Pharmaceutical composition comprising micronized progesterone, method for its preparation and use

UKRAINE

(19) and A (11) 77451 (13) C2

(51) IPC (2006)

А61К 31 / 57А61К 36/48 (2006.01) А61К 36/28 (2006.01) А61Р 5/24 (2006.01)

MINISTRY OF EDUCATION SCIENCE OF UKRAINE

STATE DEPARTMENT OF INTELLECTUAL PROPERTY

DESCRIPTION

TO THE INVENTORY PATENT

(54) PHARMACEUTICAL COMPOSITION ON THE BASIS OF MICRONIZED PROHESTERONE, THE METHOD OF IGORING AND APPLICATION

1

(21) 20040503542

(22) Nov 13, 2002

(24) 15.12.2006

(86) PCT / РР02 / 03879, dated 13.11.2002

(31) 01/14653

(32) 13.11.2001

(33) RR

(46) Dec 15, 2006, Bul. No. 12, 2006

(72) Bezen Antoine, BE, Bese Jerome, RR

(73) BEZEN ENTNASONAL BELGIK, BE

(56) EP 0598337 A, 25.05.1994

MO 9737642 A, 16.10.1997

υδ 5140021 A, August 18, 1992

AP 60258110 A, 20.12.1985

(57) 1. A pharmaceutical composition comprising micronetized progesterone, soya lecithin, and at least one oil selected from the group consisting of sunflower oil, olive oil, sesame oil, oliripackum and almond oil.

2. The pharmaceutical composition of claim 1, wherein the ratio of progesterone / oil (s) is from 0.15 / 1 to 3/1, preferably from 0.25 / 1 to 2/1, more preferably from 0.40 / 1 to 1/1, and most of the most 0.67 / 1.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the ratio of lecithinose / oil (s) is from 0.005 / 1 to 0.3 / 1, preferably from 0.01 / 1 to 0.2 / 1, more preferably from 0.040 / 1 to 0.1 / 1 and most preferably 0.067 / 1.

4. A pharmaceutical composition according to any one of the preceding claims. 1-3, characterized in that it contains estrogen or its derivative of the ester type, preferably selected from the group consisting of 17 β-estradiol, estrone, 17α-etinyl estradiol, estradiol valerate or phytoestrogens, with the most preferred being 17β -stradial

2

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that at least the progesterone is in a suspended state in an oil or oils.

6. The pharmaceutical composition of claim 1 to 5, which is bathed in that it is presented as a soft capsule.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein each dosage unit thereof comprises from 2 mg to 600 mg of micronized progesterone, preferably from 30 mg to 300 mg, most preferably from 100 mg to 200 mg.

8. A method for the preparation of a pharmaceutical composition according to any one of claims 1 to 6, comprising the following sequence of operations, wherein:

- in the process of mixing process the mixing of oils selected from the group, including sunflower oil, olive oil, sesame oil, canola oil and almonds, with lecithin soy for obtaining the mixture;

- When stirred, the micronized progesterone is added to the resulting mixture to obtain a homogeneous suspension.

9. The use of micronized progesterone, soya lecithin and at least one oil selected from the group consisting of sunflower oil, olive oil, sesame oil, rapeseed oil and almond oil, for preparing a medicament intended to treat a physiological condition, with insufficient secretion of progesterone.

10. The use of claim 9, wherein the medicament also contains an estrogen or one of its derivatives such as ether selected from the group consisting of 17β-estradiol, estrone, 17 sec / -ethinyl estradiol, valerate estradiol or phytoestrogens, with the most preferred being 17 β-estradiol.

iA (11) 77451 (13) C2

The present invention relates to a pharmaceutical composition comprising finely crushed progesterone, soya lecithin and at least one oil, an ointment from a group of oils that includes sunflower oil,

olive oil, sesame oil, rape and almonds.

The invention also relates to pharmaceutical

tent means containing this pharmacist

composition.

