Pharmaceutical anti-tuberculosis combined composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with combined pharmaceutical composition, which possesses anti-tuberculosis action. Composition is made in form of solid drug form, which contains combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride ad active ingredient, and pharmaceutically acceptable auxiliary substances.

EFFECT: composition is characterised by high therapeutic activity.

10 cl, 2 tbl, 4 ex

 

The invention relates to medicine, specifically to a combined anti-TB drugs, and can be used for treatment of tuberculosis.

Despite the significant progress achieved in recent decades in many areas of medicine, including the treatment of tuberculosis, is still quite high incidence of TB. The main problems of tuberculosis treatment are limited Arsenal of anti-tuberculosis drugs and the rapid development of resistance of Mycobacterium tuberculosis to applied drugs.

In the standard chemotherapy of tuberculosis as the primary and most effective anti-TB drug isoniazid is used - isonicotinic acid hydrazide. Featuring high therapeutic activity of isoniazid and has a strong toxic effect. But its major drawback is the rapid development of drug resistance of Mycobacterium tuberculosis, which significantly reduces its effectiveness. Resistance of Mycobacterium tuberculosis to isoniazid develops in 70% of patients and 30% of patients become chronic patients.

The development of resistance of mycobacteria is much slower in case of simultaneous use of several drugs. However, the combined therapy of patients with drug-what Oleson due to the complexity and duration of selection of effective drugs, and the course of therapy exercise his or irregularly, or not getting to the end, which causes a return of the disease, the rapid emergence of secondary drug resistance. Therefore, the world Health Organization (who) recommends the rejection of mono - and combined therapy and necessitates the use of combined anti-TB drugs in a single dosage form.

In the patent of Russian Federation №2182483 features combined anti-tuberculosis drug, which contains isoniazid, and pyrazinamide or ethambutol hydrochloride. However, the presence in its composition of only two active components are not completely removes the above-mentioned disadvantages of combination therapy and requires the use of additional anti-TB drugs.

To reduce the development of drug resistance of Mycobacterium tuberculosis have been proposed multicomponent anti-TB drugs, containing three or more active substances. For example, in U.S. patent No. 5104875, 1992, describes pharmaceutical combined preparation containing rifampicin, Thiacetazone and, optionally, isoniazid or ethambutol.

Standard course of combination therapy for TB is isoniazid and rifampicin, which usually add other however, ercolania drugs - pyrazinamide and/or ethambutol. You know the combined means containing one tablet of isoniazid, rifampicin, pyrazinamide and ethambutol (drugs in Russia: a Handbook. M: Attraversare, 2003, p. B-490).

In the patent of Russian Federation №2195937, 2003, offers a combined antituberculosis drug containing as an active start to the combination of isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine, and as excipients metozel methyl cellulose ethers containing 14-30% metaxylene groups (prototype).

However, the known compositions have a number of disadvantages. During the course of use of the above drugs, there are marked toxic effect and the occurrence of side effects. In addition, in the known combined compositions of the mutual influence of ingredients leads to a significant reduction in the bioavailability of the beginning of the current, which degrades the efficiency in the treatment of tuberculosis and causes a return of the disease and the development of drug resistance.

As an alternative was proposed combined TB, comprising a therapeutically effective amount of the current to the beginning, which contains a combination of lomefloxacin, protionamide, pyrazinamide, ethambutol hydrochlo is Yes and pyridoxine hydrochloride and pharmaceutically acceptable auxiliary substances (patent RF №2247560, the prototype). However, in some cases, treatment of tuberculosis, it is not efficient enough.

Thus, the creation of combined anti-TB drugs is associated with resolution of several problems is the selection of effective combinations of drugs and their relations, which helps to overcome resistance to drugs, as well as the compatibility of various drugs during the manufacturing process and storage.

The present invention is the development of highly efficient combined anti-TB compound, which has a high antimicrobial activity against Mycobacterium tuberculosis and minimal toxic side effects.

The problem is solved in that the proposed pharmaceutical composition with anti-TB activity includes a therapeutically effective amount of the current to the beginning, which contains a combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride and at least one pharmaceutically acceptable excipient

The proposed combination of active ingredients is new for combined anti-TB drugs, are chosen empirically and allows to obtain a technical result, according to stuudy the task, namely, a significant increase antimycobacterial activity in comparison with the prototype.

