Pharmaceutical composition, method for preparing it and multiphase pharmaceutical preparation for ovulation inhibition in mammal

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains as a first active agent, 6β, 7β; 15β, 16β-dimethylenene-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount according to a daily dose after the administration of the composition and making approximately 2 to approximately 4 mg, and as a second active agent, 17a-ethinylestradiol (ethinylestradiol) in an amount according to a daily dose and making approximately 0.01 mg to approximately 0.05 mg together with one or more pharmaceutically acceptable carriers or additives. The composition contains drospirenone applied on inert carrier particles. A method for preparing a pharmaceutical composition involves spraying of the drospirenone and ethinylestradiol solution on the inert carrier particles. The pharmaceutical preparation according to the invention contains a number of separately packed and individually taken daily dosage units of the described compositions in a single package used for oral administration for at least 21 days running with said daily dosage units containing the combination of drospirenone and ethinylestradiol. The composition may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: invention provides higher oral bioavailability of drospirenone.

20 cl, 5 dwg, 5 ex

 

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 ethinylestradiol for inhibition of ovulation.

Background of the invention

Oral contraceptives contain a combination of components such as the gestagen and estrogen 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 gestagen-like 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 per 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 is g, together with one or more pharmaceutically acceptable carriers or additives.

In addition to the active substances provides that in accordance with the present invention can be used ester or prodrug of drospirenone, such as 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 quantities of the ethinyl estradiol, appropriate daily dose after administration of the composition comprising 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, a 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 is astorino in water and aqueous buffers substance at different pH values. Moreover, drospirenone programmirovaniya 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 a microscope; no 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 E. what about on the surface of the particles of inert carrier, followed by the introduction of particles, containing on its surface drospirenone 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% h is STIC - ≤10,0 µm and 50% of particles ≤3,0 µm. Moreover, there are no particles larger than 20 microns, and ≤10 particles have a diameter of -≤15 µm ≤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, in particular 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 ovulate is, the composition in accordance with this invention has a 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 mo is et to include the period average 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 in this case, 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 preparation, such as 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 according to the 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 an alternative implementation this invention relates to a contraceptive drug, which includes 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 levonorgestrel in the 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 AK the active agent in the drug may also remain constant throughout, at least 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 preparation, such as three - or four-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 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, nao is Orot, 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 the daily dosage units containing no active agent may then be introduced within 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 itinerant Adeola in number, comprising from 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 method daily doses of medicines, 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 IU is greater least 21 days in a row, each of the 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 or less daily dosage units containing no 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 ethinylestradiol in an amount 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 the Russian region. 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 or more 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, such as 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 capsules.

The tablets may optionally be coated with a suitable film-forming the second agent, for example, hypromellose, hydroxypropylcellulose or ethylcellulose, which may be optionally added a suitable additive, such as a softener, such as glycerin, propylene glycol, diethylphthalate or createtemporary, filler, such as sucrose, sorbitol, xylitol, 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 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 drugs the military 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 envisaged that the 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 polyera or pokr is the case with silicone or 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 or its derivatives or 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, in B.W.Barry, "Dermatological Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York-Basel, 1983, or Y.W.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 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 mg
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 hydroxypropylmethyl the pulp 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 continuously applying a suspension for coating 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.

Figure 2 and figure 4 present the results of dissolution of drospirenone from the nuclei of tablets and film-coated tablets, respectively. In most cases, more than 70% of the active agent p who was storaas 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 given in 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 etinilestradiol on the bottle.

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 ethinyl estradiol 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. The obtained average values, comprising 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 that the phase follow-up. The treatment was preceded by a washout phase, component 1 month.

After a certain period of time was determined by selected Central and peripheral parameters: LH (luteinizing hormone), FSH (follicle stimulating 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 s the population (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 progesterone, as well as setting ovulation while loops". Supported by the hormones of 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:

- on the and of the study drug are equally good in regard to subjective and objective tolerance.

When using both drugs was observed adverse metabolic effects. 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 for inhibiting ovulation in a mammal, comprising ethinylestradiol and particles of inert carrier containing drospirenone on their surface, where
drospirenone is present in the composition in an amount corresponding to a daily dosage dose of about 2 mg to about 4 mg, and ethinyl estradiol is present in the composition in an amount corresponding to the daily drug dose from about 0.01 mg to about 0.05 mg

2. The pharmaceutical composition according to claim 1, where the specified composition includes particles of inert carrier containing levonorgestrel on their surface.

3. The composition according to claim 1 or 2, where the specified composition additionally includes carriers or excipients that serve as promoters of dissolution of both active substances.

4. The pharmaceutical composition according to claim 3, where specified the media or excipient is selected from the group including carboxymethylcellulose, hydroxypropylcellulose, hypromellose, gelatinizing starch, gelatin and polyvinylpyrrolidone.