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In addition, the present invention relates to a process for preparing a given pharmaceutical composition, as well as its use.

Progesterone is a hormone that is synthesized in the female body, mainly as an egg cell during the phase that belongs to the period that occurred after the formation of the germ cell, or to the period of the formation of the luteinizing hormone (progesterone), more precisely, cells are synthesized of the yellow body and, to a lesser extent, adrenal glands and the placenta during the second half of pregnancy. Non-endocrine synthesis of progesterone, in particular, synthesis at the neuronal level, is also possible.

The inadequacy of progesterone secretion in a woman may lead to the loss of her biological characteristics: her childbearing function, the ability to withstand the influence of the hormones that promote sexual maturation in human men (exposure to the skin condition), to resist the action of the estrogen, male sex hormone (with the emergence of signs caused excessive influence of a male sex hormone: tides, psychogenic disorders, for example, anxiety, depressive state, overweight, etc. ...). Such insufficient progesterone can lead to functional disorders and their various clinical manifestations, in particular:

- premenstrual syndromes;

- disorders of the menstrual cycle through dis-vulva or anovulation;

- the emergence of benign mastopathy;

- perimenopause and menopause.

However, oral ingestion of progesterone has a serious disadvantage, due to weak intestinal absorption and intense hepatic metabolism (a short period of plasma half-life) of this hormone. To date, it is known that only vaginal, rectal, and intramuscular methods of administering a pharmaceutical agent can maintain progesterone at the level of the physiological phase of the formation of a luteinizing hormone (progesterone) within several hours of admission after its introduction.

In the description of the application for the grant of the patent [for the wine-course BE 76 0036007 BAVORATORIREZ ΒΕ3ΙΝ3-IZSOUEZSO] the solution of the technical task of improving the quality and enhancing the integrity of the absorption of the natural progesterone-mediated tract was already proposed. Indeed, here was developed the technology of cooking soft capsules containing finely crushed progesterone, suspended free-standing suspension. The synergistic result obtained by the fine grinding of pro-gesterone and the use of molecules containing long-chain lipidic acids undoubtedly allowed the use of existing bioenergetic progesterone reagents with oral administration. The composition was widely recognized worldwide. It is sold in France under the trade mark BITROSSEZTAKI®.

The oil, which serves as the basis for the preparation of a pure suspension in ustSOZTAN®, is peanut oil.

Peanuts (Agassy Lurodae) is a bean a year-old plant, which in the period of flowering attracts yellow flowers of the butterfly family.

But now, for 15 years, the emergence of allergic

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The reaction to peanuts is considered as a complex allergic-logical problem.

[Yuijiy et al., Ba Rgevve MeSiAlE, Vol. 28, p.1553], on the basis of observations, came to the conclusion that the increase in the number of cases of allergic reaction to peanuts among the broad populations is estimated at 1.3%.

Described cases of early sensitivity to peanuts in babies who have never consumed peanuts in its usual appearance, but have acquired this sensitivity of the mother's womb (iip yigo) or with the consumption of mother-milk milk, milk obtained in hollow houses, which has in its composition vegetable liquor (peanut oil), or through medicines prepared in the form of oil solutions.

BITROSETZAKI ® can be prescribed for many therapeutic indications, including as an add-on to the luteinizing phase (lactobacillus) progesterone during the fertilization cycle in the lining (ip νίίΓο) (Είν - fertilization in the test tube), as well as in case of a threat of release, in order to prevent repetition emit due to the lack of state of the phase of the formation of luteinizing hormone (progesterone) up to the twelfth week of pregnancy. Proceeding from this, in principle, there is the theoretical possibility to expose the effect of YUTROSETZ ^ in-utero (ip iiyego).

