Tablet containing steroid hormones

UKRAINE

(19) and A (11) 92011 (13) C2

(51) IPC (2009)

А61К 9 / 00А61К 31 / 56А61К 31 / 568А61Р 5/24 (2006.01) А61Р 5/26 (2006.01) А61Р 5/30 (2006.01) А61Р 5/44 (2006.01)

MINISTRY OF EDUCATION SCIENCE OF UKRAINE

STATE DEPARTMENT OF INTELLECTUAL PROPERTY

DESCRIPTION

TO THE INVENTORY PATENT

(54) TREATMENT OF STEROID HORMONES

1

(21) a200712054

(22) 15.03.2006

(24) 27.09.2010

(86) PCT / ЕР2006 / 002358, 15.03.2006

(31) 10 2005 015 128.0

(32) 31.03.2005

(33) YE

(46) September 27, 2010, No. 18, 2010

(72) KRUMME MARKUS, YB / YUS, RADLEMAIRALBERT, YUE, GENERAL SASHA, YEA, DITTGHENMICHAEL, YEA, JENSEN KAYT, IZ

(73) ЛТС ЛОМАНН ТЕРАПИ-ЗЮСТЕМЕ AG, YUE, BAER SHERING PHARMA AKTSIENGESELLSHAFT, YEA

(56) ΆΟ 03/015748 A2, 27.02.2003

No 00/42992 A2, 27.07.2000

(57) 1. A film-based application system for trausmucosal administration of a steroid hormone containing:

a) 0.01 - 50 wt. % steroid hormone from the group that

contains estrogen, preferably ethinyl estradiol, progesterone, predominantly drospirenone, dienogest, gestodene, levonorgestrel or ciproterone acetate, androgen, predominantly testosterone, dihydrotestosterone, 7a-methyl-19-nortestosterone (MEICT), MEICT-17-acetate, 7α-methyl-11? -fluorine-19-nortestosterone (θE-ΜΕΝΤ),

methotrolone, nandrolone, oxandroloneabo androstenedione, corticosteroid, predominantly hydrocortisone, hydrocortisone-21-acetate, methylprednisolone acetonate, prednisone, deflazacort, deflazacortalcohol, fluocortolone, fluocortolangidrate or fluocortholone-21-pivalate, or a mixture of these steroid hormones, and

b) 50 to 99.99 wt. % carrier in the group including cellulose, cellulose derivatives, poly-ivinylpyrolidone, copolymers of vinylpyrrolidone and vinyl acetate, crichal, starch derivatives, gelatin, gelatin derivatives, and combinations thereof, with the application system being:

2

- surface area from 1 to 10 cm², preferably from 5 to 8 cm²,

- the unit weight of the surface from 50 to 250 g / m², preferably from 100 to 150 g / m²,

- a thickness from 40 to 130 microns, preferably from 50 to 100 microns, and the steroid hormone is dissolved in the formulation.

2. The film-like application system of claim 1, wherein the carrier is methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethyl cellulose (HPMC), or a combination thereof.

3. A film-like application system according to claim 1, characterized in that the carrier is hydroxypropylmethyl cellulose (HPMC).

4. The film-like application system of claim 3, wherein it further comprises a plurality of auxiliary substances which contribute to the dissolution of the steroid hormone and the formation of a second carrier phase.

5. Film application system according to claim 4, characterized in that

steroid hormone dissolved in a liquid auxiliary substance.

6. A film-like application system according to one of claims 1 to 5, characterized in that it has a weight of from 2 to 15. %, preferably from 3 to 8 wt. % and especially preferably 5 wt. % steroid hormonal mono.

7. A film-like application system according to one of the preceding claims, characterized in that it is completely dissolved in the oral cavity in less than 30 minutes, preferably less than 15 minutes.

8. A film-like application system according to one of the preceding claims, characterized in that the Iodrin steroid hormone is from 1.0 to 4.3.

9. A film-like application system according to one of claims 1-8, characterized in that it is mu-coadhesive.

iA (11) 92011 (13) C2

σ>

3

92011

4

10. The film-like application system according to one of claims 1 to 9, wherein the steroid hormone is testosterone, 7a-methyl-19-nortestosterone (MENET), or 7a-methyl-11? -Fluoro-19-nortestosterone (eE-MENT).

