RU2269342C2 - Pharmaceutical combination of ethynylestradiol and drospirenone for using as contraceptive - Google Patents

Abstract

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising drospirenone as the first active agent in the amount corresponding to daily dose from 2 to 4 mg in administration of the composition, and ethynylestradiol as the second active agent in the amount corresponding to daily dose from 0.01 to 0.05 mg in combination with one or some pharmaceutically acceptable vehicles or additives. Drospirenone as a component of the pharmaceutical composition is in the finely divided form. The preparation comprises some separately packages and individually taken medicinal units placed in the unit package and designated for oral administration for at least 21 days at a time and indicated daily medicinal units comprise the combination of drospirenone and ethynylestradiol. The preparation can comprise 7 and less daily doses no containing any active agent or containing ethynylestradiol only. The combination of ethynylestradiol and drospirenone provides the safety contraceptive activity due to using the maximal dose of drospirenone being without adverse effects, in particular, excessive diuresis.

EFFECT: improved and valuable properties of combination.

34 cl, 5 dwg, 5 ex

Description

Technical field

The present invention relates to a pharmaceutical composition comprising drospirenone and ethinyl estradiol, a method for producing a drospirenone solution, methods for inhibiting ovulation by the administration of drospirenone, and the use of drospirenone and ethinyl estradiol to inhibit ovulation.

BACKGROUND OF THE INVENTION

Oral contraceptives containing a combination of components such as gestagen and estrogen have been used since the 1960s. The earliest contraceptive preparations included 21 tablets containing a combination of active agents and 7 tablets containing no active agent, the amount of each active agent in each tablet being the same (the so-called “single phase preparations”). Subsequently, preparations were developed, including tablets containing various amounts and proportions of active agents throughout the administration cycle (the so-called "multiphase preparations").

Reliability of the contraceptive is mainly provided by a component such as gestagen. The daily dose should be at least the minimum of the dose necessary so that the used gestagen effectively inhibits ovulation. Estrogen helps increase the action of gestagen to suppress ovulation and ensure cycle stability. Since the advent of oral contraceptives, the daily dose of gestagen has been declining due to the development of new and more effective gestagens than those used in earlier contraceptives. There was also the opportunity to reduce the daily dose of estrogen.

6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) is known from DE 2652761, which describes its use as a diuretic.

DE 3022337 describes a progestogen-like activity of a compound and its use as a contraceptive agent with a dose of 0.5-50 mg drospirenone per day. It is also indicated that the mechanism of action of the compound is very similar to the mechanism of action of the natural hormone of the corpus luteum, progesterone, and that it does not cause an increase in blood pressure, so it can be taken by women with high blood pressure or potential hypertension. It is further indicated that drospirenone can be administered together with ethinyl estradiol in an amount of 0.03-0.05 mg per day.

DE 3051166 describes the use of drospirenone for the treatment of gynecological disorders, as well as for contraception with a dose of 0.5-50 mg per day.

EP 398460 describes the use of drospirenone for the treatment of disorders induced by androgens, aldosterones, and hormonal disorders, as well as for contraception with a dose of 0.5-50 mg, preferably 1-10 mg per day. Together with it, ethinyl estradiol can be administered in a dose of 0.02-0.04 mg per day.

US 5756490 describes pharmaceutical combination preparations comprising 23 or 24 dosage units containing a combination of progestogen and estrogen, as well as 4-10 dosage units containing only estrogen. Drospirenone is mentioned as a possible, but not preferred, progestogen compound, and ethinyl estradiol is mentioned as a possible, but not preferred, estrogenic compound.

SUMMARY OF THE INVENTION

In the studies leading to the present invention, it was unexpectedly found that reliable contraceptive activity requires a still undetermined minimum dose of drospirenone. In a similar manner, a preferred maximum dose has been established at which unpleasant side effects, in particular excessive diuresis, can essentially be prevented.

Accordingly, according to a first aspect, the present invention relates to a pharmaceutical composition comprising, as a first active agent, 6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to the daily dose after administration of the composition in an amount of about 2 to about 4 mg, and, as a second agent, 17α-ethinyl estradiol (ethinyl estradiol) in an amount corresponding to a daily dose of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives.

In addition to the active substances themselves, it is contemplated that an ester or prodrug of drospirenone, for example, oxyiminopregnancarbolactone, described in WO 98/24801, can be used in accordance with the present invention. Likewise, it is contemplated that ethinyl estradiol esters or ethers may be included in the composition.

In accordance with a further aspect, the present invention relates to a method for inhibiting ovulation in mammals, in particular in humans, comprising administering to said mammal a drospirenone in an amount of about 2 to about 4 mg per day, together with ethinyl estradiol in an amount of about 0 , 01 to about 0.05 mg per day, with the indicated amounts effectively inhibiting ovulation in said mammal.

