Prolonged-release oral tedisamil composition retained in stomach

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutics, more specifically a prolonged-release composition of tedisamil or its pharmaceutically acceptable salt to be used in prevention and treatment of atrial fibrillation, atrial flutter and myocardial ischemia, containing 5 to 40 wt % of tedisamil or its pharmaceutically acceptable salt, 30 to 85 wt % of a water-swellable polymeric matrix containing hydroxypropylmethylcellulose (HPMC) of high or medium viscosity and hydrohyethyltcellulose (HEC) of high or medium viscosity in the ratio HPMC/HEC=1/0.85-1/1.2, 2.5 to 5 wt % of a salt capable to recover carbon-dioxide gas in the gastric medium, and 0.5 to 10 wt % of alginic acid.

EFFECT: invention allows providing tedisamil composition expressing improved bioavailability and causing less by-effects of gastrointestinal tract.

5 cl, 6 ex, 4 tbl, 2 dwg

 

The technical field to which the invention relates

The present invention relates to a new composition containing tedisamil or its pharmaceutically acceptable salt with a slow release, with the delay property in the stomach, and use of this composition in the prevention and treatment of atrial fibrillation, atrial flutter and myocardial ischemia.

The level of technology

Tedisamil connection is developed in the form of its sesquifumarate salt is a compound that blocks potassium channels, which is characterized by a limited therapeutic window and is chemically described as 3',7'-bis(cyclopropylmethyl)-Spiro[cyclopentane-1,9'-[3,7]diazabicyclo-[3.3.1]-nonan], (2E)-2-butenedioate(2:3)

It was shown that the compound is effective in the conversion of atrial fibrillation to normal sinus rhythm and maintaining sinus rhythm after cardioversion. It also has anti-ischemic properties. Tedisamil acts as a blocker myocardial potassium channels, and in higher concentrations also sodium channels. He does not have a negative inotropic effect, and it does not affect the level of potassium in the serum. In addition, in clinical studies it has been successfully used with commonly used drugs and warfarin. In addition, heart gli is aside, atenolol and glibenclamide had no clinically meaningful effect on the pharmacokinetics of tedisamil.

Disclosure of invention

In clinical studies it was found that tedisamil used in the form of tablets with immediate-release caused some negative effects, mostly adverse effects gastro-intestinal tract in the form of diarrhea and abdominal pain, which were probably caused by high peak concentrations of compounds in plasma with the use of a composition with immediate-release. In addition, it was concluded that the low values of the smallest concentrations believed to be responsible for the limitation of efficiency, especially in maintaining sinus rhythm after cardioversion.

As the first solution to the aforementioned problems, with the goal of reducing peak concentrations in plasma were developed composition with modified release, described in WO 02/26214. In WO 02/26214 disclosed compositions, for example, tedisamil delayed release, with largely independent of the ionic strength of the release when exposed to the fluids of the gastrointestinal tract. However, apparently, the full availability of the active compound in these compositions with delayed release was low (57% compared with the composition immediately released the eat).

The present invention is to provide a composition that causes fewer side effects from the gastrointestinal tract and has a bioavailability of at least 70% compared to the composition with the immediate-release and, preferably, at least 75%.

It was found that the above problems can be solved in the composition tedisamil delayed release, having the properties of delays in the stomach. This is particularly surprising in view of the fact that the absorption tedisamil in the proximal gastrointestinal tract is much worse than the absorption in the distal intestine (the ileum).

Detailed description of the invention

The present invention relates to compositions with delayed release, having the properties of delays in the stomach. These properties delays in the stomach can be obtained by applying a floating system of drug delivery, described B. N. Singh, and K. H. Kim (J. Controlled Release 2000, 63, 235-259), preferably having a density less than 1.0 g/cm3or use swelling or increase in volume of the delivery system, i.e. the compositions, which swells in the stomach to such an extent that it can pass through the pyloric sphincter (link: J.Timmermans and A.J.Moes, The cut-off size for gastric emptying of dosage forms, J.Pharm. Sci. 1993, 82(8), 854).

Under samenlevingsvormen is the (gradual) release of the active substance from the dosage form over a time interval from 2 to 8 hours or more. This period usually begins with the application of the dosage form, or with the beginning of the test for solubility in vitro (placing dosage forms in the environment (dissolution). In the present invention compositions with delayed release compared with compositions immediate-release, in which a large part of the active substance (i.e. at least 80%) is released after 45 minutes after administration dosage forms or from the beginning of the test for solubility in vitro.

