Pharmaceutical combination of ethinylestradiol and drospirenone uses as contraceptive

FIELD: medicine, pharmaceutics.

SUBSTANCE: as a first active agent a pharmaceutical composition contains drospirenone in the amount equal to a daily dose when administering the composition and making 2 to 4 mg, and as a second active agent - ethinylestradiol in the amount equal to a daily dose and making 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives. Drospirenone as a part of the pharmaceutical composition has a particle surface area more than 10000 cm2/g. Preferentially, drospirenone is fine-grained or sprayed from a drospirenone solution by inert carrier particles. The preparation contains a number of separately packed and individually taken daily dosage units in a single package used for oral administration for at least 21 days running with said daily dosage units containing a combination of drospirenone and ethinylestradiol. The preparation may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: combination of drospirenone and ethinylestradiol provides reliable contraceptive activity ensured by the use of a maximum dose of drospirenone which causes no side effects, particularly, excess diuresis.

29 cl, 5 dwg

 

The technical field

The present invention relates to a pharmaceutical composition comprising drospirenone and ethinyl estradiol, the method of obtaining the solution of drospirenone, methods of inhibiting ovulation by injection of drospirenone, as well as to the use of drospirenone and ethinyl estradiol for the inhibition of ovulation.

Background of the invention

Oral contraceptives contain a combination of components such as the gestagen and estrogen, is used with the 1960s, The earliest contraceptives included 21 tablet containing a combination of active agents, and 7 pills containing no active agent, and the amount of each active agent in each tablet was the same (so-called "single-phase drugs"). Were subsequently developed drugs, including pills containing various amounts and ratios of active agents in the cycle of administration (the so-called "multiphase drugs").

The reliability of the contraceptive mainly provides such a component as a gestagen. Daily intake should be at least the minimum dose required to apply gestagen effectively inhibited ovulation. Estrogen promotes the action of progestogen to suppress ovulation and stability of the loop. With time and the advent of oral contraceptives daily dose of progestogen decreased due to the development of new and more effective progestogen, than those used in earlier contraceptive drugs. It has also become possible to reduce the daily dose of estrogen.

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

In DE 3022337 described gestagenna activity of the compound and its use as a contraceptive agent in a dose comprising from 0.5 to 50 mg of drospirenone in the day. Also indicated that the mechanism of action of compounds very similar to the mechanism of action of the natural hormone luteum, progesterone, and that it does not cause high blood pressure, so it can be taken by women with high blood pressure or potential hypertensive patients. Further shown that drospirenone may be introduced together with ethinyl estradiol in number, amounting to 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 at a dose which accounts for 0.5-50 mg per day.

EP 398460 describes the use of drospirenone for the treatment of disorders induced by androgens, aldosterone, and hormonal disorders, as well as for contraception in a dose comprising from 0.5 to 50 mg, preferably 1-10 mg 3 day. It may be entered levonorgestrel in a dose of, for example the soup of 0.02-0.04 mg per day.

US 5756490 describes the preparations pharmaceutical combinations 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 gestagenna connection and levonorgestrel mentioned as a possible, but not preferred estrogenic compound.

Brief description of the invention

In the course of research that led to the present invention, it was unexpectedly found that for reliable contraceptive activity requires not installed still minimal dose of drospirenone. In this way was established preferred maximum dose, which essentially can be prevented unpleasant side effects, in particular excessive diuresis.

Accordingly, according to the first aspect of the present invention relates to pharmaceutical compositions comprising as a first active agent 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-Carrollton (drospirenone) in an amount corresponding to a daily dose after injection of the composition in 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 comprising 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, provided that, in accordance with the present invention can be used ester or prodrug of drospirenone, for example, accionemprendedora.com described in WO 98/24801. In this way it is envisaged that the composition may be included complex or simple esters, ethinyl estradiol.

In accordance with the following aspect of this invention relates to a method of inhibiting ovulation in a mammal, in particular humans, including the introduction of a given mammal of drospirenone in an amount constituting from about 2 to about 4 mg per day, together with ethinyl estradiol in amounts of about 0.01 to about 0.05 mg per day, the number of effectively inhibit ovulation in the specified mammal.

In accordance with another aspect of this invention relates to the use of drospirenone in combination with ethinyl estradiol to obtain a pharmaceutical preparation intended for inhibiting ovulation in a mammal, in particular humans, the composition includes an amount of drospirenone, corresponding to a daily dose after administration of the composition comprising from about 2 to about 4 mg, and ethinyl estradiol, corresponding to a daily dose after administration of the composition, for example the soup from about 0.01 to about 0.05 mg

Brief description of drawings

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

Figure 1 is a graphical depiction of the rate of dissolution of drospirenone in vitro from the nuclei of tablets, while V1-V7 mean party containing fine drospirenone and V8 means the party, containing microcrystalline drospirenone;

Figure 2 is a graphical depiction of the rate of dissolution of drospirenone in vitro from the nuclei of tablets, with different lines represent different analytical batch;

Figure 3 is a graphical depiction of the rate of dissolution of drospirenone in vitro from film-coated tablets, with different lines represent different analytical batch;

4 is a graphical depiction of the dissolution rate of ethinyl estradiol in vitro from the nuclei of tablets, with different lines represent different analytical batch; and

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

Detailed description of the invention

Drospirenone, which can be essentially obtained, mainly, as described, for example, in US 4129564 or in WO 98/06738, is a moderately soluble in water and aqueous buffers substance at different pH values. Moreover, drospirenone PE groupprovides in the inactive isomer in acidic conditions and hydrolyzed under alkaline conditions. Therefore, in order to provide a high bioavailability of the compounds, it is advisable to apply it in the form of contributing to its rapid dissolution.