In accordance with another aspect, the present invention relates to the use of drospirenone in combination with ethinyl estradiol for the manufacture of a pharmaceutical preparation for the purpose of inhibiting ovulation in mammals, in particular in humans, the composition comprising an amount of drospirenone corresponding to a daily dose after administration of a composition of about 2 mg to about 4 mg; and the amount of ethinyl estradiol corresponding to the daily dose after administration of a composition of about 0.01 to about 0.05 mg.

Brief Description of the Drawings

The invention is further described with reference to the drawings, in which:

figure 1 is a graphical representation of the dissolution rate of drospirenone in vitro from the nuclei of tablets, with V1-V7 mean batches containing finely divided drospirenone, and V8 means a batch containing macrocrystalline drospirenone;

figure 2 is a graphical representation of the dissolution rate of drospirenone in vitro from the nuclei of tablets, with different lines representing different analytical parties;

figure 3 is a graphical representation of the dissolution rate of drospirenone in vitro from film-coated tablets, with different lines representing different analytical lots;

4 is a graphical representation of the in vitro dissolution rate of ethinyl estradiol from tablet cores, with different lines representing different analytical lots; and

5 is a graphical depiction of the in vitro dissolution rate of ethinyl estradiol from film-coated tablets, with different lines representing different analytical lots.

DETAILED DESCRIPTION OF THE INVENTION

Drospirenone, which can be essentially prepared essentially as described, for example, in US 4,129,564 or WO 98/06738, is a substance which is sparingly soluble in water and in aqueous buffers at various pH values. Moreover, drospirenone regroups into an inactive isomer under acidic conditions and hydrolyzes under alkaline conditions. Therefore, in order to ensure high bioavailability of the compound, it is advisable to use it in a form that promotes its rapid dissolution.

It was unexpectedly found that if drospirenone in the pharmaceutical composition is finely divided (so that the particles of the active substance have a surface area of more than 10,000 cm ² / g and the following particle size distribution, determined under a microscope: no more than 2 particles in a particular batch with a diameter of over 30 μm, preferably ≤20 particles with a diameter of ≥10 μm and ≤30 μm), then the active compound from the composition is rapidly dissolved in vitro (“quick dissolution” means the dissolution of at least 70% of those approximately 30 minutes, in particular at least 80% for approximately 20 minutes, from a tablet formulation containing 3 mg of drospirenone in 900 ml of water at 37 ° C, determined using the XXIII blade method described in USP using the described in the United States Pharmacopeia an instrument for determining dissolution 2 at 50 rpm). Instead of finely grinding drospirenone, it can be dissolved in a suitable solvent, such as methanol or ethyl acetate, and sprayed onto the surface of the particles of an inert carrier, followed by the introduction of particles containing drospirenone on its surface into the composition.

Without being limited by any particular theory, it appears that the in vitro dissolution rate of drospirenone is related to the in vitro dissolution rate, leading to the rapid absorption of drospirenone in vitro after oral administration of the compound. This is an advantage because the isomerization of the compound in the gastric environment and / or hydrolysis in the intestine is significantly lower, which ensures high bioavailability of the compound.

As for ethinyl estradiol, which is also a sparingly soluble substance, although less sensitive to decomposition than drospirenone, under conditions prevailing in the gastrointestinal tract, it is also advisable to apply it in finely divided form or spray it from a solution, for example, in ethanol, on the surface particles of an inert carrier. This provides an additional advantage by facilitating a more uniform distribution of ethinyl estradiol in the composition, which otherwise would not be easy to carry out, since ethinyl estradiol is administered in extremely small amounts. If ethinyl estradiol is in micronized form, then it preferably has the following particle size distribution determined under a microscope: 100% of the particles have a diameter of ≤15.0 μm, 99% of the particles ≤12.5 μm, 95% of the particles ≤10, 0 μm, and 50% of the particles - ≤3.0 μm. Moreover, there are no particles larger than 20 μm, and ≤10 particles have a diameter of ≥15 μm and ≤20 μm.

In order to obtain a higher dissolution rate, it is preferable to include carriers or additives that facilitate the dissolution of both active substances. Examples of such carriers and excipients include substances readily soluble in water, such as cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatinized starch, gelatin or polyvinylpyrrolidone. In particular, it seems that polyvinylpyrrolidone is especially conducive to dissolution.