In one embodiment of the invention swelling composition swells in the stomach to such an extent that it can no longer pass through the pyloric sphincter. This alternative implementation of the present invention comprises from 5 to 40 wt.% (preferably from 10 to 30 wt.%) tedisamil or its pharmaceutically acceptable salt, from 30 to 85 wt.% swelling in water of the polymer, and optionally, the amplifier swelling (preferably from 0.5 to 10 wt.%, more preferably from 1 to 4 wt.% and most preferably 3 wt.%). The amplifier swelling increases the rate of swelling and the swelling degree. An example of the amplifier swelling is alginic acid.

In a preferred embodiment of the invention the above-mentioned system is combined in the system of drug delivery, which platinum, and swells. The preferred implementation is tvline of the present invention comprises from 5 to 40 wt.% (preferably from 10 to 30 wt.%) tedisamil or its pharmaceutically acceptable salt, from 30 to 85 wt.% swelling in water of the polymer and from 2.5 to 5 wt.% salt is able to yield gaseous carbon dioxide in the gastric environment, the composition has the property of flotation, and swelling, which leads to a delay in the stomach. Optional added amplifier swelling (preferably from 0.5 to 10 wt.%, more preferably from 1 to 4 wt.% and more preferably 3%).

Despite the fact that the coating is not required to achieve the desired effect of the present invention, the composition is not necessarily covered with the coating material to achieve other desirable effects, such as masking the taste or the giving of color.

Suitable coating materials known in the art and include, for example, HPMC, acrylic polymers, ethylcellulose (see Graham Cole ed., Pharmaceutical Coating Technology, London, Taylor & Francis Ltd.; 1995).

There is some swelling in water of the polymers that can be used to obtain compositions with delayed release. Examples of swelling in water of the polymers include hypromellose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC).

The cellulose ethers which can be used in the present invention, are known in the field of technology available in pharmaceutical brands and have different srednemolekulyarnye mass, that leads to different viscosities of the solutions of these cellulose ethers. In the context of this patent application hydrophilic polymers can be characterized by their viscosity 2% wt./wt. aqueous solution having a low viscosity (less than about 1000 MPa), medium viscosity (from about 1000 MPa to about 10000 MPa) and high viscosity (greater than about 10000 MPa). Hydrophilic polymers hydroxypropylmethylcellulose (HPMC) of varying degrees of viscosity, which can be used in the present invention, available from Dow Chemical Co. under the trade name Methocel (from Shin Etsu under the trade name Metolose®.

Examples of low viscosity polymers include Methocel E5®, Methocel E-15LV®, Methocel E50LV®, Methocel K100LV(and Methocel F50LV®, 2% aqueous solutions of which at 25°C have a viscosity of 5 MPa, 15 MPa, 50 MPa, 100 MPa and 50 MPa, respectively).

Examples of medium viscosity HPMC include Methocel E4M (and Methocel K4M, 2% aqueous solutions of which at 25°C have a viscosity of 4000 MPa).

Examples of high viscosity HPMC include Methocel K15M (and Methocel K100M®, 2% aqueous solutions of which at 25°C have a viscosity of 15,000 MPa and 100,000 MPa).

Hydrophilic polymers of hydroxyethyl cellulose (HEC) of varying degrees of viscosity, which can be used in the present invention, available from AQUALON under the trade name Natrosol (and from Amerchol Corporation under the trade name Cellosize®).

Examples of polymers of low Vya the bones are Natrosol L (and Natrosol J®, 2% aqueous solutions of which at 25°C, have a viscosity of 10 MPa and 20 MPa, respectively).

Examples of medium viscosity polymers include Natrosol G (and Natrosol K®, 2% aqueous solutions of which at 25°C have a viscosity of 200 MPa and 1500 MPa, respectively).

Examples of polymers of high viscosity include Natrosol M (and Natrosol HH®, 2% aqueous solutions which have a viscosity at 25°C 4000 MPa and 90,000 MPa, respectively).

In a preferred embodiment of the present invention the composition comprises a mixture of hydroxypropylmethylcellulose high or medium viscosity (HPMC), hydroxyethyl cellulose high or medium viscosity (HEC), described in WO 02/26214.

