Method of obtaining dabigatran-containing drug compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining suspension of polymorphic form I of salt of methanesulfonic acid and dabigatran etexilate of formula I . Method is characterised by the following: polymorphic form I of dabigatran etexilate methanesulfonate with melt temperature tmelt 180±3°C is suspended in mixture with talc in solution of hydroxypropylcellulose in isopropyl alcohol at temperature in the range from 12 to 22°C with obtaining suspension by method of circulation dispersion at temperature not higher than 30°C. Invention also relates to obtained in said way suspension for obtaining dabigatran etexilate methanesulfonate pellets. Invention also relates to dabigatran etexilate methanesulfonate pellets used for thrombin inhibition, and to method of obtaining said pellets by dispersion of said suspension on isolated tartaric acid cores in fluidised bed.

EFFECT: claimed invention provides industrial method of obtaining pellets of dabigatran etexilate methanesulfonate, presents only in one polymorphic form.

27 cl, 5 ex

 

In the present invention proposes an improved method in the fluidized bed to obtain a new medicinal composition containing etexilate of dabigatran formula 1

not necessarily in the form of its pharmaceutically acceptable salts, as well as a new medicinal composition itself.

The background to the present invention

The compound of formula 1 described in the prior art and first described in the application W098/37075. It is an effective inhibitor of thrombin, which can be used, for example, for the prevention of postoperative deep vein thrombosis and prevention of stroke, primarily for the prevention of stroke in patients with atrial fibrillation. In the application WO 03/074056 described the preferred acid additive salt methanesulfonic acid and etexilate of dabigatran (i.e. the methanesulfonate of etexilate of dabigatran).

The compound is usually administered orally. First of all, you can use the so-called compositions of the pellets, as described, for example, in the application WO 03/074056. These compositions are compositions in which the layer of the active agent contains a binder and optionally a separating agent, and surrounding the core material deposited on a mostly spherical core material, which consists of a pharmaceutically acceptable organizes the th acid or contains it. Layer the core layer and the active agent are separated from each other by a so-called separating layer. Schematic structure of this type, containing the active agent, are shown in figure 1 in the application WO 03/074056.

In the present invention proposes a method that can be used on an industrial scale to obtain pellets of the active agent, dabigatran, and which allows to obtain the composition in preparative scale. An additional objective of the present invention is to develop a method which allows to obtain the composition of the playback quality.

As described in the application WO 05/028468, acid additive salt of etexilate of dabigatran and methanesulfonic acid exists in different polymorphic forms. Another objective of the present invention is to develop a method of producing a pharmaceutical composition, containing only one polymorphic form of the active agent, methansulfonate of etexilate of dabigatran.

Detailed description of the present invention

As described in the application WO 05/028468, acid additive salt of etexilate of dabigatran and methanesulfonic acid exists in different polymorphic forms. Unexpectedly, it was found that the polymorphic form I of methanesulfonate of etexilate of dabigatran has the advantage compared to the polymorphic form II of its crystal the stabilisation properties. In this regard, the polymorphic form I can select and process more simple way in the process of obtaining and following processing stages. Therefore, according to the present invention, polymorphic form I is the most preferred form.

Generally, the different polymorphic forms of matter are characterized by different properties (including, but not limited to, stability, efficiency, technological properties during processing and so on). Therefore, it is advisable to obtain a pharmaceutical composition, which contains primarily only one polymorphic form.

In this regard, the present invention proposes a method of receiving, which allows obtaining a pharmaceutical composition containing mainly polymorphic form I active agent, methansulfonate of etexilate of dabigatran.

According to the invention the method is characterized by a series of separate stages. First get the engine 1 from pharmaceutically acceptable organic acid. In the present invention for obtaining core 1 using tartaric acid. From the material of the cores 1, obtained by the above method, then get the so-called isolated nuclei tartaric acid 3 when spraying insulating suspension 2. Then get the suspension of dabigatran 4, which is sprayed on the specified kernel floor is 3 in one or more stages by the method of coating. Finally, the pellets 5 active agent obtained by the above method, is Packed into suitable capsules.

Isolated nuclei tartaric acid 3 are characterized by a homogeneous quasi-spherical shape. Moreover, they are characterized by only minor possible defects, which are formed upon receipt of the nuclei due to the formation of co particles. The term "related particles" refers to particles of small size, stick to the outer surface of the spherical pellets and distorting quasi-spherical shape of the pellets. Ideally spherical shape and low surface roughness are of great importance for kislotoustoytchivi active substances, such as, for example, etexilate of dabigatran for which the defects are generated when the receive in connection with the accompanying particles that may be destroyed, or due to too high a degree of surface roughness larger particles of powdered tartaric acid, can cause a significant decrease in stability during storage and, consequently, to reduce the shelf life of the final product. For this reason, when processing kislotoustoytchivi active substances it is also important to apply an insulating layer of high quality with high reproducibility.

The core 1 is obtained from particles of tartaric acid size in the range of 0.2-0.8 mm, PR is doctitle 0.3-0.7 mm, first of all, preferably 0.4 to 0.6 mm (according to the analysis in an air stream), which is sprayed with a solution of tartaric acid and a binder. Solution obtain by the following method. First, tartaric acid dissolved in water mixed with a suitable binder, preferably with the Arabian gum, at elevated temperature, preferably at a temperature in the range from 30 to 70°C., especially preferably in the range of from 40 to 60°Spraybottle per kilogram of tartaric acid add 0.1-0.3 kg, especially preferably 0.15 to 0.25 kg, especially about 0.2 kg Arabian gum. The amount of water preferably is 0.6-1.0 kg, preferably 0.7-0.9 kg, especially about 0.8 kg per kilogram of tartaric acid.

According to the invention preferably first get clear solution Arabian gum in water at the above temperature. After obtaining the solution add tartaric acid preferably at a constant temperature and under continuous stirring. After adding the acid, the mixture is stirred for at least 1 h, preferably from 3 to 10 hours, especially preferably from 4 to 8 hours, especially preferably from 5 to 6 o'clock

The resulting solution is sprayed on the particles of tartaric acid with a size of 0.2-0.8 mm, preferably 0.3-0.7 mm, especially preferably 0.4 to 0.6 mm Soda is the content of particles above a specified size is at least 90%, preferably at least 95%, especially preferably at least 97%. For this particle tartaric acid are placed in an appropriate container. The container preferably is a tray in which the particles are mixed and moved during the rotation of the pallet. In the prior art there are known various constructions of the pallet, for example, a drum device for coating. Such pallets, for example, described in EP 80199, WO 83/03052, WO 95/19713 or WO 06/134133. In the scope of the present invention is enabled pallets that can be used in the method according to the invention and which optionally also known as horizontal pallets.

The acid solution and the resin obtained as described above, then sprayed on the particles, which move with the rotation of the pallet.

In the scope of the present invention includes material which is suitable for spraying and which optionally also called layer pellets. The term "pellet"is used in this context, is equivalent to the term "particle" or "core".

According to the invention preferably 1 kg of particles of tartaric acid is sprayed from 0.8 to 1.6 kg, especially preferably 1.0 to 1.4 kg, especially preferably 1.2 kg of the above acid solution and gums.

