Prolonged pharmaceutical composition drug form and method of its production (versions)

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular, to pharmacy. As medical substance composition contains therapeutically effective quantity of trimetazidine dihydrochloride, as prolonging agent - interpolymer complex of polyacrylic acid and polyethylenglucol. As additional substances composition includes: bibasic calcium phosphate, monocrystalline cellulose, basic calcium carbonate, group of sliding substances - stearic acid and/or its salts. Composition can be made in form of pills, covered with coating, contains optimal quantity of additional substances, makes it possible to sufficiently release medical substance and ensures its high bio-availability.

EFFECT: obtaining prolonged pharmaceutical composition, which has antianginal action.

16 cl, 6 tbl, 6 ex, 2 dwg

 

The technical field to which the invention relates.

The invention relates to medicine, in particular to a pharmacy, can be used in the manufacture of solid dosage forms of drugs that have antianginal action.

The level of technology

In the development of production technology of tablet dosage forms with prolonged action one of the main tasks is to ensure adequate time for the release. The optimal value of this parameter is very important as it contributes to a number of advantages in application: allows you to reduce the dose rate and reduce the cost of treatment, contributes to the preservation of homeostasis due to the lack of rapid growth of the drug concentration in the blood plasma, reduces the likelihood of side effects by maintaining the concentration at therapeutic levels. Obviously, to achieve the desired release characteristics that require a carefully developed production methods, including the analysis of possibility of application of different methods of extension for a specific medicinal product, in particular, the use of matrix systems.

U.S. patent 4814176 describes the preparation supporting release containing chitin, x is Tozan, or their mixtures, anionic polymer containing carboxylic groups, sulfopropyl or group causing similar properties, and as a pharmacologically active substances the product contains Trimetazidine a dihydrochloride. The technology consists in grinding each of the auxiliary components to the particle size of 5-500 μm, followed by mixing polymers with a pharmacologically active ingredient, the preparation of dosage forms as tablets, granules, pellets, dental cones, films or pellets into hard gelatin capsules. This patent does not contain any information regarding the release characteristics Trimetazidine dihydrochloride.

European patent No. 0673649 describes a pharmaceutical composition for extended release Trimetazidine or its salt containing the water-insoluble polymer and a plasticizer to control release. The process includes the fabrication of pellets or mini-pellets with a daily dosage of 80 mg, followed by their coverage ethylcellulose or a derivative of acrylic acid and specific plasticizers for prolonged release. Describes the release in vitro only a little more than 75% of the substance after 16 hours.

EP No. 1195160 A1 contains a description of matrix pharmaceutical tablet compo is icii with supporting release, includes 60 mg Trimetazidine dihydrochloride and hydrocolloid forming materials or hydrophobic polymers or other hydrophobic materials as prolongation, which release Trimetazidine a dihydrochloride in supporting and enhancing mode, prolonging the time to reach the supporting effect Trimetazidine up to 24 hours after oral administration. The production process matrix pharmaceutical tablet composition is a multi-stage, including a large number of equipment.

EP 1108424 describes matrix tablets for maintenance release Trimetazidine, regulation of the release of which is carried out by applying a polymer derived cellulose. The patent contains a description of the pill that contains 35 mg of Trimetazidine dihydrochloride for two daily intake. The production process matrix pharmaceutical tablet composition is a multi-stage, including a large number of equipment.

In Patent WO 03/043610 A2 presents the composition and technology of dosage forms containing Trimetazidine the dihydrochloride in the form of pellets, for which the solution is sprayed Trimetazidine dihydrochloride in water or aqueous-alcoholic medium. Then the pellets coated with polymers for controlled release of Trimetazidine digital the reed and placed in hard gelatin capsules in order to obtain stable, convenient for patients will receive the drug form.

As a prototype of the selected known dosage form (U.S. Pat. Of the Russian Federation No. 2281772 from 2005.02.14.), with antianginal action, which is a tablet consisting of a core containing a medicinal substance Trimetazidine, as well as auxiliary substances, wt.%:

Trimetazidine a dihydrochloride9,0-32,0
Hydroxypropylcellulose3,0-10,5
Hydroxyethylcellulose18,5-67,2
Sodium alginate0,1-0,6
Calcium phosphate dihydrate19,0 is 28.5
Magnesium stearinovokisly0,5-2,0
Talc0.5 to 2.0,the

and

from the shell containing the following components, wt%:

at least one component selected from the group comprising hypromellose, methylcellulose soluble or hydroxypropylcellulose 0.6 to 2.7, and tween-80 0,3-1,2, titanium dioxide pigment of 0.1 to 1.0, red ferric oxide is 0.1 to 0.8.

