylestradiol, non-micronized with a particle size of not less than 50 μm were added (the addition of 2% in excess is foreseen to compensate eventual losses in the process). It was stirred until complete dissolution. 3.0600 g of drospirenone, not micronized with a particle size of not less than 50 μm, was added (the addition of 2% in excess is foreseen to compensate eventual losses in the process), under constant agitation until completely dissolved. Once dissolved, 3,4000 g of polyvinyl pyrrolidone K-30 were added, with stirring until complete dissolution. II.2. Granulation - Drying In a planetary type mixer were placed, previously sieved by a mesh of 30 mesh: 44,0000 g of lactose monohydrate, 12.7800 g of corn starch, 15,4400 g of pregelatinized starch, 0.4000 g of croscarmellose sodium and 0.0900 g of yellow iron oxide. It was mixed for 15 to 20 minutes. Next, the binder solution containing the active ingredients, previously prepared, was added and kneaded until obtaining a suitable consistency for granulation. If necessary, it is possible to add additional solvent (6: 1 dichloromethane / methanol mixture). The wet mass was granulated by passing it through a 10 mesh mesh. It was dried in an oven at 40 ° C for 24 hours, until achieving residual levels of solvent 100 times below that admitted by the International Conference on Harmonization of technical requirements for the registration of pharmaceutical products for use in humans, in its Q3C guide . In a separate experiment, the binder solution was applied on the basis of solid particles, spraying it in the form of a spray. It was done in the following way. In a fluid bed dryer / granulator, 44 grams of lactose monohydrate, 12.780 g of corn starch, 15.44 g of pregelatinized starch, 0.400 g of croscarmellose sodium and 0.0900 were added, previously sieved by a 30 mesh. g of yellow iron oxide. They were mixed for 15 to 20 minutes. Then, the previously prepared binder solution containing the active ingredients was sprayed. The moist mass was dried at 40 ° C. II. 3. Final Blend - Compression - Coating The dried granulate was passed through 18 mesh, then adding 0.4000 g of croscarmellose sodium and 0.4000 g of magnesium stearate. It was mixed for 15 minutes. The resulting granulate was compressed into tablet cores using a rotary machine equipped with a set of smooth biconcave punches of 13/64"diameter to a weight of 80 mg / tablet and a hardness of 6-12 Stron Cobb units. compressed with 5% colorless aqueous lacquer Name of the granulated batch in the planetary type mixer: LPDIVuru and name of the granulated batch in the fluidized bed drier: LPDISpray The morphology of the components in each stage of the process has been analyzed under an electron microscope The microphotographs of Figure 1 with 200X magnification, show drospirenone crystals, with their characteristic "spatula" shape with sizes greater than 50 μm, Figures 2A to 2L show microphotographs of the therapeutically inert materials used as support for the agents In particular, Figures 2A and 2B show microphotographs of a lactose particle and a population of lacto-particles. sa, respectively; Figures 2C and 2D show microphotographs of a corn starch particle and a population of corn starch particles, respectively; Figures 2E and 2F show microphotographs of a particle of pregelatinized starch and a population of pregelatinized starch particles, respectively; Figures 2G and 2H show microphotographs of a croscarmellose sodium particle and a population of croscarmellose sodium particles, respectively; Figures 21 and 2J show microphotographs of a yellow iron oxide particle and a population of yellow iron oxide particles, respectively; Figures 2K and 2L show microphotographs of a Povidone particle and a population of Povidone particles, respectively. Figure 3 shows a microphotograph of the physical mixture of the different components. Figures 4A and 4B show microphotographs of drospirenone adsorbate particles and ethinyl estradiol on the inert components, in two approaches.

EXAMPLE 2 A batch of 1000 tablets was prepared by a procedure similar to that described in Example 1, where the mixture of volatile solvents methylene chloride / methanol was applied in a ratio of 5: 2. Results similar to those described in Example 1 were obtained.

EXAMPLE 2B This is a comparative example, where only methanol was used as solvent. Only the differences with respect to example 1 are listed below. The rest was carried out in the same way as in example 1.