Nowadays, whenever there are cases of allergies to peanuts, there is a contradiction in thoughts about the ability of peanut butter to excite an allergic reaction of the body. We can cite a number of public publications, which support this idea: [Tauiog et al., AIiygdu Sipip. Ittipoi, vol 68, p.372 (1981); Mopura Vera, etc., ReCia ^. AIiyeddu Ittipoi, Volume 5, p.184 (1994); Za'Ba'B and Baigih Ariyegdiye Ittipoiodiye, vol.2b, p.380 (1994); Se Mopiv et al., Ags. Res., Vol. 2, p.25 (1995)].

Proceeding from the situation, the applicant (Zossiece YutapSegevva) took the development of a new pharmaceutical composition with the replacement of oil peanut butter, the use of which is not associated with such a high risk of allergic reaction, while concentrating all efforts to save the benefits of the existing composition.

After numerous works and experiments in which multiflorous oils were tested, the choice came from sunflower oil, olive oil, sesame oil, rapeseed and almonds. Indeed, the use of these oils makes it possible to eliminate the risk of an allergic reaction, preserving the whole set of physico-chemical and kinetic characteristics of the already existing composition BITROSEZTAKI®, the characteristics that determined its success. Taking into account that the process of preparing already existing on this level of technology, BITROSEZTAKIK®, takes place on a scale of widespread production, including the stages, the development of which required the solving of very unproblematic issues, the applicant's merits should include the fact that he was able to modify the composition without increasing the number of problems related to its production.

In the context of the present invention, the oils can be

refined or unrefined. Refined

Oil is an oil obtained in the process of separation on

ingredients of untreated oil and exposed

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a whole number of treatment operations. Refined oil is a refined oil in which there is a small amount of impurities and is released from potentially allergenic proteins such as gluten.

In a pharmaceutical composition according to the present invention, the finely divided progesterone is preferably suspended in sunflower oil, olive oil, sesame oil, rapeseed, almonds, or in a mixture of some or all of these oils together.

The Applicant has a well-known patent [for invention υδ 5 140021], issued under the name 6ΕΝΕ3Ι3 5Υ5ΤΕΜ5ΟΟΡΡΟΡΑΤΙΟΝδ (Macheop, etc.), which describes a capsule containing a finely divided pro-gesteron contained in a suspended state in one of oils listed above. In this pa-tent, among the presented oils is called sunflower oil. However, the inventors [in favor of υδ 5,140,021] have, first of all, taken care that their subject matter differs from the pharmaceutical product υΤΡΟΟΕδΤΑΝ®, that is, the settlement on the basis of peanut butter developed and currently applied on the commercial basis by the applicant. In addition, , a finely ground progesterone, used [in the American patent ΟΕΝΕδΙδδΥδΤΕΜδ], is described as a progesterone having a different-specific granulometry other than that characteristic of υΤΡΟΟΕδΤΑΝ®.

[American Patent υδ 5,140,021] describes the preparation of progesterone capsules at the laboratory level and does not contain any information that would indicate the presence of a cap-sul preparation method under production conditions. In addition, the progesterone capsule according to the American patent does not contain lecithin soy, an element that is an essential marking that characterizes the pharmaceutical composition according to the present invention. Indeed, soya lecithin plays the role of a substance that provides a suspended state of particles of progesterone in sunflower, and, at the same time, a lubricant that ensures the burying of the content encapsulation in industrial production.

The present invention relates to a pharmaceutical composition comprising finely divided progesterone, soya lecithin and at least one oil selected from the group consisting of sunflower oil, olive oil, sesame oil, rapeseed and almonds.

According to a more preferred embodiment of the use of the pharmaceutical composition according to the invention, the finely ground progesterone is suspended in any of the above-mentioned oils, or in a mixture of individual or all of these oils together.

In the context of the present invention, the term "subcoaved progesterone" is to be understood as a progesterone of at least 80% of particles characterized by granulometric values ​​of 1 to 15 μm, preferably in a situation in which 50% of particles have granulometric ratios ranging from 1 to 10 μm, but the most prevailing is the situation in which 25% of particles have granulometricindicators from 1 to 5 mm. These granulometric readings are determined using a laser gravolometer such as Maywegp. The measurement procedure is described in the examples of the invention according to this patent application for an invention.