The ratio of HPMC high or medium viscosity and HEC high or medium viscosity ranges from 1/0,85 to 1/1,2, preferably from 1/0,9 to 1/1,1, even more preferably from 1/0,95 to 1/1,05, and most preferably 1/1. The composition optionally may contain HPMC of low viscosity. In this case, the ratio of HPMC high or medium viscosity and low viscosity HPMC is in the range from 1/0,01 to 1/0,2, and preferably from 1/0,01 to 1/0,1 and even more preferably from 1/0,02 to 1/0,05.

As salts, are able to release gaseous carbon dioxide can be applied carbonates of alkali metals, preferably sodium carbonate, potassium carbonate or sodium bicarbonate. Can be added to the acid, for example imona acid and maleic acid. The preferred carbonate is sodium bicarbonate, and the preferred acid is citric acid.

Can be applied to other auxiliary materials, such as lubricants (for example, sodium stearyl fumarate (Pruv®), glycerol beginat (Compritol 888 ATO), glidant (for example colloidal silicon dioxide (Aerosil®)), leavening agents (such as sodium starch glycolate (Primojel®)), fillers (such as mannitol), dyes and antioxidants.

The present invention also relates to a method of manufacture of the composition described above, characterized in that

(1) the core is compressed from a mixture comprising from 5 to 40 wt.% tedisamil or its pharmaceutically acceptable salt, from 30 to 85 wt.% swelling in water of the polymer matrix and from 2.5 to 5 wt.% salt is able to yield gaseous carbon dioxide in the gastric environment, and optionally from 0.5 to 10 wt.% amplifier swelling.

(2) the core is not necessarily coated.

In a preferred embodiment, the components of HPMC (K4M and E5) and HEC are mixed. The resulting mixture is mixed with a mixture of shredded citric acid and sodium bicarbonate, and alginic acid. Added shredded sesquifumarate tedisamil and the mixture is stirred. Screened and lubricant is added, followed by mixing with the filler. The active substance can be added is in a pre-granulated to form a powder mixture, used for pressing. Alternatively, the powder mixture for tabletting can be made using the procedure of mixing with the subsequent process (wet or dry) granulation. The mixture of components is then pressed into tablets using commercially available equipment (e.g., Courtoy(R0) with the use of regulating the flow agents, such as colloidal silica, and lubricating agents such as talc, sodium stearyl fumarate or magnesium stearate. The content of hydrophilic cellulose in the final composition is from 30% to 85%, preferably from 33% to 70%, whereas the content tedisamil or salt tedisamil ranges from 5% to 40%, preferably from 10 to 30%. To improve the rheological properties of the powder and prevent sticking of the powder to painting the walls or perforators content of regulating the flow and lubricating agents is constant. The content of glidant is from 0 wt.% up to 5 wt.%, preferably from 2 to 5% and most preferably about 3 wt.%. The content of the lubricant is from 2 wt.% up to 4 wt.% and preferably about 3 wt.%. To ensure masking of the taste of the tablet core may be covered with 2-4% in mass ratio mixture of the polymer with pigments or without them. A typical mixture coating commercially available, for example, as Opadry(USE®.

N the present invention can be used for the introduction of active compounds tedisamil the mammal, in particular, a person in need. Application tedisamil especially useful in the prevention and treatment of atrial fibrillation, atrial flutter and myocardial ischemia.

Thus, the present invention also relates to the application tedisamil or its pharmaceutically acceptable salts in the manufacture delayed in the stomach dosage form for the prevention or treatment of atrial fibrillation, atrial flutter or myocardial ischemia in a mammal, and especially in humans.

The following examples are intended solely for further explanation of the invention in more detail, and therefore, these examples in any case should not be considered as limiting the scope of invention.

Example 1. Manufacturer of uncoated compositions with modified release, with a 100% dissolution in vitro after 4-6 hours, containing 150 mg tedisamil in the form of sesquifumarate.

Loading capacity 1.5 kg, equivalent 4286 tablets, was made with the following composition:

39
ComponentQuantity (g)
Sesquifumarate tedisamil1028
HPMC (K4M)193
HPMC (E5)
HEC (HX250PH)193
Colloidal anhydrous silica26
Sodium fumarate21

The procedure of manufacture is as follows:

- Screened necessary amount of colloidal anhydrous silica.

- Mix the required quantity tedisamil of sesquifumarate, HPMC K4M, HPMC E5, HEC HX250 PH and sifted colloidal anhydrous silica.

- The required amount of sodium fumarate sifted and mixed with the mixture tedisamil.