It was unexpectedly discovered that if the drospirenone in the form of pharmaceutical compositions connoissance (so that the particles of the active substance have a surface area of more than 10000 cm2/g and the following distribution of particle sizes, determined under the microscope: not more than 2 particles in a party with a diameter greater than 30 μm, preferably ≤20 particles with a diameter amounting to ≥10 mm and ≤30 μm), the rapid dissolution of the active compounds of the composition occurs in vitro ("rapid dissolution" means the dissolution of at least 70% within about 30 minutes, in particular at least 80% within about 20 minutes of tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37°C, determined by means described in the USP XXIII paddle method with the use described in the US Pharmacopoeia of the device for determining dissolution 2 at 50 rpm). Instead of the fine grinding of drospirenone can be dissolved in a suitable solvent, for example methanol or ethyl acetate, and spraying it on the surface of the particles of inert carrier, followed by the introduction of particles containing on their surface, drospirenon is, in composition.

Without limitation to any specific theory, it appears that the rate of dissolution of drospirenone in vitro is associated with a dissolution rate in vitro, leading to a rapid absorption of drospirenone in vitro and after oral administration of the compounds. This is an advantage because the isomerization of the compounds in the gastric environment and/or hydrolysis in the intestine significantly below that provides high bioavailability of the compounds.

As for ethinyl estradiol, which is also moderately soluble substance, though less susceptible to decay than drospirenone, in the conditions prevailing in the gastrointestinal tract, also its application in micronized form or spraying from solution, for example, in ethanol, on the surface of the particles of inert carrier. This provides the additional advantage of facilitating a more uniform distribution of ethinyl estradiol in the composition, which otherwise would be difficult to implement because of levonorgestrel administered in extremely small quantities. If levonorgestrel is in microselectron, it preferably has the following particle size distributions determined under the microscope: 100% of particles have a diameter of ≤15,0 µm, 99% of particles ≤12.5 μm, 95% of particles ≤10,0 µm and 50% of particles ≤3,0 µm. More tor the, there are no particles larger than 20 microns, and ≤10 particles have a diameter of ≥15 µm and ≤20 ám.

In order to get a higher dissolution rate, preferably enabling carriers or additives promoting dissolution of both active substances. Examples of such carriers and excipients include substances which are readily soluble in water, such as derivatives of cellulose, carboxymethylcellulose, hydroxypropylcellulose, hypromellose, gelatinizing starch, gelatin or polyvinylpyrrolidone. In particular, it appears that the polyvinylpyrrolidone is particularly helps dissolve.

The composition in accordance with this invention preferably includes drospirenone in amounts corresponding to a daily dose comprising from about 2.5 to 3.5 mg, in particular about 3 mg. Number ethinyl estradiol preferably corresponds to a daily dose comprising from about of 0.015 to about 0.04 mg, particularly from about 0.015 mg to about 0,03 mg More specifically, the composition includes an amount of drospirenone, corresponding to a daily dose comprising from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 g to about 0,03 mg

It was found that in addition to its ability to inhibit ovulation composition according to data from what rutenium has pronounced protivoallergennymi properties and therefore can be used for prevention or treatment-induced androgen disorders, in particular acne. Such application may be independent or related to its above-mentioned use as a contraceptive. Moreover, since the drospirenone is an antagonist of aldosterone, it has diuretic properties and is therefore suitable for combating properties of levonorgestrel on water retention.

In accordance with a specific option for its implementation the invention relates to a pharmaceutical preparation consisting of a number of separately Packed and individually recoverable daily dosage units placed in a single package and intended for oral administration for at least 21 days in a row, in which each of the said daily dosage units includes a combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg

In accordance with one variant of implementation of the drug further includes 7 and less of the daily dosage units containing no active agent. Alternatively, the regimen of the drug may include a period of 7 days or less, does not require taking the medicine. However, to comply with the scheme appropriate to include in the package corresponding to the number of dummies, this is the case of the total number of daily dosage units of the drug will be at least 28. The inclusion of dummies or free from drug days then will cause renewed bleeding.

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

In suitable embodiments, the implementation of this drug, the number of daily dosage units comprising the combination of drospirenone and ethinyl estradiol, may be 21, 22, 23 or 24, and the number of daily dosage units containing no active agent, may be 7, 6, 5 or 4, respectively. In accordance with another embodiment of this drug, the number of daily dosage units comprising the combination of drospirenone and ethinyl estradiol is 28 or a multiple of 28, for example, 2 to 4, in particular 2 or 3 times by 28.

In accordance with Iternational option for its implementation the invention relates to a contraceptive drug, comprising a number of separately Packed and individually recoverable daily dosage units placed in a single package and intended for oral administration for at least 28 consecutive days in which at least 21 indicated daily dosage unit includes a combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, and in which 7 and less of the daily dosage units contain only ethinylestradiol in an amount of approximately from about 0.01 to about 0.05 mg.

The inclusion of a suitable amount of dosage units containing only levonorgestrel can provide high contraceptive reliability, low follicular development and satisfactory control of the cycle with minor bleeding between menstrual periods or lack of it.