The flow rate of air in the method according to the present invention is related to the size of the party. Standardized flow rate of air supplied per kilogram of tartaric acid cores of the present invention is preferably in the range from 0.5 to 2 (m3/h)/kg, preferably from 0.75 to 1.5 (m3/h)/kg, especially preferably from 0.9 to 1.1 (m3/h)/kg of the air flow Rate refers to the amount of dry air supplied into the rotating layer of pellets per hour.

If, for example, one party includes 1000 kg of tartaric acid cores, the standardized flow rate of air is 1.0 (m3/h)/kg, which corresponds to the actual air flow rate of 1000 m3/h Temperature of air flow for drying according to the present invention, is preferably less than 90°, especially preferably less than 80°C. ideally, the temperature of the air stream is in the range from 35 to 75°C.

The temperature of the pellets (temperature forming layer pellets) of the present invention is preferably in the range from 30 to 50°C., especially preferably from 36 to 44°C, ideally from 38 to 42°C.

The relative pressure is preferably 1-3 mbar, especially preferably 1.5 to 2.5 mbar, especially preferably from 1.8 to 2.2 mbar. Relative pressure refers to the pressure difference between the pressure in the pan and atmospheric pressure. The pressure in the supp is not preferably should be reduced, to prevent leakage of dust-like particles of acid.

The sputtering is carried out at a certain speed spray. Spraying speed refers to the amount of the acid solution and the resin, which is sprayed on a rotating layer of pellets per hour. The rate of dispersion depends on the lot size according to the present invention. Standardized velocity dispersion of the present invention per kilogram of feed crystals of tartaric acid is preferably in the range from 0.2 to 0.4 (kg/h)/kg, preferably from 0.25 to 0.35 (kg/h)/kg, especially preferably from 0.28 to 0.32 (kg/h)/kg If, for example, one party includes 1000 kg of crystals of tartaric acid, standardized spraying speed is 0.3 (kg/h)/kg, which corresponds to the actual speed of the spray 300 kg/h

After spraying the first portion of the acid solution and the resin particles of tartaric acid with a size of 0.2-0.8 mm and distribution solution for the rotation of the pallet, to wet the particles of tartaric acid spray a fine powder tartaric acid. Powder tartaric acid consists of small particles of tartaric acid size <100, preferably <75, especially preferably <50 μm (according to the analysis in an air stream). The content of particles above a specified size should be at least 85%, preferably at least 90% primarily preferably at least 94%. According to the present invention per 1 kg of feed particles tartaric acid is applied preferably 0.4 to 1.2 kg, especially preferably 0.6 to 1.0 kg, especially preferably 0.8 kg of the above powder tartaric acid. After spraying the above powder tartaric acid, material intended for spray dried to a product temperature of approximately 30-50°C., preferably about 40°Statem again sprayed the acid solution and gums.

To ensure uniformity of spherical particles, spraying acid solution and gums and spraying powder tartaric acid are conducted alternately. The total number of acid solution and gum and powder, tartaric acid, expect at least 100, preferably from 150 to 350, especially preferably from 200 to 300, especially preferably about 250 to parties of the same size, and the above-described stage of the method is repeated an appropriate number of times.

After completion of the method obtained core 1 is dried. Drying is preferably carried out at a temperature of 50-70°C., preferably 55-65°C for 24 to 72 h, preferably 36-60 hours

After receiving cores tartaric acid 1 they need to apply so-called insulating layer, which avoids any interaction of the active substance from the core of tartaric acid in the end is the same time.

The core material isolated by spraying insulating suspension 2 on kernel tartaric acid 1 obtained by the method described above. To obtain an insulating suspension 2, the container loads the ethanol, and then add the hypromellose and dimethylpolysiloxane, which are dissolved under stirring, then add talc and receive a suspension.

Using hydroxypropylmethylcellulose and talc is preferred over, for example, Arabian gum, and talc. Using hydroxypropylmethylcellulose mixed with talc allows to obtain an insulating layer of constant quality in a reproducible way. Such quality and reproducibility were tested on an industrial scale.

To obtain an insulating suspension 2 per kilogram of ethanol is preferably used 0,04-0,06 kg, especially preferably 0,046-0.05 kg of hydroxypropylmethylcellulose. According to the present invention, in addition to hydroxypropylmethylcellulose first of all, preferably in an insulating suspension 2 add dimethylpolysiloxane to avoid foaming. The number of dimethylpolysiloxane, which is added under stirring in the process of obtaining an insulating suspension 2 is preferably 0.6 to 1.2 g, especially preferably 0.8 to 0.9 g / kg ethanol. Finally add the talc and under stirring receive a suspension. Per kilogram of ethanol used preferably 0.04 to 0.06 kg, especially preferably 0,046-0.05 kg of talc.

Obtained in this way isolating suspension 2 is sprayed on pre-obtained pellets tartaric acid 1 in continuous mode dispersion in a standard horizontal installation for coating. Per kilogram of feed nuclei tartaric acid spray 1 0.5-0.8 kg, preferably 0.55 to 0.75 kg, especially preferably 0.6 to 0.7 kg isolating suspension.

The sputtering is carried out at a certain speed spray. Spraying speed indicates the number of insulating suspension 2 sprayed on the pellets 1 per hour. The spray rate of the method according to the present invention depends on the size of the party. Standardized velocity dispersion of the present invention is preferably in the range from 0.01 to 0.1 (kg/h)/kg, preferably from 0.02 to 0.04 (kg/h)/kg, especially preferably from 0.025 to 0,035 (kg/h)/kg per kilogram of the feed pellets tartaric acid 1. If, for example, one party includes 1200 kg of tartaric acid cores, standardized spraying speed is 0,027 (kg/h)/kg, which corresponds to the actual speed of the spray 32 kg/h If, for example, one party includes 600 kg of tartaric acid cores, standardized spraying speed is 0,035 (kg/h)/kg, which is relevant to the duty to regulate the actual nebulization rate of 21 kg/h

During the specified continuous process engine continuously dried in a stream of air at temperatures up to 70°C, preferably from 25 to 70°C.

The air flow rate indicates the amount of dry air which is fed into the rotating layer of pellets per hour. The flow rate of air in the method according to the present invention depends on the size of the party. Standardized flow rate of air of the present invention is preferably in the range from 1.0 to 2.5 (m3/h)/kg, preferably from 1.2 to 2.0 (m3/h)/kg, especially preferably from 1.40 to 1.85 (m3/h)/kg per kilogram originally supplied cores tartaric acid 2. If, for example, one party includes 600 kg of tartaric acid cores 2, the standardized flow rate of air is to 1.83 (m3/h)/kg, which corresponds to the actual air velocity of 1100 m /h If, for example, one party includes 1200 kg of tartaric acid cores 3, the standardized flow rate of air is of 1.42 (m3/h)/kg, which corresponds to the actual air flow rate of 1700 m3/PM

Contains the active substance pellets 5 is produced by spraying a suspension of the active substance 4 on isolated nuclei tartaric acid 3 obtained above. According to the present invention has great value obtaining suspenzionnogo substance 4, as the homogeneity and temperature suspension of the active substance 4 are directly connected with the quality of the pellets containing the active substance.