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During previous studies on the choice of alcohol, the applicant unexpectedly found for himself that the combination of soy lecithin with selected oils, in accordance with the present invention, was very interesting, since it did not change the granulometry of finely ground progesterone, suspended oil. In addition, no significant differences were observed between the composition of peanut butter and the oil containing oil, which is used according to the invention, taking into account the granulometric distribution of the finely divided progesterone suspension.

As for other oils, for which tests were conducted, the results of the tests showed that their granulometric indices were different and depended on the presence of soya lecithin in the product under study or not. Nourished with peanut butter, selected in accordance with the present invention, the oils have proven favorably in terms of physical and chemical properties, which in the complexprovide:

- comparable solubility at saturation by finely crushed progesterone;

- comparative granulometric indices of su-emphasis;

- comparative indices of the decomposition (dissolution) in the tinplate (PI νАΐΓΟ).

However granulometric indices and solubility at saturation to a large extent influence the biological activity of progesterone in the living organism (ip νÀνο).

Thus, the choice of these oils makes it possible to perfectly optimize the granulometric redistribution of finely crushed progesterone in the oil suspension, as well as the small amounts of dissolved progesterone in the oil, therefore, provide a set of necessary conditions for maintaining the level of biological activity of the progesterone in a living organism (ipnAnO), a similar to that which is achieved through the help of υΤΕΟΟΕδΤΑΝ®.

The pharmaceutical composition obtained as an embodiment of the present invention is characterized by a ratio of progesterone / oil (s), which is from 0.15 to 1/1 to 3/1, preferably from 0.25 to 1/1, more preferably from 0.40 / 1 to 1/1 and most preferably 0.67 / 1.

The pharmaceutical composition obtained as an example embodiment of the present invention is characterized by a soy / oil (s) ratio of lecithin, which is from 0.005 1 to 0.3 / 1, preferably from 0.01 / 1 to 0.2 / 1, more preferably from 0.040 / 1 to 0.1 / 1, most preferably, 0.067 / 1.

The pharmaceutical composition of the present invention may also contain estrogen or its derivatives of type ester, preferably selected from the group consisting of 17-βestradiol, estrone, 17os-ethinyl estradiol, valeratetetradiol or phyto-estrogens, with the most preferred being 17-β-estradiol.

The pharmaceutical composition of the present invention may be presented in the form of a soft capsule, in the same-latin state (deiyie), in the form of a tablet or in the form of a suspension containing the mixture.

If the pharmaceutical composition of the wine

the course integrates into some kind of pharmaceutical

sib, each dosage unit contains from 2 mg to

600 mg of finely ground progesterone, predominantly

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but from 30 mg to 300 mg, even more preferably from 100 mg to 200 mg.

The acceptance of the pharmaceutical composition according to the invention can be administered orally or vaginally, depending on the therapeutic indications.

Vaginal administration is considered as an oral truce in the event of vitiating side effects caused by the presence of progesteron, for example, drowsiness after oral suction, or because of contraindications to oral administration, for example, in hepatopathy.

The pharmaceutical composition, obtained as an embodiment of the present invention, is characterized by the fact that the capsule contains gelatin or its equivalents.

The present invention also relates to a method for preparing a pharmaceutical composition comprising finely crushed progesterone, soya lecithin and, at least, one oil selected from the group consisting of sunflower oil, olive oil, sesame oil, rape and almonds.

This method includes the following sequenceoperations, in which:

- In the process of mixing, mix the oil (s) with soybean meal to obtain a mixture;

- When stirring to the resulting mixture, give finely crushed progesterone to obtain a homogeneous suspension.

This suspension can be used as a su-suspension medicine, in addition, it can be given as soft capsules or as a gelatinous product. In this case, it can beused as a storage compartment for absorbent-based basis, presented in the form of powder.