In the first example, 16 ml of methanol was used alone. This amount (16 ml) is the same volume as the 16 ml methylene chloride / methanol (6: 1) used in example 1. When step n II was carried out. l. Dissolution of the active ingredients and the binder solution ", it is important to note that this amount of 16 ml of methanol was not sufficient for the total dissolution of the drospirenone because the solubility of the methanol was very low.Remember that in example 1 drospirenone was completely dissolved, however, although the process continued in accordance with example 1, where in step 11, 2. Granulation - drying "a planetary type kneader was used and the granulate was kneaded. The name of the final granulated batch is: LPDIMet-16ml. Considering the above, an additional experiment was carried out in which step "II 1. Dissolution of the active ingredients and binder solution" methanol was added until total dissolution. The required amount was 154.3 ml of methanol. Said high necessary amount of methanol is generally excessive for an industrial granulation process. The process continued in accordance with Example 1, in which step "II, 2. Granulation - Drying" a fluid bed dryer was used and the granulate was sprayed. The name of the final granulated batch is: LPDIMet-154ml.

EXAMPLE 3 Differential calorimetric scan It is demonstrated by differential calorimetric scanning (DSC) - using a Shimadzu DSC-60 equipment at 10 ° C / min, with nitrogen flow of 30 ml / min as purge gas -, the absence of the endothermic signal characteristic fusion of the crystalline state of Drospirenone in the adsorbate obtained according to Example 1. The various inert components and Drospirenone were analyzed by DSC before the preparation of the adsorbate of drospirenone and ethinylestradiol according to Example 1. Figure 5 shows a graph of the differential calorimetric scan of lactose monohydrate alone; Figure 6 shows a graph of the differential calorimetric scan of drospirenone in crystalline state (Start temperature of the endotherm To = 198.9 ± 0.8 ° C).

Figure 7 shows a graph of the differential calorimetric scan of magnesium stearate; Figure 8 shows a graph of the differential calorimetric sweep of corn starch; Figure 9 shows a graph of the differential calorimetric scan of the pregelatinized starch; Figure 10 shows a graph of the differential calorimetric yellow iron oxide scan; Figure 11 shows a graph of the differential calorimetric scan of croscarmellose sodium (AC-Di-Sol); Figure 12 shows a graph of the differential calorimetric scan of Povidone K30. Figure 13 shows a graph of the differential calorimetric scan of the mixture of inert excipient components or placebo with the absence of drospirenone and ethinylestradiol. Figure 14 shows a graph of the differential calorimetric scanning of the mixture of the components of the adsorbate in the state of simple mixing, where the fusion signal of the drospirenone in crystalline state has been marked particularly (fusion endotherm at 197 ° C). Figure 15 shows a graph of the differential calorimetric scan of the granulate obtained in Example 1 containing drospirenone and ethinylestradiol adsorbed on the inert excipients where the absence of the fusion signal of the drospirenone in the crystalline state is highlighted. This absence of signal indicates the loss of the crystalline state of drospirenone as a consequence of the process applied in Example 1, where when subjecting the granulate to drying, the presence of polyvinylpyrrolidone in the solution of drospirenone and ethinylestradiol, acts through the formation of a three-dimensional polymer network, preventing the crystalline growth of both active compounds, so that the drugs are deposited on the particles of excipients in an amorphous state. EXAMPLE 4 Comparative profiles of drospirenone solution Dissolution profiles of drospirenone were obtained from compressed tablets obtained according to Example 1 and comparative example 2B in which "methanol only" was used, by means of a dissolution apparatus designated in the Pharmacopoeia US Ed. No. 27, Apparatus 2, at 50 rpm and 900 ml of distilled water thermostated at 37 ° C. The dissolution profiles of drospirenone were also obtained from tablets containing drospirenone in crystalline state with different particle sizes. The results of the quantity of drug dissolved at different times are summarized in the following table: Table 2 Samples: LPOl: Lot of tablets with crystalline Drospirenone not micronized with average particle size > 100 μm LP02: Lot of tablets with crystalline Drospirenone non-micronized with average particle size = 100 μm LP03: Lot of tablets with crystalline Drospirenone non-micronized with average particle size = 70 μm LPDIVuru and LPDISpray: Lot of tablets with drospirenone adsorbates and Ethinylestradiol in amorphous form obtained according to example 1, (ie, the use of a mixture of methylene chloride and methanol). For LPDIVuru the granulation was carried out in a planetary type kneader and the granulate was kneaded, and for LPDISpray the granulation was carried out in a fluid bed dryer and the granulate was sprayed. LPDIMet-16ml and LPDIMet-154ml: Lot of tablets with adsorbates of drospirenone and ethinylestradiol in amorphous form obtained according to Comparative Example 2B (ie, use of methanol only). In the first, 16 ml of methanol was used (the same amount as in example 1. Drospirenone did not completely dissolve, see example 2B) and in the last 154 ml of methanol were used in order to completely dissolve the drospirenone.