In this case, the amount of each active agent in the drug may also remain constant throughout at least a 21-day period (two-phase preparation) or the number of one or both active agents can vary over at least a 21-day period, forming a multiphase product, for example, three - or four-drug, essentially described, p is the iMER, in EP 148724. Upon receipt of multiphase drug instead of ethinyl estradiol may be included natural estrogen, such as estradiol, for example, in an amount constituting from about 0.5 to about 4 mg per day.

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

In accordance with one possible implementation of the method of inhibiting ovulation this method includes the introduction of the specified mammal each day of at least 21 consecutive days of daily drug doses, comprising the combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, with subsequent introduction of every day of the 7 days in a row daily dosage units containing no active agent or, on the contrary, the absence of the administration of medical units within 7 days or less.

In suitable embodiments, the implementation of this method daily dosage units comprising the combination of drospirenone and ethinyl estradiol, can be entered for 21, 22, 23 or 24 consecutive days, and daily the dosage unit, not containing the active agent can then be introduced for 7, 6, 5 or 4 days in a row, respectively. Moreover, daily doses of medicines, which includes a combination of drospirenone and ethinyl estradiol, can be entered within 28 days. In accordance with one variant of this implementation method daily dosage units comprising the combination of drospirenone and ethinyl estradiol, administered for 2-4, preferably 2 or 3 times for 28 consecutive days, followed by the introduction of daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21, 22, 23 or 24 consecutive days, and then the introduction of daily dosage units containing no active agent, or the absence of the introduction of daily dosage units for 7, 6, 5 or 4 days in a row.

Alternatively, this method includes the introduction of every day of at least 21 consecutive days of daily drug doses, which includes a combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, with subsequent introduction of each day from the 7 days or less consecutive daily doses of medicines containing only ethinylestradiol in an amount of about 0.01 to about 0.05 mg

In accordance with this alternative way daily is karstenia dose containing a combination of drospirenone and ethinyl estradiol, can be appropriately entered for 21, 22, 23 or 24 consecutive days, and daily doses of medicines, including only levonorgestrel, can then be inserted within 7, 6, 5 or 4 days in a row, respectively. In accordance with the following embodiment of this method daily doses of medicines, containing a combination of drospirenone and ethinyl estradiol, administered for 2-4, preferably 2 or 3 times, for 28 consecutive days, followed by the introduction of daily drug doses, comprising the combination of drospirenone and ethinyl estradiol for 21 days in a row, and then the introduction of daily drug doses, only consists of ethinyl estradiol for 7 days in a row.

When used in accordance with this invention the pharmaceutical preparation may be in the form of a number of separately Packed and individually-to-find daily dosage units placed in a single package and intended for oral administration for at least 21 consecutive days, with each of the said daily dosage units includes a combination of drospirenone in an amount constituting from about 2 mg to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg

As indicated above, the package may also include 7 eliminee daily dosage units, not containing an active agent (or may contain 7 or less empty "places", for example, in the form of empty cells in the exhaust packing, marking the day that happens the introduction of daily drug doses).

Alternatively, the pharmaceutical preparation may be in the form of a number of separately Packed and individually recoverable daily dosage units placed in a single package and intended for oral administration for at least 28 consecutive days in which at least 21 indicated daily dosage unit includes a combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, with the specified single package additionally includes 7 or less daily dosage doses containing only levonorgestrel in number of 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 may be obtained by a method comprising the presence of drospirenone and, if desired, ethinyl estradiol in micronized form in a specified dosage form or sprayed from a solution onto particles of an inert carrier in a mixture with one and the multiple pharmaceutically acceptable additives, contributing to the dissolution of drospirenone and ethinyl estradiol in such a way as to ensure rapid dissolution of drospirenone, and preferably ethinyl estradiol after oral administration. 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 glycolate, starch, and lubricating agents such as talc, magnesium stearate, calcium stearate, colloidal silicon dioxide or stearic acid, as well as binders, such as polyvinylpyrrolidone, cellulose derivatives, carboxymethylcellulose, hydroxypropylcellulose, hypromellose, methylcellulose or gelatin, to receive oral dosage forms such as tablets, pills or the capsule.

The tablets may optionally be coated with a suitable film-forming agent, such as hypromellose, hydroxypropylcellulose or ethylcellulose, to which may be added optional suitable additive, for example, a softener, such as glycerin, propylene glycol, diethylphthalate or createtemporary, filler, such as sucrose, sorbitol, xylitol, glucose or lactose, a dye, such as hydro is led titanium, etc.

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

A single package containing the above daily doses of medicines can be obtained in a manner analogous to the method of obtaining other contraceptives for oral use. This can be, for example, conventional blister packaging or any other packaging suitable for this purpose, for example, a package containing the right amount of dosage units (in this case, at least 21, or, for special occasions, or a multiple of 28 28) in a sealed blister pack with a basis of cardboard, paper, foil or plastic, coated with a suitable coating. Each cell in the blister package may be numbered or marked in some other way, for example, starting with the first of at least 21 drug dose containing a combination of drospirenone and ethinyl estradiol, followed by 7 or less empty cells or 7 and less than therapeutic doses that do not contain an active agent or containing only ethinylestradiol (although the numbering may begin with the first of 7 and less medicinal doses, containing only ethinylestradiol).

Also provides the W this composition may be in the form of a composition for parenteral administration, such as subcutaneous implant or transdermal composition. To get implants active agents may be suitably connected to one or more polymers that are using gradually corroded or dissolved, for example, silicone polymers; ethylene vinyl acetate, polyethylene or polypropylene.

