Nanostructured sildenafil base, its pharmaceutically acceptable salts and cocrystals, their compositions method of preparing them and pharmaceutical compositions containing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns a stable composition of nanostructured Sildenafil inhibiting cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDEV) containing a nanostructured Sildenafil base or its pharmaceutically acceptable salts having an average particle size of less than approximately 500nm, a stabilising agent, wherein the composition is prepared in a microfluidics-based continuous-flow tank reactor, and the composition possesses a semi-amorphous structure. The group of inventions also concerns a method for preparing the composition of nanostructured Sildenafil; using the above composition for preparing the pharmaceutical composition for treating male or female sexual dysfunction and pulmonary arterial hypertension.

EFFECT: group of inventions provides the improved solubility of the composition.

8 cl, 11 ex, 14 dwg

 

Field of the INVENTION

The present invention is directed to nanostructured (in the form of nanoparticles) basis of sildenafil, its pharmaceutically acceptable salts and co-crystals, compositions containing them, process for their preparation, containing their pharmaceutical compositions.

Nanoparticles grounds of sildenafil, its pharmaceutically acceptable salts and co-crystals, compositions containing them in accordance with the invention, have an average particle size of less than about 500 nm. The basis of sildenafil and its salts, in particular the citrate sildenafil inhibits cGMP-specific phosphodiesterase type 5 (PDEV), an enzyme that regulates blood flow in the penis. The composition of the invention useful in the treatment of male or female sexual dysfunction and pulmonary arterial hypertension (LAS).

PRIOR art

A. Prior art relating to education/obtaining nanoparticles

Development of nanoparticles for pharmaceutical applications has to deal with the emergence of new technologies for the development of production solutions custom systems for drug delivery. Delivery systems of medicines should positively affect the rate of absorption, distribution, metabolism and excretion of drugs or other related chemicals in the body. In addition, the delivery system l�of drugs should allow the medication to reach its receptor target and affect the signal transmission and the activity of this receptor. Materials for drug delivery should be compatible with him, it's easy to contact your specific medication, and have the ability to degrade into fragments after applying that, or undergo metabolism or excreted via normal excretory route.

Another approach is to obtain the active ingredient in the form of nanoparticles.

Compositions in the form of nanoparticles is described, for example, in US 5298262, US 5318767, US 5328404, US 5336, US 5340564, US 5466440, US 5552160, US 5560931, US 5573783, US 5593657, US 6045829, US 6264922, US 6428814, US 6592903, US 6656504, US 6976647.

The nanoparticles of the active pharmaceutical ingredients can be obtained using, for example, the methods of grinding, homogenization, precipitation, or methods of supercritical fluids, which are known in the art. Methods of obtaining compositions in the form of nanoparticles is also described in US 5718388, US 5862999, US 5665331, US 5543133, US 5534270, US 5510118, US 5470583, US 2009/0028948 and EP 1658053.

B. Prior art relating to the sildenafil citrate

The sildenafil citrate is designated chemically as 1-[[3-(6,7-Ligero-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

The sildenafil citrate is a crystalline powder from white to whitish color with a solubility of 3.5 mg/ml in water and a molecular weight 666,7.

Sposobem receipt was first described in US 5250534. It is known that sildenafil citrate can be used for the treatment of erectile dysfunction, as discussed in US 6469012.

The drug sildenafil citrate is prepared in the form of blue tablets rounded-diamond-shaped, film-coated, equivalent to 25 mg, 50 mg and 100 mg citrate sildenafil for oral administration, and it is commercially available under the name Viagra.

In addition, in WO 1999/021562 described that the PDEV inhibitors can be applied for the treatment of female sexual dysfunction.

Pharmacological properties

Oral sildenafil citrate is rapidly absorbed with peak plasma concentrations (Cmax)appearing within 1 hour. Absolute bioavailability of 41%. Food slows absorption, but does not affect the area under the curve of concentration of sildenafil in plasma (AUC). AUC and Cmaxwere proportional to dose in the range of a single dose of sildenafil citrate from 1.25 up to 200 mg.

Absorption and distribution

Oral sildenafil citrate is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) after oral dosing on an empty stomach. When Viagra take with food with high fat content, the rate of absorption is reduced, with an average slowdown of tmax60 min and average reduction of Cmax29%.

Side effects

<> It is known that sildenafil citrate, taken orally, may cause headache, flushing, visual effects, dyspepsia. The use of oral sildenafil citrate is contraindicated in subjects taking organic nitrates.

Due to the low solubility of sildenafil citrate in water (3.5 mg/ml), low (41%) bioavailability and side effects in the art there is a need to strengthen

lipophilicity/bioavailability/increased absorption/reduction

side effects/reducing the dosage/reduction of food effect with a view to overcoming these and other problems associated with the use of conventional drugs sildenafil citrate prior art. In addition, these problems can be solved by surface modification to reduce presystemic metabolism, or by modifying the metabolism of sildenafil citrate. In addition to traditional medication of sildenafil citrate transdermal/topical application could enhance the bioavailability and/or reduce the time needed to achieve the desired effect of sildenafil citrate. The present invention satisfies this need.

Description of the INVENTION

In the present invention is described nanostructured (in the form of nanoparticles) basis of sildenafil, its pharmaceutically acceptable�Lee and co-crystals, their compositions with enhanced

lipophilicity/bioavailability/increased absorption and dissolution rate/reduced side effects/reduced

dosage/reduced food effect.

As shown in the following examples, not every combination of stabilizers will result in the formation of stable nanoparticles.

It was found that stable nanoparticles of sildenafil can be obtained in a continuous flowing manner, preferably in a continuous flow method on the basis of microjet technology, using selected stabilizers. The expression is usually used for sildenafil base sildenafil, its pharmaceutically acceptable salts and co-crystals.

The invention includes the base of the nanostructured sildenafil, its pharmaceutically acceptable salts and co-crystals having an average particle size of less than about 500 nm.