- The resulting powder mixture is pressed into tablets (estimated weight kernel: 350 mg).

Example 2. The manufacture of coated compositions with modified-release with 100% dissolution after 8-12 hours in vitro, containing 150 mg tedisamil in the form of sesquifumarate.

Loading capacity 1.5 kg, equivalent 3529 tablets, was made with the following composition:

ComponentQuantity (g)
The core tablets
Tedisamil sesquifumarate849
HPMC (K4M)285
HPMC (E5)49
HEC (HX250PH)285
Colloidal anhydrous silica14
Sodium fumarate18
The shell
The polyacrylate dispersion 30% in mass ratio1)73,5
HPMC (E5)2,2
Talc (micro-talc)11
Distilled waterApproximately 417
1)for example, Eudragit NE30D(Röhm Pharma)

The mass increase due to the cover shell is approximately 10 mg/tablet.

The procedure of manufacture is as follows:

- Mix the required quantity tedisamil of sesquifumarate, HPMC K4M, HPMC E5, HEC HX250 PH and sifted colloidal anhydrous silica.

- The required amount of sodium fumarate sifted and mixed with the mixture tedisamil.

- The resulting powder mixture is then pressed in t is blecki (estimated weight kernel: 425 mg).

Tablets are coated shell with spray on tablets suspension coating, consisting of 30% in mass ratio of the dispersion of a polyacrylate polymer, HPMC E5 and suspension of talc in water (estimated weight of tablets: 435 mg).

Example 3. Manufacturer of floating increasing in volume compositions containing 138 mg tedisamil in the form of sesquifumarate.

Loading capacity of 1.0 kg, equivalent 1351 tablet was made with the following composition:

ComponentQuantity (g)
Tedisamil sesquifumarate299,1
Mannitol (25)200
HPMC (K4M)193
HEC (HX250PH)193
Glyceryl beginat (Compritol 888)40,5
Alginic acidof 37.8
Sodium bicarbonate24,3
Anhydrous citric acid6,76
HPMC (E5)between 6.08

The procedure is for drinking, preparing is as follows:

- Mix the required amount of HPMC (K4M), HPMC (E5) and HEC.

- Crushed anhydrous citric acid and added to the above mixture. Added anhydrous sodium bicarbonate and alginic acid, and the powders are mixed.

- Added and mixed crushed tedisamil sesquifumarate.

- Sifted through a sieve of 0.5 mm and added glyceryl beginat. Added mannitol, and the powders are mixed.

- The resulting powder mixture is pressed into tablets (estimated weight of tablets: 740 mg).

Example 4. The manufacture of compositions tedisamil immediate-release formulation containing 119,7 mg in the form of its dihydrochloride.

Loading capacity 144,8 kg, equivalent to 800,000 tablets, was made with the following composition:

ComponentQuantity (g)
Tedisamil hydrochloride60,00
Lactose monohydrate60,00
stearic palmitic acid6,00
Talcof 5.40
Colloidal anhydrous silica0,60
Opadry Y-1 7000 White14,08

The procedure of manufacture is as follows:

- Mix the required quantity tedisamil dihydrochloride, lactose monohydrate, talc and colloidal anhydrous silica.

- Added stearic palmitic acid, and the powders are mixed.

- The resulting powder mixture is pressed into tablets (estimated weight of tablets: 165 mg).

Tablets are coated shell with spray on tablets suspension coating Opadry Y-1 7000 White in water (estimated weight of tablets: 181 mg).

Example 5. Partially balanced crossover study of a single dose, comparing two different compositions with modified-release (MR) salt tedisamil, the composition of the immediate-release (IR) and floating increasing in volume (FE) composition.

Tedisamil was administered to 20 healthy male volunteers in the age range from 18 to 45 years. Each subject was regularly received three of the following compositions in a single dose:

A: the composition described in example 1 (15 subjects have analyzed data).

B: the composition described in example 2 (14 subjects have analyzed data).

D: the composition described in example 3 (13 subjects have analyzed data).

E: twice the composition described in Primera (15 subjects have analyzed data).

Were determined in plasma concentrations, and evaluated information about the adverse reactions, using non-leading questions.

Pharmacokinetic data

Presented in Table 1, normalized to the dose pharmacokinetic parameters show that the tablet FE had a larger impact compared to IR (shaded), and therefore was selected for the study and repeated administration.