11. A film-like application system according to one of the preceding claims, characterized in that it further comprises at least one auxiliary substance from the group of flavor additives, colorants, penetration promoters, sweeteners,

fillers, plasticizers, dissolving agents, pH stabilizers, disintegrant.

12. A film-like application system according to one of the preceding claims, characterized in that it releases a steroid hormone with a bioavailability of at least 25%, preferably at least 50%, in a precursor application.

13. A film-like application system according to one of the preceding claims, characterized in that it releases the steroid hormone with a bioavailability of 70-75% in the precursor application.

The invention relates to a pharmaceutical composition in the form of a film-like system for introducing steroid hormones through the mucosa.

Different forms of the introduction of steroid hormones are described. Implants, plaster and gels are also used in addition to conventional oral administration. Such forms of application are aimed atcontinuous, as uniformly distributed over a long period of release of steroid hormones. However, for different purposes, it would be desirable to administer, which contributed to the rapid increase in the concentration of steheroid hormone in the blood 3 in order to restore the physiological state, for example, in the case of deficiency of testosterone in men, it is necessary to achieve an intrinsic maximum concentration of pre-conditions to achieve high concentration of mountains -monu in the blood in a short time is the rapid introduction of the hormone and high bioavailability.

Rapid release of active substances can be achieved by administration through the mucous membrane. For this, there are known forms of application that are disintegrated in an aqueous medium, for example, in the oral cavity. Buccal systems for release such as patches, sucking pills, chewing gums, films and tablets that are to be removed are known.

Particular attention should be paid to film-like systems, so-called wrappers (EIS 5,948,430). After the introduction of the cavity into the oral cavity, the actin-in substance is released. For a rapid increase in the concentration of the active substance in the blood, use a rapid resorption of the active substance through the mucous membrane of the mouth. The poor solubility or resorption can not be compensated for by increasing the cloak, since the size of the container is limited by the size of the oral cavity, because the thick clouds decompose very slowly.

Active substances that form part of the current, depending on the place of absorption in buccal or sublingual use is absorbed by the mucous membrane of the oral cavity. Such uses have many advantages compared with oral administration, for example, the avoidance of the effect of the first passage, the rapid onset of action, as well as gastrointestinal meta-bolism.

When developing a system for buccal or sub-bloating use, mucoadhesia plays

decisive role. Materials that are associated with the mucilaginous layer of the biological membrane, are usuallycalled as "mucoadhesive". Mucoadhesive polymers are used in numerous forms for use in order to improve the systematic bioavailability of certain active substances when pog-lining with different mucous membranes. To such compositions of medicinal substances are tablets, patches, lozenges, films, semi-solids and powders. Polymers should have certain physical and chemical properties to be mucoadhesive. For example, such polymers, due to the content of the number of hydrogen bundle groups, should preferably be anionically hydrophilic, have sufficient wetting ability on the surface of the mucilage, and sufficient flexibility to soak a mucous membrane or a crack in the fabric.

However, the main problem that occurs during the development of systems for buccal or sublingual application is the low rate of flow of the active substance through the mucous epithelium-flax tissue, resulting in low bioavailability of the active substance.

The ability of a medicinal substance to penetrate through the mucous membrane of the human oral cavity depends primarily on the fat solubility of the medicinal substance, which is expressed through the ratio of the oil / water dispersion, as explained by the example of the carboxylic acids, alkylphenylacetic acids, fatty acids, amphetamines and phenfluramines, acetanilides and steroids.

In the case of steroids, it was noted that their beech-capillary absorption is bi-exponentially dependent on the oil / water distribution coefficient. For sublingual absorption, the advantageous value of iodine P is from 1.6 to 3.3. For a number of derivatives of progesteronewas shown that with decreasing the value of Iodine P (increase of hydrophilicity), the penetration constantubstance through the mucous membrane decreases.