For a better interpretation of the results shown in Table 2, they are represented in Figure 17. From this figure it is observed that the batches of tablets with drospirenone in crystalline state, with different particle sizes, exhibit a very slow speed of dissolution, while the batch of LPDIVuru tablets, according to the present invention shows a drospirenone dissolution rate of at least 80% within 20 minutes. Also, in Table 2 it can be seen that the USE OF METHYLENE CHLORIDE AS SOLVENT PROVIDES SIGNIFICANTLY BETTER RESULTS COMPARED WITH THE USE OF METANOL ONLY AS A SOLVENT.

EXAMPLE 5 Comparative profiles of dissolution of ethinylestradiol Dissolution profiles of ethinylestradiol were obtained from compressed tablets obtained according to Example 1 and with example 2B in which "methanol only" was used, by means of a dissolution apparatus designated in the Pharmacopoeia US Ed. No. 27, Apparatus 2, at 50 rpm and 900 ml of distilled water thermostated at 37 ° C. The dissolution profiles of ethinylestradiol were also obtained from tablets containing ethinylestradiol in crystalline state with different particle sizes. The results of the quantity of drug dissolved at different times are summarized in the following table: Table 3 Samples: LPOl: Lot of tablets with crystalline non-micronized ethinylestradiol with average particle size > 100 μm LP02: Lot of tablets with crystalline non-micronized ethinylestradiol with average particle size = 90 μm LP03: Lot of tablets with crystalline non-micronized ethinylestradiol with average particle size = 80 μm LPDIVuru and LPDISpray: Lot of tablets with adsorbates of drospirenone and ethinylestradiol in amorphous form obtained according to example 1, (ie, the use of a mixture of methylene chloride and methanol). For LPDIVuru the granulation was carried out in a planetary type kneader and the granulate was kneaded, and for LPDISpray the granulation was carried out in a fluid bed dryer and the granulate was sprayed. LPDIMet-16ml and LPDIMet-154ml: Lot of tablets with adsorbates of drospirenone and ethinylestradiol in amorphous form obtained according to Comparative Example 2B (ie, use of methanol only). In the first, 16 ml of methanol was used (the same amount as in example 1. Drospirenone did not completely dissolve) and in the last, 154 ml of methanol were used in order to completely dissolve the drospirenone. For a better interpretation of the results shown in Table 3, they are represented in Figure 18. From this figure it is observed that batches of ethinylestradiol tablets in crystalline state, with different particle sizes, exhibit a very slow speed of dissolution, while the batch of tablets according to the present invention LPDIVuru shows a dissolution rate of ethinylestradiol of at least 80% within 20 minutes.

Likewise, in Table 3 it can be seen that the USE OF METHYLENE CHLORIDE AS SOLVENT PROVIDES SIGNIFICANTLY BETTER RESULTS COMPARED WITH THE USE OF METANOL ONLY AS A SOLVENT.