As for the transdermal compositions, they can be obtained in the form of matrices or membranes or in the form of liquid or viscous compositions in oil or hydrogels. When getting transdermal patches you want to apply an adhesive compatible with the skin, such as polyacrylate, silicone adhesive or polyisobutylene, and the film made, for example, polyethylene, polypropylene, ethylene vinyl acetate, polyvinyl chloride, polyvinylidenechloride or polyester, and a removable protective film, e.g. made from polyester or coated with silicone or a fluoropolymer. To obtain a transdermal solutions or gels can be used in water or organic solvents, or a mixture thereof. Transdermal gels can optionally contain one or more suitable gelling agents or thickeners, such as silicone, tragakant, starch or its derivatives, cellulose is whether its derivatives, either polyacrylic acid or its derivatives. Transdermal formulations may also respectively include one or more substances, amplifiers, absorption through the skin, such as salts of bile acids or their derivatives, and/or phospholipids. Suitable transdermal compositions can, for example, be obtained in a manner analogous to the method described in WO 94/04157 3-ketodesogestrel. Alternatively, the transdermal compositions can be obtained in accordance with the method described, for example, Barry BW, "Dermatological Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York - Basel, 1983, or Chien YW, "Transdermal Controlled Systemic Medications", Marcel Dekker Inc., New York - Basel, 1987.

The present invention is further described in the following examples in no way limit the invention as it is claimed.

EXPERIMENTAL PART

Example 1

Obtaining tablets containing drospirenone and ethinyl estradiol

Received core tablets having the following composition:

fine drospirenone3,00 mg
fine ethinyl estradiol0.03 mg
the lactose monohydrate48,17 mg
corn starch14,40 is g
modified starch9,60 mg
polyvinylpyrrolidone 250004,00 mg
magnesium stearate0,80 mg

loading into the granulator fluidized bed 31,68 kg of corn starch, 21,12 kg of modified starch, 6,60 kg of micronized drospirenone, 0.066 kg of finely ethinyl estradiol and 105,974 kg of lactose monohydrate and activating a fluidized bed. An aqueous solution 8,80 kg polyvinylpyrrolidone 25,000 in 46,20 kg of purified water was continuously sprayed on the fluidized bed during the drying, heating a stream of air fluidized bed. At the end of the process 1,76 kg of magnesium stearate were sucked into the granulator and mixed with the granules, maintaining a fluidized bed. The obtained granulate is extruded in the kernel for tablets by pressing using a rotary tablet press.

2,22464 kg hydroxypropylmethylcellulose 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 pigment iron oxide suspended in 10,26 kg of purified water with stirring and homogenization. Solution and suspension were combined and used to cover the core tablets by continuous coating suspension for pok is itia in a machine for coating.

Example 2

Dissolution of drospirenone tablets

The rate of dissolution of drospirenone tablets obtained in example 1 was determined by means described in the USP XXIII paddle method with the use described in the US Pharmacopoeia of the device for determining dissolution 2, including 6 closed glass vessels and 6 blades. Tablets were placed in 900 ml 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 microcrystalline drospirenone (but in other respects identical to the tablets obtained in example 1)had a very low rate of dissolution of drospirenone, while all the batches of fine drospirenone had a dissolution rate, making more than 70% within 30 minutes.

2 and 4 represent the results of the dissolution of drospirenone from the nuclei of tablets and film-coated tablets, respectively. In most cases, more than 70% of the active agent is dissolved within 30 minutes. Thus, the film coating had no significant effect on the rate of dissolution.

Example 3

The dissolution rate of ethinyl estradiol tablets in vitro

The dissolution rate of ethinyl estradiol tablets obtained in accordance with the description, privedennym example 1 was determined by means described in the USP paddle method in accordance with the description given in example 2 for drospirenone. The results are presented in figure 3 and 5, showing the dissolution rate of the core tablets and film-coated tablets, respectively. In both cases, more than 70% of the active agent is dissolved within 30 minutes. Thus, the film coating had no significant effect on the rate of dissolution.

Example 4

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

In an open, crossover study involved 42 healthy women aged 18 to 35 years after obtaining their written consent. The aim of the study was to determine the relative bioavailability of drospirenone and ethinyl estradiol from tablets containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, compared with the oral suspension containing 6 mg of drospirenone and 0.06 mg of ethinyl estradiol per vial.

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

The absolute bioavailability of drospirenone defined in the two studies, was 76±13% after oral administration of 2 mg of drospirenone 8 young healthy women, and 85±24% after oral administration microcrystalline suspension containing 3,13 mg of drospirenone, 6 women in postmenopausal period.

Oral bioavailability of ethinyl estradiol were determined by the results of several studies averages, components from 36 to 59%, as published in the report, testified to the effect after the first dose.

Example 5

Contraceptive efficacy of compositions containing drospirenone and ethinyl estradiol

Open, randomized trial, which was attended by 52 women volunteers aged 20-35, who gave written consent were included 1 cycle pre-treatment, 3 of the main loop with the reception of two different tablets containing 2 and 3 mg of drospirenone, respectively, but in other respects corresponding to the tablets obtained in example 1, and phase clinical follow-up. The treatment was preceded by a washout phase, comprising 1 month.

After a certain period of time was determined by selected Central and peripheral parameters: LH (luteinizing hormone), FSH (folliculotropic the Mering hormone), 17β-estradiol, progesterone, cervical indicator, crystallization mucus ferning. The ovaries were examined by ultrasound. In addition, it was determined SHBG, CBG (corticosteroidresponsive globulin), prolactin, total testosterone, Androstenedione, DHEA-S and selected metabolic parameters (serum glucose, triglyceride, cholesterol, LVM, LDL). Recorded indicators of blood pressure, heart rate, body mass and control cycle.