Table 1
Pharmacokinetic data
Pharmacokinetics of free base tedisamil
Treatment optionnTmaxhCmaxng/mlAUC0-tNg*h/mlAUC (Ng*h/mlT h
E 119,7 mg151,477233700377010,8
A 150 mg
The ratio A/E
153,23361 0,398 3000 0,6473050 0,646compared to 8.26
B 150 mg
The ratio of B/E
14of 3.64388 0,4283080 0,6643190 0,67510,5
D 138 mg
The ratio D/E
133,54347 0,4163250 0,7623330 0,7669,23

The actual levels of free base tedisamil plasma (group values)achieved with single dose of 138 mg FE (composition D) and 119,7 mg IR (composition E), shown in figure 1. The resulting impact was slightly higher (AUC 113%; AUC means area under the curve (0→infinity)) for a track IR in comparison with FE and twice the peak level of plasma for a track IR compared to FE.

Tolerance

It is known that tedisamil causes adverse effects such as gastro-intestinal tract, mainly the complaints of the type of diarrhoea, and this was confirmed in this study for the IR tablets. After a single dose 119,7 mg IR six of the 15 subjects complained of 10 adverse events gastro-intestinal tract is (diarrhea 6-x, abdominal pain 4-x). 10 effects on the gastrointestinal tract 6 were identified as moderate. After a single dose of 138 mg FE three of the 13 subjects complained of adverse effects of gastrointestinal tract (disorder of language features 2-x, abdominal pain 1. Dysfunction of the language was once defined as moderate.

Adverse effects developing during treatment are presented in table 2.

Table 2
Adverse effects gastro-intestinal tract in the study of a single dose, comparing the IR composition with the composition FE
MedDRA SOCThe preferred indicatorFE 138 mg (n=13)IR 119,7 mg (n=15)
N%nN%n
Disorders of the gastro-
intestinal
tract
Any215,4 364010
Abdominal pain NOS17,7116,72
Pain in upper part of abdomen213,32
Diarrhea NOS533,36
Dysfunction of the tongue NOS1)17,72
N: number of subjects with the phenomenon
%: percentage of affected subjects with the phenomenon
n: number of events
1)NOS=not otherwise specified

Example 6. The exploration of multiple receiving, comparing the composition of the immediate-release (IR), f is otherwuse increasing in volume (FE) composition of salt tedisamil.

Tedisamil was administered to healthy male volunteers in the age range from 18 to 45 years. A total of 18 subjects were divided into 2 parallel groups receiving the following composition in a single dose for 7 days:

D1: twice a day the composition described in example 3 (9 subjects).

E1: twice a day the composition described in example 4 (9 subjects).

Pharmacokinetic data

In part of the study and repeated administration was taken as the curve of the plasma in the steady state after administration of the morning dose. Normalized dose exposure (AUC) after administration of the composition FE was approximately 80% from the impact of tablet IR, and Cmaxwas approximately 60%, see Table 3 (from both groups full curve PK was obtained from 8 subjects).

Table 3
Pharmacokinetic data in the steady state
Pharmacokinetics of free base tedisamil
Treatment optionnTmax hCmax ng/mlAUCss (ng*h/mlT h
E1 to 59.8 mg BID 81,5589326012,3
D1 138 mg BID
The ratio of FE/IR
83798 0,5886250 0,83211
BID=twice a day
ss=stationary state

The actual received dose varied significantly; tablet FE were taken twice daily at a dose of 138 mg in terms of free base, and IR tablets twice daily dose 59,58 mg in terms of free base. This has led to increased exposure to approximately 90% and higher plasma levels by 35% (group values) for the composition of FE in contrast to IR, as shown in figure 2.

Tolerance to multiple reception

This study was conducted comparing the results of tolerance to a single reception for the IR tablets, where six of the nine subjects complained of 23 side-effects gastro-intestinal tract (bloating 9-x, liquid stool 4-x, diarrhea 4-x, watery stools 1st, abdominal pain 4-x, urgent defecation 1). Flatulence and loose stools were described as moderate once, and pain in the stomach twice. Opposite the harbour is in, in the case of FE tablets only three of the nine subjects complained of three side-effects gastro-intestinal tract (bloating 1-x, liquid stool 1-x, diarrhea 1-x). They all were of mild severity. Some adverse effects were related to other organ systems, and they were more or less evenly distributed in the two groups.

All adverse effects gastro-intestinal tract that occur during treatment are presented in Table 4.