Since there are two parallel pathways for buccal absorption, it has been postulated that substances are characterized by the best penetration of at least the same solubility in water and oil. However, this assertion was opposed to the fact that in the homologous series with increasing hydrophobic penetration also increases.

Other parameters for assessing the penetration of active substances through the mucous membrane of the cheek are

5

92011

6

physical and chemical properties, such as solubility and rate of dissolution. The solubility of the active substance in the oral cavity determines the concentration gradient, which in turn determinesdiffusion pressure. High solubility results in high diffusion pressure. In this case, the volume of liquid present in the oral cavity is only a few milliliters.

The steroid hormones described here are characterized by solubility from 30 μg to a maximum of 1 mg in this volume. However, the number of medicines necessary for medical purposes is greater in the case of all substances. υδ 6,264,981 describes the various capabilities that meet these requirements. In the case of weak acids or bases, i.e., ionogenic compounds, a buffer formulation is described in øδ6,264,981. Bufferity leads to the fact that said substances exist in an ionized form and thus capable of better dissolving the form of salts. However, descriptions of steroid hormones without much effort can not be converted into salt form.

Was investigated the ability to usevarious chemicals as agents to improve penetration and absorption, when sucking through the mucous membrane, and compatibility and safety played an important role. However, in the concentration necessary to increase penetration through the mucous membrane, the use of many known promoters of penetration potentially prizes-led to irritation and / or damage to the drainage membrane.

Since promoters penetrate the "definition" of damage to the mucous membrane, to motility deficiencies to improve penetration by the help of such promoters of penetration is the destruction of the cheek mucus shell, for example, because of the destruction of the upper layers of cells and the decrease in the number of desmosomes, as well as the agitation of the epithets -leaf cheeks with salts, sodium lauryl sulfate or salty acids.

Steroid hormones are a lyophilic compound, which dissolves very poorly in the outflow. Taking into account the metabolic clearance of testosterone (S. Shapd, J. S. Saiip, V. δίατοθνϊο, A. Beid, E., And., And S. Lisaz, B. Epiphany, MeIa, 89, 2936-2941 , 2004) and the pharmacological parameters for buccal tablets of testosterone in men for such a buccal-adhesive table-load account for the bioavailability value, which is 25% (K. B. Viizieu, M. B. Vousse, V. Vosigheg, P. Ragbiap, 3. B. Chaggipidop, B. Epbosigip 175, 813-819, 2002).

Since film-like systems for buccal use are limited in their area, such are thick, then for some steroids, bioavailability of 25% is inadequate. The area of ​​the cloud is surrounded by a free buccal area, which is about 7 cm² on each side. If the area is large, then its uniform and reliable use is less likely. In addition, by increasing the number of applications of clouds or by excessive "sealing" of the cavity without pre-dental efforts, it is impossible to achieve an increase in the concentration of the dissolved active substance in the place of absorption (mucous membrane of the cheek), since in the yes-

In this case, the risk of accidentally swallowing the active substance together with the newly-formed saliva increases.

Therefore, for the purpose of very rapid and significant resorption, films that are the main material, so i dissolve the active substance in a very short period of time (preferably less than 15 light-lines), and thus prepare them for resorption through the chelating mucosa. In addition, for acceleration, it is not advisable to use a number of buccally-used films with insignificant availability. Restoration of the conditions that were in the oral cavity before the use of the first film, in the process of using such a number of films will require a complete replacement of salivation of the oral cavity. In addition, in order to achieve a permanent and reproducible resorption, it is necessary to ensure full re-absorption or removal of the previous wool. As a result of this method, the time interval between the application of two volumes is at least 30 minutes

The solubility of steroid hormones, which are not able to ionization in the physiological ranges of pH values, are insufficiently soluble with iodine value 1,0 to 4,3, with the same resorption can not be improved and other methods described in ıδ6,264,981 (cyclodextrins, inclusion compounds).

The rate of dissolution of the main material and the active substance when used in the oral cavity is very important, since there is constantly formed from about 0.5 to 3 ml / min fresh alean. This saliva when swallowed falls into the gastro-intestinal tract (and this process can not be controlled). There, the active substance, as well as in oral use, is influenced by such negative factors as slow absorption and the metabolic effect of the first passage.