The absorbent base may be maltodextrin and / or its derivatives, silicones (calcium oxide, etc.) and / or its derivatives, cyclodextrin and / or derivatives thereof, cellulose powder and / or derivatives thereof, as well as their combination, or any other primary pharmacy stores that have acquired similar properties.

The so treated powder may be presented in the gelatinous state or in the compressed form. Gelatinous or compressed pro-

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The duct containing this powder may also include binders, cleavable substances, solvents and / or lubricants.

The present invention also relates to the use of finely ground progesterone, soya lecithin and at least one oil selected from the group consisting of sunflower oil, olive oil, sesame oil, rapeseed and almonds, for the preparation of a medicinal product intended for the treatment of a physiological condition associated with insufficient secretion progesterone

Examples of such physiological states can be called insufficiency of the luteinizing hormone (progesterone), menstrual irregularities, premenstrual syndromes, mastodynia, benign mastopathy, premenopausal, infertility due to the lack of a luteinizing hormone (progesterone), fears associated with the period of menopause, local contraception , prevention of the usual vikida in case of insufficiency of luteinizing hormonal (progesterone), the threat of premature birth, acne on the face, baldness, the prevention of osteoporosis, uterine cancer and pilepsiyu.

The present invention also vykorystannyatonko crushed progesterone, lecithin soya and at least one oil selected from the group schoskladayetsya of sunflower oil, olive oil, vegetable oil, sesame, canola and almond and estrohenudlya preparation of a medicament for th treatment of physiological state , associated with insufficient secretion of progesterone. Estrohe-on or one of its derivatives such ester allegiance etsya advantage in choosing a substance in the group schovklyuchaye 17-β estradiol, estrone, 17a-ethinyl-estradiol, valerate estradiol or phyto-estrogens, the most preferred are 17-β estradiol .

Further, for a better understanding of the application material, examples of the invention are provided, which illustrate but do not limit the scope of its protection.

Example 1: Pharmaceutical composition in the form of a soft capsule according to the invention The composition of the capsule capsule of the present invention is given in the teachings of Table 1 below.

Table 1

<tr><td><p>The name of the warehouse</p></td><td><p>Storage</p><p>Percentage content (%)</p><p>Per unit (mg)</p></td><td><p>Function</p></td><td><p>Link to the standard</p></td></tr><tr><td><p>Active substance:</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Slender crushed progesterone</p></td><td><p>40.00</p></td><td><p>100.00</p></td><td><p>Active substance</p></td><td><p>Rp.Eig.3th view.</p></td></tr><tr><td><p>Inert solvents:</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>Oil or oil mixture according to the invention</p></td><td><p>59.60</p></td><td><p>149.00</p></td><td><p>Solvent</p></td><td><p>Rp.Eig.3th view.</p></td></tr><tr><td><p>Lecithin soy</p></td><td><p>0.40</p></td><td><p>1.00</p></td><td><p>Emulsifier</p></td><td><p>iZR 24, ΝΡ 19, p. 2471</p></td></tr>

The applicant also prepared capsules of 500 mg, similar to 250 mg capsules described above. Capsules for 500g contain 200 mg of finely ground pro-herterone, 2 mg lecithin of soy and, for example, 289 mg of sunflower oil.

Example 2: Study of the solubility of fine finely progesterone in different oils

To select the optimum oilseed for replacing it with peanut butter, while retaining allphysical and chemical properties of the already existing composition,

the following vegetable oils have been tested for solubility in them of progesterone:

- peanut butter;

- olive oil;

- sunflower oil with high content of oleic acid;

- rapeseed oil;

- almond oil;

- soybean oil;

- sesame oil;

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- corn oil.

The following were prepared

do:

- concentrated solution: the content of progesteronolium

- dilute solution: concentrated solution tetrahydrofuran (THP) acetonitrile

Magnetic stirring lasted for a minute.

After this, saturated solutions were prepared as follows:

standard roses

A0098 10mgder 20ml

1ml10ml (der) 20ml within 5

Saturated solutions in each of the oils during the day were mixed at ambient temperature, then filtered through a nylon filter of a 25 mm diameter syringe with a size of 0.45 mm.