Table 4
Adverse effects gastro-intestinal tract in the study of repeated administration of the composition IR in comparison with the composition FE
MedDRA SOCThe preferred indicatorFE 276 mg (n=9)IR 119,7 mg (n=9)
N%nN%n
Disorders of the gastro-
intestinal
tract
Any3 33,33666,723
Abdominal pain NOS222,22
Pain in upper part of abdomen111,12
Urgent bowel movements111,11
Diarrhea NOS111,11222,24
Flatulence111,11555,69
Loose stools111,1 1333,34
Watery stools111,11
N: number of subjects with the phenomenon
%: percentage of affected subjects with the phenomenon
n: number of phenomena

Conclusion

In relation to adverse effects such as gastro-intestinal tolerance to tedisamil in the form of a salt in floriuda increasing in volume (FE) tablet is much better than in the composition of the immediate-release. In the data presented, the difference is especially noticeable in conditions of repeated administration in spite of the fact that the effect was almost two times higher in the FE group.

1. Composition tedisamil or its pharmaceutically acceptable salt with a slow release for use in the prevention and treatment of atrial fibrillation, atrial flutter and myocardial ischemia, containing from 5 to 40 wt.% tedisamil or its pharmaceutically acceptable salt, from 30 to 85 wt.% swelling in water of the polymer matrix containing hypromellose (receiver array) in the high or medium viscosity and hydroxyethyl cellulose (BORE) high or medium viscosity ratio receiver array/BORE=1/0,85-1/1,2, from 2.5 to 5 wt.% salt is able to yield gaseous carbon dioxide in the gastric environment, and from 0.5 to 10 wt.% alginic acid.

2. Composition tedisamil or its pharmaceutically acceptable salt with a slow release according to claim 1, in which the pharmaceutically acceptable salt is sesquifumarate salt or dihydrochloride.

3. Composition tedisamil or its pharmaceutically acceptable salt with a slow release according to claim 1, characterized in that the salt is able to yield gaseous carbon dioxide in the gastric environment selected from the group consisting of sodium carbonate, potassium carbonate and sodium bicarbonate.

4. A method of manufacturing a composition according to claim 1, characterized in that
(1) the core of pressed from a mixture comprising from 5 to 40 wt.% tedisamil or its pharmaceutically acceptable salt, from 30 to 85 wt.% swelling in water of the polymer matrix containing hypromellose (receiver array) high or medium viscosity and hydroxyethyl cellulose (BORE) high or medium viscosity ratio receiver array/BORE=1/0,85-1/1,2, 2.5 to 5 wt.% salt is able to yield gaseous carbon dioxide in the gastric environment, and from 0.5 to 10 wt.% alginic acid.
(2) the kernel optional cover shell.

5. Application tedisamil or its pharmaceutically acceptable salts in the manufacture of doses is trated form with a delay in the stomach according to claim 1 to obtain drugs for prevention and treatment of atrial fibrillation, atrial flutter or myocardial ischemia.



 

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32 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a class of sulphur-containing compounds of general formula R1-S(O)n-CH2-CH2-SR2, where n = 1 or 2, when n = 1 R2 = (X=Cl, Br, H2PO4), R1= lower alkyl, substituted or unsubstituted aryl; when n = 2 R2=H, C(O)CH3, SO3Na, (X=Cl, Br, H2PO4) R1=straight or branched C1-C8 alkyl, substituted alkyl; aryl, substituted aryl, with antiarhythmic activity, as well as medicinal agents and pharmaceutical compositions based on said compounds.

EFFECT: proposed compounds in low doses have antiarhythmic activity, have low toxicity and can be used as active substances in medicinal agents for treating and preventing heart rhythm disorder.

11 dwg, 4 cl, 45 ex

FIELD: medicine.

SUBSTANCE: present invention concerns pharmaceuticals, particularly method of reducing risk of drug-caused torsade de pointes, according to which Azimilide and Aspirin and, additionally optionally Statin are introduced to the patient.

EFFECT: reduced risk of torsade de pointes ensured by introduction of specified pharmaceutical combination.

4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: there is offered application of glutaric acid derivatives of general formula where R1 = imidazole, indole, R2 = COOH, H, or its pharmaceutically acceptable salt as an antiarrhythmic drug (versions), a medical product, a pharmaceutical composition and method of appropriate prescription. There is presented effectiveness of Nαglutaryl-L-histidine, Nαglutaryl-L-tryptophan in arrhythmia caused by adrenal heart rhythm disorder, in nicotine arrhythmia and acute occlusive myocardium disorder.