Suspension of the active substance 4 is obtained from methansulfonate of etexilate of dabigatran in polymorphic form I. Polymorphic form I is characterized by a melting temperature tpl.180±3°C (according to differential scanning calorimetry (DSC), the maximum peak, the heating rate 10°C/min). Obtaining polymorphic form I is described, for example, in the application WO 05/028468 (see especially example 1). The term "active substance"used in the description of the present invention, if not stated otherwise, denotes a polymorphic form I metacarbonate of etexilate of dabigatran.

To obtain a suspension of the active substance 4, isopropyl alcohol is heated in a nitrogen atmosphere to a temperature in the range from 12 to 22°C. Then, while stirring the resulting substance add hydroxypropylcellulose in vacuum or by using a circulating dispersion. Preferably the method is carried out using special disperser system rotor-stator, for example, Ultra Turrax company Jahnke &Kunkel, or CONTI TDS 4 firms Ystral GmbH. Circulation dispersion indicates that the dispersant is connected with the container, and the resulting isopropyl alcohol flow through the disperser on recir elational system. In the system, the rotor-stator creates a vacuum, which is required for pumping the solid phase. Liquid and solid phase are received in the chamber of dispergator on two separate lines and in the process of paging the solid phase moistened. Since the process occurs during circulation, it is called the circulation dispersion.

The container in which carry out the process, in turn, provided with a stirrer, which provides optimal mixing of the suspension of etexilate of dabigatran with low energy consumption (for example, a system for mixing Visco Jet firm Visco Jet GmbH or an air-jet mixer). Moreover, the container is not necessarily provided with a double jacket. Isopropyl alcohol is preferably used in nearly anhydrous form (99,5%). Hydroxypropylcellulose served in a vacuum or by using a circulating dispersion at 2000-4000 rpm, preferably at 2900 Rev/min When added to a container, the mixture is stirred with a speed of, for example, 600 rpm

After 30-60 minutes the dissolution process complete. Then begin to apply the active substance, the methanesulfonate of etexilate of dabigatran, and excipient talc, also in vacuum or preferably using circulating dispersion.

According to the present invention by way of the circulation of the dispersion can be obtained suspensio much faster compared with conventional mixing.

Before receiving the suspension, it is recommended to grind the active substance. The preferred distribution of the particles of the active substance in size when X90is less than 14 microns. The value of X90denotes the average size of 90% of the particles, which is not more than the specified distribution of the particles by volume. The size of the particles of the present invention can, for example, be determined by laser diffraction (Fraunhofer diffraction).

Duration of stages of mixing and swelling is 30 min of stirring speed of 400 to 800 rpm, preferably 600 rpm Then the suspension is sent to the system circulation dispersion within 3-10 min at speed 2000-4000 rpm, preferably 2900 rpm Cycle dispersive mixing is usually repeated up to 6 times.

To get the suspension 4 in 1 kg of isopropanol added from 0.05 to 0.5 kg, preferably from 0.1 to 0.3 kg, especially preferably from 0.15 to 0.25 kg of active substance. The number of hydroxypropylcellulose per 1 kg of isopropyl alcohol is from 0.01 to 0.1 kg, preferably from 0.02 to 0.07 kg, especially preferably of 0.03 to 0.05 kg Quantity of talc per 1 kg of isopropyl alcohol is 0.005 to 0.07 kg, preferably from 0.01 to 0.05 kg, especially preferably from 0.02 to 0.04 kg

Sootnoshenie the active substance and hydroxypropylcellulose is preferably in the range of from 3:1 to 7:1, preferably from 4:1 to 6:1, especially preferably about 5:1, based on the weight of the two components in the suspension of the active substance according to the present invention. The ratio of the active substance and talc is preferably in the range of from 4:1 to 8:1, preferably from 5:1 to 7:1, especially preferably from 6:1 to 6.5:1, based on the weight of the two components in the suspension of the active substance according to the present invention.

The concentration of the active substance in suspension of the active substance of the present invention is preferably 10-25 wt.%, preferably 11-20 wt.%, first of all, preferably 12-19 wt.%. The total concentration of components in the suspension of the active substance, hydroxypropylcellulose and talc of the present invention is preferably 14-40 wt.%, preferably 15-30 wt.%, first of all, preferably 16 to 25 wt.%.

In the present invention, unless otherwise specified, the concentrations presented in wt.%.

Unexpectedly, it was found that the temperature selected for receipt of the suspension 4, has a very significant influence on the characteristics of the final product. In order to obtain the product in a particular polymorphic form of the active substance with a high reproducibility, the temperature during the whole production process should be maintained at the level of the e less than 30°C. If the suspension 4 to get or even keep at too high a temperature, such conditions can lead to changes in the polymorphic form of the active substance that will have a negative impact on the efficiency of the final composition. First of all, it is preferable that the temperature of the process to obtain the product was in the range of from 0 to 30°C., especially preferably in the range of from 5 to 30°C.

In order to prevent the sedimentation of the suspension is stirred during the entire production process, including sputtering. The stirring speed in the container is preferably 300-500 rpm, especially preferably 400 rpm

The resulting suspension of the active substance 4 stored at temperatures below 30°C until the next processing stage. Preferably the following processing of the suspension 4 is carried out in a period of not more than 48 hours If the suspension is to receive and keep, for example, at 22°C, preferably additional processing should be done within 60 hours

One object of the present invention proposes a method of obtaining a suspension of 4 polymorphic form I of methanesulfonate of etexilate of dabigatran in isopropyl alcohol, and this method is that the temperature during the production and storage of the suspension is always supported at the level of less than 30°C., preferably in the range from 0 to 30°C, first and foremost is preferably in the range from 5 to 30°C, while the ingredients of the suspension type using circulating dispersion.

Another object of the present invention proposes a suspension of 4 polymorphic form I of methanesulfonate of etexilate of dabigatran in isopropyl alcohol, which is obtained by the method described above.

Another object of the present invention features the use of suspension 4 polymorphic form I of methanesulfonate of etexilate of dabigatran in isopropyl alcohol as a starting material to obtain the pharmaceutical composition methansulfonate of etexilate of dabigatran.

Another object of the present invention features the use of a suspension of the active substance 4 of the present invention as a starting material to obtain the pharmaceutical composition methansulfonate of etexilate of dabigatran, and suspension 4 receive within 48 h and stored at a temperature not exceeding 30°C.

Another object of the present invention features the use of a suspension of the active substance 4 of the present invention as a starting material to obtain the pharmaceutical composition methansulfonate of etexilate of dabigatran, and a suspension of 4 get in for 60 h and stored at a temperature not higher than 22°C.

To obtain a final composition of outdoor activities the substance 5, suspension of the active substance 4 obtained by the above method, spray on isolated nuclei tartaric acid 3 described above.

Another object of the present invention proposes a method of obtaining a pharmaceutical composition methansulfonate of etexilate of dabigatran 5, the method consists in the fact that the suspension of the active substance 4 of the present invention is sprayed on isolated nuclei tartaric acid 3.

Another object of the present invention features pharmaceutical composition methansulfonate of etexilate of dabigatran 5, which is obtained by spraying a suspension of the active substance 4 of the present invention on the isolated core tartaric acid 3.

Obtaining pellets of the active substance 5 of the present invention method in the fluidized bed is divided into three stages:

1 - preliminary heat source pellets 3,

2 - phase spray (application of active substances),

3 - drying the pellets of the active substance 5.