Therefore, the object of the present invention was to develop dissolved in the oral cavity of the steroid hormone release system that is not capable of ionization at physiological pH values, with iodine P value from 1.0 to 4.3 preferably free of charge adding a release promoter steroid hormones, which are included in the compound, with high bioavailability, in particular, more than 50%, while the maximum level in the blood (= maximum concentration) of the steroid hormone occurs within 60 minutes.

The object of the present invention is solved by dissolving the oral cavity of the release system, which comprises from 0.01 to 50% by weight, preferably from 2 to 15% by weight, of at least one steroid hormone from 50 to 99.99% by weight, preferably from 80 to 98 wt.% Of base material. As the main material (carrier), cellulose and its derivatives, such as methylcellulose, ethylcellulose hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), and poly-M-vinylpyrrolidones, vinyl pyrrolidone and vinyl acetate copolymers, starch derivatives, gelatin derivatives, gelatin derivatives and their combinations.

Preferably, the release system comprises from 2 to 15% by weight, particularly preferably from 3 to 8% by weight steroid hormone, in particular androgen, and from 80

7

92011

8

to 98% by weight of the base material, in particular the derivative of the cellulose.

Particularly preferred is the release of a 5% w / w steroid hormone from the group that includes testosterone, 7 & lt; / RTI & gt; methyl 19,

norethosterone and 7 (/ -methyl-11-fluoro-19-

nortetestosterone, and 95 wt. % hydroxypropylmethyl cellulose (HPMC).

According to the invention, the release system, which dissolves in the oral cavity, is predominantly film-like. Such film-forming systems are also called "wraps". Film-release systems according to the invention in the preferred form of execution may be mukoed hemispheric. Under this notion is understood the ability to adhere to the mucous membrane, and in particular, such that after the introduction of the next disconnection, the release system from the mucous membrane is unfeasible.

Film-like release systems according to the invention have a surface area of ​​1 to 10 cm², preferably from 5 to 8 cm² and especially preferably 7cm². At the same time, their unit weight is between 50 and 250 g / m², preferably from 100 to 150 g / m². The latter depends on the thickness, which ranges from 40 to 130 μm, preferably from 50 to 100 μm.

The film-release system dissolves in the oral cavity, preferably for less than 30 minutes, especially preferably for less than 15 minutes. Steroid hormone, which is eliminated from the buccal-applied system of release and gets into the blood circulation system, promotes a rapid increase in the concentration of this hormones in the blood. In this case, the maximum value ofconcentration of such a steroid hormone in the bloodbecomes most achieved during less than 60 minutes-lin, especially preferably in 15-30 minutes afteruse.

Characteristic of the release system according to the invention is the high bioavailability of steroid hormones and the ability to achieve pulse-like changes in the concentration of the hormone in the blood with a significant weakening. Thus, the system of release provides an opportunity to carry pulsating, circadian or similar, adapted to the natural rhythm of mountain-monologue therapy.

With the release system, the bioavailability of steroid hormones can be reduced to at least 25%, preferably at least 50%. Due to the particularly preferred form of action, the steroid hormone is released at a bioavailability of 70 to 75%.

The film-like release system, along with an esoteric carrier material and a steroid hormonal monomine, may also contain other substances, for example, flavoring additives, dye promoters, sweeteners, fillers, liquid, preferably lipophilic auxiliaries that are able to dissolve the steroid hormone and form a friend. a phase in a predominantly hydrophilic material, dissolving agents, pH stabilizers, bonding agents. In the predominant form, the release system does not contain promotional

impregnation troughs, absorption amplifiers and / or penetration promoters.

Preferably, the release system is used for pulsating treatment in a circadian rhythm. The throbbing release of the drug substance all contributes to a better (chronopharmaceutical) treatment of diseases with oscillatory rhythm in their pathogenesis such as asthma, arthritis, tonsillar cancer and other cancers, diabetes, cardiovascular diseases, diseases of the gallbladder and neuralgic diseases.