EFFECT: effective in arrhythmia.

5 cl, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula II or their pharmaceutically acceptable salts, where R1 is H or C1-C10 alkyl; R2 is H or C1-C10 alkyl; n ranges from 0 to 4; p ranges from 0 to 1; R3 and R4 represent H, as well as to pharmaceutical compositions based on said derivatives and methods of treating cardiac arrhythmia using these compositions.

EFFECT: increased effectiveness of composition and method of treatment.

15 cl, 12 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new benzopyran derivatives of formula (I) whereat X is NR6, R6 is hydrogen atom r C1-4-alkyl group; Y is bond SO, SO2; Z is C1-4-alkyl group (whereat C1-4-alkyl group can be arbitrary substituted with 1-5 atoms of halogen) or phenyl group (whereat phenyl group can be arbitrary substituted with C1-4-alkyl group); W is hydrogen atom, halogen atom, hydroxy group, C1-6-alkoxygroup, C1-4-alkyl group, C1-6-alkyl sulphonylamino group; R1 and R2 independently of each other represent C1-3-alkyl group; R3 is hydrogen atom, hydroxy group or methoxy group; m is integer number from 0 to 4; n is integer number from 0 to 4; V is ordinary bond; R4 is hydrogen or C1-6-alkyl group; and R5 is - hydrogen atom,- C1-6-alkyl group,- C3-8-cycloalkyl group or C3-8-cycloalkenyl group or - C6-14-aryl group (whereat every C6-14-aryl group can be arbitrary substituted with 1-3 R12 whereat R12 is halogen atom) and pharmaceutical composition thereof.

EFFECT: compounds are applicable as antiarrhythmic drug.

27 cl, 60 tbl, 20 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to pharmaceutical medicinal forms, which are applied for controlled and/or directed delivery of active substance to definite part of gastrointestinal tract of human or animals. Pharmaceutical medicinal forms preferably include active substance N-(2-(2-phthalimidoetoxy)acetyl)-L-alanyl-D-glutamic acid (LK 423).

EFFECT: also described are methods of treating chronic inflammatory diseases of gastrointestinal tract of human and/or animals applying pharmaceutical medicinal forms of claimed invention.

21 cl, 5 ex, 3 tbl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention relates to pharmacological industry, in particular to composition for prevention or treatment of pathological processes and supporting high level of functional activity of organism. Preventive composition for prevention or treatment of pathological process and supporting high level of functional activity of organism, includes combination of one or several extracts of medicinal plants, which contain substances of phenol nature and carrier, as carrier biocompatible polymer with definite particle size is used.

EFFECT: composition has definite ratio substance of phenol nature : biocompatible polymer.

2 cl, 5 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to chemical - pharmacological industry and concerns solid medicinal form of matrix type, which has anti-inflammatory, analgesic and febrifugal activity, with prolonged release, which contains ketoprofen as active substance and target additives with following ratio of ingredients, wt %: ketoprofen - 35-57, cellulose derivative -7-17, colloidal silicon dioxide - 2-7, stearic acid and/or its salts -0.5-1, calcium hydro phosphate dehydrate - the remaining part.

EFFECT: prolonged release of active substance, tablet strength, simplicity of obtaining medicinal form.

6 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: claimed invention relates to field of medications, in particular to peroral mediations with retarded release, which contain at least 20 mgA of ziprazidone and substance ensuring retarded release. In addition invention relates to methods of treating patient by introduction of said dosage forms.

EFFECT: in ensuring efficient levels of ziprazidone in blood during long period of time.

44 cl, 2 dwg, 15 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: antitumoral composition contains taurolipidine, taurultam or their admixture in concentration approximately 0.1-160 mg/ml in combination with biodecomposable adhesive, including the fibrinous hermetic possessing ability to stick to a tissue of a live organism. Invention also concerns a way of processing for the prevention or the inhibition of growth of cancer cells consisting in drawing of an antitumoral composition on certain area of a tissue of a live organism after excising of a tumour. The composition is put on a tissue of an organism by a layer in the thickness from 0.1 to 10 mm.

EFFECT: invention allows preventing with high degree of efficiency repeated development of a tumour after its excising from organism tissues.