These three production stage is carried out in the installation of the fluidized bed. In the installation of fluidized bed according to the present invention through the product to which you want to apply the coating, flow stream, preferably air flow. The material, which is located in the installation, set into motion and this motion is supported when is propuskanii air flow, moreover, the type of movement is controlled by various specific inserts. Examples of suitable plants with fluidized bed include granulator GPCG (firm Glatt), installation for coating Precision Coater (firm Aeromatic), installation for coating (firm Huttlin), installation for coating Aircoater (firm Innojet). It is established that the so-called installation Wurster Coater described in the patent EP 0711593 is primarily suitable for carrying out the process in the fluidized bed according to the present invention.

In the process of obtaining isolated source tartaric acid pellets are placed in a container for a product, get psevdogiganty layer using air flow and at the same time pre-heated.

The airflow serves with the use of the fan through the bottom hole in the container (in vacuum), and the flow of air can be fed under pressure. As the air source can be used by the air, which is heated or processed to a certain level of humidity or water content. The preferred level of humidity in the air flow adjusted to 3 g/kg

In the container for a product in the zone supply air set perforated plate. In the area of the air outlet is installed fabric filter or sieve, which prevent leakage of the pellets from cutting the upstream reservoir for the product. As soon as reaches the desired temperature of the product, begin phase spray.

On the plate are one or more nozzles for spraying. A high degree of perforation in the plate in the area of the nozzles for spraying allows you to accelerate the flow of the source of tartaric acid pellets 3 that need to be spraying a suspension of the active substance upstream, thereby spraying a suspension of the active substance in a parallel thread. Pellets can be fed in a stream of air directed vertically through one or more pipes (installation Wurster Coater or Precision Coater), or you may submit a spiral or circular direction in the air flow in the container for the product and the area of lower pressure (installation Kugelcoater or Aircoater). Before the deposition of pellets coated or after the deposition of volatile components dried or removed. The formation of a uniform layer structure of the active substance is provided by the circulating movement of the pellets. Because the original pellets of tartaric acid in the beginning of the process are characterized by relatively small size, you must first use a low pressure spray and low speed spray. During the spraying parameters, i.e. speed and spray pressure spray, and air flow rate and temperature of the air flow the gradual is but increase, to ensure optimal movement of the pellets and the optimum temperature of the product.

To ensure high homogeneity and uniformity of the obtained pellets of the active substance 5 should maintain product temperature, pressure spraying, the spraying speed, the temperature of the air source and the air flow rate within a certain range. The control of these parameters according to the present invention also reduces the decomposition of the active substance, to ensure reproducible content of the active substance pellets 5 and, accordingly, reduction of losses during spraying, as well as a reduction in the formation of large aggregates (clumps of several pellets). Reduced formation of aggregates directly affects the output, because such aggregates can be separated at the final stage of screening the pellets of the active substance 5.

The term "product temperature" means the temperature which prevails in the layer pellets. First, in the container for a product load isolated tartaric acid pellets 3, as described above, and these pellets are heated. They are preferably heated to a temperature of 30-50°C, preferably 30-48°C, especially preferably 34-44°C. After reaching this temperature the pellets are sprayed with a suspension of the active substance 4.

The temperature of the air flow really invented the Yu is preferably 90°C, first of all, preferably below 40-80°C, especially preferably 55-57°C.

The term "spray pressure" means the pressure of the compressed air sprayed through the nozzle used for spraying a suspension of the active substance 4. The spray pressure of the present invention is preferably in the range from 1.0 to 4.0 bar, preferably from 1.5 to 4.0 bar, preferably from 2.0 to 4.0 bar.

"Spraying speed" refers to the amount of suspension of the active substance 4, which is sprayed onto a fluidized bed of pellets per hour. The rate of dispersion depends on the size of the party in the method according to the present invention. Standardized velocity dispersion of the present invention per 1 kg supplied isolated tartaric acid pellets 3 is preferably in the range of 4-45 (g/min)/kg or 2-30 (g/min)/kg, preferably 4.5 to 30 (g/min)/kg, especially preferably 6-26 (g/min)/kg

If, for example, one party includes 270,56 kg tartaric acid pellets 3, standardized spraying speed is 7,39 (g/min)/kg, which corresponds to the actual speed of the spray 2000 g/min

The term "air flow rate" refers to the amount of dry air, which is served in a fluidized bed of pellets per hour. The air flow rate depends on the size of the party in the method according to the present invention. With andarizona the flow rate of air per 1 kg of the isolated tartaric acid pellets 3 of the present invention is preferably in the range from 10 to 35 (m/h)/kg, from 10 to 30 (m/h)/kg, preferably from 14 to 30 (m/h)/kg, especially preferably from 18 to 28 (m/h)/kg

If, for example, one party includes 270,56 kg tartaric acid pellets 3, the standardized flow rate of air is 20 (m/h)/kg, which corresponds to the actual flow rate of air 5411 m/h

After spraying the entire suspension of the active substance, the active substance pellets are dried for a certain period of time, preferably within 10-30 min, especially preferably 20 minutes In the drying process, the product temperature should be maintained preferably in the range from 20 to 40°C, and to ensure continuous fluidization.

After the process is finished, the product is extracted from the container gravimetrically, and pellets of etexilate of dabigatran sift through the appropriate sieve, for example, vibrating sieve (cell diameter of 1600 μm).

The amount of suspension of the active substance 4, which is sprayed into the preferred conditions, depends not only on the concentration of the active substance suspension 4, but the size of the party served the isolated tartaric acid pellets 3 and the required quantity of the active substance in the final pellets (so-called active substance). The content of active substance in the active substance pellets 5 primarily preferably is in the range from 15 to 50 wt.%. According to the present invention, the content of active substance in the active substance pellets 5 is preferably 20-45 wt.%, first of all, preferably 36-42 wt.%.

If according to the present invention using a suspension of the active substance 4 in which the concentration of the active substance first and foremost is preferably about 15 wt.%, and the total concentration of the other components of the active substance, hydroxypropylcellulose and talc, approximately 25 wt.%, then, to obtain pellets with the required content of the active substance, for example, 40% of active substance in the 5 pellets obtained from 1 kg of isolated tartaric acid pellets 3, it is necessary to use approximately of 4.83 kg of a suspension of the active substance 4 of the present invention. You can also use the excess suspension of the active substance 4 (5%)to compensate for any possible losses during spraying.

If you want high content of active substances in the isolated tartaric acid pellets 5, the total weight of the party and, in this case the first volume, it is necessary to increase continuously in the process of spraying a suspension of the active substance 4. To provide content, for example, 40 wt.% the active substance in isolated pellets 3, it is necessary to increase the total mass of approximately twice and is velicity bulk density of the material for spraying 5 approximately 1.4 times (i.e. to increase the volume to a greater extent than mass). Indicated a sharp increase in the mass and before the total volume of material to spray 5 may have a negative effect on the sputtering process on an industrial scale, for example, complicated process standard drying material for spraying 5 and the necessity to use complex technological processes.

Another object of the present invention features pharmaceutical composition methansulfonate of etexilate of dabigatran 5, obtained by spraying a suspension of the active substance 4 of the present invention on the isolated core tartaric acid 3 as described above.