A method of manufacturing investsoglashenij form is carried out using wet granulation, pelletizing the obtained granules and applying the membrane from the aqueous suspension, preferably by sputtering.

Release Trimetazidine dihydrochloride in the body of the dosage forms is carried out for 8 hours, which provides a constant level of drug in the blood.

The disadvantages described dosage form, and method of its manufacture is that described the drug does not protect release Trimetazidine in the acidic environment of gastric juice, resulting in a lack of prolongation of the release Trimetazidine, do not maintain therapeutic concentration of Trimetazidine during the day.

Disclosure of inventions

The task of the invention to provide pharmaceutical compositions Trimetazidine based on the new matrix system, the creation of domestic antianginal drug, suitable to receive two times a day, as a basic drug Preductal", so before each reception level of the active substance in the blood is pharmaceutically meaningful level, ensuring the protection of the myocardium during the whole time of day, especially during night and morning hours; ensuring the manufacturability of a tablet form of the drug: obtaining tablets with high mechanical strength with a small pressing force

This object is achieved in that the developed prolonged pharmaceutical composition having antianginal effect, containing Trimetazidine a dihydrochloride in an effective amount, prolonging the polymer and pharmaceutically acceptable excipients suitable for use in extended compositions, characterized by the fact that as prolonging polymer contains ionic or donor-acceptor interpolymer complexes of complementary macromolecules (CIT).

As of interpolymer complexes used products of intermolecular interactions chemically complementary macromolecules (polianionov and polycation or donors and acceptors of protons).

The preferred member of this class is a composite polymeric carrier (CIT) - interpolymer complex of poly (methacrylic (poly (acrylic) acid and polyethylene glycol.

To other members of the CPN can be attributed complexes copolymers hydroxyanisole esters with poly (acrylic acid.

The basis of stabilizing relations macromolecules can form hydrophobic interactions, the formation of polymer-polymer salt, polyelectrolyte complexes.

Prolonged pharmaceutical composition as auxiliary substances, ensure the sustained sufficient weight pills (filler), may contain at least one substance selected from the group of: calcium phosphate, calcium dihydrophosphate, calcium hydrogen phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, calcium carbonate, basic; as auxiliary substances, prevent sticking and ensure shank length (moving), it can contain at least one substance selected from the group of: stearic acid and/or its salts.

Preferably prolonged pharmaceutical composition contains Trimetazidine a dihydrochloride and excipients in the following ratio of ingredients, wt.%:

Trimetazidine a dihydrochloride10,0-25,0
CIT5,0-50,0
Moving0.5 to 1.5
Filler5,0-75,0,

at the same time as the CPN, it preferably contains a complex of poly (methacrylic acid with polyethylene glycol.

Prolonged pharmaceutical composition preferably may be in the form of coated solid dosage forms, preferably in the form of tablets.

Also proposed VA is ianti methods of manufacturing solid dosage forms based on the proposed composition.

One of the variants of the ways is to manufacture a prolonged solid dosage forms with antianginal action, namely, that receive the first granules, which are mixed Trimetazidine a dihydrochloride, calcium phosphate dihydrate, moisten the mixture with an alkaline solution CPN, granularit her moist granulate is dried, perform a dry granulation; to obtain a second granulate is mixed with calcium phosphate dihydrate, CAS, the resulting mixture is moistened with water, granularit her moist granulate is dried, carry out dry granulation, and then both of the obtained granulate is mixed, optivault stearic acid and/or its salts and tabletirujut, after what is applied polymer protective membrane from the aqueous suspension.

The second variant of the method of manufacturing a prolonged dosage forms is that mix Trimetazidine a dihydrochloride, one component from the group comprising calcium hydrogen phosphate, microcrystalline cellulose, calcium carbonate, basic and composite polymeric carrier, the resulting mixture bitteroot, and then granularit obtained granulate optivault stearic acid and/or its salts and tabletirujut, then put a protective polymer shell of an aqueous suspension.