The composition in accordance with this invention preferably includes drospirenone in an amount corresponding to a daily dose of about 2.5 to 3.5 mg, in particular about 3 mg. The amount of ethinyl estradiol preferably corresponds to a daily dose of from about 0.015 to about 0.04 mg, in particular from about 0.015 mg to about 0.03 mg. More specifically, the composition comprises an amount of drospirenone corresponding to a daily dose of about 3.0 to about 3.5 mg, and ethinyl estradiol in an amount corresponding to about 0.015 to about 0.03 mg.

It was found that in addition to its ability to inhibit ovulation, the composition in accordance with this invention has pronounced anti-androgenic properties and therefore can be used for the prevention or treatment of androgen-induced disorders, in particular acne. Such use may be independent or concomitant with the above use as a contraceptive. Moreover, since drospirenone is an antagonist of aldosterone, it has diuretic properties and is therefore suitable for counteracting water retention properties of ethinyl estradiol.

In accordance with a specific variant of its implementation, the present invention relates to a pharmaceutical preparation consisting of a number of separately packaged and individually extractable daily dosage units placed in a single package and intended for oral administration for at least 21 consecutive days, in which each of said daily dosage units includes a combination of drospirenone in an amount of about 2 to about 4 mg and ethinyl estradiol in an amount of about 0.01 to about 0.05 mg.

In accordance with one embodiment, the preparation further comprises 7 or less of the indicated daily dosage units not containing an active agent. Alternatively, a dosage regimen may include a period of 7 days or less that does not require the administration of a drug. However, in order to comply with the scheme, it is advisable to include the appropriate number of pacifiers in the package, in which case the total number of daily dosage units of the drug will be at least 28. The inclusion of pacifiers or drug-free days will then cause the bleeding to resume.

The preparation may be a single phase composition, i.e. a preparation in which the amount of each active agent remains constant over the course of at least a 21-day period, or the amount of one or both active agents can vary over a period of at least 21 days, forming a multiphase preparation, for example, two - or a three-phase preparation, essentially described, for example, in EP 148724. When receiving a multiphase preparation, instead of ethinyl estradiol, natural estrogen, such as estradiol, for example, in an amount of about 0.5 to about about 4 mg per day.

In suitable embodiments of the preparation, the number of daily dosage units comprising a combination of drospirenone and ethinyl estradiol may be 21, 22, 23, or 24, and the number of daily dosage units not containing an active agent may be 7, 6, 5, or 4, respectively. In accordance with another embodiment of this preparation, the number of daily dosage units comprising a combination of drospirenone and ethinyl estradiol is 28 or a multiple of 28, for example, 2-4, in particular 2 or 3 times 28.

According to an alternative embodiment, the present invention relates to a contraceptive preparation comprising a number of individually packaged and individually extractable daily dosage units placed in a single package and intended for oral administration for at least 28 consecutive days, in which at least at least 21, said daily dosage unit comprises a combination of drospirenone in an amount of about 2 to about 4 mg and ethinyl estradiol in an amount of about was 0.01 to about 0.05 mg, and wherein 7 or less said daily dosage units contain ethinylestradiol alone in an amount ranging from about 0.01 to about 0.05 mg.

The inclusion of a suitable number of dosage units containing only ethinyl estradiol can provide high contraceptive reliability, low follicular development and satisfactory control over the cycle with little or no bleeding between periods.

In this case, the amount of each active agent in the preparation may also remain constant throughout the entire at least 21-day period (biphasic preparation), or the amount of one or both active agents may vary over the course of the at least 21-day period forming a multiphase preparation, for example, a three- or four-phase preparation, essentially described, for example, in EP 148724. When producing a multiphase preparation, instead of ethinyl estradiol, a natural estrogen such as estradiol, for example measures in an amount of from about 0.5 to about 4 mg per day.

In suitable embodiments of this preparation, the number of daily dosage units including a combination of drospirenone and ethinyl estradiol may be 21, 22, 23, or 24, and the number of daily dosage units containing only ethinyl estradiol may be 7, 6, 5, or 4, respectively.

In accordance with one embodiment of the method for inhibiting ovulation, said method comprises administering to said mammal every day from at least 21 consecutive days a daily dosage dose comprising a combination of drospirenone in an amount of about 2 to about 4 mg and ethinyl estradiol in an amount of from about 0.01 to about 0.05 mg, followed by the daily administration of a daily dosage unit containing no active agent for 7 or less consecutive days, or, conversely, the absence of Ia dosage units for 7 days or less.