The results showed that both LH and FSH are clearly suppressed in both of the studied drugs. Accordingly, during all three cycles of treatment, the secretion of estradiol and progesterone strongly decreased with the exception of 3 volunteers treated with a preparation containing 2 mg of drospirenone. The result, in principle, was confirmed by the additional ultrasonic research. The maturation of the follicle occurred in a few cases when receiving both of the studied drugs. Despite the fact that taking the drug containing 2 mg of drospirenone, was diagnosed three cases of ovulation (one of which was described as "ambiguous"and the other as "error while taking the pill"), has not been established statistical difference (p>0,05) between the two studied drugs in the hormones LH, FSH, estradiol and prog is sterone, as well as setting ovulation while loops". Supported by hormones, cervical function was severely reduced, cervical index ("spinnbarkeit") and crystallochemistry cervical mucus also strongly reduced as a result of taking both of the studied drugs. Prolactin increased minimally and SHBg and CBg were increased for both drugs. The amount of triglycerides and HDL when receiving both drugs increased, while LDL was decreased. Total cholesterol remained largely unchanged in both groups studied. Tolerance to accept oral glucose remained essentially unchanged or slightly decreased. The content of testosterone, Androstenedione and DHEA-S decreased minimally.

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

After three months of receiving the findings that:

Both the investigational product are equally good in regard to subjective and objective tolerance.

When using both drugs was observed adverse metabolic the definition of the phenomena. HDL experienced a positive effect in terms of improvement.

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

1. Pharmaceutical composition in the form of oral dosage forms intended for inhibiting ovulation in a mammal and/or treatment of acne in female mammals, comprising as a first active agent drospirenone in amounts corresponding to a daily dose with the introduction of the composition and comprising from about 2 to 4 mg, and as a second active agent ethinylestradiol in an amount corresponding to a daily dosage of from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, with the specified drospirenone has a surface area of more than 10,000 particles cm2/year

2. Pharmaceutical composition in the form of oral dosage forms intended for inhibiting ovulation in a mammal and/or treatment of acne in female mammals, comprising as a first active agent drospirenone in amounts corresponding to a daily dose with the introduction of the comp the positions and comprising from about 2 to 4 mg, and as a second active agent ethinylestradiol in an amount corresponding to a daily dosage of from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, at least 70% of the drospirenone dissolved from the composition within 30 min, as determined in accordance with those described in USP XXIII paddle method II using as a medium for dissolving water at 37°C and the stirring speed of 50 rpm

3. The composition according to any one of claims 1 or 2, where the drospirenone is in micronized form or sprayed from a solution of drospirenone particles of inert carrier.

4. The composition according to any one of claims 1 or 2, in which the levonorgestrel is in micronized form or sprayed from a solution onto particles of an inert carrier.

5. The composition according to any one of claims 1 or 2, where one or more pharmaceutically acceptable carriers is a sugar, sugar alcohol and/or starch, and sugar is selected from the group comprising lactose, glucose and sucrose, the sugar alcohol is selected from the group comprising mannitol, sorbitol and xylitol, and the starch is selected from the group comprising wheat, corn or potato starch, modified starch and sodium starch glycolate.

6. The composition according to any one of claims 1 or 2, in which the one or more pharmaceutically acceptable carriers selected from the group includes polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropylcellulose, hypromellose, methyl cellulose and gelatin.

7. The composition according to any one of claims 1 or 2 containing drospirenone in amounts corresponding to a daily dose of from about 3.0 to 3.5 mg and ethinylestradiol in an amount corresponding to from about of 0.015 to 0.03 mg.

8. The composition according to any one of claims 1 or 2, in the form of tablets, pills or capsules.

9. The pharmaceutical preparation intended for inhibiting ovulation in a mammal and/or treatment of acne in female mammals, including a number of separately Packed and individually recoverable daily drug doses, placed in one package and intended for oral administration for at least 21 consecutive days, the daily drug dose contain a combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, with the specified drospirenone has a surface area of more than 10,000 particles cm2/year

10. The pharmaceutical preparation intended for inhibiting ovulation in a mammal and/or treatment of acne in females of mammalian what were comprising a number of separately Packed and individually recoverable daily drug doses, placed in one package and intended for oral administration for at least 21 consecutive days, the daily drug dose contain a combination of drospirenone in an amount constituting from about 2 to about 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, at least 70% of the drospirenone dissolved from the composition within 30 min, as determined in accordance with the described in the Pharmacopoeia USA XXIII paddle method II using as a medium for dissolving water at 37°C and the stirring speed of 50 rpm

11. The drug according to any one of p or 10, where the drospirenone is in micronized form or sprayed from a solution of drospirenone particles of inert carrier.

12. The drug according to any one of p or 10, in which the levonorgestrel is in micronized form or sprayed from a solution onto particles of an inert carrier.

13. The drug according to any one of p or 10, additionally comprising 7 or less daily dosage doses that do not contain an active agent intended for oral administration after a period of at the ore 21 days in a row, the total number of daily drug doses is at least 28.

14. The drug according to any one of p or 10, in which the number of daily drug doses, comprising the combination of drospirenone and ethinyl estradiol, is 21, 22, 23 or 24 in which the number of daily drug doses that do not contain an active agent, is 7, 6, 5 or 4.

15. The drug according to any one of p or 10, in which the number of daily drug doses, comprising the combination of drospirenone and ethinyl estradiol is 28 or a multiple of 28.