5. The composition according to claim 4, where the specified media or excipient is polyvinylpyrrolidone.

6. The composition according to claim 1, where at least 70% of the drospirenone is dissolved from the specified dosage units for 30 min, where the dissolution is determined in accordance with those described in USP XXIII paddle method II using water at 37°C in the environmental quality of the dissolution and the stirring speed of 50 rpm

7. The composition according to claim 1, where the drospirenone is present in an amount corresponding to the daily drug dose from 2.5 mg to 3.5 mg

8. The composition according to claim 7, where the drospirenone is present in an amount corresponding to a daily dosage dose of approximately 3 mg

9. The composition according to claim 1, where the ethinyl estradiol is present in an amount corresponding to a daily dosage dose of 0.015 mg to about 0.03 mg.

10. The composition according to claim 1, where the specified composition has the form of oral dosage units.

11. The composition of claim 10 where the specified oral dosage unit is in the form of tablets, capsules or pills.

12. Pharmaceutical preparation for inhibiting ovulation in a mammal, consisting of a number of separately packaging the bathrooms and individually extracted oral dosage units, as defined in paragraph 10 or 11, is placed in the package, and intended for oral administration for at least 21 days in a row.

13. The drug is indicated in paragraph 12, where the number of oral dosage units, as defined in PP and 11 is 28 or a multiple of 28.

14. The drug is indicated in paragraph 13, where the number of oral dosage units, as defined in PP and 11 is 2 times 28, 3 times in 28 or 4 times to 28.

15. The drug 14, additionally comprising 7 or less per oral dosage units containing no active agent intended for oral administration after a period of at least 21 days in a row, the total number of oral dosage units is at least 28.

16. The drug 14, in which the number of oral dosage unit as defined in claim 10 or 11, is 21, 22, 23 or 24, and in which the number of daily drug doses that do not contain an active agent, is 7, 6, 5 or 4.

17. Pharmaceutical preparation for inhibiting ovulation in a mammal, consisting of a number of separately Packed and individually extracted oral dosage units placed in a packaging and intended for oral administration for a period of time of at least 28 consecutive days, where at least 21 indicated orally dosed the first unit defined in claim 10 or 11, and where 7 or less these oral dosage units contain one ethinylestradiol in an amount of from about 0.01 mg to about 0.05 mg

18. The drug on 17, in which the number of oral dosage unit as defined in claim 10 or 11, is 21, 22, 23 or 24, and in which the number of oral dosage units containing no active agent is 7, 6, 5 or 4.

19. A method of obtaining a pharmaceutical composition as defined in claim 1, where the method includes spraying the solution of drospirenone on the surface of the particles of inert carrier with the subsequent inclusion of particles in the composition.

20. A method of obtaining a pharmaceutical composition as defined in claim 2, where the method includes spraying the solution of drospirenone on the surface of the particles of inert carrier and spraying of the solution of ethinyl estradiol on the surface of the particles of inert carrier with the subsequent inclusion of particles in the composition.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical vaginal composition for reducing or relieving uterine dysrhythmia. The composition contains an antidysrhythmia drug in the concentration of 1 wt % to 12.5 wt % and a pharmaceutically acceptable carrier providing prolonged release. The carrier contains a bioadhesive, water-swellable, water-insoluble, cross-linked polycarboxylic acid polymer such as polycarbophil. The drug is specified in prilocaine, mepivacaine, bupivacaine, ropivacaine, ethidocaine, mexiletine, procainamide, moracizin, propaphenone and flecainide.

EFFECT: invention provides reducing or relieving uterine dysrhythmia with prolonged release of said drugs with creating adequate local concentrations and low blood concentrations.

9 cl, 33 ex

FIELD: medicine.

SUBSTANCE: invention provides using a prepared compound of a ghrelin splicing version for preparing an effective drug preparation activating body weight and food intake gain and/or stimulating growth hormone release, as well as for treating or preventing cachexia, lipodystrophy and muscle atrophy.

EFFECT: higher clinical effectiveness.

6 cl, 6 dwg, 13 ex

Treatment method // 2397778

FIELD: medicine.

SUBSTANCE: invention relates to medicine, and deals with treatment of pathologic states connected with increased level of growth hormone (GH) or insulin-like growth factor 1(IGF). For this purpose realised is complex treatment which includes introduction of growth hormone antagonist and somatostatin or somatostatin analogue in developed doses and regimens.

EFFECT: method ensures normalisation of GH and IGF-1 levels in patients resistant to monotherapy with somatostatin analogues during at least 6-month treatment course.

15 cl, 1 tbl, 1 dwg, 1 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: invention relates to pharmacology and medicine and represents pharmaceutical composition for parenteral introduction, including diaspartate or disuccinate or diglutamate salt of somatostatin analogue of formula III, where C-2 atom is in (R) or (S) configuration, or their mixture, and where R stands for NR10R11(C2-C6)alkylene or guanidine(C2-C6)alkylene and each of R10 and R11 independently represents H or C1-C4alkyl and water, in which pH value constitutes from 3.0 to 7.0, forming after injection gel-like system-depot in case of contact with liquid medium in organism, in which salts of somatostatin analogues are characterised by ratio salt/base within the interval from 0.1 to 2 and from said gel-like system-depot in patient's organism continuously released is salt of somatostatin analogue: diaspartate, disuccinate or diglutamate during long period of time from 1 to 90 days.