In suitable embodiments of this method, daily dosage units, including a combination of drospirenone and ethinyl estradiol, can be administered for 21, 22, 23, or 24 consecutive days, and daily dosage units not containing an active agent can then be administered over 7, 6 , 5 or 4 consecutive days, respectively. Moreover, daily dosage doses, including a combination of drospirenone and ethinyl estradiol, can be administered for 28 consecutive days. In accordance with one embodiment of the method, daily dosage units, including a combination of drospirenone and ethinyl estradiol, are administered 2-4, preferably 2 or 3 times, for 28 consecutive days, followed by daily dosage units, including a combination of drospirenone and ethinyl estradiol, in for 21, 22, 23 or 24 consecutive days, and then the introduction of daily dosage units that do not contain an active agent, or the absence of the introduction of daily dosage units for 7, 6, 5 or 4 days in a row.

Alternatively, the method comprises administering daily from at least 21 consecutive days a daily dosage dose comprising a combination of drospirenone in an amount of about 2 to about 4 mg and ethinyl estradiol in an amount of about 0.01 to about 0 , 05 mg, with the subsequent administration of a daily dosage dose containing only ethinyl estradiol in an amount of from about 0.01 to about 0.05 mg every day for 7 or less consecutive days.

According to this alternative method, daily dosage doses containing a combination of drospirenone and ethinyl estradiol can be suitably administered for 21, 22, 23, or 24 consecutive days, and daily dosage doses including only ethinyl estradiol can then be administered for 7, 6, 5 or 4 consecutive days, respectively. In accordance with a further embodiment of the method, daily dosage doses containing a combination of drospirenone and ethinyl estradiol are administered 2-4 times, preferably 2 or 3 times, for 28 consecutive days, followed by daily doses, including the combination of drospirenone and ethinyl estradiol, in for 21 consecutive days, and then the introduction of daily dosage doses, including only ethinyl estradiol, for 7 consecutive days.

When used in accordance with this invention, the pharmaceutical preparation may take the form of a number of separately packaged and individually delivered daily dosage units placed in a single package and intended for oral administration for at least 21 consecutive days, with each of these daily dosage units includes a combination of drospirenone in an amount of about 2 mg to about 4 mg and ethinyl estradiol in an amount of about 0.01 to about 0.05 mg.

As indicated above, a package may also include 7 or less daily dosage units that do not contain an active agent (or may contain 7 or less empty "places", for example, in the form of empty cells in an exhaust package, indicating days on which there is no daily dosage dosage doses).

Alternatively, the pharmaceutical preparation may take the form of a series of individually packaged and individually extractable daily dosage units placed in a single package and intended for oral administration for at least 28 consecutive days, in which at least 21 of the indicated daily dosage unit includes a combination of drospirenone in an amount of from about 2 to about 4 mg and ethinyl estradiol in an amount of from about 0.01 to about 0.05 mg, wherein said single package further includes takes 7 or less daily dosage doses containing only ethinyl estradiol in an amount of from about 0.01 to about 0.05 mg. The composition in accordance with this invention can be obtained by any method known in the pharmaceutical field. In particular, as indicated above, the composition can be obtained by a method comprising the presence of drospirenone and, if desired, ethinyl estradiol in finely divided form in the indicated dosage form, or sprayed from solution onto particles of an inert carrier in a mixture with one or more pharmaceutically acceptable additives that promote dissolution of drospirenone and ethinyl estradiol in such a way as to ensure rapid dissolution of drospirenone, and preferably ethinyl estradiol after oral administration and I. Examples of suitable additives include fillers, for example, sugars, such as lactose, glucose or sucrose, sugar alcohols, such as mannitol, sorbitol or xylitol, starch, such as wheat, corn or potato starch, modified starch or sodium starch glycolate, lubricants, such as talc, magnesium stearate, calcium stearate, colloidal silicon dioxide or stearic acid, as well as binders such as polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypr methyl cellulose, methyl cellulose or gelatin, for the preparation of oral dosage forms, such as tablets, pills or capsules.

If appropriate, a suitable film-forming agent may be applied to the tablets, for example hydroxypropyl methyl cellulose, hydroxypropyl cellulose or ethyl cellulose, to which a suitable additive, for example, an emollient, such as glycerin, propylene glycol, diethyl phthalate or triacetate glycerol, an excipient such as sucrose, may be added. glucose or lactose, a colorant such as titanium hydroxide, etc.

This composition can also be obtained in liquid form, for example, in the form of a solution, suspension or emulsion, together with conventional diluents or additives in a manner known per se in the pharmaceutical field.

A single package containing the daily dosage doses described above can be obtained in a manner analogous to the method for preparing other contraceptives for oral use. This can be, for example, an ordinary blister pack or any other packaging suitable for this purpose, for example, a package containing the desired number of dosage units (in this case, at least 21, or, for special cases, 28 or a multiple of 28 ) in a sealed blister pack with a base of cardboard, paper, foil or plastic coated with a suitable sheath. Each cell of the blister pack may be numbered for convenience or labeled in some other way, for example, starting with the first of at least 21 drug doses containing a combination of drospirenone and ethinyl estradiol, followed by 7 or less empty cells or 7 or less dosage doses not containing an active agent or containing only ethinyl estradiol (although numbering may also begin with the first of 7 or less dosage doses containing only ethinyl estradiol).