16. The drug is indicated in paragraph 15, where a multiple number of 28 daily drug dose is 2-4 times.

17. The drug according to any one of p or 10, additionally including the number of daily drug doses, containing a combination of drospirenone and ethinyl estradiol, equal to 21, 22, 23 or 24, and the number of daily drug doses that do not contain an active agent, equal to 7, 6, 5 or 4.

18. The drug according to any one of p or 10, intended for oral administration for at least 28 consecutive days in which at least 21 of the daily drug dose contains a combination of drospirenone in an amount of about 2 to 4 mg and ethinylestradiol in an amount of about 0.01 to about 0.05 mg, and in which 7 and less of the daily drug dose contains only this is nilestriol in number, comprising from about 0.01 to 0.05 mg

19. The drug on 17, in which the number of daily drug doses, containing a combination of drospirenone and ethinyl estradiol, is 21, 22, 23 or 24, and the number of daily drug doses, only contains levonorgestrel, is 7, 6, 5 or 4.

20. The drug according to any one of p or 10, in which the number of daily drug doses, which includes a combination of ethinylestradiol and drospirenone used for oral administration is 2 or 3 times during the period of 28 days in a row, followed by the introduction of a combination of ethinylestradiol and drospirenone for 21, 22, 23 or 24 consecutive days and subsequently the introduction of daily drug doses that do not contain an active agent, with or without the introduction of daily drug doses for 7, 6, 5 or 4 days in a row.

21. The drug according to any one of p or 10, where the daily drug dose is a tablet, pill or capsule.

22. The use of drospirenone in combination with ethinyl estradiol to obtain pharmaceutical compositions intended for inhibiting ovulation in a mammal, the composition is intended for oral administration and comprises drospirenone in amounts corresponding to a daily dose of introducing a composition that comprises from about 2 to 4 mg, and also includes etisilat the diol in number, the corresponding daily dose of injection of the composition comprises from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, it also specified drospirenone has a surface area of more than 10,000 particles cm2/year

23. The use of drospirenone in combination with ethinyl estradiol to obtain pharmaceutical compositions intended for inhibiting ovulation in a mammal, the composition is intended for oral administration and comprises drospirenone in amounts corresponding to a daily dose of introducing a composition comprising from about 2 to 4 mg, and also includes ethinylestradiol in an amount corresponding to a daily dose of introducing a composition comprising from about 0.01 to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives, at least 70% of the drospirenone dissolved from the composition within 30 min, as determined in accordance with the procedure outlined in The USP XXIII paddle method II using as a medium for dissolving water at 37°C and the stirring speed of 50 rpm

24. The use according to any one of p or 23, where the drospirenone is in micronized form or sprayed from a solution onto particles of an inert carrier.

25. The use according to any one of p or 23, where K is the number of drospirenone corresponds to a daily dose, component of from about 2.5 to 3.5 mg.

26. The use according to any one of p or 23, where the number of ethinyl estradiol corresponds to a daily dose comprising from about of 0.015 to 0.03 mg.

27. The use according to any one of p or 23, where the levonorgestrel is in micronized form or sprayed from a solution onto particles of an inert carrier.

28. The use according to any one of p or 23, where the dissolution of ethinyl estradiol occurs in such a way that at least 70% dissolved within 30 min, as determined in accordance with those described in USP XXIII paddle method II using as a medium for dissolving water at 37°C and the stirring speed of 50 rpm

29. The use according to any one of p or 23, where oral administration is carried out in the form of tablets, capsules or pills.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula representing (2S)-3-(4-cyano-3-fluorphenoxy)-N-(4-cyano-3-methylpheniyl)-2-hydroxy-2-methylpropionamide which exhibits action modulating androgen receptor activity.

EFFECT: production of a pharmaceutical composition and a method of treating or preventing the conditions caused by androgen receptors.

3 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to testosterone amplifier, to a drug which prevents, relieves and/or treats symptoms or diseases caused by testosterone deficiency and to an additive for treating menopausal disorders in males. As an active ingredient, vitamin K (vitamin K2, menaquinone-4 or menaquinone-7) 10 mcg to 100 mg is used.

EFFECT: inventions provide higher endogenous testosterone levels.

5 cl, 9 dwg, 2 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to treating male patients suffering bronchial asthma early acquired androgen deficiency. That is ensured by a singular therapy 10 mg once a day combined with andriol 40 mg twice a day in the morning and in the evening. The therapeutic course makes 2 months.

EFFECT: potentiation of a bronchodilating effect of singular with no side effects.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to psychiatry and gynecology, and can be used in treatment of endometriosis in women with anxiety-and-depressive disorders. For this purpose one month after performing laparoscopy at the background of drug hormonal treatment during 6 months phenotropil in dose 100 mg/day is additionally administered for 90 days.

EFFECT: administration of phenotropil in said dose and introduction regimen makes it possible to reduce anxiety-and-depressive symptoms, and has positive impact on functional state of immune and vegetative nervous system.

4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to chemical-pharmaceutical industry, and concerns a transbuccal delivery system including a matrix of: (a) an effective amount of one or more active ingredients; (b) an amount of one or more polyethylene glycols or their derivatives of molecular weight within 1000 to 8000, sufficient to maintain the required hardness and matrix disintegration; (c) 0.05-2 wt % of one or more suspending agents of matrix mass; (d) 0.05-2 wt % of one or more liquidity agents of matrix mass; and (c) 0.05-2 wt % of one or more sweeteners of matrix mass.