The release system is particularly advantageous in the treatment, in which the pathway through a single daily application within a short time, preferably less than 60 minutes, reaches an increase in the concentration of the steroid hormone in the blood. Such a system may be used individually as part of androgen therapy once in the morning in order to to achieve a high-end time high concentration of androgen in the blood.

Steroid hormones according to the invention may be estrogens, progesterones, androgens, as well as corticosteroids, the value of Iodine R which is between 1.0 and 4.3.

Preferred estrogen is ethinyl estradiol. The major progesterones are drospirenone, di-ngest, gestodene, levonorgestrel, cyproteronate-tat.

Within the scope of the invention, suitable corticosteroids are hydrocortisone, hydrocortisone-21-acetate, methylprednisolone acetonate, prednisone, deflaccharide, deflazacort-based alcohol, fluocortolone or fluocorticolonid hydrate, fluocortolone-21-pivalate.

In the framework of the invention, suitable androgens are testosterone, dihydrotestosterone 7a-methyl-19-nortetestosterone (MENAT), MENAT-17-acetate, 7a-methyl-113-fluoro-19-nortetestosterone (ER-MEAT), sitherolone, methanolone, nandrolone, oxandrolone androstenedione.

The range of values ​​for Iodine P for all examples ranges from 1.0 to 4.3.

Advantageously according to the invention are provided to the release systems containing androgens MENAT or R-MENAT.

Particular advantage is given to release systems containing 95% HPMC and 5% MENET or ER-MENET.

The following examples explain the use of suitable release systems ("clouds"). Table 1 shows the dried folds of various compositions

Example 1:

5 g of MEGN are placed in 700 ml ethanol / water (50:50) solution and stirred until full dilution. If necessary, the dissolution process is post-fed by ultrasound. Then add 95 g of hydroxypropylmethylcellulose (HPMC) and stir until it is completely dissolved. The mixture is degassed, smoothed with the appropriate box and dried. Obtain a thin film with a thickness of 50 to 100 μm. By selecting samples of the appropriate size,

9

92011

10

receive transparent clouds, the content of which is 1.5 MG.

Example 2:

3g of menthol and 2g of thymol are added to 26g of LLM3333 (= a mixture of mono and diglycerides of oleic acid) and 4g Tadeep 80 (= polyoxyethylene sorbitan monoleate). The mixture is stirred to dissolve the tweed-rye substances. Then, in this mixture, add 5 g of MENAT, stir until the dissolution of the active substance. In a 600 g mixture of ethanol / water (50:50), add 60 g of HPMC and mix until it is completely dissolved. The organic phase is slow and with rapid mixing is added to the aqueous phase, andform a thick creamy mass. After the degasification of the mixture and its smoothing, the mixture is dried. Odor-rust a thin, transparent film whose thickness is

50 to 100 μm. When selecting samples of the appropriate size, transparent clouds are obtained, the content of which is 1.5 mg in the form of MEN.

Example 3:

5 g of MEGAT is placed in a mixture of 20 g of ΛΜΜ33 300.10 g of octanol and 5 g of lecithin. The mixture is stirred to dissolve solids. Then in 600g water place 60g of HPMC and mix until complete dissolution. The organic phase is rapidly added to the aqueous phase, and a dense cream mass is formed. After degassing the mixture and its smoothing, the mixture is dried. Obtain a thin transparent film, the thickness of which makes from 50 to 100 μm. When selecting samples of the appropriate size, transparent clouds are obtained, the content of which is 1.5 MG.

Table 1

Compositions of dried clouds on the basis of ΜΕΝΤ

<tr><td><p>Prickle</p></td><td><p>ΜΕΝΤ</p><p>(%)</p></td><td><p>HPMC</p><p>(%)</p></td><td><p>ΑΤΜΟ3 300 (%)</p></td><td><p>Tumeep 80 (%)</p></td><td><p>Octanol</p><p>(%)</p></td><td><p>Lecithin</p><p>(%)</p></td><td><p>Menthol</p><p>(%)</p></td><td><p>Timol</p><p>(%)</p></td></tr><tr><td><p>1</p></td><td><p>5</p></td><td><p>95</p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td><td><p></p></td></tr><tr><td><p>2</p></td><td><p>5</p></td><td><p>60</p></td><td><p>26</p></td><td><p>4</p></td><td><p></p></td><td><p>-</p></td><td><p>3</p></td><td><p>2</p></td></tr><tr><td><p>3</p></td><td><p>5</p></td><td><p>60</p></td><td><p>20</p></td><td><p>-</p></td><td><p>10</p></td><td><p>5</p></td><td><p>-</p></td><td><p>-</p></td></tr>