Nanostructured basis of sildenafil, its pharmaceutically acceptable salts and co-crystals in accordance with the invention has an average particle size of 500 nm to 50 nm, preferably from 350 nm to 50 nm, preferably from 100 nm to 50 nm.

Further, the invention relates to stable compositions of nanostructured sildenafil containing:

(a) nanostructured basis of sildenafil, its pharmaceutically acceptable�e salts or co-crystals, having an average particle size of less than about 500 nm;

(b) at least one anionic polyelectrolyte or a stabilizer, or a mixture thereof, or any additional stabilizer for steric and electrostatic stabilization.

The composition according to the invention is obtained in a flow reactor with continuous action, preferably in a flow reactor continuous action on the basis of microjet technology.

Compositions in accordance with the invention comprise a base of sildenafil or its pharmaceutically acceptable salt or co-crystal having an average particle size of less than about 500 nm, preferably from 500 nm to 50 nm, preferably from 350 nm to 50 nm, preferably from 100 nm to 50 nm.

In the compositions according to the invention: (a) basis of sildenafil or its pharmaceutically acceptable salt or co-crystal is present in amounts selected from the group consisting of: from approximately 99.5% to about 0.001% or from about 95% to about 0.1%, and from about 90% to about 0.5% mass/mass based on the total combined weight of the base of sildenafil or its pharmaceutically acceptable salt or co-crystal and at least one stabilizer or polyelectrolyte, not including other excipients; (b) the stabilizer or the polyelectrolyte is present in amounts selected from the group consisting of: from about 0.5% to prima�but 99.999% mass/mass, from about 5.0 percent to about 99.9% mass/mass and from about 10% to about 99.5% mass/mass based on the total combined dry weight of the base of sildenafil or its pharmaceutically acceptable salt or co-crystal and at least one stabilizer, not including other excipients.

In the compositions according to the invention the basis of sildenafil or its pharmaceutically acceptable salt or co-crystal can be used in a phase selected from a crystalline phase, amorphous phase, semi-crystalline phase, polimorfnoe phase, and their mixtures in any polymorphic form.

To obtain compositions according to the invention can be used anionic polyelectrolytes, preferably nucleic acids, proteins, teichoic acids, polypeptides and polysaccharides (such as pectin, carrageenan, alginates, carboxymethylcellulose (natural polyelectrolytes)) and poly(styrelseledamot sodium) (PSS) and polyacrylic acid and its derivatives, crosslinked with allyl ethers, either with sucrose or pentaerythritol (e.g. Carbopol 2623, Carbopol R, Carbopol 980, Pemulen TR1, Pemulen TR2), polymers and copolymers based on poly(meth)acrylate (Eudargit®) (synthetic); non-ionic stabilizers, preferably polyvinylpyrrolidone, poly(2-ethyl-2-oxazoline), poly(methyl vinyl ether), polyvinyl alcohol, copolymer attelboro ester of acetic acid, and 1-ethenyl-2-pyrrolidinone (copolymers of PVP/VA), polyethylene glycol and its derivatives (e.g. PEG 2000, 6000, 35000), block copolymers of ethylene oxide and propylene oxide and their derivatives (e.g. Pluronic 10500, 6100, 6800) polyoxyethylene esters of sorbitol and fatty acids (for example, commercially available products tween®, such as, for example, tween® 20 and tween® 80 (ICI Speciality Chemicals)); and as an additional stabilizer can be preferably used derivatives of hydroxypropyl cellulose, sodium lauryl sulfate, dodecylbenzenesulfonate sodium, succinates of tocopherolacetate, polyethoxysiloxane castor oil and derivatives thereof, any cationic stabilizers, preferably lauryldimethylamine chloride, alkylbenzyldimethylammonium chloride, alkylbenzyldimethylammonium bromide, benzyltrimethylammonium bromide, benzalkonium chloride, hexadecyltrimethylammonium bromide.

Advantages of compositions of the invention include, but are not limited to: (1) smaller tablet or other solid dosage forms and favorable transdermal/topical application; (2) smaller doses of drug required to obtain the same pharmacological effect as compared with conventional forms of sildenafil citrate; (3) increased bioavailability as compared to conventional forms of sildenafil citrate; (4) improved pharmacokinetic profiles; (5) increased soon�the motion for dissolution of the nanoparticles of sildenafil citrate, compared with the conventional forms of the same active compound; (6) modified the metabolism of nanoparticles of sildenafil citrate.

Another aspect of the invention is a method of producing nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals, comprising mixing the corresponding solution of the base of sildenafil or its pharmaceutically acceptable salt or co-crystal with a solution of one or more than one stabilizer or polyelectrolytes or mixtures thereof, if desired, in the presence of a pharmaceutically acceptable acid or base, in a flow reactor with continuous action.

Preferably, the method of obtaining the composition according to the invention is carried out by (1) dissolving the base of sildenafil or its pharmaceutically acceptable salt or co-crystal and perhaps one or more than one stabilizer, or polyelectrolyte, or a mixture thereof in a suitable solvent; (2) addition of a song from a stage of (1) to a solution containing one or more than one polyelectrolyte or a stabilizer, or a mixture thereof, if desired, in the presence of a pharmaceutically acceptable acid or base; and (3) deposition of the composition from step (2).

Preferably, the method of obtaining the composition according to the invention is carried out by (1) dissolving the base of sildenafil or its pharmaceutically acceptable salt or co-crystal� and one or more than one stabilizer in a suitable solvent; (2) addition of a song from a stage of (1) to a solution containing one or more than one polyelectrolyte or a stabilizer, or a mixture thereof, if desired, in the presence of a pharmaceutically acceptable acid or base; and (3) deposition of the composition from step (2).

Another preferred form of the invention is one where the method of obtaining the composition is carried out by (1) dissolving the base of sildenafil or its pharmaceutically acceptable salt or co-crystal and one or more than one stabilizer in a suitable solvent; (2) addition of a song from a stage of (1) to a solution of pharmaceutically acceptable acid or base; and (3) deposition of the composition from step (2).