To remove clumps and aggregates that can be formed, the pellets of the active substance obtained by the above method, pass through a sieve with a certain cell size. The cell size of course depends on the active ingredient content in the pellets. With little content, you can use a sieve with small cells.

Finally, the obtained pellets of the active substance is Packed in commercial capsules, preferably in capsules from hydroxypropylmethylcellulose.

The following examples are provided to further illustrate the present invention.

Determination of particle size of tartaric acid using air analyzer

Installation and parameters

Installation: air analyzer, such as Alpine AND 200 LS

SITA: if necessary

Supplied weight: 10 g/sieve

The analysis duration: 1 min/sieve, then 1 min up to the maximum mass loss of 0.1 g

Preparation obraza product

The substance is placed in a mortar, and any units and destroy lumps under intensive grinding. The sieve with a rubber gasket and the lid is placed on the scale, zero them, and on the sieve is weighed 10.0 g of the crushed substance. A sieve with all its content, rubber gasket and cover are transferred into the analyzer. The timer is set for 1 min and the material is processed within the specified time when the sifting air analyzer. Then the residue is weighed and the weight recorded. This process is repeated until the weight of the residue after treatment in air analyzer will not be<0,1,

Example 1

Getting the original pellets

In a standard mixer with ellipsoidal bottom and a stirrer was heated to 480 kg of water at 50°C and with stirring was added 120 kg Arabian gum. Stirring is continued at constant temperature until a clear solution is formed. Then in a clear solution (usually 1-2 hours) with stirring was added 600 kg of tartaric acid. Tartaric acid was added at a constant temperature and continuous stirring. After you have completed the program reagents added and the mixture was stirred for approximately 5-6 hours

1000 kg of tartaric acid was added slowly rotating (3 rpm) horizontal unperforated tray with spray system and metering system for feeding powder (for example, Driamat 2000/2 .5). Before spraying for the sieve analysis of a selected sample of the acid, the particle size of tartaric acid should be in the range of 0.4-0.6 mm solution of the acid and the resin obtained as described above was sprayed on the particles tartaric acid, obtained by the above method. In the process of atomizing air flow rate was 1000 m3/h at a temperature of 35-75°C. the Relative pressure was 2 mbar, and the rotational speed of the pallet was 9 rpm Nozzles are located at a distance of 350-450 mm from the feed holes of the material.

A solution of acid and gum sprayed alternately, as described below. After spraying approximately 4.8 kg of a solution of acid and gum particles tartaric acid with a size of 0.4-0.6 mm and distribution solution to wet the particles of tartaric acid was sprayed approximately 3.2 kg of powdered tartaric acid. Specified powdered tartaric acid is a fine particle size <50 μm. Just need 800 kg of powdered tartaric acid. After spraying and distribution of powdered tartaric acid, the resulting material was dried until the temperature of the product n is reached 40°C. Then sprayed the acid solution and gums.

These cycles were repeated until the complete consumption of the acid solution and gums. After the process is complete, the acid pellets were dried in a tray with a rotation speed of 3 rpm for 240 minutes To prevent clumping after drying included periodic rotation mode with a speed of 3 rpm for 3 min every hour. In this case, the pallet rotates at a speed of 3 rpm for 3 min with an interval of 1 h, and then stops. Pellets acid is then transferred to a dryer and dried at 60°C for 48 hours And finally determined the distribution of particle size by the method of sieve analysis. The particle size of the product should be 0.6 to 0.8 mm. Specified fraction of the particles should be>85%.

Example 2

Applying an insulating layer on the source pellets

To obtain an insulating slurry in the mixer was loaded 666,1 (to 347.5) kg of ethanol, was added 33,1 (17,3) kg hydroxypropylmethylcellulose under stirring with a speed of approximately 600 rpm and received the solution. Then in the same conditions was added 0,6 (0,3) kg dimetikona. Immediately before use with stirring was added 33,1 (17,3) kg of talc and received a suspension.

1200 (600) kg pellets acid poured in apparatus for coating (e.g., GS-Coater, model 600/model 1200), and they were sprayed described is use insulating suspension in a rotating pallet continuous spraying for several hours with a spray rate of 32 kg/h in the case of 1200 kg of a mixture or 21 kg/h in the case of 600 kg of the mixture. Pellets also continuously dried in a stream of air at a temperature up to 70°C.

After unloading apparatus for applying coatings GS-Coater, isolated source pellets were fractionally during sifting. Received product fraction, particle diameter of which was ≤1.0 mm and stored until use.

Example 3

Obtaining a suspension of etexilate of dabigatran

The container was purged with nitrogen, and the whole process was carried out at continuous transmission of nitrogen.

1028,325 kg of isopropyl alcohol were loaded into the container. Before adding 50,416 kg hydroxypropylcellulose (Klucel EF) temperature of isopropyl alcohol was maintained in the range from 12 to 22°C. Hydroxypropylcellulose was pumped into the resulting alcohol loaded in a disperser (model CONTI TDS 4 firms Ystral GmbH), using a recirculation system dispersion. The stirring speed in the container was 600 rpm for 30 minutes was selected sample (100 ml) hydroxypropylcellulose and was passed through a sieve with a mesh size of 250 μm. If there is an opaque solution containing visible to the eye particles, the cycle of dissolution was repeated twice within 15 minutes If there is a clear solution that does not contain lumps, started adding active substances, methansulfonate of etexilate of dabigatran. 252,006 kg of active substance and 40,359 kg of talc loaded serial is Ino using a recirculation system dispersion. After stirring for 30 min, the suspension of the active substance was dispersively for up to 10 min at 2900 rpm, depending on the quality of the suspension of the active substance cycle dispersing-mixing can be repeated up to 6 times. The quality of the suspension of the active substance was controlled by passing 100 ml of a suspension of the active substance through a sieve with a mesh size of 500 μm after each cycle, the dispersing-mixing. Throughout the process the temperature of the suspension should not exceed 30°C. the Temperature during storage and when spraying the final suspension of the active substance is maintained at <18°C. If the suspension is kept at temperatures below 30°C, then further processing should be done within a period not exceeding 48 hours If, for example, a suspension was obtained and kept at a temperature of 22°C, then further processing should be done within 60 hours If the suspension is kept, for example, at a temperature of 35°C, then further processing should be carried out within 24 hours

To prevent precipitation, the suspension of the active substance was stirred during the whole process of obtaining and sputtering.

Example 4

Obtaining pellets of the active substance, etexilate of dabigatran

In the experiment used the installation of fluidized bed (GPCG PRO 300). The suspension was sprayed through a nozzle with a hole diameter of 2.2 mm

In the container was loaded 270,561 kg pellets tartaric acid, obtained as described in example 2, and layer pellets were heated. After reaching the temperature of the layer of pellets to 39°C began the process of atomization. The suspension obtained as described in example 3 was sprayed during the seven cycles of 10 min each, increasing the spray rate of from 120 kg/h to 420 kg/h

The suspension is continuously stirred. The temperature of the air flow was maintained at a level of not more than 75°C. the air flow Rate was approximately 7500 m /H. the spray Pressure was in the range of from 3 to 4 bar.