In the comparative study of specific activity against M. tuberculosis strain H37Rv (ILO), the claimed composition and the prototype model exudative necrotic TB mice was determined as the average life of animals after infection with a lethal dose of the office in different experimental groups of animals; studied microbiological method in vivo bactericidal and bacteriostatic activity; estimated morphological methods the nature of reparative processes in parenchymatous organs in the treatment of experimental tuberculosis of mice studied groups.

The determination of specific anti-TB activity of drugs in vivo studies were performed on inbred male mice of BALB/c obtained from the vivarium of the research RAMS. Mice weight - 22-23 grams. Mice were infected by intravenous M. tuberculosis strain H37Rv from the collection of the Institute Pasteur (France) in the lateral tail vein at a dose of 5×106CFU/mouse.

The tested drugs were injected intragastrically daily (except weekends) for 4 weeks 18 days after infection. According to the program of study within 4 weeks after the start of treatment of the experimental animals were taken from experiment method the cervical disloca and to determine the number of colony forming units (CFU) M tuberculosis (MBT) in the lungs of mice and histological examination of the tissues of the lung, liver and spleen.

To determine the number of bacteria (CFU office) in the lungs of infected mice lungs homogenized in 2 ml of physiological solution was prepared by serial 10-fold dilution of the original suspension in physiological solution and 50 μl of each dilution was placed on a Petri dish, covered with agar, Dubo. Petri dishes coated with suspensions of lung cells were incubated for 21 days at 37°C, and then counted the number of colonies on plate and determined the number of CFU of bacteria in the lungs by the formula:where N is the number of colonies in the lungs. Histological study of the pieces of lung, spleen and liver were fixed with 10% buffered formalin, were placed in paraffin, preparing histological sections, which were stained with hematoxylin and eosin.

The main indicators of resistance of the animal to the TB are term survival after infection, the number of CFU office in the organs of infected animals, genotype to tuberculosis, and the degree of pathological changes of internal organs.

Mice of the control group not receiving any drugs, survival after lethal doses of infection 25.5±0,26 days. Mice treated with investigational drugs at the time of the end is ecene and slaughter (46 days after infection) were alive. The results of microbiological studies in vivo are presented in table 1.

Table 1
The quantity sown M.tuberculosis H37Rv from the lungs of mice after intravenous infection at a dose of 5×106CFU/mouse 4 weeks after starting treatment
Groups of animalsSOME of the office (M±SEM)
Control animalsfell
The prototype of 25 mg/kg(3,7±0,37)×108
The composition 25 mg/kg invention(8,8±0,65)×107

According to the data obtained indicators SOME office in the group of animals treated with the new composition, were approximately an order of magnitude lower than in the experimental group treated with the prototype, i.e. the change in the composition of the combined drug - prototype (replacement lomefloxacin on levofloxacin) unexpectedly increased bacteriostatic activity of the drug is almost 10 times.

In the histological studies of the comparative therapeutic efficacy following data were obtained. Intravenous office in mice developing exudative-eroticheskii inflammatory process, affecting various parenchymal organs. Control animals died from generalized tuberculosis in 25 days. By the time of his death in lung, liver and spleen observed the plethora, the sludge of erythrocytes in the blood vessels of medium and large caliber identified young and Mature forms of PAL. Around the vessels are formed of cellular infiltrates consisting of mono - and polynuclear; the number varies in different organs.

Especially large pneumonic foci are formed in the lungs, where, along with macrophages and lymphocytes are determined by the large accumulation of PAL. Among alveolar macrophages predominate lipobay, which on histological sections have foamy cytoplasm due to numerous granules neutral lipid. These cells are determined by the accumulation of the office. When the destruction of lipophages the office fall into vnutriarterialno the space around them concentrate of PAL. Therefore, the presence of foam cells (PC), especially destroyed their forms, reflects the activity of specific inflammation in mice, which is most pronounced in animals of the control group. In the terminal period of the process of cellular infiltrates occupy up to 70% histological slice; their composition is determined by large accumulations PC, here are concentrated PAL forming zone of necrosis. The edge with the centers of the alveoli partially or completely filled with edema fluid, contain fibrin and debris of the destroyed cellular elements. In areas of the parenchyma preserving the air, millionarie septum thickened due to interstitial edema and infiltration of mono - and polynuclear. These cells are defined in the extended loops of the capillary network. In the liver of mice of the control group in addition to the exudative reaction, the formation of perivascular infiltrates pays attention to the development of degenerative changes of hepatocytes, especially expressed in the terminal period of inflammation. Cells of the hepatic beams have enlightened vacuolation the cytoplasm, often with signs of destruction. In areas of necrosis determined by PAL. The spleen of control mice depleted lymphocytes, there has been a proliferation of stromal elements, the formation of diffuse mononuclear infiltrates, which are determined by PAL.