The method is carried out by (a) using two different solvents miscible with each other, where the basis of sildenafil or its pharmaceutically acceptable salt or co-crystal is soluble only in one of them, or (b) use the same solvent in two stages, where the polyelectrolyte complex of the founding of sildenafil or its pharmaceutically acceptable salt or co-crystal forms nanostructured particles, practically, with the restriction that the applied polyelectrolyte, stabilizer(s) is soluble in the solvents used.

As a flow reactor continuous action� preferably using a flow reactor with continuous action-based microjet technology, described in the publication Microfluid Nanofluid DOI 10.1007/s 10404-008-0257-9 authors I. Hornyak, V. Borcsek and F. Darvas.

If in the method of the invention using two different solvent for chemical precipitation, they must be miscible with each other, where sildenafil is soluble only in one of them. Such solvents can preferably be dimethyl sulfoxide, ethanol, isopropanol, tetrahydrofuran, acetone, methyl ethyl ketone, dimethylformamide, diethylene glycol ethyl ether, pyridine. For the formation of polyelectrolyte complex is preferably possible to use a solution water-based.

The particle size of nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals can be influenced by the solvent, the flow rate and the ratio sildenafil - stabilizer.

Another aspect of the invention is directed to the good/instantaneous re-dispersibility of the solid nanosized forms of sildenafil in biologically relevant environments, such as in physiological solution, the solution pH of 2.5 HCI.

Another aspect of the invention is a pharmaceutical composition comprising a stable nanostructured basis of sildenafil or its pharmaceutically acceptable salts or co-crystals, or a composition in accordance with the invention and possibly pharmaceutically reception�Amie excipients.

A pharmaceutical composition according to the invention can be prepared: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, ear, local, buccal, nasal and local administration; (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized preparations, buccal films, tablets, capsules; (C) in a dosage form selected from the group consisting of drugs controlled release, quickly melting drugs, drugs, sustained release, prolonged release preparations, preparations pulsed release and mixed drugs, a rapid release and controlled release; or (d) any combination of (a), (b) and (C).

Compositions can be prepared by adding different types of excipients for oral administration (solid, liquid), vaginal, rectal, local (powders, ointments, gels, or drops) or local injection and the like.

The most preferred dosage form according to the invention is buccally film and gel dosage form, although you can use any pharmaceutically acceptable Lek�Stenou form.

For oral delivery in the human body, nanoparticles can also be administered in the form of their aqueous dispersion in the quality of the finished dosage form. This is the way of delivery without additional processing after the formation of the nanoparticles. However, the low solubility of the drug or polymer in the aqueous medium or the bad taste of the drug may require the inclusion of colloidal particles in a solid dosage form, i.e. in capsules and tablets.

Alternative aqueous dispersion of colloidal particles can be included in solid dosage form is a liquid, for example, by granulation of suitable fillers with colloidal dispersion with the formation of the granulate. These pellets can then be filled into capsules or pressed into tablets. Alternative by layering the dispersion, for example, on sugar pills as carriers in a fluidized bed to obtain a solid form of nanoparticles. These ways of manufacturing cores of tablets or pellets, or pills could potentially follow stage coverage with obtaining tablets with a film coating, or granules coated in a capsule as finished dosage forms.

Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions,suspensions or emulsions, as well as sterile powders for recovery in sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and the like), suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters, such as ethyloleate. Appropriate fluidity can be maintained, for example, through the use of a coating such as lecithin, by maintenance of required particle size in the case of dispersions and by the use of surfactants.

Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders and granules. In such solid dosage forms, the active agent is mixed with at least one of the following: (a) one or more than one inert excipient (or carrier) such as sodium citrate or disodium phosphate of calcium; (b) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (C) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia gum; (d) humectants, such as glycerol; (e) leavening agents, such as agar-agar, calcium carbonate�, potato or tapiokovogo starch, alginic acid, certain complex silicates and sodium carbonate; (f) the dissolution retarders, such as paraffin; (e) accelerators suction, such as Quaternary ammonium compounds; (h) wetting agents such as cetyl alcohol and glycerylmonostearate; (i) adsorbents, such as kaolin and bentonite; and (j) materials for film coatings, such as esters of methacrylic acid/methacrylate, polyvinylacetate, acatitla cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills dosage form may also comprise buffering agents.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the basis of sildenafil or its pharmaceutically acceptable salts or co-crystals of the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers agents and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl SP�RT ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, peanut oil, wheat germ, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, esters of sorbitol and fatty acids, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, sweetening, flavoring and flavoring agents.

The pharmaceutical compositions of the invention exhibit enhanced lipophilicity/bioavailability/increased absorption and dissolution/reduced side effects, they can be used in reduced dosage in the treatment of male and female sexual dysfunction and pulmonary arterial hypertension compared with the conventional form of sildenafil citrate.

The present invention also is directed to methods for the treatment of erectile dysfunction, female sexual dysfunction and pulmonary arterial hypertension (LAS), using a new sildenafil in the form of nanoparticles, disclosed in this application.

A. Preferred characteristics of the nanoparticles of sildenafil according to the invention

1. Improved bioavailability

Intended�up, what is the composition of nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals according to the invention exhibit increased bioavailability, faster onset of action, reduced food effect and require smaller doses as compared with the previously known conventional drugs sildenafil citrate.

Example 1:

Comparison of bioavailability of two drugs sildenafil in dogs. The aim of this study was to investigate the relative bioavailability of buccal drug test (composition of nanosized sildenafil) of example 9 and reference tablets Viagra, introduced in oral conditions.

Animals

Dog breed Beagle is appropriate, not related to rodents, for pharmacokinetic studies and acceptable to regulators. These dogs are readily available, easy to handle, contain and meter, and they are suitable for the study of the curve of plasma from each individual animal.