It is also contemplated that the composition may be in the form of a composition for parenteral use, such as a subcutaneous implant or transdermal composition. To obtain implants, the active agents can be suitably combined with one or more polymers, which, when used, gradually corrode or break down, for example silicone polymers; ethylene vinyl acetate, polyethylene or polypropylene.

As for transdermal formulations, they can be obtained in the form of matrices or membranes, or in the form of liquid or viscous formulations in oil or hydrogels. When producing transdermal patches, it is necessary to use an adhesive compatible with the skin, such as polyacrylate, silicone glue or polyisobutylene, as well as a film made, for example, of polyethylene, polypropylene, ethylene vinyl acetate, polyvinyl chloride, polyvinylidene chloride or polyester, and a removable protective film made of for example, from polyester, or coated with silicone or fluoropolymer. To obtain transdermal solutions or gels, water or organic solvents, or mixtures thereof can be used. Transdermal gels may additionally contain one or more suitable gelling agents or thickeners, such as silicone, tragacanth, starch or its derivatives, cellulose or its derivatives, or polyacrylic acid or its derivatives. Transdermal formulations may also suitably include one or more substances, skin absorption enhancers, such as bile salts or derivatives thereof, and / or phospholipids. Suitable transdermal formulations can, for example, be prepared in a manner analogous to the method described in WO 94/04157 for 3-ketodesogestrel. Alternatively, transdermal formulations may be prepared according to a method described, for example, in BW Barry, "Dermatological Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York-Basel, 1983, or YW Chien, "Transdermal Controlled Systemic Medications" , Marcel Dekker Inc., New York - Basel, 1987.

The present invention is further described in the following examples, in no way limiting the scope of the invention as claimed.

EXPERIMENTAL PART

Example 1

Obtaining tablets containing drospirenone and ethinyl estradiol

Received the core tablets having the following composition:

finely divided drospirenone 3.00 mg finely divided ethinyl estradiol 0.03 mg lactose monohydrate 48.17 mg corn starch 14.40 mg modified starch 9.60 mg polyvinylpyrrolidone 25000 4.00 mg magnesium stearate 0.80 mg

loading 31.68 kg of corn starch, 21.12 kg of modified starch, 6.60 kg of finely ground drospirenone, 0.066 kg of finely ground ethinyl estradiol and 105.974 kg of lactose monohydrate in the fluidized bed granulator and activating the fluidized bed. An aqueous solution of 8.80 kg of polyvinylpyrrolidone 25000 in 46.20 kg of purified water was continuously sprayed onto the fluidized bed during drying, heating the air flow of the fluidized bed. At the end of the process, 1.76 kg of magnesium stearate was sucked into the granulator and mixed with the granules, maintaining a fluidized bed. The resulting granulate was pressed into tablet cores by compression using a rotary tablet press.

2.22464 kg of hydroxypropyl methylcellulose and 0.44528 kg of macrogol 6000 were dissolved in 14.67 kg of purified water, 0.44528 kg of talc, 1.22430 kg of titanium dioxide and 0.06050 kg of iron oxide pigment were suspended in 10.26 kg of purified water with mixing and homogenization. The solution and suspension were combined and used to coat the tablet cores by continuously applying the coating suspension in a coating machine.

Example 2

Dissolution of drospirenone from tablets

The dissolution rate of drospirenone from the tablets obtained in Example 1 was determined using the XXIII blade method described in the U.S. Pharmacopeia using the U.S. Pharmacopeia solution dissolution device 2, including 6 closed glass vessels and 6 blades. The tablets were placed in 900 ml of water at 37 ° C (± 0.5 ° C) and stirred at 50 rpm.

The results are presented in figures 1, 2 and 4. From figure 1 it is clear that the party, designated as V8 and containing macrocrystalline drospirenone (but in other respects identical to the tablets obtained in example 1), had an extremely low dissolution rate of drospirenone, while while all batches containing finely divided drospirenone had a dissolution rate of more than 70% for 30 minutes.

Figures 2 and 4 present the results of dissolution of drospirenone from tablet cores and film-coated tablets, respectively. In most cases, more than 70% of the active agent dissolved in 30 minutes. Thus, the film coating did not significantly affect the dissolution rate.