In the experimental mice therapeutic groups treated with the prototype and the claimed composition, the picture of tuberculous inflammation in the lungs, liver and spleen as well as in the control, is a progressive. The most characteristic changes are observed in the lungs, where they develop exudative-necrotic inflammatory process affecting 55-70% of the parenchyma. In both treatment groups everywhere are defined by major merging between pneumonitis the e tricks, containing a significant amount of PAL, including the stage of destruction. The basis of pneumonic foci are foamy macrophages in the cytoplasm which concentrate the office (Roy and others, 1997). Many macrophages have destroyed the cytoplasm. Around such cells are of PAL that reflects the high specific activity of inflammation in both treatment groups. However, in animals treated with the composition according to the invention pays attention to the low detection rate of micronecrosis than in the group of animals receiving the prototype or the control group. As part of pneumonic foci of PAL often are diffuse, do not form large clusters, as in the 3rd group (prototype), and especially in control animals. This indicates a more pronounced therapeutic activity of the claimed drug compared to the comparison drug.

The results of histological research suggests that the claimed composition has a more pronounced positive effect on the dynamics of tuberculous inflammation in experimental animals compared to the prototype. Thus, the studies found an increase in the average lifespan of mice treated with therapy drugs in the studied doses compared to control animals, whereas the ω set microbiologically, what a bacteriostatic effect of the claimed composition in vivo against M. tuberculosis H37Rv in acute models of exudative necrotic TB almost an order of magnitude exceeded the bacteriostatic effect of the drug is the prototype, shown histologically more pronounced therapeutic activity of a new composition in comparison with the prototype due to a lower detection rate micronecrosis lung tissue and BAL. On the basis of obtained data we can conclude that the composition according to the invention has a more pronounced therapeutic effect against .tuberculosis than currently in the prototype.

Included in the composition pyridoxine hydrochloride prevents or reduces the toxic effects on the body, seen in the application of anti-TB drugs. The study of the toxicity of the new drug showed that after two weeks intragastric administration to rats at a dose of 500 mg/kg (at the current beginning) Hematology (red blood cells, hemoglobin, leukocytes, reticulocytes, platelets) and biochemical (total lipids and glucose) blood parameters as indicators of toxicity did not differ from the control. Not marked structural abnormalities in organs and tissues, not found irritating new composition to the mucous membrane of Zheludok what about the intestinal tract.

Thus, on the basis of the results of biological studies the conclusion can be made about the high therapeutic efficacy of new drugs and its application as a drug.

Preferably, the compositions contain ingredients acting early in the following ratio, parts by weight:

Levofloxacin is 1.0,

Protionamide - 0,4-1,2,

Pyrazinamide - 1,35-2,75,

Ethambutol hydrochloride - 1,4-3,3,

Pyridoxine hydrochloride - 0.01 to 1.0.

The proposed drug is preferably carried out in a variety of solid dosage forms - tablets, capsules, granules, powders. As auxiliary substances may be used substances commonly used in the pharmaceutical industry for the production of solid dosage forms, such as starch, sugar, cellulose and its derivatives, gelatin, polyvinylpyrrolidone, polyethylene oxide, calcium phosphate, lubricant, wetting agent, as nutriceuticals, esters of polyoxyethylenesorbitan and fatty acids (twins), esters sorbitan and fatty acids (spany), preferably starch, including modified, lactose, microcrystalline cellulose, nutritionstrategywales, polyvinylpyrrolidone, lubricant. Examples of the latter include stearic KIS the PTA and/or its salts - calcium stearate, magnesium stearate, zinc stearate, talc, colloidal silica, Aerosil, polyethylene glycol, hydrogensource vegetable oil, liquid paraffin. The new composition may also contain flavoring agents, colorants and/or flavorings. Preferably, the preparation is made in the form of pills, which can be a shell. The presence of the latter improves the appearance and organoleptic properties of the dosage form, protects it from mechanical damage. Preferably the shell is based on a derivative of cellulose, such as oksipropilmetiltselljulozy, or ready-mix brand "Opadry".