It should be noted that the dried systems behind the prime-order 1 contain a monomolecular disperse steroid hormone, while in the cases of 2 and 3 steroid hormone is represented as a solution in the oil phase, which is part of the main material as a separate phase. Through the use of liquid, mainly lipophilic auxiliary substances that are capable of dissolving the steroid hormone and forming a second phase in a substantially (preferably hydrophilic) material, film-like systems containing steroid hormones may be obtained as a "two-phase system"

Experimental data

During the clinical examination of healthy men, suitable materials were determined on the basis of MENNET for clinical application. Important aspects of the study relate to the level of active substance in the blood, which is achieved by the cloud and time interval, as well as the general compatibility. Explore three different dosages of the cavity. Each patient in the course of cross-examination is given all three doses once. Intermediates of the medicinal product carry the phase exemption from previously adopted means, which is at least 48 hours.

Three doses are determined in such a way that there is a real possibility of measuring the level of MENAT in the blood by a well-known method, even with a dense bioavailability at least at high doses, and on the other hand, in case of high bio-dullness, theoretically possible maximum values ​​are in the safe range, which is determined by the clinical and preclinical investigated-nami.

Dosage groups are 0.5mg, 1.5mg and 3.0mg. The magnitude of the dosage is determined by the size plate. The used blanket contains 0.225mgMENT / 1cm². When dosage of 0.5mg surface areaoblank is 2.22cm² (composition a) when pre-mined 1.5m, the surface area of ​​the cloud is 6.67 cm² (composition b), and at a dosage of 3,0 mg, the surface of the two wafers is 6.67 cm². The lacer puts a blanket on the mucous membrane of the cheek. At least the dosage is always used, the case, the average dosage - on the left, and most doses - on both sides.

In general, 11 men aged from 23 to 42 years old are taking part in the study, which take possession of no noticeable side effects. Local compatibility is very high. As a result of the visual inspection of the place of application, there were no signs of unwanted local reactions. Subjects have their own subjective impressions of local-level compatibility when using the Visual Analogue Scale. And here too there are no signs of undesirable effects.

Cloudy with a large number of applications ro-complex within 15 minutes. In some cases, this process goes on for longer; maximum duration in one case was 33 minutes. The above data confirms the assumption that in case of a significant increase in the dissolution time of the substrate, bioavailability decreases.

Cloudy on the basis of ΜΕΝΤ unexpectedly characterized by high bioavailability of about 70 to 75% (Table 2).

11

92011

12

Table 2

Bioavailability of the cloud on the basis of ΜΕΝΤ

<tr><td><p>Processing</p></td><td><p>Composition</p></td><td><p>Dosage</p><p>(mg)</p></td><td><p>AiC (0-IIAAS)</p><p>average</p><p>geometer.</p><p>[mghd / ml]</p></td><td><p>AiC (0-IIAA) average geometry.normalized dosage [nghh / ml]</p></td><td><p>AiC (0-IIAA) average geometry.normal dosing [nghh / ml]</p></td><td><p>Bioavailability</p><p>[%]</p></td></tr><tr><td><p>AND</p></td><td><p>and</p></td><td><p>0,50</p></td><td><p>3.78</p></td><td><p>3.78</p></td><td><p>4.98</p><p>(after the vnutrivenn.Introduction</p><p>0.5mg MENN)</p></td><td><p>75.9</p></td></tr><tr><td><p>IN</p></td><td><p>B</p></td><td><p>1.50</p></td><td><p>11.00</p></td><td><p>3.67</p></td><td><p>73.6</p></td></tr><tr><td><p>WITH</p></td><td><p>B</p></td><td><p>3.00</p></td><td><p>21.10</p></td><td><p>3.52</p></td><td><p>70.6</p></td></tr>

Individual variation of total exposure is 2?%.