Example 3

The rate of dissolution of ethinyl estradiol from tablets in vitro

The dissolution rate of ethinyl estradiol from tablets prepared in accordance with the description given in Example 1 was determined using the blade method described in the US Pharmacopoeia in accordance with the description given in Example 2 for drospirenone. The results are presented in FIGS. 3 and 5, showing the dissolution rates of tablet cores and film-coated tablets, respectively. In both cases, more than 70% of the active agent was dissolved within 30 minutes. Thus, the film coating did not significantly affect the dissolution rate.

Example 4

Bioavailability of drospirenone and ethinyl estradiol from tablets containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol

An open, cross-sectional study involved 42 healthy women aged 18 to 35 years after receiving their written consent. The aim of the study was to determine the relative bioavailability of drospirenone and ethinyl estradiol from a tablet containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, compared with an oral suspension containing 6 mg of drospirenone and 0.06 mg of ethinyl estradiol per vial.

Bioavailability was determined using the concentration in serum of each active agent as parameters. Compared to the oral suspension, the relative availability of drospirenone and ethinyl estradiol from tablets was 107 and 117%, respectively. Therefore, it was concluded that both drospirenone and ethinyl estradiol are completely released from tablets in vivo.

The absolute bioavailability of drospirenone, determined as a result of two studies, was 76 ± 13% after oral administration of 2 mg of drospirenone to 8 healthy young women, and 85 ± 24% after oral administration of a microcrystalline suspension containing 3.13 mg of drospirenone to 6 postmenopausal women period.

The oral bioavailability of ethinyl estradiol was determined by the results of several studies, the obtained average values ranging from 36 to 59%, published in the reports, indicated that the effect was achieved after the first dose.

Example 5

Contraceptive efficacy of formulations containing drospirenone and ethinyl estradiol

An open, randomized trial in which 52 female volunteers aged 20-35 years took part, giving written consent, included 1 pretreatment cycle, 3 main cycles with two different tablets containing 2 and 3 mg of drospirenone, respectively, but other respects corresponding to the tablets obtained in example 1, as well as the phase of subsequent medical supervision. The treatment was preceded by a washout phase of 1 month.

At certain time intervals, the selected central and peripheral parameters were determined: LH (luteinizing hormone), FSH (follicle-stimulating hormone), 17β-estradiol, progesterone, cervical index, mucus crystallization, fern phenomenon. Ovarian function was checked by ultrasound. In addition, SHBG, CBG (corticosteroid-binding globulin), prolactin, total testosterone, androstenedione, DHEA-S and selected metabolic parameters (serum glucose, triglyceride, cholesterol, LVM, LDL) were determined. Blood pressure, heart rate, body weight, and cycle control were recorded.

The results of the study showed that both LH and FSH were clearly suppressed by both of the studied drugs. Accordingly, during all three treatment cycles, the secretion of estradiol and progesterone decreased significantly, with the exception of 3 volunteers who received a drug containing 2 mg of drospirenone. The result obtained, in principle, was confirmed by additional ultrasound studies. Follicle maturation occurred in several cases when taking both of the studied drugs. Despite the fact that when taking a drug containing 2 mg of drospirenone, three cases of ovulation were diagnosed (one of which was described as “ambiguous,” and the other as “mistake when taking the pill”), there was no statistical difference (p> 0 , 05) between the two studied drugs in relation to the hormones LH, FSH, estradiol and progesterone, as well as the parameter "ovulation during treatment cycles." Supported by hormones, cervical function was greatly reduced, the cervical index ("spinnbarkeit") and crystallizability of cervical mucus were also greatly reduced as a result of taking both of the studied drugs. Prolactin increased minimally and SHBg and CBg increased for both drugs. The amount of triglycerides and HDL levels with both drugs increased, while LDL levels decreased. The total cholesterol content remained mostly unchanged in both study groups. Tolerance to oral glucose remained essentially unchanged or slightly decreased. The content of testosterone, androstenedione and DHEA-S decreased minimally.

Subjective and objective tolerance were good in both groups. This was also the case with cycle control, with the exception of the first cycle when taking 2 mg of drospirenone. Blood pressure, heart rate and body weight in most cases remained constant or showed a slight tendency to decrease.

After three months of admission, conclusions were drawn that:

both studied drugs are equally good with respect to subjective and objective tolerance;

when using both drugs, no negative metabolic phenomena were observed. HDL experienced a positive effect in terms of increase.

The results confirmed the results of earlier studies that 2 mg of the drug drospirenone is in the threshold region of inhibition of ovulation, while 3 mg of the drug drospirenone has a pronounced effect on the inhibition of ovulation in all studied cases.