EXAMPLE 6 Due to its low aqueous solubility, drospirenone and ethinylestradiol often have a low dissolution rate. Increasing the rate of dissolution of very poorly soluble drugs in water remains one of the most challenging aspects of the development of pharmaceutical products. The solid dispersion of very little water-soluble drugs in water-soluble surfactant carriers increases the dissolution and bioavailability of the drug. The nature of Drospirenone and Ethinylestradiol dispersed in the matrix of polyvinylpyrrolidone K-30 was studied. In this comparative example, Example 1 was repeated but it was done without the use of Povidone (polyvinylpyrrolidone K-30) in the dissolution step. A photomicrograph was obtained by means of electron microscopy. An electronic microscopy equipment owned by the UNLP (National University of La Plata, Argentina) was used in order to obtain the microphotographs.

Microphotographic images of the Drospirenone and Ethinylestradiol crystals obtained in the same manner as in Example 1 but without polyvinylpyrrolidone K-30 revealed that there were precipitates of microcrystals on the excipients. In contrast, in the photomicrograph of granules with Drospirenone and Ethinylestradiol obtained by wet granulation as in Example 1 (with polyvinylpyrrolidone K-30: solid dispersion matrix), the image did not exhibit microcrystals precipitated on the excipients. Furthermore, when performing the Dissolution Test with the aforementioned USP apparatus, the results indicated that the solid dispersion of Drospirenone and Ethinylestradiol is released more rapidly from the solid dispersion (with polyvinylpyrrolidone K-30) than from the pure crystalline drug ( without polyvinylpyrrolidone K-30). Accordingly, an improved product is obtained by adding a water soluble polymer, such as polyvinylpyrrolidone K-30 (Povidone) in the manner described herein. The foregoing is a detailed description of particular embodiments of the invention. It should be recognized that those with knowledge in this art, in light of the present description, can make changes in the specific embodiments disclosed herein and still obtain a similar or similar result, without departing from the spirit and scope of the invention.

Claims (24)

1. A pharmaceutical composition comprising drospirenone and ethinylestradiol in amorphous form, adsorbed on a therapeutically inert solid support, in combination with pharmaceutically acceptable excipients, characterized in that the composition comprises measurable amounts of the volatile solvent methylene chloride.

2. The pharmaceutical composition according to claim 1, characterized in that the composition comprises measurable amounts of both volatile solvents: methylene chloride and methanol.

3. The pharmaceutical composition according to claim 1 or 2, wherein the inert solid support is selected from the group consisting of corn starch, pregelatinized starch, lactose, croscarmellose sodium, yellow iron oxide and polyvinylpyrrolidone or mixtures of one or more of them, in combination with pharmaceutically accepted excipients.

4. The pharmaceutical composition according to any of claims 1 to 3, characterized in that at least 80% of the drospirenone and at least 80% of the ethinylestradiol are dissolved from said composition within 20 minutes in an assay performed in a dissolution apparatus according to the United States Pharmacopeia, Issue number 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rpm.

5. A method for preparing the pharmaceutical composition according to any of the preceding claims 0, comprising the following steps: i) dissolving drospirenone and ethinylestradiol in a volatile solvent or mixture of volatile solvents, wherein at least one of the volatile solvents is methylene chloride, ii) optionally adding a water soluble polymer, iii) mixing until dissolution, iv) apply the resulting solution on a support or of therapeutically inert solid particles and v) dry the granulated adsorbate obtained.

6. The method of claim 5, wherein the volatile solvent is a mixture of methylene chloride and methanol.

7. The method of claim 6, wherein the mixture of methylene chloride and methanol is a mixture of methylene chloride / methanol [9 to 4]: [3 to 0.5] v / v.

8. The method of claim 7, wherein the methylene chloride mixture is a 6: 1 v / v methylene chloride / methanol mixture.

9. The method of any of claims 5 to 8, wherein a water soluble polymer is added in step 2 of claim 5.

10. The method of claim 9, wherein the water soluble polymer is polyvinyl pyrrolidone.

11. The method of any of claims 5 to 10, wherein the solid, therapeutically inert support is selected from among corn starch particles, pregelatinized starch, lactose, croscarmellose sodium, yellow iron oxide, polyvinylpyrrolidone or mixtures of one or more of them.

12. The method of any of claims 5 to 11, wherein additionally the dried granulated adsorbate is combined with pharmaceutically acceptable excipients for compressing the tablets.