Systemic effect was investigated in the same three dogs for both test and reference substance. This group size is optimal for pharmacokinetic studies in large animals.

Animals received food for dogs Ssniff Hd-H, manufactured by firm Ssniff, Spezialdiaten GmbH. Food was offer�n daily 300 g/dog at about the same time. The next morning, the remaining feed was removed.

Before the injections, the animals were starved over night and day treatment 1 hour before injections animals received approximately 150 g of standard diet. Other 150 g of feed were offered in approximately 4 hours after administration.

Introduction

The relative bioavailability of the drugs of sildenafil was investigated in a single dose (25 mg/dog are non-toxic oral dose), in the two-period case study. Buccal introduction was carried out by placing nanostructured solid drug on the surface of the mucous membrane in front of the mouth and holding his mouth for 15 min, to allow absorption of the drug. The drug was dissolved in the mouth, and by 15 min residue of the administered dose was not.

The collection of blood and separation of plasma

To determine levels in plasma sildenafil approximately 3 ml of blood was collected in plastic bottles with a lithium salt of heparin as an anticoagulant. The time points of blood collection are shown below for both periods: before dosing (0 min), 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 6 h, 9 h, 12 h, 24 h and 48 h after dosing.

Blood was drawn from v. cephalica antebrachii or v. saphena sterile disposable needles. After taking the blood samples were kept chilled laid out on shaved ice before centrifugation. Plasma samples received�by centrifugation of blood at 2000 g for 10 min at 4°C within 60 min after blood sampling. The separated plasma (approximately 1 ml) was transferred into Eppendorf tubes. Plasma samples were immediately frozen and stored in a freezing apparatus for low-temperature freezing (-20±5°C) until analysis.

Concentration of sildenafil was determined using reliable chromatographic bioanalytical method.

Pharmacokinetic evaluation

The pharmacokinetic evaluation was performed by the analytical Department ATRC using the software WinNonlin Professional Version 4.0.1 (Pharsight Corporation, USA). Individual curves of plasma levels versus time was evaluated using compartmental method.

Results

As oral administration of tablets Viagra and buccal introduction nanostructured sildenafil (in both cases, the dose of 25 mg) resulted in a detectable concentrations in serum, exhibiting a biphasic profile in the interval 15 min - 48 h. Buccal absorption of nanostructured sildenafil occurred with faster emergence. Plasma concentrations for buccal administration can be detected within 15 min after administration, whereas in this time of sildenafil in plasma could not be detected after administration of the tablet. In addition, the concentration of sildenafil in plasma for the buccal administration were still high after 30 min (Fig.2).

The area under the curve d�I the whole study period (0-48 h) (AUC last), Cmaxand tmaxcalculated on the basis of curves and determined the relative bioavailability (Frei) for nanoscale drug compared to a commercially available drug (Fig.12 (table 1)). Two drugs and two routes of administration have very similar pharmacokinetic profile, with almost identical values of tmax. Exposure values (AUC) and Cmaxare lower for buccal injection relative bioavailability of 62% compared with oral introduction available with the sale of the drugs (Fig.1, Fig.12 (table 1)).

Overall, buccally introduction nanostructured sildenafil results in a more rapid appearance of sildenafil in plasma and to a similar kinetic profile with a lower bioavailability. In addition, no effect of the feeding/fasting could not be expected in the case of buccal administration.

Fig.1: Concentrations of sildenafil in serum at early time points after oral administration of the reference tablet and buccal introduction 25 mg/kg of nanostructured sildenafil.

Fig.2: concentration of sildenafil in the serum after oral administration of the reference tablet and buccal introduction 25 mg/kg of nanostructured sildenafil.

Fig.12 (table 1): the Main pharmacokinetic parameters p�orally the introduction of Viagra and buccal introduction of sildenafil in the form of nanoparticles.

2. Solubility and dissolution profiles of the compositions of nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals according to the invention

Composition of nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals of the invention have increased solubility and dissolution profile due to the reduced particle size and the formation of nanostructured particles. Rapid dissolution entered the active agent is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability.

Example 2:

Definition of Cmax

The solubility of nanostructured sildenafil citrate of example 9 compared to the reference API was determined in distilled water by measurements in the ultraviolet and visible spectral range UV-VIS (Helios spectrophotometer Alfa UV) at a wavelength of 292 nm and room temperature. Re-dispersed sample was filtered through 0.45 μm disposable syringe filter. To verify the presence of the nanoparticles in the solution was irradiated with a red laser sensor operating at a wavelength of 670 nm. If dispersion is not observed, the filtering was successful, and the solution did not contain nanoparticles.

The solubility of nanostruc�mirovogo sildenafil citrate is 24.5 mg/ml, that is 6.8 times higher than the solubility of sildenafil citrate in distilled water.

Fig.3: Enhancement of solubility of sildenafil citrate drug in the form of nanoparticles.

Example 3:

The increased rate of dissolution of nanoscale compositions

The dissolution rate of nanostructured sildenafil citrate of example 9 compared to the reference API was determined in distilled water by measurements (Agilent 8453) at a wavelength of 292 and room temperature. 37.5 mg reference sildenafil citrate, was suspended in 1.5 ml of distilled water, whereas 40,76 mg powder nanostructured sildenafil citrate containing 37.5 mg of sildenafil citrate was suspended in 1.5 ml of distilled water. The suspension was stirred for 1 h, 1,3 and 5 min, and then filtered through 0.45 μm disposable syringe filter. To verify the presence of the nanoparticles in the solution was irradiated with a red laser sensor operating at a wavelength of 670 nm. If dispersion is not observed, the filtering was successful, and the solution did not contain nanoparticles.

The results showed a significant difference. In the first second amount of dissolved sildenafil citrate from nanostructured sildenafil citrate was 6,19 times higher compared to the benchmark.

Fig.4: dissolution Profile of nanostructured sildenafil citrate compared�Oia with the standard of sildenafil citrate.