Preferred amounts of the ingredients beginning of the current in a single dose is: for levofloxacin from 180 mg to 220 mg, more preferably 200 mg to protionamide from 135 to 165 mg mg, more preferably 150 mg, pyrazinamide from 333 mg 440 mg, more preferably 370 mg, ethambutol hydrochloride from 292 mg to 400 mg, more preferably 325 mg and pyridoxine hydrochloride from 5 to 15 mg, more preferably 10 mg

In the framework of the present invention, the term levofloxacin implies also hydrates and salts of levofloxacin, such as hydrochloride, levofloxacin. Preferably levofloxacin is used in the form of a hemihydrate. This explanation also applies to other active the ingredients of the current start - the protionamide, pyrazinamide, ethambutol and pyridoxine.

In a preferred embodiment, the composition contains as levofloxacin hemihydrate levofloxacin.

Preferably the composition contains as an auxiliary ingredients multifunctional filler is a filler, dry binder and disintegrant, binder, plasticizer, giving tabletas mass plasticity and increases the strength of the resulting tablets-cores (from 190 N to 240 N) glidant improving fluidity tabletas mass (from 3.0 g/s to 6 g/s), superdisintegrants, providing faster raspadaemost tablets-cores, and a lubricant, preventing when pelletizing the accumulation of mass on the punches, mashing matrices and providing popping pills-nuclei of them.

The preferred ratio of ingredients of the inventive compositions is, g:

Levofloxacin

(in recalculation on 100%levofloxacin) - 0,2000

Protionamide - 0,1500

Pyrazinamide - 0,3700

Ethambutol hydrochloride 0,3250

Pyridoxine hydrochloride - 0,0100

Multifunctional filler - 0,0090÷0,1600

Povidone - 0,0010÷0,0210

Macrogol - 0,0005÷0,0084

Superdisintegrants - 0,0130÷0,2400

Glidant (moving matter) - 0,0048÷0,0950

Lubricant (grease) - 0,0050÷0,1000

Shell

Pincourt the athel - 0,0065÷0,1200

Plasticizer - 0,0018÷0,0330

Pigment - 0,0008÷0,0150

The dye is 0.0001÷0,0020

As a multi-functional filler preferably pregelatinized starch as a binder agent is povidone as a plasticizer - macrogol, as superdisintegrants - sodium croscarmellose, as glidants - colloidal silicon dioxide and talc as lubricant is sodium stearyl fumarate, stearic acid, and salts of stearic acid, preferably calcium stearate and/or magnesium.

As the foaming agent, it is preferable to use hypromellose, as plasticizer - macrogol 6000 and glycerol, as glidant - talc, pigment - titanium dioxide as a colorant such as iron oxide yellow.

In another aspect of the invention features the use of a combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride for the manufacture of pharmaceutical compositions with anti-TB activity.

In a preferred embodiment, obtaining the inventive dosage forms can be made by wet granulation followed by addition of dry granules of lubricant, forming a final mixture of ingredients with the formation of the dosage forms of a given configuration and R is smera and if necessary, the application shell.

The invention is illustrated by the following examples (see Table 2), which are only illustrative but not restrictive.

Example 1. Levofloxacin 200 mg (1 M.Ch.), protionamide 150 mg (0.75 in M.Ch.), pyrazinamide - 370 mg (1,85 M.Ch.), ethambutol hydrochloride 325 mg (1,625 M.Ch.), pyridoxine hydrochloride 10 mg (0.05 M.Ch.), excipients 200 mg, including pregelatinized starch - 52,9 mg, povidone - 10.0 mg, colloidal silicon dioxide and 6.3 mg, nitrocresols - of 80.6 mg, talc - of 18.9 mg, lubricant - 31,5 mg Average weight of tablets 1260,0 mg (the number of ingredients in mg is indicated per 1 tablet).

Pre-sifted powders substances levofloxacin (as hemihydrate), protionamide, pyrazinamide, ethambutol hydrochloride powder and starch pregelatinization mix until smooth, granularit aqueous solution of povidone with macrogol, dry and grind the resulting granulate.

Due to the low content of pyridoxine hydrochloride in the composition tabletas mass to achieve a uniform distribution in tablets pre-prepared mixture of pyridoxine hydrochloride and colloidal silicon dioxide. For this purpose, sifted powder pyridoxine hydrochloride mixed with sifted powder of silicon dioxide colloidal, and the resulting mixture was manually is receiveit through a sieve.