Claims (34)

1. A pharmaceutical composition in the form of an oral dosage form intended to inhibit ovulation in mammals and / or treat acne in female mammals, containing, as the first active agent, drospirenone in an amount corresponding to a daily dose when the composition is administered and is from about 2 to 4 mg, and as the second active agent, ethinyl estradiol in an amount corresponding to a daily dose of from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers and whether additives, while the specified drospirenone has a surface area of particles of more than 10000 cm ² / g 2. A pharmaceutical composition in the form of an oral dosage form for inhibiting ovulation in mammals and / or treating acne in female mammals, containing, as a first active agent, drospirenone in an amount corresponding to a daily dose when the composition is administered and is from about 2 to 4 mg, and as the second active agent, ethinyl estradiol in an amount corresponding to a daily dose of about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers and whether additives, while the specified drospirenone is in finely ground form. 3. A pharmaceutical composition in the form of an oral dosage form intended to inhibit ovulation in mammals and / or treat acne in female mammals, containing, as a first active agent, drospirenone in an amount corresponding to a daily dose when the composition is administered and is from about 2 to 4 mg, and as the second active agent, ethinyl estradiol in an amount corresponding to a daily dose of from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers of silt and additives, wherein at least 70% of drospirenone is dissolved from the composition within 30 minutes, as determined in accordance with the blade method II described in US Pharmacopoeia XXIII using water as a medium for dissolving at 37 ° C. and at a stirring speed of 50 rpm 4. The composition according to any one of claim 1 or 3, where drospirenone is in finely divided form or sprayed from a drospirenone solution onto particles of an inert carrier. 5. The composition according to any one of claims 1, 2 or 3, in which ethinyl estradiol is in finely divided form or sprayed from solution onto particles of an inert carrier. 6. The composition according to any one of claims 1 to 3, where one or more pharmaceutically acceptable carriers is sugar, sugar alcohol and / or starch, wherein sugar is selected from the group comprising lactose, glucose and sucrose, sugar alcohol is selected from the group consisting of mannitol , sorbitol and xylitol, and starch is selected from the group consisting of wheat, corn or potato starch, modified starch and sodium starch glycolate. 7. The composition according to any one of claims 1 to 3, in which one or more pharmaceutically acceptable carriers are selected from the group consisting of polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose and gelatin. 8. The composition according to any one of claims 1 to 3, containing drospirenone in an amount corresponding to a daily dose of from about 3.0 to 3.5 mg, and ethinyl estradiol in an amount corresponding to from about 0.015 to 0.03 mg. 9. The composition according to any one of claims 1, 2 and 3, in the form of tablets, pills or capsules. 10. A pharmaceutical product designed to inhibit ovulation in mammals and / or treat acne in female mammals, comprising a number of individually packaged and individually extractable daily dosage doses placed in a single package and intended for oral administration for at least 21 consecutive days, with this indicated daily dosage doses contain a combination of drospirenone in an amount of from about 2 to about 4 mg and ethinyl estradiol in an amount of from about 0.01 to about 0.05 m Together with one or more pharmaceutically acceptable carriers or additives, wherein said drospirenone has a particle surface area more than 10,000 cm ² / g. 11. A pharmaceutical preparation intended to inhibit ovulation in mammals and / or treat acne in female mammals, comprising a series of individually packaged and individually extractable daily dosage doses placed in a single package and intended for oral administration for at least 21 consecutive days, with this indicated daily dosage doses contain a combination of drospirenone in an amount of from about 2 to about 4 mg and ethinyl estradiol in an amount of from about 0.01 to about 0.05 m Together with one or more pharmaceutically acceptable carriers or additives, wherein said drospirenone is in micronized form. 12. A pharmaceutical product designed to inhibit ovulation in mammals and / or treat acne in female mammals, comprising a series of individually packaged and individually extractable daily dosage doses placed in a single package and intended for oral administration for at least 21 consecutive days, with this indicated daily dosage doses contain a combination of drospirenone in an amount of from about 2 to about 4 mg and ethinyl estradiol in an amount of from about 0.01 to about 0.05 m , together with one or more pharmaceutically acceptable carriers or additives, wherein at least 70% of drospirenone is dissolved from the composition within 30 minutes, as determined in accordance with USP XXIII paddle method II using water as a dissolution medium at 37 ° C and at a stirring speed of 50 rpm 13. The drug according to any one of claim 10 or 12, where drospirenone is in finely divided form or sprayed from a drospirenone solution onto particles of an inert carrier. 14. The drug according to any one of claim 10 or 12, in which ethinyl estradiol is in micronized form or sprayed from solution onto particles of an inert carrier. 