Another variant of the manufacturing methods about onirovanie dosage form is that mix Trimetazidine a dihydrochloride, one component from the group comprising calcium dihydrophosphate, microcrystalline cellulose, calcium carbonate, basic, and composite polymeric carrier, the resulting mixture is moistened alcohol solution of composite polymer carrier, granularit her moist granulate is dried, carry out dry granulation, after which the granules are mixed, optivault stearic acid and/or its salts and tabletirujut, then put a protective polymer shell of an aqueous suspension.

Brief description of drawings

Figure 1 presents the release of Trimetazidine (TMZ) from the model of tablets according to the invention.

Figure 2 presents the release of TMZ from tablets Preductal MB, firms servie, France.

The implementation of the invention

As filler in the dosage form of the present invention can be applied excipient capable of receiving the tablets of the desired mass, at least one selected from the group comprising cellulose or derivatives of cellulose, such as microcrystalline cellulose, lactose, calcium carbonate, calcium hydrogen carbonate, calcium phosphate, calcium dihydrophosphate, calcium hydrogen phosphate dihydrate, calcium sulfate dehydrate. It is desirable to apply the filler in a quantity close to the bottom is redely interval mass of filler. The preferred fillers are inorganic phosphate such as dibasic calcium phosphate.

As a moving substance in the composition of this invention can be used one or more compounds able to resolve the problems associated with the formation of tablets, such as stearic acid and/or its salts.

The pharmaceutical composition is made in solid dosage form, mostly in the form of tablets containing 15 mg - 80 mg of the active substance. The mass of the obtained tablet is preferably from about 100 mg to about 300 mg

Most preferred is a composition for dosage forms with antianginal action, consisting of a core and a shell in which the core contains as excipients calcium phosphate dihydrate, magnesium stearinovokisly and additionally as prolonging component composite polymeric carrier, in the following ratio of components, g:

Trimetazidine0, 035
Calcium phosphate dihydrate0,1425
CIT0,07
Magnesium stearate 0,0025
Weight0,25

Mainly, as the CPN was used polymeric complex of poly (acrylic (poly (methacrylic) acid and polyethylene glycol.

The use of film-forming polymers allows to obtain a durable protective shell to achieve the following objectives: to prolong pharmacodynamic parameters by applying a film coating to protect the dosage form from the action of environmental factors during storage, to give the tablets a beautiful appearance.

The following examples illustrate ways to obtain pharmaceutical compositions without limiting the scope of claims of the invention.

Example 1. Obtaining granules by wet granulation. Mix sifted Trimetazidine a dihydrochloride (175,0 g), calcium phosphate dihydrate (514,5 g) and add 5% alcoholic solution of CPN (420,0 ml), again mix. Wet weight granularit and dried at a temperature of 40-50°C. to a residual moisture of 2.0 to 3.0%. The dried pellets are cooled to room temperature and conduct a dry granulation. The dry granulate optivault add sifted magnesium stearinovokisly. The mixture is stirred until a homogeneous tablet mass. Then the mass tabletirujut. The resulting tablet cores are passed through patriciafinance shell.

Example 2. Getting the bushings separate granulation. As the humidifier is used by 0.1-5% solution of the CPN, which is obtained by dissolving the appropriate amount of pre-sifted checkpoint in caustic soda solution. With the purpose of obtaining a granulate 1 mix sifted Trimetazidine a dihydrochloride (140.0 g), calcium hydrogen phosphate dihydrate (70,0), add 5% solution checkpoint, again mix. The wetted mass should not have inclusions from a poor distribution of the humidifier and should be well Kotkovets. The wetted mass is subjected to wet granulation. Wet weight granularit and dried at a temperature of 40-60°C. to a residual moisture content of 2.0 to 3.0%.

In the preparation of the granulate 2 mix the sifted calcium phosphate dihydrate (500.0 g), CPN (278,5 g), add purified water and mixed until homogeneous. The obtained wet mass granularit and dried at a temperature of 40-60°C. to a residual moisture content of 2.0 to 3.0%.