EFFECT: invention ensures obtaining compositions which include diaspartate or disuccinate or diglutamate salt of somatostatin analogue with retarded release.

17 cl, 5 ex, 4 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to medicine and can be used as an effective remedy for precise delivery of DNA complexes with molecular conjugates to certain organs and tissues in mammals. The technical effect is ensured by introduction of modified nuclear localisation signal (NLS) that shall allow for conjugates to form complexes with plasmid DNA containing a suicidal gene, and also shall provide higher conjugate concentration in tumour cell nuclei that leads to intensification of cytotoxic properties of doxorubicine.

EFFECT: higher effectiveness of tumour cell exposure.

3 cl, 5 dwg, 6 ex

Peptide vectors // 2361876

FIELD: chemistry.

SUBSTANCE: invention relates to cytotoxic compounds with directional effect, which are peptide derivatives of camtothecin, doxyrubicin and palitaxel, their pharmaceutical compositions and use in making medicinal agents for treating pathological conditions, related to aberrant or undesirable proliferation, migration and/or physiological activity of cells.

EFFECT: agents are highly effective.

43 cl, 79 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the somatostatin antagonists which are used in the method of binding one or several somatostatin receptor subtypes -1, -2, -3, -4 and -5 in man and animal, in the method of revealing the somatostatin antagonist effect in man and animal, in the method for stimulating the growth hormone release in man and animal, in the method for stimulating insulin release in man and animal, in the method of enhancing the wound healing in man and animal, in the method for stimulating angiogenesis in man and animal, in the method of treatment of a disease or condition in suffering man or animal, where the said disease or condition is selected from the group consisting of dwarfism, cachexia, emaciation and diabetes II.

EFFECT: treatment of many diseases.

7 cl, 1 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: method involves determining hemoglobin level in peripheral blood, erythrocytes deformability index, vegetative Kerdo index and non-enzymatic fibrinolysis duration. Hemoglobin level is multiplied by 0.809, erythrocytes deformability index is multiplied by 3.247 and the two products are summed. Vegetative Kerdo index value is multiplied by 0.804, non-enzymatic fibrinolysis duration is multiplied by 0.365 and the products are summed. The second sum is subtracted from the first one and 20.89 is added to the difference. General organism fatigue quantitative estimate is obtained in this way. General organism fatigue value being less than 5 points, organism working capacity is evaluated as satisfactory. The value being from 5 inclusive to 37, moderate fatigue degree is considered to be the case. The value being from 37 inclusive to 69, medium severity fatigue is considered to be the case; from 69 inclusive to 100, fatigue level is considered to be above the medium level. The value being equal to or greater than 100 points, expressed general organism fatigue is considered to be the case.

EFFECT: high accuracy of estimate.

7 tbl

FIELD: medicine, gynecology, endocrinology, homeopathy.

SUBSTANCE: one should introduce complex homeopathic preparations into acupuncture points - cerebrum-compositum, tonsilla-compositum and placenta-compositum. Moreover, injections of cerebrum-compositum should be carried out for points T14, PN45 (din-chuan'), VB21 (2), and injections of tonsilla-compositum - for points T14, VB21 (2), GI4 (2). Injections of each preparation should be carried out once-twice weekly during menstrual cycle. Injections of placenta-compositum should be carried out for points E36 (2), Rp6 (2) twice-thrice weekly during the second phase of menstrual cycle. Therapeutic course should be started on the 5th-7th d of menstrual cycle, each point should be injected with 0.2-0.5 ml preparation. In case of anovulatory cycles and amenorrhea it is necessary to carry out additional injections of ovarium-compositum preparation during the first phase of menstrual cycle for points E36 (2), Rp6 (2) once-twice weekly. The innovation enables to correct hormonal disorders.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a diacetate of racemic 18-ethyl-gona-1,3,5(10),8(9)-tetraene-3,17β-diol, having anti-implantation and antioxidant activity with low uterotropic action. Presence of antioxidant activity in said steroid is essential since compounds with such action can be agents for preventing oestrogen-dependent breast cancer.

EFFECT: compounds exhibit anti-implantation and antioxidant activity with low uterotropic action, which is an advantage over agents used in practice.

1 cl, 1 ex, 4 tbl

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

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, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical compositions for local application. Claimed compositions include sildenafil, minoxidil, testosterone, or alprostadil, euphyllin, yohimbine, or sildenafil, minoxidil, yohimbine as active agents respectively. Claimed compositions also contain hydrogenated lecithins in combination with cholesterol, emulsifying agent, preservative and demineralised water in specified weight ratios.

EFFECT: group of inventions ensures fast penetration through skin and complex therapy of erectile dysfunction taking into account impact on psychogenic and endocrine factors.

3 cl, 4 tbl, 7 ex

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