Then the pellets were dried in the container for a product when the temperature of the air flow is at least 20°C. but not more than 70°C with air velocity of 6000 m /h for about 20 minutes

Dry pellets were passed through a vibrating screen with a mesh size of 1.6 mm and kept in containers with desiccant until use.

Example 5

Examples of formulations

The following typical compositions of the pellets of the active substance, obtained as described in example 4 was Packed in capsules from hydroxypropylmethylcellulose.

IngredientAmount(mg) per capsuleAmount(mg) per capsule
Active substance 1 86,48(1)126,83(2)
Arabian gum4,436,50
Tartaric acid88,56129, 9mm
Hydroxyethylmethylcellulose 29102,23with 3.27
Dimethylpolysiloxane 3500,040,06
Talc17,1625,16
Hydroxypropylcellulose17,3025,37
Capsule GPMC60(3)70(4)
Only276,2387,1
(1)corresponds to 75 mg of the free base of the active substance,(2)corresponds to 110 mg of the free base of the active substance,(3)the mass of the capsule is approximately 60 mg
(4)the mass of the capsule is approximately 70 mg

One object of the present invention affords the tsya one of the above pharmaceutical compositions by itself.

Another object of the present invention features pharmaceutical composition, which contains 60-90 mg, preferably 70-80 mg, especially preferably about 75 mg of etexilate of dabigatran formula I. In another object of the present invention features pharmaceutical composition, which contains 90-130 mg, preferably 100-120 mg, preferably 105-115 mg, especially preferably approximately 110 mg of etexilate of dabigatran formula I.

Another object of the present invention features pharmaceutical composition, which contains 60-90 mg, preferably 70-80 mg, especially preferably about 75 mg of etexilate of dabigatran formula I in the form of polymorphic form I of methansulfonate. Another object of the present invention features pharmaceutical composition, which contains 90-130 mg, preferably 100-120 mg, preferably 105-115 mg, especially preferably approximately 110 mg of etexilate of dabigatran formula I in the form of polymorphic form I of methansulfonate.

Another object of the present invention features pharmaceutical composition, which, in addition to etexilate of dabigatran formula I in the form of polymorphic form I of methansulfonate contains hydroxyethylmethylcellulose.

Another object of the present invention features pharmaceutical composition, which, in addition to ataxiatelangiectasia formula I in the form of polymorphic form I of methansulfonate, contains dimethylpolysiloxane.

Another object of the present invention features pharmaceutical composition, which, in addition to etexilate of dabigatran formula I in the form of polymorphic form I of methansulfonate, contains the following components: Arabian gum, tartaric acid, hydroxymethylcellulose, dimethylpolysiloxane, talc, and hydrophobically.

Another object of the present invention features pharmaceutical composition, which, in addition to etexilate of dabigatran formula I in the form of polymorphic form I of methansulfonate, contains mainly the following components:

Arabian gum, tartaric acid, hydroxymethylcellulose, dimethylpolysiloxane and talc, as well as hydrophobically.

Another object of the present invention features pharmaceutical composition, which contains 60-90 mg, preferably 70-80 mg, especially preferably about 75 mg of etexilate of dabigatran formula I, and the composition is intended for the prevention of postoperative deep vein thrombosis and prevention of stroke, primarily for the prevention of stroke in patients with atrial fibrillation. Another object of the present invention features pharmaceutical composition, which contains 90-130 mg, preferably 100-120 mg, preferably 105-115 mg, especially preferably CA is approximately 110 mg of etexilate of dabigatran formula I, and the composition is intended for the prevention of postoperative deep vein thrombosis and prevention of stroke, primarily for the prevention of stroke in patients with atrial fibrillation.

1. The method of obtaining suspension4polymorphic form I salt methanesulfonic acid and etexilate of dabigatran formula I

characterized in that
polymorphic form I of methanesulfonate of etexilate of dabigatran, which is characterized by a melting temperature tpl.180±3°C (according to differential scanning calorimetry (DSC, heating rate 10°C/min), suspended in a mixture with talc in solution hydroxypropylcellulose in isopropyl alcohol at a temperature in the range from 12 to 22°C,
moreover, obtaining the suspension shall be implemented by the method of circulating the dispersion at a temperature not exceeding 30°C.

2. The method according to claim 1, characterized in that first of all hydroxypropylcellulose dissolved in isopropyl alcohol at a temperature in the range from 12 to 22°C, and then in the specified solution suspended polymorphic form I of methanesulfonate of etexilate of dabigatran and talc.

3. The method according to claim 1 or 2, characterized by the fact that 1 kg supplied isopropyl alcohol added is from 0.05 to 0.5 kg of methanesulfonate of etexilate dabigatran the A.

4. The method according to claim 1 or 2, characterized by the fact that 1 kg supplied isopropyl alcohol add from 0.01 to 0.1 kg hydroxypropylcellulose.

5. The method according to claim 1 or 2, characterized by the fact that 1 kg supplied isopropyl alcohol add 0.005 to 0.07 kg of talc.

6. Suspension4suitable to obtain pellets of methanesulfonate of etexilate of dabigatran obtained by the method according to claim 1.

7. Suspension4suitable to obtain pellets of methanesulfonate of etexilate of dabigatran obtained by the method according to claim 2.

8. Suspension4suitable to obtain pellets of methanesulfonate of etexilate of dabigatran obtained by the method according to claim 3.

9. Suspension4suitable to obtain pellets of methanesulfonate of etexilate of dabigatran obtained by the method according to claim 4.

10. Suspension4suitable to obtain pellets of methanesulfonate of etexilate of dabigatran obtained by the method according to claim 5.

11. Suspension4according to claim 6, characterized in that the concentration of the active substance is 10-25 wt.%.

12. Suspension4according to claim 6, characterized in that the total concentration of components: the active substance, hydroxypropylcellulose and talc, is 14-40 wt.%.

13. Suspension4according to claim 7, characterized in that the concentration of the active substance is 10-25 wt.%.

14. Suspension4according to claim 7, characterized in that the total concentration of components: the active substance, hydroxypropylcellulose and talc, is 14-40 wt.%.

15. Suspension4according to claim 8, characterized in that the concentration of the active substance is 10-25 wt.%.

16. Suspension4according to claim 8, characterized in that the total concentration of components: the active substance, hydroxypropylcellulose and talc, is 14-40 wt.%.

17. Suspension4according to claim 9, characterized in that the concentration of the active substance is 10-25 wt.%.

18. Suspension4according to claim 9, characterized in that the total concentration of components: the active substance, hydroxypropylcellulose and talc, is 14-40 wt.%.

19. Suspension4according to claim 10, characterized in that the concentration of the active substance is 10-25 wt.%.

20. Suspension4according to claim 10, characterized in that the total concentration of components: the active substance, hydroxypropylcellulose and talc, is 14-40 wt.%.

21. Application suspension4according to any one of claim 6 to 20 as a starting material to obtain pellets5methansulfonate of etexilate of dabigatran.

22. The method of obtaining pellets5methansulfonate of etexilate of dabigatran, characterized in that the suspension4according to any one of claim 6 to 20 dispersed in the isolated nuclei of tartaric acid3method fluidized bed.

23. The method of obtaining pellets5methansulfonate etaix the LVL of dabigatran on p.22, characterized in that the temperature of the product isolated nuclei tartaric acid3support level 30-50°C.