EFFECT: development of the transbuccal delivery system to be prepared conventionally, preparation of a dry powder and enabled pressing with applying a common device for tablets manufacturing.

25 cl, 4 ex, 6 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: for treatment patients with hypogonadism with obstructive sleep apnea syndrome before substitutive therapy with androgens CPAP- therapy is carried out. After that CPAP- therapy is realised simultaneously with therapy with testosterone medications until its normal level is recovered.

EFFECT: method allows to carry out substitutive therapy of hypogonadism in patients with syndrome of obstructive sleep apnea, who have relative contraindications to administering androgens.

3 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula I , its pharmaceutically acceptable salt or stereoisomer, where X is -CH- or -N-; n equals 0, 1, 2 or 3; m equals 0, 1 or 2; R1 and R4 are each independently selected from hydrogen, halogen, cyano, perfluoroC1-6alkyl, C1-10alkyl, C2-10alkenyl, C3-8cycloalkylC0-10alkyl, R5 is hydrogen; R2 and R3 are each independently selected from hydrogen, hydroxyC0-10alkyl, perfluoroC3-6alkyl, C1-10alkyl, C3-8cycloalkylC0-10alkyl, (C0-10alkyl)1-2aminocarbonyloxyC0-10alkyl, C3-8heterocyclylcarbonyloxyC0-10alkyl, to their use in making a medicinal agent with activity which his mediated with androgen receptor modulation (SARM), as well as to a pharmaceutical composition and preparation method thereof.

EFFECT: novel compounds which can be used as androgen receptor modulators (SARM) are obtained and described.

15 cl, 5 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention claims 19-nor-D-homosteroids with mixed androgenic/progestagenic profile and oral activity, preventing bone mineral density (BMD) loss in trabecular bones, with zero liver toxicity, with structure of the formula (I) , where R1 is O, R2 is methyl or ethyl, and R3 is hydrogen.

EFFECT: improved efficiency of composition and treatment method.

9 cl, 3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention relates to topical formulation with: spironolactone nanoparticles, containing medium-diameter nanoparticles measured by photonic correlation spectroscopy technique, in the range approximately 300 nm to 900 nm, and dispersion of solid polar lipids crystals in polar liquid, with additional stabiliser. The nanoparticles are included in crystal structure formed by solid polar lipids crystals; the lipids mentioned being directed their hydrophilic ends outside, and hydrophobic ends inside, relative to spironolactone nanoparticles. Items of the patent application are also as follows: method of producing the formulation, the crystal lattice arrangement of solid polar lipids crystals with spironolactone nanoparticles included, and use of the nanosuspension with structure mentioned for medication producing, intended for therapy in anti-androgen responding conditions.

EFFECT: achieving of high stability formulation and increased bioavailability of spironolactone.

17 cl, 4 ex, 8 tbl, 11 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I) or its pharmaceutically acceptable salt, or an enantiomer wherein n = 0 or 1; a - b means -CF=CH or -CHFCH2; R1 represents (C1-C3)-alkyl wherein alkyl is unsubstituted; R2 represents hydrogen atom; R3 is chosen from (C1-C4)-alkyl, (CH2)n-cycloheteroalkyl and (CH2)n-aryl; or R2 and R3 form in common 6-membered saturated ring condensed with 5-membered aromatic ring system comprising 2 heteroatoms chosen from nitrogen atom (N), and pharmaceutical compositions. Compounds of the formula (I) represent modulators of androgen receptors (AR) possessing tissue-selective effect. Proposed compounds are useful as androgen receptors agonists in osseous and/or muscle tissue in antagonizing AR in male patient prostate or in female patient uterus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

36 cl, 2 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and relates in particular to medication for women, which has contraceptive and protective action against inflectional diseases: herpes, HIV infections, viral disease. Medication for vaginal application, possessing contraceptive and protective against inflectional diseases action contains actively-acting components and target base. As actively-acting components medication contains contraceptive, bactericidal, anti-inflammatory preparations, and as target base it contains gel-forming biocompatible polymers and L-lysin hydrochloride with specified component ratio per 1 g. Medication presents gel, ointment, cream, liniment.

EFFECT: medication not only has contraceptive action, but also makes it possible to simultaneously prevent sexually transmitted infection diseases.

3 cl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to gynaecology, and can be used for female contraception. Inventions include methods of female contraception. That is ensured by the multiple administration of a dosage form started in a day of month marked either by 'n+3', or 'n+4', or 'n+5', or 'n+6' date and taken out in a day marked by 'n' number of the next month for at least two cycles where 'n' is a date either within 1 to 25, or 1 to 24, or 1 to 23, or 1 to 22 respectively. Also, the inventions involve female contraception kits containing at least two dosage forms and patient information leaflets according to the declared modes of contraception. Besides, the inventions comprise a dosing regimen reminder system adjusted in such a manner that it allows to choose one specific date either within 1 to 25, or within 1 to 24, or within 1 to 23, or within 1 to 22 regardless of a month, as a date when the dosage form is always taken out and a date when a new dosage form shall be used either through three, or through four, or through five, or through six days thereafter respectively.

EFFECT: inventions provide convenient administration of contraceptives with maintained efficacy of contraception and its increase in certain cases.

1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: multiphase pharmaceutical preparation for ovulation inhibition in mammal contains a number of individually packed and individually removed daily units placed in a single package, and used for oral administration for at least 21 days running; specified daily units contain a combination of oestradiol and drospirenone. A daily unit contains 0.5 to 4 mg of oestradiol and 2 to 4 mg of drospirenone. At least 70% of specified drospirenone are released from specified unit within 30 minutes.