To ground the granulate add a pre-prepared mixture of pyridoxine hydrochloride with silicon dioxide colloidal, sodium croscarmellose, talc, lubricants (sodium stearyl fumarate, stearic acid and a salt of stearic acid) and ready weight tabletirujut. Get tablet cores with an average weight 1,2600 g and strength 200÷250 N.

The obtained tablets-kernel is applied film-forming composition on the basis of the foaming agent hypromellose. To a solution of foaming agent added gomogenizirovannogo suspension consisting of talc, titanium dioxide, iron oxide yellow, glycerol and the solution of macrogol 6000. The application shell is carried out to obtain a satisfactory film thickness. Received the tablet, film coated liner satisfy regulatory requirements in the pharmaceutical agent. Dissolution, % release of levofloxacin and protionamide on Wednesday dissolution - 0,N solution of hydrochloric acid after 45 minutes (HPLC) - 99 and 95, respectively, the content of active substances in one tablet (HPLC) - 200 mg (levofloxacin), 150 mg (protionamide), 370 mg (pyrazinamide), 325 mg (ethambutol hydrochloride) and 10 mg (pyridoxine hydrochloride). The resulting tablets have a shelf life of over 2 years.

Example 2. Levofloxacin 200 mg (1 M.Ch.), protionamide - 80 mg (0.4 M.Ch.), pyrazinamide - 270 mg (1,35 M.Ch.), e is amatola hydrochloride 280 mg (1,4 M.Ch.), pyridoxine hydrochloride, 20 mg (0.1 M.Ch.), excipients (starch - to 36.0 mg, lactose 55,0 mg, microcrystalline cellulose - 50.0 mg, polyvinylpyrrolidone - 15,0 mg, polyethylene glycol, 5 mg, talc - 11.0 mg, calcium stearate - 8.0 mg). Average weight of tablet 1030,0 mg (the number of ingredients in mg is indicated per 1 tablet).

A mixture of levofloxacin, protionamide, pyrazinamide and ethambutol hydrochloride with microcrystalline cellulose, lactose and a part of the starch (70%) granularit using a solution of polyvinylpyrrolidone in aqueous alcohol, which is added to the polyethylene glycol, and dried. Dry granules are milled, mixed with pyridoxine hydrochloride, the remainder of the starch, the talc and the calcium stearate and tabletirujut.

Example 3. Levofloxacin - 100 g (1 M.Ch.), protionamide 120 g (1,2 M.Ch.), pyrazinamide 275 g (2,75 M.Ch.), ethambutol hydrochloride - 330 g (3,3 M.Ch.), pyridoxine hydrochloride, 100 g (1.0 M.Ch.), excipients, corn starch - 25,0 g, microcrystalline cellulose - 72.5 g, silicon dioxide is 2.5, Microcrystalline cellulose and silicon dioxide are mixed to obtain a pre-mixture. This mixture, in turn, is mixed with levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride and starch. The mixture is filled hard gelatin capsules are eligible what about the size, using conventional machine for filling capsules.

Example 4. Levofloxacin - 60,0 g (1 M.Ch.), protionamide - 45,0 g (0,75 M.Ch.), pyrazinamide 111 g (1,85 M.Ch.), ethambutol hydrochloride 97.5 g (1,625 M.Ch.), pyridoxine hydrochloride and 0.6 g (0,01 M.Ch.), excipients polyvinylpyrrolidone - 9.7 g, corrigent taste (Matricaria) - 10.2 g, flavor - 10.3 g, manitol - to 332.8 g, nutriceuticals - 17,5, Moistened with a solution of polyvinylpyrrolidone mixture of the remaining ingredients, granularit on the device for producing granules and dried. Receive granules for the preparation of water-dispersible suspension oral administration.

Table 2
IngredientsContent parts by weight
Examples
1234
Levofloxacin1,01,01,01,0
Protionamide0,750,41,20,75
Pyrazinamide1,851,352,751,85
Ethambutol hydrochloride1,6251,43,31,625
Pyridoxine hydrochloride0,050,11,00,01
Excipients1,00,91,06,34

1. Pharmaceutical composition with anti-TB activity comprising a therapeutically effective amount of the current to the beginning, which contains a combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride, and at least one pharmaceutically acceptable auxiliary substance.

2. The pharmaceutical composition according to claim 1, characterized in that includes the ingredients of the current start in the following ratio, parts by weight:

Levofloxacin1,0
Protionamide0,4-1,2
Pyrazinamide1,35-2,75
Ethambutol hydrochloride1,4-3,3
Pyridoxine hydrochloride0,01-1,0

3. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of solid dosage forms.