3. Crystallographic structure of nanostructured compositions of the founding of sildenafil or its pharmaceutically acceptable salts or co-crystals according to the invention

The chemical stability of solid drugs affect the crystalline state of the drug. Many drug substances exhibit polymorphism. Each crystalline state has a different chemical reactionary. Stability of drugs in their amorphous form is usually lower than the stability of drugs in their crystalline form, in connection with the higher free energy of the amorphous state.

Reduced chemical stability of solid drugs due to mechanical loads, such as grinding, is related to the change in the crystalline state.

The chemical stability of solid drugs is also affected by differences in surface area. For the reaction, which proceeds on a solid surface medications, the increase in surface area can increase the amount of drugs involved in the reaction.

Example 4:

The determination of the crystallographic structure

Stable compositions of amorphous/partially crystalline/crystalline/polymorphic base of sildenafil or its pharmaceutically acceptable salts or co-crystals according to the invention exhibit significantly enhanced Rast�almost due to a larger surface area compared to crystalline benchmark.

The structure of the nanoparticles of sildenafil citrate of example 9, obtained by forming a polyelectrolyte complex, using Carbopol 971 (polymer of acrylic acid crosslinked with allyl ethers), was investigated using analysis of x-ray diffraction (powder diffractometer Philips PW1050/RTG 1870). Measurements showed that the composition of the nanostructured sildenafil citrate are partially crystalline. Wide angle of reflection between 2θ values of 15 and 20 indicates the amorphous structure of HPMC 971. The characteristic angles of reflection of the crystal of sildenafil citrate can be found in the diffraction DWP nanosized sildenafil citrate, but at a lower intensity. This showed that the formation of nanoparticles results in partially crystalline form of the citrate of sildenafil. X-ray diffraction pattern shown in Fig.6.

Based on these diffraction patterns can be concluded that the particle size of the reference sildenafil citrate is 1-2 μm, however, the nanosized sildenafil citrate has a particle size less than 100 nm.

Fig.5: X-ray diffraction pattern of the reference sildenafil citrate, nanostructured sildenafil citrate according to the invention and HPMC 971.

4. Profiles re-dispersibility of the compositions of nanostructured grounds with�ldenafil or its pharmaceutically acceptable salts or co-crystals according to the invention

An added feature of the compositions of nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals of the present invention is that the dried nanoparticles stabilized by surfactant(s) can be re-dispersed instantly or with the use of traditional re-dispersing agents such as mannitol, sucrose.

Example 5:

Test re-dispersibility

Test re-dispersibility was conducted to determine the solubility of nanostructured sildenafil citrate of example 9 in distilled water. 15 mg of lyophilized nanostructured sildenafil citrate and mannitol 50 re dispersible in 10 ml of distilled water with vigorous stirring. The size of the particles re-dispersed sample was evaluated using DSR (dynamic light scattering) (instrument Nanotrac, Mictrotrac Co., USA).

The average size of the particles re-dispersed nanostructured sildenafil citrate (based on the average intensity) is d=230 nm, whereas the value of d(90) is 368 nm, as shown in Fig.7.

A significant benefit that can be obtained as a result of formation of the nanoparticles is that the nanoparticles of sildenafil citrate according to the present invention can repeat�but disperse after the procedure of drying/receiving solid preparation, and they have similar average particle size. Having such average particle size after re-dispersing dosage form may lose the benefits obtained due to the formation of nanoparticles. The nanoscale suitable for the present invention is the average particle size of less than about 290 nm.

Fig.6: Size and size distribution of the nanoparticles of sildenafil citrate before and after re-dispersion.

5. Reinforced to increase lipophilicity profiles of suction and permeability of nanostructured compositions of the founding of sildenafil or its pharmaceutically acceptable salts or co-crystals according to the invention

Due to the phospholipid nature of cell membranes, a certain degree of lipophilicity is often a requirement to medicinal connection not only to ensure that it is absorbed through the intestinal wall after oral administration, but also, perhaps, to ensure that it exerts its pharmacological action on the target tissue (F. Kesisoglou et al. /Advanced Drug Delivery Reviews 59 (2007) 631-644).

The lipophilicity of sildenafil can be improved by the use of lipophilic stabilizer and/or stabilizers having a lipophilic side groups on the polymer frame and/or amphiphilic stabilizers during nanosurgery. Due to lipophilic nature or whether�filnik side groups used stabilizer not only the lipophilicity but the absorption and permeability of the nanoparticles of sildenafil according to the present invention can be improved.

For example, using chitosan can increase the paracellular permeability of the epithelium of the small intestine, which is characteristic of increased absorption through the mucosa.

Most of the amphiphilic copolymers used in drug delivery, contains either polyester or poliaminokislotnom derivative as the hydrophobic segment. Most of the polyesters of interest for the pharmaceutical industry, belong to the family of poloxamers, that is, block copolymers of polypropylene glycol and polyethylene glycol.

Example 6:

Comparative tests of permeability in vitro

In vitro experiments were performed in vertical diffusion Franz cell equipped with an automatic dispenser (Hanson Microette TM Topical&Transdermal Diffusion Cell System, Hanson Research Corporation). During the experiments the permeability of 300 μl of a solution of sildenafil citrate was placed on the membrane Prorafil as donor phase. The effective area of the surface diffusion amounted to 1.767 see In all cases the acceptor phase consisted of distilled water. The measurements were carried out at 37°C, and examined 6 parallel samples.

To test the permeability of the suspension of 24.5 mg/ml of the reference sildenafil citrate and the solution of 24.5 mg/ml nanostructured qi�rata sildenafil of example 9 was obtained and used after filtration. In both cases, the permeable amount was measured, as shown in Fig.8.

The results showed a significant difference. In the first 30 minutes the number of last sildenafil citrate from donor solution obtained from nanostructured sildenafil citrate, was 390% higher compared to the benchmark.