24. The method of obtaining pellets5methansulfonate of etexilate of dabigatran according to article 22, characterized in that the temperature of the air flow is below 90°C.

25. The method of obtaining pellets5methansulfonate of etexilate of dabigatran according to article 22, characterized in that the standardized speed of the spray, which is sprayed suspension4active substances on isolated nuclei tartaric acid3is in the range from 4 to 45 g/min per 1 kg of used isolated nuclei tartaric acid3.

26. The method of obtaining pellets5methansulfonate of etexilate of dabigatran according to article 22, characterized in that a standardized amount of air supplied is preferably in the range of 10-35 m3/h per 1 kg of used isolated nuclei tartaric acid3.

27. Pellets5methansulfonate of etexilate of dabigatran for the inhibition of thrombin obtained by the method according to p-26.



 

Same patents:

FIELD: medicine.

SUBSTANCE: thrombosis is prevented in the patients suffering cardiovascular diseases and chronic pain by prescribing the preparation tenoxicam 20 mg 1 tablet a day in the period of exacerbation of pain syndrome.

EFFECT: method enables reducing a risk of thrombotic complications and managing pain syndrome in the patients suffering cardiovascular diseases and chronic pain.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to biotechnology and represents a polypeptide construction for treatment, prevention and relief of disorders, associated with an adhesion of platelets and platelet-mediated aggregation or its dysfunction, which includes one or more single-domain antibodies, aimed against the von Willebrand factor (vWF), and one or more single-domain antibodies aimed against serum albumen (SA). The invention also relates to nucleic acid, coding such polypeptide construction, to compositions, containing the said construction, and to its application for obtaining medications for prevention, treatment and relief of the said disorders.

EFFECT: claimed invention makes it possible to extend an assortment of medications for treatment, prevention and relief of disorders, associated with the platelet adhesion and platelet-associated aggregation or its dysfunction.

15 cl, 30 dwg, 32 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the chemistry of sulphur-containing and terpene compounds and specifically to 2-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}thionyl)ethanoic acid of structural formula I: . 2-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}thionyl)ethanoic acid can also be used in medical practice as an agent for preventing haemophilia.

EFFECT: obtaining a novel compound which can be used in medicine as an agent having antiaggregant action, for preserving blood preparations and preventing thrombosis.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a pharmaceutical composition possessing antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory action, normalising lipid and carbohydrate metabolism, more specifically to the pharmaceutical composition of the substance Pijavitum (hereinafter referred to Pijavitum) made from lyophilised medicinal leech. The above pharmaceutical composition is presented in the form of an enteric coated tablet.

EFFECT: coating prevents the active ingredients of Pijavitum from destruction under action of the enzymes and acid medium of the stomach.

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, in particular to hematology, and can be applied for prevention of formation and/or stabilisation of pathological thrombi. Claimed is application of, at least, one antibody, which inhibits factor XII. Also claimed is pharmaceutical preparation, which contains, at least, one antibody inhibiting factor XII.

EFFECT: inventions make it possible to prevent growth of three-dimensional intra-luminal thrombus without manifestations of effect of hemostasis.

7 cl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to experimental pharmacology, and concerns methods for controlled platelet aggregation decrease in vitro. That is ensured by administering mexidol to plasma containing 200-220 thousand/mcl of platelets immediately after plasma sampling. Mexidol is used in the concentration of 0.1 to 0.8 mg/ml of an incubation mixture. The incubation is conducted for 10-15 minutes at room temperature.

EFFECT: method provides platelet aggregation to a desired value.

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology and can be used to produce biologically active collagen peptides from marine hydrobionts. Patiria pectinifera starfish is dehydrated with 96% ethyl alcohol and then demineralised with 1-2 N solution of an inorganic acid with ratio of the raw material to inorganic acid of 1:(3-5) for 1-3 days. The demineralised raw material is washed from traces of acid and water-soluble impurities with distilled water, after which the material is hydrolysed with an alkali solution with ratio of raw material to the alkali solution of 1:(3-5) in order to remove non-collagen proteins and washed with distilled water at temperature of 2-4°C. The obtained starfish collagen shells are homogenised. The homogenate is diluted with distilled water; pH of the suspension is brought to a value equal to 8.0-8.5 with an alkali solution and hydrolysed with 1% collagenase solution with ratio of homogenate to enzyme of (100-200):1 and temperature of 30-40°C for 3-5 hours, pH 8.5-7.0. The enzyme is inactivated at 80-90°C for 10-15 minutes. The hydrolysate solution is filtered to remove non-hydrolysed collagen, subjected to ultra-filtration through a 30 kD membrane filter to remove the inactivated enzyme; the end product, having antitumour, anticoagulant, wound-healing, anti-inflammatory, antioxidant activity, capacity to inhibit collagenase and angiotensin converting enzyme and which is a complex of collagen peptides with a high-molecular weight component weighing 22-23 kD, is concentrated in a vacuum and lyophilised.

EFFECT: obtaining a product, having antitumour, anticoagulant, wound-healing, anti-inflammatory and antioxidant activity.

2 cl, 7 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to therapy and pulmonology, and can be used for selection of tactics of treating thromboembolism of pulmonary artery. For this purpose computered tomography with bolus enhancement is performed to patient, areas of affection located more distally than thrombotic embolus are examined and number of respiratory movements per minute is taken into account. Presence of occluded vessel or vessels in examined areas is identified. Occlusion of segmental branch of pulmonary artery, located more distally than embolus, is assessed in one point irrespective of degree of vessel occlusion. Occlusion of each of lobar branches in case of affection of right middle lobar, left middle- and upper lobar branches of pulmonary artery is assessed in 2 points. Occlusion of upper lobar branch of pulmonary artery on the right, lower lobar branch of pulmonary artery on the left is assessed in 3 points. Occlusion of right lower lobar branch of pulmonary artery is assessed in 4 points. Occlusion of left main pulmonary artery is assessed in 7 points. Occlusion of right main pulmonary artery is assessed in 9 points. Occlusion of both main pulmonary arteries and/or pulmonary trunk is assessed in 17 points. After that, points are summed up. If the sum of points is from 1 to 6, anticoagulation therapy is performed with heparin. If the sum of points constitutes from 7 to 10 at rate of respiratory movements (RRM) lower than 18, another anticoagulation therapy is performed, at RRM more than 18 - thrombolytic therapy is performed. If the sum of points constitutes from 11 to 17, thrombolytic therapy is performed.

EFFECT: method provides possibility of operative objective assessment of degree of pulmonary bed affection and beginning of required therapy in due time.

5 dwg, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of pharmaceutics and medicine and deals with pharmaceutical composition with delayed release, which contains as active ingredient octreotide or its pharmaceutically acceptable salt and two different linear copolymers of polylactide and glycolide (LCPG), characterised by molar ratios lactide/glycolide 75:25 and different values of viscosity, for prolonged supportive treatment of patients with acromegaly and for treatment of severe forms of diarrhoea and hyperaemia, associated with malignant carcinoid tumours and tumours, cells of which produce vasoactive intestinal peptide.

EFFECT: group of inventions ensure stably high level and fast achievement of required level of impact of active substance.