Both the value of Cmax and the total exposure indicate a significant linearity of the dosage. Nibbles are reached within 15-30 minutes, then these values ​​decrease rapidly; in more than 4 hours it is possible to detect the missing concentrations of the medium.

To determine the serum level of MENN, the method of PX-MS (liquid-chromatography-mass spectrometry) is used (especially developed and confirmed for this purpose). The method is induced by negative chemical ionization (N01 = pediatric spetis and iopiza iiop) and allows to achieve

High sensitivity, which allows measuring the concentration to a lower limit value of approximately 60 pg / ml (Iomega iitia, iiaipiisiisioop).

In order to carry out measurements in the case of devices with low sensitivity, the RH-MS method is also used, which instead uses N-type electron ionization (EI = eIesiogo iopizaIiop).

In general, the concentration of MENT can also be determined by other methods that are also used to detect steroid hormones. Examples of radioimmunoassay are RH-MS or HPLC methods (Highly Effective Liquid Chromatography).

Table 3

An overview of the pharmacokinetic parameters of the studied dosages of clouds on the basis of MNNT

<tr><td><p>Processing</p></td><td><p>Composition</p></td><td><p>Dosage</p><p>(mg)</p></td><td><p>Fly is the average geometric. (SO) [ng / ml]</p></td><td><p>^ ah mean value (range) [h]</p></td><td><p>AiC (0-IIAAS) deoteap (SU) [nghh / ml]</p></td></tr><tr><td><p>AND</p></td><td><p>and</p></td><td><p>0,50</p></td><td><p>3.29 (67.8%)</p></td><td><p>0.25 (0.25-2.00)</p></td><td><p>3.78 (44.5%)</p></td></tr><tr><td><p>IN</p></td><td><p>B</p></td><td><p>1.50</p></td><td><p>8.98 (39.4%)</p></td><td><p>0.50 (0.25-0.75)</p></td><td><p>11.0 (17.8%)</p></td></tr><tr><td><p>WITH</p></td><td><p>B</p></td><td><p>3.00</p></td><td><p>18.2 (31.2%)</p></td><td><p>0.50 (0.25-0.75)</p></td><td><p>21.1 (16.2%)</p></td></tr>

SU = coefficient of variation

The results of clinical trials with the use of ΜΕΝΤ suggest that for the effective prevention of hypogonadal complications in men, the serum concentration of the substance should be at least 0,3 ng / mg (approximately 1 nmol / l). It is about 10 lower than the smallest concentration of testosterone.

Such a level of concentration by means of a MECNT-based region is achieved without problems. When given pharmacokinetics, a cloud based on MENN can be used for intravenous administration. Due to the short half-life of the cup, it is appropriate to use where the non-prolonged but very effective release of the androgen is desirable. Under the "short term" in this case, the time period is less than 60 minutes, preferably 15 to 30 minutes.

The advantage of such an application, which restricts the cases of urgent need, isthat the inhibitory effect on the testicular function is

minimal, while it does not significantly damage the corresponding physiological functions. Unlike androgen-free products with a long-term release, when using the release system in conjunction with androgen as an active substance, there is no disorder of gonadal synthesis of testosterone nor inhibition of spermatogenesis.

Therefore, the scope of the use of the release system according to the invention, with androgen as an active substance, is a single daily application for the restoration of circadian rhythm in adolescent men. The age-related decline in endogenousconcentration of testosterone in men is mainly characterized by the fact that the circadian rhythm is lost. An increase in testosterone levels in the morning is no longer observed. Because of this, experts find a large discrepancy in the level of testosterone, young and old men in conducting an in-vivo blood test, while at carrying out an analysis of the evening, only slight differences can be noticed.

13

92011

14

With the help of the release system, according to the guideline, one can replenish the age-related deficiency of androgen with respect to its rhythm, and it almost does not affect the autogenic pro-

testosterone development test. This method makes it possible to treat patients in a very simple and convenient way.

Computer layout M. Lomalov 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