Fig.7: Increased permeability when using nanostructured sildenafil citrate

6. Faster profiles of wetting the surface of the nanostructured compositions of the founding of sildenafil or its pharmaceutically acceptable salts or co-crystals according to the invention

To dissolve the citrate of sildenafil, the surface must first be wet the surrounding liquid. Nanosized partly crystalline forms have chemically randomised surface which exhibits a hydrophobic and hydrophilic interactions due to the nature of the stabilizer(s) and active pharmaceutical ingredient that can lead to improved wettability. If the surface of the nanoparticles of sildenafil citrate according to the invention is functionalized by hydrophilic groups/stabilizer bar(s), a higher degree of hydrophilicity causes more rapid wetting of the surface and faster dissolution compared to the original crystalline form. This is improved property �of ancaster sildenafil citrate of the present invention is confirmed by the results of the test re-dispersibility. Due to the greater surface area of nanostructured particles of sildenafil citrate and hydrophilic groups of the stabilizer(s) wetting of the surface occurs faster than the wetting of the crystal forms.

Example 7:

Visual observation of wettability of nanostructured grounds of sildenafil or its pharmaceutically acceptable salts or co-crystals

Wettability of nanostructured particles of sildenafil citrate was investigated in distilled water and visualized using a stereomicroscope equipped with a CCD camera. 0.1 mg of a powder of reference and nanostructured sildenafil was placed on the glass, and then to the powder was added one drop of distilled water. The nanostructured powder of sildenafil citrate began to swell immediately, wetting was complete, whereas the particles of the reference sildenafil citrate remained in their aggregated state, as shown in Fig.8.

Fig.8: Wettability of the reference sildenafil citrate (a) and nanostructured sildenafil citrate of example 9 (b) observed using a stereomicroscope at 40X magnification

B. Composition

In the present invention, the proposed composition of nanoscale grounds of sildenafil, its pharmaceutically acceptable salts and co-crystals in the form of nanostructured particles, sod�rashie at least one stabilizer, to stabilize its steric and/or electrostatic means.

The stabilizers preferably contact or interact with the basis of sildenafil, its pharmaceutically acceptable salts and co-crystals, but not chemically interact with them.

Nanoparticles grounds of sildenafil, its pharmaceutically acceptable salts and co-crystals according to the invention can be formed by formation of the complex, using biocompatible or biodegradable polyelectrolyte, or can be obtained by means of deposition of a solvent - precipitant, using stabilizer(s). The stability of the obtained colloidal solution of nanosized sildenafil citrate can be increased by combining the formation of the complex with steric or electrostatic stabilization of the particles. Moreover, using an additional stabilizer, the particle size of the base of sildenafil, its pharmaceutically acceptable salts and co-crystals according to the invention can be reduced and adjusted.

The particle size of the nanoparticles grounds of sildenafil, its pharmaceutically acceptable salts and co-crystals

The invention comprises nanoparticles of the founding of sildenafil, its pharmaceutically acceptable salts and co-crystals, which have an average particle size of less than about 500 nm as measured by dynamic suitor�of seania.

By "average particle size less than about 500 nm" means that at least 50% of the nanoparticles of the founding of sildenafil, its pharmaceutically acceptable salts and co-crystals has a particle size less than the average in number/intensity, i.e. less than about 500 nm, etc., when measured by the method noted above.

Example 8:

Obtaining nanostructured sildenafil

During the experiments, the nanoparticles of sildenafil citrate nanoparticles were obtained in a flow reactor continuous action on the basis of microjet technology. As initial solution used 250 mg of sildenafil citrate (SD), dissolved in 100 ml of distilled water. The resulting solution was passed through a reactor apparatus with a flow rate of 3 ml/min, using the feeder. At this time, using a second feeding device, a solution of 2.5-25 mg of HPMC 971 (CD) (Lubrisol), dissolved in 100 ml of distilled water was passed into a mixing device at a flow rate of 1 ml/min, where it was mixed with a solution containing a citrate of sildenafil, coming from the first reactor unit. Nanoparticles continuously receive at atmospheric pressure due to the formation of polyelectrolyte complex with a solution of HPMC 971 flowing into the mixing device. The obtained colloidal solution directed black�W second reactor apparatus, goes into the device dynamic light scattering (Nanotrac) - integrated device that can continuously determine the particle size of the obtained nanoparticles. The size of the nanoparticles can be adjusted in wide range by changing the speed of the current; pressure and number of used HPMC 971 (see Fig.9). The particle size of the particles of sildenafil citrate at best was 74 nm (see Fig.13 (table 2)). Changing the flow velocity, the particle size can be varied from 70 up to 500 nm.

Fig.9: particle Size and size distribution of the nanoparticles of sildenafil citrate using different relations AFI: polyelectrolyte.

Fig.13 (table 2): the Effect of current velocities on the particle size of sildenafil citrate.

Example 9:

Development of nanostructured sildenafil citrate

During the experiments, the nanoparticles of sildenafil citrate was obtained in a flow reactor continuous action on the basis of microjet technology. As initial solution used 200 mg of sildenafil citrate (SD), dissolved in 60 ml of distilled water. The resulting solution was passed through a reactor apparatus with a flow rate of 4 ml/min, using the feeder. At this time, using a second feeding device, a solution of 50 mg of dodecylbenzenesulfonate sodium (SDBS), dissolved in 100 ml of distilled water, prop�Scully in a mixing device at a flow rate of 1 ml/min, where it was mixed with a solution containing a citrate of sildenafil, coming from the first reactor unit. Nanoparticles continuously receive at atmospheric pressure due to the precipitating effect of SDBS solution that is injected into the mixing device. The obtained colloidal solution is directed through the second reactor apparatus is in the device dynamic light scattering (Nanotrac) - integrated device that can continuously determine the particle size of the obtained nanoparticles. The size of the nanoparticles can be adjusted in wide range by changing the speed of the current (see Fig.10). The particle size of the particles of sildenafil citrate at best amounted to 263 nm (see Fig.14 (table 3)). Changing the flow velocity, the particle size can be varied from 263 up to 769 nm.