4. The pharmaceutical composition according to claim 3, characterized in that it is made in tablet form.

5. The pharmaceutical composition according to claim 4, characterized in that it contains as inactive ingredients pregelatinized starch, povidone, macrogol, colloidal silicon dioxide, sodium croscarmellose, talc, sodium stearyl fumarate, stearic acid and a salt of stearic acid.

6. The pharmaceutical composition according to claim 4, characterized in that it has a shell.

7. The pharmaceutical composition according to any one of p-6, characterized in that it contains ingredients beginning of the current in a single dose in the next number, mg:
levofloxacin 200 mg, protionamide 150 mg, pyrazinamide - 370 mg of ethambutol hydrochloride 325 mg and pyridoxine hydrochloride - 10 mg

8. The pharmaceutical composition according to claim 7, characterized in that includes levofloxacin in gamig the dratha.

9. Applying a combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride for the manufacture of a composition with anti-TB activity.

10. The use according to claim 9, in which levofloxacin is used in the form of the hemihydrate.



 

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2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine. The group of inventions involves pharmaceutical compositions containing 5-azacytidine for the oral introduction wherein the compositions release a cytidine analogue substantially in stomach, a method of treating an individual suffering a disease associated with abnormal cell proliferation which involves the oral introduction of the pharmaceutical composition into the individual, using 5-azacytidine for preparing the pharmaceutical composition for treating the disease associated with abnormal cell proliferation.

EFFECT: invention provides higher clinical effectiveness.

9 tbl, 9 ex, 23 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical and nutriceutical tablets. Composition for tabletting contains matrix with lubricant, which is included into its composition. Said matrix with lubricant included into its composition consists of oily liquid, finely dispersed in oil-insoluble material. Said matrix constitutes from 0.3 to 8.8% of composition and composition does not contain stearate. Claimed is method of manufacturing composition for tabletting and tablet, manufactured by tabletting said composition.

EFFECT: invention makes it possible to improve lubrication of dry nutriceutical and/or pharmaceutical compositions during tabletting.

24 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: composition of a solid quick-disintegrating tablet of low frangibility contains 1 to 20 wt % of ethyl cellulose as a binding agent and 2 to 15 wt % of a disintegrating agent. The ethoxy group content in ethyl cellulose is found within the range of 44 % to 54.9%. Viscosity of 5% ethyl cellulose makes a value within the range of 3 sP to 200 sP as mixed with solvents toluene/ethanol, 80:20. The disintegrating agent is specified in a group consisting of crossed-linked povidone, croscarmellose sodium salt (crossed-linked carboxymethyl cellulose sodium salt), starch glycolate sodium salt, low-substituted hydroxypropyl cellulose and guar gum. The composition may additionally contain an active pharmaceutical ingredient. What is also described is a method for preparing the quick-disintegrating tablet of low frangibility by direct compression.

EFFECT: invention provides creating the quick-disintegrating mechanically solid tablet of low frangibility for fast and effective delivery of the active ingredient into the nasal cavity.

27 cl, 8 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly gastoenterology, reflexotherapy, physiotherapy. It involves a conventional drug-induced therapy of chronic pancreatitis. It is added with the antidepressant azaphen 75 mg daily in clinically apparent affective disorders, 50 mg daily in subclinically apparent affective disorders for 30 days. Magnetic laser puncture is performed with considering a vegetative balance state. One biologically active point is exposed to modulated wave length 1.3 mcm, frequency 2.4 Hz, magnetic induction 50 mT for 10-30 seconds. Sympathicotonia requires sequential sedation of the point GI 4 and toning of the points. E 25, E 36, MC 6. Vagotonia requires toning of the point GI 4 and sedation of the points E 25, E 36, MC 6. It is accompanied with transcutaneous magnetic laser exposure at wave length 0.89 mcm with using a magnetic tip 150 mT. A solar plexus area, a projection of pancreas, a projection of gall bladder are covered for 2 minutes. In manifested pain syndrome, the exposure starts at the frequency of 820 Hz to be decreased to 80 Hz. In weak pain syndrome, the frequency of 360 Hz is gradually decreased to 80 Hz. In the absence of pain syndrome, the exposure is applied at the frequency of 80 Hz.

EFFECT: method normalises a psychoemotional sphere, daily chronobiorhythms, vegetative balance state, reduced length of treatment, prolongs a remission period.

2 ex, 2 tbl

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