Saturated solutions were diluted to 1/200: saturated solution 0.5 ml

tetrahydrofuran (THP) 50 ml

acetonitrile (der) 100 ml

Results (saturated concentration of progestero-

rona in relation to the oils under study) are shown in tabs 2, 3 below:

Table 2

<tr><td><p>Investigated oil</p></td><td><p>Concentration in the state of vitality (mg / ml)</p></td><td><p>Relative tolerance * to the concentration indicator in the saturation state (%)</p></td></tr><tr><td><p>Peanut Butter</p></td><td><p>16.77</p></td><td><p>-</p></td></tr><tr><td><p>Rape oil</p></td><td><p>18.14</p></td><td><p>+ 8.2%</p></td></tr><tr><td><p>Sunflower oil</p></td><td><p>17.50</p></td><td><p>+ 4.4%</p></td></tr><tr><td><p>Sunflower oil with high content of oleic acid</p></td><td><p>8.29</p></td><td><p>-50.6%</p></td></tr><tr><td><p>Olive oil</p></td><td><p>17.46</p></td><td><p>+ 4.1%</p></td></tr>

Table 3

<tr><td><p>Investigated oil</p></td><td><p>Concentration in saturation (mg / ml)</p></td><td><p>Relative Tolerance * on the Concentration Index in Saturation (%)</p></td></tr><tr><td><p>Peanut Butter</p></td><td><p>18.80</p></td><td><p>-</p></td></tr><tr><td><p>Almond oil</p></td><td><p>18.98</p></td><td><p>+ 1.0%</p></td></tr><tr><td><p>Soybean oil</p></td><td><p>16.19</p></td><td><p>-13.9%</p></td></tr><tr><td><p>Sesame oil</p></td><td><p>19.80</p></td><td><p>+ 5.3%</p></td></tr><tr><td><p>Corn oil</p></td><td><p>15.60</p></td><td><p>-17.0%</p></td></tr>

* Peanut Butter = Reference Oil (Reference Oil)

Rape oil, sunflower oil, olive oil, sunflower oil and almonds successfully passed the test for solubility in saturated state.

Among the various suppliers of oils, for example, can be called the following manufacturers:

- olive oil: BEZZIEREIR;

- sunflower oil: ΗΕΝΡΥ BAMOTTE.

Example 3: Making Soft Capsules Thin

chopped progesterone of the present invention

The method of manufacturing soft capsules based on a finely chopped progesterone according to this invention includes operations in which:

- prepare capsules in accordance with any of the conventional methods known to a person skilled in the art.

Fill a set of 2300000 capsules, ensuring the maintenance of progesterone content of 100 mg per each capsule, and in the process of filling:

- carry out the control of the atmosphere, providing the temperature of the environment 22 ° С ± 3 ° С and relative humidity 35% ± 10%.

Weigh the following ingredients: progesterone 230,00kg

sunflower oil 342,70 kg

soya lecithin 2.30 kg

Provides a mixer with a capacity of 600

liters under vacuum.

Enter in the mixer under vacuum 3/4 of the amount of sunflower oil and add soy lecithin.

Repeatedly create a vacuum in the mixer (from 0,7 bar to 0,9 bar), and then provide work at a low speed from 10 revolutions per minute to 15 revolutions per minute.

Add progesterone in vacuum, and then re-add the rest of the quarter of sunflower oil and bring the temperature to 23 ° С ± 3 ° С.

Then, an intensive mixing is performed to obtain a homogeneous state.

With intense mixing in the mixer, a pressure of up to 1 bar is formed.

Provide continuous sifting with the help of a sieve with a cell size of 500 pounds, and the mixture is moved to a storage bin.

Create a vacuum in storage bins, and then provide conditions for mixing with speed from 2400 to 2000 revolutions per minute for 15 minutes. Once again, the vacuum is mixed again for 30 minutes at a speed of 2,000 revolutions per minute to 2500 revolutions.