Fig.10: particle Size and size distribution of the nanoparticles of sildenafil citrate using different relations AFI: precipitator.

Fig.14 (table 3): the Effect of current velocities on the particle size of sildenafil citrate.

Example 10:

Obtaining nanostructured reason sildenafila

During the experiments the nanoparticles grounds of sildenafil was obtained in a flow reactor continuous action on the basis of microjet technology. As initial solution used 100-300 mg of sildenafil citrate (SD) and 60-1000 mg polyvine�marketing of alcohol (PVA, Mw=30000-70000) dissolved in 60 ml of distilled water. The resulting solution was passed through a reactor apparatus with a flow rate of 1-10 ml/min, using the feeder. At this time, using a second feeding device, of 0.001-0.1 M solution of sodium hydroxide (NaOH) was passed into a mixing device at a flow rate of 1-10 ml/min, where it was mixed with a solution containing a citrate of sildenafil, coming from the first reactor unit. Nanoparticles continuously receive at atmospheric pressure due to the precipitating effect of the NaOH solution that is injected into the mixing device. The obtained colloidal solution is directed through the second reactor apparatus is in the device dynamic light scattering (Nanotrac) - integrated device that can continuously determine the particle size of the obtained nanoparticles. The size of the nanoparticles can be adjusted in wide range by changing the speed of the current. The particle size of the particles of the base of sildenafil in the best case was $ 349 nm (see Fig.11). Changing the flow velocity, the particle size can be varied.

Fig.11: particle Size and size distribution of nanoparticles grounds of sildenafil, while the use of different relations AFI: precipitator.

Example 11:

Medication in the form of buccal films containing the basis of sildenafil, the pharmaceutical�ski acceptable salts and co-crystals in the form of nanoparticles

Films were obtained using a methylcellulose polyethylene glycol 400 : Carbopol R in the ratio of 0.3:1.0 to:0,7. A total of 1% wt/V of polymer solution was allowed to stir for 6 hours and stand overnight to remove all the trapped air bubbles. Added nanostructured sildenafil citrate, and the solution was poured into a Petri dish and dried in an oven at 60°C until dry. The film was carefully removed from the Petri dish, checked for any defects and cut to fit the size required for testing.

1. Stable composition of the nanostructured sildenafil, inhibiting cGMP-specific phosphodiesterase type 5 (PDEV), containing:
(a) nanostructured basis of sildenafil or its pharmaceutically acceptable salt having an average particle size of less than about 500 nm;
(b) the stabilizer is poly(acrylic acid), crosslinked with allyl ethers or dodecylbenzenesulfonate sodium,
where the composition is prepared in a flow reactor continuous action on the basis of microjet technology, the method comprising:
(1) dissolution of sildenafil citrate in water;
(2) adding to the solution from step (1) aqueous solution of the stabilizer is poly(acrylic acid), crosslinked with allyl ethers or dodecylbenzenesulfonate sodium; and
(3) the deposition composition�and with stage (2),
and where the composition of the nanostructured sildenafil has polimorfnoe structure.

2. A composition according to claim 1, wherein the average particle size is from 500 nm to 50 nm, preferably from 350 nm to 50 nm, preferably from 100 nm to 50 nm.

3. The method of obtaining the composition of the nanostructured sildenafil, inhibiting cGMP-specific phosphodiesterase type 5 (PDEV), containing (a) a nanostructured sildenafil citrate having an average particle size of less than about 500 nm; (b) the stabilizer is poly(acrylic acid), crosslinked with allyl ethers or dodecylbenzenesulfonate sodium, including
(1) dissolution of sildenafil citrate in water;
(2) adding to the solution from step (1) aqueous solution of the stabilizer is poly(acrylic acid), crosslinked with allyl ethers or dodecylbenzenesulfonate sodium; and
(3) the deposition composition from step (2),
where the method is carried out in a flow reactor continuous action on the basis of microjet technology.

4. A pharmaceutical composition inhibiting cGMP-specific phosphodiesterase type 5 (PDEV), containing nanostructured composition according to claim 1 or 2 together with pharmaceutically acceptable auxiliary substances.

5. Pharmaceutical composition according to claim 4, wherein the composition is prepared in a dosage form for buccal administration.

6. Use nanostruct�risovannoy composition according to claim 1 or 2 for obtaining a medicinal product for the treatment of diseases, associated with cGMP-specific phosphodiesterase type 5 (PDEV).

7. The use of nanostructured composition according to claim 1 or 2 or the pharmaceutical composition according to claim 4 or 5 to obtain a pharmaceutical composition for the treatment of male or female sexual dysfunction and pulmonary arterial hypertension.

8. The use according to claim 7, where the composition has:
- increased solubility in water,
- instant re-dispersibility in physiological environments,
- enhanced percutaneous permeability,
- enhanced absorption in the gastrointestinal tract of man,
- more rapid onset of action,
to reduce the applied dose.



 

Same patents:

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SUBSTANCE: invention refers to a moulded sorbent with the antibacterial properties for treating endometritis, representing nanodispersed mesoporous carbon having a specific adsorption surface of no more than 50 m2/g and a crushing strength of not less than 20 kg/cm2, containing polyvinylpyrrolidone in an amount of not less than 5.0%, characterised by the fact that it is presented in the form of cylinders 2-4mm in diameter, 15-25mm long with one inner circular passage, to a method of treating it, as well as to a method of treating endometritis.

EFFECT: higher clinical effectiveness.

3 cl, 10 ex, 2 tbl

FIELD: nanotechnology.