18 cl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition is used for treatment of by-effects and idiphatic syndromes caused by opioids, contains a matrix and a pharmaceutically active substance, and the matrix is executed from ethyl cellulose or polymer on a basis of ethyl cellulose and at least one acyclic spirit; thereat the matrix is diffused and practically not bulking up, and contains naloxone as a pharmaceutically active substance, released from the matrix invariant and prolonged, in amount of 1-50 mg, 5-30 mg preferably, and the most preferably in amount of 5-20 mg.

EFFECT: composition is tolerant at storage.

19 dwg, 16 ex, 2 cl

FIELD: medicine; pharmacology.

SUBSTANCE: peroral pharmaceutical dosed out form for treatment of the conditions bound to secretion of acid in a stomach, includes an acid-sensible inhibitor of the proton pump and antagonist of H2-molecular switchers, with the delayed and-or prolonged liberation of the proton pump acid-sensible inhibitor, and fast liberation of antagonist of H2-molecular switchers.

EFFECT: maximum suppression of acid in a stomach after the first dose and throughout all course of treatment.

69 cl, 4 dwg, 7 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to solid dosed composition for pain treatment, containing: nucleus including active pharmaceutical ingredient and matrix, an coating including physical compound of polyvinyl acetate, polyvinyl pyrrolidone and active pharmaceutical ingredient, where active pharmaceutical ingredient and matrix are interconnected in such a way that release of pharmaceutical ingredient placed within nucleus from matrix is controlled, and release of composed active ingredient placed within nucleus occurs more slowly than release of active pharmaceutical ingredient placed in coating matrix. Yet nucleus and coating active pharmaceutical ingredient is the same and considered to tramadole or its stereoisomer or pharmaceutically acceptable salt. Invention also refers to tablet containing specified composition. Composition under invention provides pain relief not later than 2 hour after primary introduction in one dosage; pain relief lasts within at least 24 hours after introduction.

EFFECT: agent is characterised by high efficiency.

14 cl, 7 dwg, 9 tbl, 6 ex

FIELD: veterinary pharmacology, pharmaceutical technology.

SUBSTANCE: invention proposes a veterinary medicinal agent showing attractive taste. This agent comprises substrate as a granule or tablet that is attractive for animals wherein finely divided particles possessing a physiologically compatible solid carrier with neutral taste are incorporated into substrate. Indicated finely divided particles of carrier have average diameter 0.09-0.8 mm, and a cover prepared from a veterinary active substance is applied on particles wherein layer of an active substance is coated by a protective layer of a physiologically compatible polymeric matrix. Method for preparing a veterinary medicinal agent involves the following steps: (1) cover comprising active substance or veterinary active substance is applied on particles with average diameter 0.09-0.8 mm consisting of physiologically compatible solid carrier of neutral taste to provide the complete covering particles by the active substance; (2) masking protective layer representing physiologically compatible polymeric matrix is applied on this cover comprising active substance, and this protective layer prevents direct contact of active substance with tasting and olfactory cells and saliva of animal; (3) indicated particles having a double cover are mixed thoroughly with substrate that is attractive for animal, and (4) mixture comprising substrate and particles with double cover are pressed to obtain tablets or granules designated for administration. Also, invention describes using indicated finely divided carrier particles with a double cover in preparing a veterinary drug. Invention provides easy administration of veterinary active substances with unfavorable taste in animals.

EFFECT: improved preparing method, improved and valuable properties of compositions.

20 cl, 2 tbl, 5 ex

FIELD: pharmacy.

SUBSTANCE: invention relates to medicinal agents, in particular, to a tablet degrading in the mouth cavity and containing the following components: 1) agent of benzimidazole type that inhibits activity of proton pump as microgranules covered by an enterosoluble envelope layer and covered additionally by at least one pH-dependent methacrylic copolymer-base barrier envelope; 2) at least one antacid as granule, and 3) mixture of excipients containing at least one loosing agent, one diluting agent, a lubricant and, possibly, agent promoting to swelling, agent promoting to penetrability, sweetening agents, correcting agents and dyes. Also, invention relates to methods for preparing a tablet and its using for treatment of digestive tract disorders. Invention provides prevention of dissolving and/or destruction of an enterosoluble envelope in mouth cavity or in stomach that is provided by applying definitive accessory substances of barrier envelope on an enterosoluble envelope for preparing a tablet degrading in mouth.

EFFECT: improved and valuable properties of preparation.

34 cl, 8 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

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