15. The drug according to any one of paragraphs.10-12, further comprising 7 or less daily dosage doses containing no active agent, intended for oral administration after a period of at least 21 consecutive days, while the total number of daily dosage doses is at least 28. 16. The drug according to any one of paragraphs.10-12, in which the number of daily dosage doses, including a combination of drospirenone and ethinyl estradiol, is 21, 22, 23 or 24, and in which the number of daily dosage doses not containing an active agent is 7, 6 5 or 4. 17. The drug according to any one of paragraphs.10-12, in which the number of daily dosage doses, including a combination of drospirenone and ethinyl estradiol, is 28 or a multiple of 28. 18. The drug according to 17, where the number multiple of 28 daily dosage doses is 2-4 times. 19. The drug according to any one of paragraphs.10-12, additionally including the number of daily dosage doses containing a combination of drospirenone and ethinyl estradiol equal to 21, 22, 23 or 24, and the number of daily dosage doses not containing an active agent equal to 7, 6, 5 or 4. 20. The drug according to any one of paragraphs.10-12, intended for oral administration for at least 28 consecutive days, in which at least 21 of these daily dosage doses contain a combination of drospirenone in an amount of from about 2 to 4 mg, and ethinyl estradiol in an amount of from about 0.01 to about 0.05 mg, and in which 7 or less of the indicated daily dosage doses contains only ethinyl estradiol in an amount of from about 0.01 to 0.05 mg. 21. The drug according to claim 19, in which the number of daily dosage doses containing a combination of drospirenone and ethinyl estradiol is 21, 22, 23, or 24, and the number of daily dosage doses containing only ethinyl estradiol is 7, 6, 5, or 4. 22. The drug according to any one of paragraphs.10-12, in which the number of daily dosage doses, including a combination of ethinyl estradiol and drospirenone, used for oral administration is 2 or 3 times for a period of 28 days in a row, followed by a combination of ethinyl estradiol and drospirenone for 21, 22, 23, or 24 consecutive days and subsequently by administering a daily dosage dose that does not contain an active agent or without administering daily dosage doses for 7, 6, 5, or 4 consecutive days. 23. The drug according to any one of paragraphs.10-12, where the daily dosage is in the form of tablets, pills or capsules. 24. The use of drospirenone in combination with ethinyl estradiol for the preparation of a pharmaceutical composition intended to inhibit ovulation in mammals, the composition being intended for oral administration and includes drospirenone in an amount corresponding to a daily dose of the composition and comprising from about 2 to 4 mg, and also includes ethinyl estradiol in an amount corresponding to a daily dose of the composition and comprising from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable ositelyami or additives, wherein also said drospirenone has a surface area of more than 10,000 particles cm ² / g. 25. The use of drospirenone in combination with ethinyl estradiol to obtain a pharmaceutical composition intended for the inhibition of ovulation in mammals, the composition is intended for oral administration and includes drospirenone in an amount corresponding to a daily dose of the composition and comprising from about 2 to 4 mg, and also includes ethinyl estradiol in an amount corresponding to a daily dose of the composition and comprising from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, while also said drospirenone is in finely divided form. 26. The use of drospirenone in combination with ethinyl estradiol to obtain a pharmaceutical composition intended for the inhibition of ovulation in mammals, the composition is intended for oral administration and includes drospirenone in an amount corresponding to a daily dose of the composition, comprising from about 2 to 4 mg, and also includes ethinyl estradiol in an amount corresponding to a daily dose of a composition comprising from about 0.01 to 0.05 mg together with one or more pharmaceutically acceptable noses iteli or additives, while at least 70% of drospirenone is dissolved from the composition within 30 minutes, as determined in accordance with the blade method II described in the US Pharmacopoeia XXIII using water as a medium for dissolving at 37 ° C and at a stirring speed 50 rpm 27. The use according to any one of paragraphs.24-26, for the treatment of acne. 28. The use according to any one of paragraphs.24-26, where drospirenone is in finely divided form or sprayed from solution onto particles of an inert carrier. 29. The use according to any one of paragraphs.24-26, where the amount of drospirenone corresponds to a daily dose of about 2.5 to 3.5 mg. 30. The use according to any one of paragraphs.24 or 26, where the amount of ethinyl estradiol corresponds to a daily dose of from about 0.015 to 0.03 mg. 31. The use according to any one of paragraphs.24-26, where ethinyl estradiol is in micronized form or sprayed from solution onto particles of an inert carrier. 32. The use according to any one of paragraphs.24-26, where the dissolution of ethinyl estradiol occurs in such a way that at least 70% is dissolved within 30 minutes, as determined in accordance with described in US Pharmacopoeia XXIII blade method II using as a medium for dissolving water at 37 ° C and at a stirring speed of 50 rpm 33. The use according to any one of paragraphs.24-26, where the oral administration is carried out in the form of tablets, capsules or pills. 34. The use according to any one of paragraphs.24-26, where the mammal is a female.

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