10 cl, 5 ex, 3 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: microspheres contain diclofenac in the form of an acid included in a matrix of a biodegradable polymer specified in a group consisting of polylactide and polylactide-co-glycolide; an average size of microspheres falls within the range of 5 to 150 mcm; a degree of diclofenac inclusion makes 5-50%, and the said microspheres release 60 to 95% diclofenac for 14 days.

EFFECT: extended range of methods for preparing injectable agents for treating inflammatory conditions, such as rheumatoid arthritis, osteoarthritis and rheumatoid spondylitis characterised by the prolonged diclofenac release.

4 cl, 3 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, namely to pharmaceutical drug forms, containing poly-ε-caprolactone, and methods of obtaining them, an application and methods of treatment with their application.

EFFECT: application of a poly-ε-caprolactone matrix makes it possible to provide properties, constraining from abuse (such as resistance to crushing or grinding).

32 cl, 14 dwg, 14 ex, 14 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of microparticle formation. The claimed method includes providing the first anion-including solution, and providing the second cation-including solution, mixing the said first and second solutions in the presence of the first compound with a molecular weight of at least 20kDa in order to form a porous matrices. Porous matrices are formed by precipitation of salt, which contains the said anion and the said cation, with the said first compound being, at least, partially included into the porous matrices. The method includes further cross-linking of the said first compound in the porous matrices and dissolution of the porous matrices with formation of microparticles, which contain the said cross-linked first compound.

EFFECT: invention is aimed at provision of high matrix loading with the first compound, stability of the formed microparticles in water and easiness of a polymer formation, as well as preservation of function of the first compound, for instance, enzymatic activity or oxygen adsorption.

6 cl, 10 dwg, 1 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the general mixture for production of rapidly decomposable tablets in the process of direct tabletting. The claimed mixture contains 90-98 weight parts of the pulverised mannit with water content from 0.3 to 1% by weight and 2-10 weight parts of cross-linked sodium-carboxymethylcellulose. The general mixture has the area of BET surface in the range from 1.5 to 4.0 m2g. The invention also relates to application of the said general mixture for preparation of tablets, including vitamins, mineral substances, microelements, functional food components, plant components and extracts, synthetic and natural dyes and flavours, as well as substances, possessing pharmacological action.

EFFECT: invention relates to the tablet composition, which contains an active compound and/or a flavour, and is prepared with application of the general mixture as a shape-forming material/ The invention ensures facilitation of direct tablet pressing, as well as obtaining tablets with the improved hardness.

14 cl, 1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: composition for vaginal application includes granules, obtained from crystalline cleaved starch. The composition also includes a plasticiser and a therapeutic preparation, selected from metronidazole, miconazole nitrate, medroxyprogesterone acetate. The granules can be easily obtained by pressing/spheronisation. The granules are in a form of a vaginal suppository, a tablet or a capsule. Also described is a method of introduction of the vaginal composition to a patient.

EFFECT: granules by the invention possess better distribution and delay in the fornix, middle part of vagina mucosa and near vagina orifice in comparison with a composition, where as a granule excipient used is microcrystalline cellulose and without crystalline cleaved starch.

12 cl, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to granules as a laxative, containing particles of magnesium oxide of formula Mg2+1-xZn2+x)O (1) with the average diameter of secondary particles 0.1-25 mcm and apparent specific volume 3-20 ml/g. In formula (1) X represents number from 0 to 0.02, content of magnesium oxide particles constitutes from 80 to 95 wt %. Granules also include mannitol and carmellose and have the average particle diameter 0.2-0.4 mm and bulk density 0.4-0.7 g/ml. Content of particles in granules, which have particle diameter from less than 500 mcm to not less than 355 mcm, constitutes from 30 to 45 wt %, content of particles, which have particle diameter from less than 355 mcm to not less than 180 mcm constitutes from 40 to 50 wt %, content of particles, which have particle diameter from less than 180 mcm to not less than 150 mcm, constitutes from 10 to 28 wt %.

EFFECT: granules of magnesium oxide possess good solubility, attractive taste and outlook and do not leave sense of roughness in the oral cavity.

4 cl, 7 tbl, 2 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using mixed metal compounds for preparing a drug preparation for neutralisation of gastric acid or buffer action thereon, as well as for treatment of a condition or a disease related to high gastric levels of acid. The mixed metal compound is a compound of formula (I): MII1-aMIIIaObAn-c.zH2O (I), wherein MII and MIII mean a two-valence and three-valence metal respectively, An- means an n-valence anion, 0.2≤a≤0.4, 0.2≤b≤1.5, 2+a is equal to 2b+Σcn, Σcn<0.9a, and z is equal to 2 or less. According to the invention, the mixed metal compound is presented in the form of a granulated material, wherein a diametre of 50 wt % of the granules makes 106 to 1180 mcm with the material comprising 50 wt % of the mixed metal compound, 3 to 12 wt % of noncovalent water and no more than 47 wt % of an excipient on granulated material weight basis. The mixed metal compound in the form of the granulated material represents a compound of formula (I) or a compound of formula (III): MII1-xMIIIx(OH)2An-y·mH2O (III) ; wherein MII and MIII mean a two-valence and three-valence metal respectively, An- means an n-valence anion, x=Σyn, 0<x≤0.4, 0<y≤1, and 0≤m≤10.

EFFECT: invention provides the buffer action on gastric acid, causing no effect of rebound acid hypersecretion.

46 cl, 3 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics and consists in presenting a pharmaceutical composition applicable for the effective administration of low-molecular drug preparation and polymer compounds, such as peptides and proteins by a method, other than injection, and a method for preparing the given composition. The pharmaceutical composition for transmucosal administration contains (a) a positively or negatively charged drug preparation at pH of the prepared composition, (b) a pharmaceutically acceptable low particle having a size not less than 1 nm and no more than 50 mcm, and (c) a pharmaceutically acceptable coating polymer charged opposite in sign to the drug preparation at the above pH with a particle surface coated with a coating polymer, the drug substance fixed on the surface of the given particle by means of the coating polymer; and the complex is formed by a non-covalent interaction of the given low particle and the coating polymer, and a concurrent electrostatic interaction of the coating polymer and the drug preparation.

EFFECT: group of inventions provides higher stability, as well as control of the transmucosal absorption of the given drug preparation.

17 cl, 8 ex, 13 tbl, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a layer for mechanical protection of dosage forms, containing two or more plasticizing agents, wherein the first plasticizing agent represents first polyethylene glycol of average molecular weight between 3000 and 6000, and the second plasticising agent represents second polyethylene glycol of average molecular weight between 5000 to 7000. The above layer for mechanical protection is found on an enteric coated granule. The declared invention also refers to the pharmaceutically acceptable enteric solid dosage forms comprising the layer for mechanical protection, and to methods for preparing and using the above layer.

EFFECT: declared invention prevents the mechanical damage of the solid dosage forms, especially compression, as well as provides their resistance to gastric acid.

21 cl, 1 dwg, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is described is using a pharmaceutical composition in the form of an orally disintegrated tablet containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active substance and crospovidone as a disintegrating agent in ratio 2:1 respectively, as a motor stimulating and anorectic agent.

EFFECT: preparing motor stimulating and anorectic agent.

16 dwg, 34 tbl, 13 ex

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