The dried granules 1 and 2 is cooled to room temperature, mixed and spend the dry granulation. The dry granulate optivault add sifted magnesium stearinovokisly (10.0 g). The mixture is stirred until a homogeneous tablet mass. Then the mass tabletirujut. Set the desired weight of the core tablet and the necessary pressure. For the successful application of plenos the second shell in the fluidized bed a measure of the strength of the pressure should be not less than 80 N, and the abrasion of not more than 3%. Thus, the obtained values of this indicator allows to make a conclusion about the possibility of drawing on the data kernel film coating under the conditions of fluidization. The resulting tablet cores are passed through the coating film cover.

Example 3. A method of obtaining a pharmaceutical composition by dry granulation (briquetting). In a clean, dry mixer load pre-sifted dry powders Trimetazidine dihydrochloride (140.0 g), CPN (280,0 g), calcium dihydrophosphate (570,0 g) and stirred for 10-15 minutes the resulting mass bitteroot correct for these purposes the equipment. Briquettes milled, passed through a granulator and calibrated. To the obtained granulate add sifted magnesium stearate (10.0 g), stirred for 10-15 minutes the resulting mass tabletirujut on a rotary press. Tablets should have a convex shape, smooth edges, a smooth, uniform surface, without the risks. Uniformity of dosing, impurities, microbiological purity meets the requirements of the global Fund XI.

Obtained by different technological methods of tablet cores are passed through the coating film cover. For coating tablets-kernel as a foaming agent, resistant to gastric juice, it is possible to apply the aqueous suspension, for example, Acrylic-out, or Collicut® MAE 100 P, or Collicut® MAY 30 D.

The acrylic has a composition of: a copolymer of methacrylic acid with acrylate 1:1 (..IV) 40,0%, titanium dioxide (..IV) 15,0%, talc (..IV) 37,25%, triethylcitrate (..IV) of 4.8%, silicon oxide, colloidal anhydrous (..IV) of 1.25%sodium bicarbonate (..IV) 1,2%, sodium dodecyl sulfate (..IV) of 0.5%.

Collicut® MAE 100 P and Collicut® MAE 30 D is a copolymer (1:1) of methacrylic acid and ethyl acrylate in the form of a 30%aqueous dispersion.

Film-forming solutions may optionally contain dyes and pigments.

As the foaming agent in the production of tablets Trimetazidine you can apply Opadry II (hypromellose (HPMC), lactose monohydrate, Polydextrose, macrogol, titanium dioxide, iron oxide yellow, iron oxide red).

The application shell carried out in a known manner (fluidization or settings of the drum type) and stop when you reach the required weight of the tablet. Weight gain of the coated tablets may be in the range from 1%to 15%.

Table 1
The composition of the granulated mixtures with CAT
The components of the mixture, g No. mixtures
123
Trimetazidine0,0350,0350,035
CIT0,01750,0350,07
Calcium phosphate dihydrate0,04370,070,122
Calcium stearate0,00090,00140,0023

Table 2
Technological and physico-chemical characteristics of the granules with CIT
No.IndexDimensionComposition 1Part 2Part 3
1Flowabilityg/s5,31±,049,95±0,1310,87±0,06
2Densityg/cm31,12±0,021,57±0,061,B1±0,02
3Porosity%81,02±0,9880,37±1,0578,20±1,06
4The compressibilityN0,20±0,040,29±0,010,35±0,02
5Residual humidity%3,52±0,064,21±0,024,35±0,03
6Bulk densityg/cm30,22±0,040,32±0020,36±0,02

A high level of rheological parameters in General and optimal dispersion of the granules in particular has allowed to draw a conclusion on expediency of use of the granulate to obtain tablets Trimetazidine. The compositions are suitable for tabletting, as they have high enough values of the flowability and bulk supply and do not indicate the likelihood of such undesirable effects, as the coating substance on the walls of the matrix, reducing its completion, etc.