SUBSTANCE: invention relates to the field of nanotechnology, namely to electronic elements consisting of the layers and containing nanomaterials in their structure. In the electronic element, comprising layers of materials with conductive and nonconductive parts, at least one layer is made of a metal matrix composite containing 25-75% (by volume) of reinforcing particles consisting of nanodiamonds with high electrical resistance and bulb-shaped carbon nanoparticles with low electrical resistance, arranged in order providing the flow of electric current in the desired direction. In the method of manufacturing of electronic elements, consisting of layer application of required materials, at least one layer is made of a metal matrix composite produced by the method of mechanical alloying of the initial particles of the matrix material and 25-75% (by volume) of nanodiamond particles, at that first the granules of composite material are obtained, then the composite material is applied on the preliminary treated process surface, the surface alignment is carried out, then local heating of those areas that need to be conductive is carried out to temperatures exceeding 1000°C, thereby transforming nanodiamonds in bulb-shaped carbon nanoparticles.

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11 cl

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2 cl, 1 ex

FIELD: chemistry.

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2 ex

FIELD: fire safety.

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1 tbl

FIELD: nanotechnology.

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7 cl, 1 dwg

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FIELD: process engineering.

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4 cl, 1 dwg

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FIELD: chemistry.

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3 cl, 1 tbl, 5 ex

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5 dwg, 2 tbl, 4 ex

FIELD: biotechnology.

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3 cl, 2 dwg, 6 tbl, 7 ex

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5 cl, 2 tbl, 3 ex

FIELD: nanotechnology.

SUBSTANCE: invention relates to the field of nanotechnology, namely to electronic elements consisting of the layers and containing nanomaterials in their structure. In the electronic element, comprising layers of materials with conductive and nonconductive parts, at least one layer is made of a metal matrix composite containing 25-75% (by volume) of reinforcing particles consisting of nanodiamonds with high electrical resistance and bulb-shaped carbon nanoparticles with low electrical resistance, arranged in order providing the flow of electric current in the desired direction. In the method of manufacturing of electronic elements, consisting of layer application of required materials, at least one layer is made of a metal matrix composite produced by the method of mechanical alloying of the initial particles of the matrix material and 25-75% (by volume) of nanodiamond particles, at that first the granules of composite material are obtained, then the composite material is applied on the preliminary treated process surface, the surface alignment is carried out, then local heating of those areas that need to be conductive is carried out to temperatures exceeding 1000°C, thereby transforming nanodiamonds in bulb-shaped carbon nanoparticles.

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11 cl

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EFFECT: invention increases the efficiency of the photoconverter element, lowers the cost and simplifies production thereof.

1 dwg

FIELD: measurement equipment.

SUBSTANCE: method to manufacture a strain gauge pressure sensor consists in polishing of membrane surface, formation of a dielectric film and strain gauge elements on it with low-resistance links and contact sites between them, using a template of a strain gauge sensitive layer in the form of strips, attachment of output conductors to contact sites in areas remote from strips of sections, connection of a recorder to the output of nano- and microelectromechanical systems (N&MEMS), energising of N&MEMS voltage, development of a normalized non-stationary field of temperatures and temperature deformations symmetrical relative to the centre of the membrane on the membrane. The non-stationary field of temperatures and temperature deformations is recorded on the recorder of the output signal of N&MEMS during impact at the membrane. They compare the produced output signal of the tested N&MEMS according to the amplitude of spectral components with the similar signal of the reference N&MEMS. If differences of amplitudes of output signals or amplitudes of spectral components of output signals do not exceed limit permissible values, which are not taken as criteria of time stability, this assembly is forwarded to subsequent operations.

EFFECT: increased time stability, resource, service life, reduced error under impact of non-stationary temperatures and increased vibration accelerations.

2 cl, 2 dwg

FIELD: physics.

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1 dwg

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2 cl, 1 tbl

FIELD: physics.

SUBSTANCE: method is based on irradiating a surface with a moving laser beam in areas of the surface of the material with an absorption coefficient of not less than 3·104 cm-1 at the laser wavelength, wherein each area is irradiated using a series of laser pulses with pulse duration of not more than 30 ns, and energy density F of the laser beam in the irradiated area is set in the range F=0.005-1.0 J/cm2 to enable splitting of the surface layer of the material without melting and forming on the surface of the material sub-micrometre cracks, slits and flakes with size ranging from 0.05 mcm to 0.8 mcm.

EFFECT: simplified method of producing micro- and nanostructures for a wide range of materials.

12 cl, 1 tbl, 7 dwg

FIELD: physics, signalling.

SUBSTANCE: invention relates to identification of material resources and can be used to label electroconductive articles. The method of making and installing non-reproducible identification label on an electroconductive article includes applying an identification number, an information grid and a non-reproducible matrix, as well as combined input of the identification number and the non-reproducible matrix into a database. The non-reproducible matrix is formed in advance separately from the article on a nanofilm by random point-by-point evaporation of areas of the nanofilm to obtain perforations of different size and shape or obtaining bulging areas of the surface of different size and shape on the nanofilm during electric discharge treatment thereof, after which the nanofilm is placed on the article by pressure sintering.

EFFECT: invention enables to obtain a non-reproducible identification label on an article, which enables to apply information and prevent forgery.

3 cl, 6 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which can be used for treating diseases mediated by an androgen receptor. In formula (I), R1 means (C2-6)alkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)fluoroalkyl, CN or halogen, R2 and R3 are identical or different and mean a hydrogen atom or (C1-9)alkyl, R4, R5, R6, R7 are identical or different and mean a hydrogen or halogen, X means CH or N, Y means either a nitrogen atom, or a carbon atom substituted by (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)fluoroalkyl, a hydrogen atom or halogen; m is equal to 0, 1 or 2.

EFFECT: invention refers to using the compounds for preparing a therapeutic agent for preventing and/or treating hirsutism, androgenetic alopecia, hypertrichosis, atopic dermatitis, disordered sebaceous gland, such as hyperseborrhea, acne, greasy skin or seborrheic dermatitis.

8 cl, 2 tbl, 26 ex

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