EFFECT: invention provides higher oral bioavailability of drospirenone.

6 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of ethinylestradiol and chlormadinone acetate combination for obtaining medication applied simultaneously for treatment of androgen-induced disorders, for substitution hormonotherapy, for treatment of dismenorea, for stabilisation of menstrual cycle, for treatment of illnesses dependent on menstrual cycle and for women's contraception, said medication being obtained in form of at least 21 hormone-containing day dose, and said combination of hormones contains from 5 to 20 mcg of ethinylestradiol and from 1 to 5 mg of chlormadinone acetate in day dose, if necessary in combination with 7-3 day doses which do not contain hormone.

EFFECT: it is demonstrated that reduction in claimed medication of ethinylestradiol amount does not influence cycle stabilisation, but it can be continuously introduced to women in pre- and perimenopause in order to achieve simultaneously all said aims, as well as for reduction of high blood pressure.

11 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to steroids with (11β)-[4-(aza-aryl)phenyl] substitutes which modulate progesterone receptors, or pharmaceutically acceptable salts and/or hydrated form, and/or prodrug thereof.

EFFECT: compounds exhibit combined activity profile of PR agonist and PR antagonist which makes them suitable for contraception and treating gynaecological disorders.

30 cl, 28 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention distinguishes 28-day and 91-day modes of taking combined oral contraceptives, possibly in combination with antidepressant (fluoxetine hydrochloride) in which full disappearance of estrogen from preparation does not take place. This presupposes that shorter influence of peaks and drops of endogenic progesterone protects against premenstrual disphoric disorder (PMDD) and against symptoms of mood disturbance in women with PMS.

EFFECT: application of estrogen and progesterone for manufacturing medication for contraception, treatment of premenstrual syndrome (PMS) or syndrome of estrogen cessation (versions), respective preparation (versions) and method of pregnancy prevention.

91 cl, 6 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the field of medicines, in particular to tetrahydroquinoline derivatives with common formula (I), where Y-X means C(O)-O, C(O)-NH, S(O)2-NH, NHC(O)-NH, NHC(S)-NH, OC(O)-NH; R6 stands for H, (1-6C)alkyl, 1- or 2-adamantyl(1-4C)alkyl, (3-9C)heteroaryl, (3-6C)cycloalkyl, (2-6C)heterocycloalkyl, alkylthio(1-4C)alkyl, phenyl(1-4C)alkyl, (3-6C)cycloalkyl (1-4C)alkyl, (2-6C)heterocycloalkyl (1-4C)alkyl, R8, R9 aminocarbonyl (1-4C) alkyl, R8, R8R9-amino (1-4C)alkyl, R8-oxycarbonyl (1-4C)alkyl, R8-oxy (1-4C)alkyl, R8-carbonyl (1-4C)alkyl or phenyl, not necessarily substituted with hydroxy, amino, halogen, nitro, trifluoromethyl, (3-9C)heteroaryl, (1- 4C)alkylcarbonylamino, (1-4C)alkylcarbonyloxy, (3-9C)heteroarylcarbonyloxy, (3-9C)heteroarylsulfonyloxy, (2-6C)heterocycloalkylcarbamoyl or diphenylamino.

EFFECT: modulating activity in respect to FSH receptor.

17 cl, 74 ex

FIELD: medicine; pharmacology.

SUBSTANCE: mainly water-free composition for oral or vaginal mucosa lubrication includes at least one polyatomic alcohol and honey as insulation agent. Invention also concerns methods of the composition application for lubrication, active component introduction and dysmenorrhea prevention or treatment. Methods involve application of mainly water-free lubricating composition including at least one polyatomic alcohol and insulation agent selected from honey and isopropylpalmitate, onto oral or vaginal mucosa to produce heating effect.

EFFECT: reduced toxicity and irritation effect.

31 cl, 1 tbl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: system of delivery of medicinal substance includes one department consisting from (i) of a kernel from thermoplastic polymer, filled with medicinal substance, (ii) an intermediate layer from the thermoplastic polymer filled with medicinal substance, and (iii) covers from the thermoplastic polymer, covering an intermediate layer and not containing medicinal substance, where the specified intermediate layer is filled (a) with crystals of the first pharmacologically active substance, and (b) the second pharmacologically active substance in the dissolved form and where the kernel is filled specified to the second pharmacologically active substance in the dissolved form. The delivery system is intended for vaginal introduction of the medicinal substance.

EFFECT: possibility of adjustment of rate of liberation of two or more active ingredients irrespective of others, at maintenance of long physical stability of system at room temperature.

51 cl, 21 dwg, 10 tbl, 4 ex

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine and concerns ethonogestrel new esters of formula 1 , 2 , 3 , applied for male and female contraception. Compositions are characterised by improved disposition profile.

EFFECT: production of composition with improved disposition profile.

3 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: modeling of ADMA-like model of gestosis in laboratory pregnant rats of Wistar line is carried out by daily introduction of inhibitor of NO-synthase L-NAME in dose 25 mg/kg from 14 to 20 day of pregnancy. Correction of endothelial dysfunction is performed by L-norvalin, which at the background of modeling is introduced intragastrically daily for 7 days in dose 10 mg/kg once per day.

EFFECT: method leads to expressed dysfunction correction under conditions of specific mechanisms of pathological process course in pregnant women.

1 ex

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