13. A pharmaceutical preparation comprising several dosage units for daily oral administration for a period of at least 21 consecutive days, wherein said dosage units comprise approximately 1 to 4 mg of drospirenone and approximately 0.01 to 0.05 mg of ethinylestradiol, characterized in that said drospirenone and said ethinylestradiol are in amorphous form, adsorbed on a therapeutically inert solid support, of any of claims 1 to 4, in combination with pharmaceutically acceptable excipients.

14. The pharmaceutical preparation according to claim 13, characterized in that it comprises drospirenone and ethinylestradiol in amorphous form, adsorbed on a solid support, selected from among particles of corn starch, pregelatinized starch, lactose, croscarmellose sodium, yellow iron oxide, polyvinylpyrrolidone or of mixtures of one or more of them in combination with pharmaceutically acceptable excipients.

15. The pharmaceutical preparation according to claim 13 or 14, characterized in that at least 80% of the drospirenone is dissolved from said dose units within 20 minutes in an assay performed in a dissolution apparatus according to the Pharmacopoeia of United States, Edition number 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rpm.

16. The pharmaceutical preparation according to any of claims 13 to 15, at least 80% of the ethinylestradiol is dissolved from said dosage units within 20 minutes in an assay performed in a dissolution apparatus according to the Pharmacopoeia of the United States, Edition number 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rpm.

17. The use of drospirenone combined with ethinylestradiol to prepare a pharmaceutical composition of any of claims 1 to 4, for the anovulation of a mammal, in particular a human, the composition comprising a quantity of drospirenone corresponding to a daily dosage, when administering the composition, from about 1 mg to 4 mg, and comprising an amount of ethinylestradiol corresponding to a daily dosage, upon administration of the composition, from 0.01 to 0.05 mg.

18. The use of claim 16, characterized in that said dosage units comprise drospirenone and ethinylestradiol in amorphous form, adsorbed on a solid support selected from among particles of corn starch, pregelatinized starch, lactose, croscarmellose sodium, yellow iron oxide, polyvinylpyrrolidone or mixtures of one or more of them in combination with pharmaceutically acceptable excipients.

19. The use of claims 17 or 18, characterized in that at least 80% of the drospirenone is dissolved from said dose units within 20 minutes in an assay performed in a dissolution apparatus according to the Pharmacopoeia of the United States, Edition number 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rpm.

20. The use of claims 17 to 19 characterized in that at least 80% of the ethinylestradiol is dissolved from said dosage units within 20 minutes in an assay performed in a dissolution apparatus according to the United States Pharmacopoeia. , Edition number 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rpm.

21. The use of claims 17 to 20, wherein daily oral administration preferably occurs over a period of at least 21 consecutive days.

22. A pharmaceutical composition comprising drospirenone and ethinylestradiol in amorphous form, adsorbed on a therapeutically inert solid support, in combination with pharmaceutically acceptable excipients, characterized in that at least 80% of the drospirenone and at least 80% of the ethinylestradiol are dissolved from said composition within 20 minutes in a test conducted in a dissolution apparatus according to the United States Pharmacopoeia, Issue No. 27, Apparatus 2, in 900 ml of distilled water at 37 ° C and stirred at 50 rp.

23. A method for the preparation of a pharmaceutical composition, according to claim 22, comprising the following steps: i) dissolving drospirenone and ethinylestradiol in a volatile solvent or mixture of volatile solvents, ii) optionally adding a water-soluble polymer, iii ) mix until the solution, iv) apply the resulting solution on a support of therapeutically inert solid particles and v) dry the granulated adsorbate obtained.

24. The method of claim 23, wherein the volatile solvent or the mixture of volatile solvents of step i) is / are solvent (s) which can (n) completely dissolve the drospirenone in the following dissolution test: the amount of 16.0 ml of the volatile solvent or the mixture of volatile solvents in a stainless steel agitation apparatus, then 0.0306 g of ethinylestradiol (not micronized with a particle size of not less than 50 μm) is added under constant stirring; The mixture is stirred until it is completely dissolved, then 3.06 g of drospirenone (not micronized with a particle size of not less than 50 μm) are added under constant stirring until the drospirenone is completely dissolved.