The mixing is complete, but the bins

leave in vacuum for 5 minutes.

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Capture according to one of the methods known from the prior art.

Example 4: Determination of granulometry of a capsule according to the present invention

Carry out a comparative granulometric pre-study of capsules υΤΡΟΟΕδΤΡΑΝ® and capsules of the present invention containing sunflower oil. The following equipment is used:

- laser granulometry Mavier's 2000

- measuring device Nubgo 2000 5M.

According to the following method: the number of specimens: 1 or 2 droppoints from the pipette. The environment: filtered saturated sun-

nickel oil

This oil is prepared by magnetic stirring and stored at a temperature of 37 ° С for an hour, then filtered through a papier-filter.

Refractive index: (average of oil) 14671.

Amount of medium: 100 ml.

Mixing speed: 1800 rpm.

Percentage content of the furnish: from 10 to 20%.

Balanced Balanced Percentage Content: &lt;3%.

Number of measurements in preparation: 2.

Measurements began after 30 minutes after the stabilization of the percentage of obsteur. The results shown in FIG. 1 show that the granulometry of the two capsules is quite comparable.

Other studies conducted by the applicant, de-montuate that the granulometric distribution of pro-hesteron in sesame oil, olive oil, rapeseed oil or almond is also comparable to the results obtained for peanut butter.

Example 5: Comparative analysis of the dilution process in the test tube (ip vAg0) of the capsule and the capsules of the present invention

A dissolving device was used that consists of rotary cartridges 5ΟΤ AX AT7.

In a 200 ml volumetric flask (class A), the precisely measured amount of 20 mg of progesterone in

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2 ml of ethanol, then the solution was subjected to an ultrasound wax and provided a predetermined amount of solution (KierIoie®®) placed in the measuring flask through the aid medium.

The sample of the solution was filtered using a syringe filter made of fiberglass porosity-1u.

7 cups were placed in a water bath at a constant temperature, and then 1000 ml of sterile solution was transferred to each of 7 cups.

One capsule was placed in each of 6 cups, after which the cassettes were immersed in solvent medium, keeping the distance of 25 mm ± 2 mm between the cassette of an idle cup.

The cartridges were stirred, and then prepared a sample of solution.

Samples were taken from each of the prescribed time intervals (5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 225, 270, 315 and 360 minutes) and examined their method of spectrophotometry using the device Zresijgorpoyotegyhie υν (λ : 248 nm).

The results of the studies presented in FIG. 2 show that the curves of dissolution in the test tube (ip vAg0) of the capsule υΤΡΟΟΕδΤΑΝ® and the capsules of the present invention containing sunflower oil are completely identical.

The physico-chemical characteristics of an already existing compositions are retained in the composition of the present invention.

Example 6: Study of the biological equivalence of the content of the υΤΡΟΟΕδΤΑΝ® capsule and the pharmaceutical composition of the present invention

The biological equivalence study was conducted to compare the values ​​of capsules according to the inventions containing 100 mg of progesterone, saturated in sunflower oil, with capsules, γΡΟΟΕδΤΑΝ®.

The studies were conducted in a group of 60 women who abstained from food.

The results of the studies confirmed the biological equivalence of the capsules of the present invention and the capsules zuHBΟΟΕδΤΑΝ® (see Figures 3 and 4).

SIZE OF PARTICLE

- CAPSULA AT THE INVENTION (OAU 221.01, lot (party) ОВІ249020

----- KAPPSULA þΤΚΟΟΕδΤΑΝΦ (РР0098, lot, (party) 5439)

FIG. 1

13

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Computer layout of T. Chopelov Signature Circulation 26 copies.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, st. Uritskogo, 45, Kyiv, SME, 03680, Ukraine

State Enterprise "Ukrainian Institute of Industrial Property", st. Glazunova, 1, Kyiv - 42, 01601