Table 3
The quality indicators nuclei tablets Trimetazidine prolonged action with CAT
No.IndexDimensionCore part 2Kernel composition 3
1Pressure strengthN93,85±0,9895,55±0,64
2Abrasion%98,67±0,5098,86±0,43

Table 4
The composition of the obtained drug form
ComponentsComposition 1Part 2Part 3
mg wt.%mgwt.%mgwt.%
Core
Trimetazidine a dihydrochloride70,03535of 17.520of 17.5
CIT64,03235of 17.54035
Calcium phosphate dihydrate64,0321286413816,5
Magnesium stearinovokisly2,012 121
Mass of nucleus200100200100200100
The shell
The weight of the shell52.440,0052,440,0052,44
Weight pills0,2051000,2051000,205100
ComponentsPart 4Part 5Part 6
mgwt.%mgwt.%mgwt.%
Core
Trimetazidine a dihydrochloride35of 17.535of 17.535of 17.5
CIT7035178,5168
Calcium phosphate dihydrate9346,51467314874
Magnesium stearinovokisly212 110,5
Mass of nucleus200100200100200100
The shell
The weight of the shell52.440,0052,440,0052,44
Weight pills0,2051000,2051000,205100

Received in accordance with the above examples of the dosage form meets all the quality indicators included in the standard documentation.

Test Dissolve tablets Trimetazidine prolonged action conducted in accordance CFC 42-0003-04 with the use of device-type "blade mesh the LCA". The technique Environment: I stage - stomach (acidic) environment pH 1,1; II stage - intestinal medium (phosphate buffer) pH of 7.2. The amount of environment - 1000 ml ± 5 ml, the rotation speed of 50 rpm Method of analysis: HPLC, spectrophotometric analysis.

The study made it possible to conclude that the tablet shell provide proper deceleration selection Trimetazidine on Wednesday dissolution. Within 2 hours of dissolution in the acidic environment in the middle freed 8,65% of the drug substance, for 8 hours of dissolution - more than 80% of the substance.

Profile release Trimetazidine from a prototype is characterized by a significant (about 40%) transition Trimetazidine from tablet dosage form in the solution within the first two hours of dissolution in an acidic medium for 6 hours of dissolution in the environment of phosphate buffer dissolve 100% of the drug substance.

Comparative analysis of the kinetics of the allocation of Trimetazidine on Wednesday dissolution showed that the release Trimetazidine tablets is slower than from tablets prototype. In particular, tablets, coated Acrylic-OUT, free order of 8.15% of the drug substance and tablets, coated Collicut, free up about 9% in an acidic environment, while prototype - 35% during the first hour of dissolution. Thus, we can conclude that the pill, pokr is taken enteric membranes, will provide more pronounced than the prototype, extension release Trimetazidine and maintain a therapeutic concentration over a long time.

In addition, were used to define test "Dissolution" in accordance with the methodology adopted for the tablets Preductal MB (basic drug comparison).

Table 5
Conditions test "Dissolution" for tablets Trimetazidine dihydrochloride and regulations release
The test conditions for the release of Trimetazidine dihydrochlorideRequirements by release Trimetazidine dihydrochloride of tablets Preductal MB
Apparatus: paddle stirrer (USP)1 h - 25-45%
Medium: phosphate buffer solution with pH 6.8;2 h - 43-63%
5 hours - not less than 70%
volume - 500 ml;
the rotation speed of the stirrer - 50 rpm

During the dissolution test we obtained the following quantitative indicators of the process for Preductal MB and saleemullah tablets Trimetazidine prolonged action:

Table 6
Comparative results release Trimetazidine from Preductal MB and the claimed composition tablets Trimetazidine prolonged action
TabletsTime, h
125
Preductal MB35,24±0,1153,62±0,2381,03±0,18
The inventive composition tablets Trimetazidine prolonged action34,94±0,0856,23±0,1095,38±0,21
1 - Preductal MB
2 tablets Trimetazidine prolonged action

To address the issue of bioequivalence tablets Trimetazidine prolonged action and Preductal MB was measured concentrations of Trimetazidine in the blood plasma of dogs at points in time defined by the study Protocol, and was calculated pharmacokinetic parameters obtained by the pharmacokinetic curves.

P the results of the conducted research, comparative pharmacokinetics and relative bioavailability of dosage forms Trimetazidine (pills, coated with a modified release 35 mg) allowed to conclude that the processes of absorption, distribution, metabolism and excretion Trimetazidine when using tablets Trimetazidine prolonged action and tablets Preductal MB ("Servier, France) are the same and dosage forms are bioequivalent.

1. Prolonged pharmaceutical composition having antianginal effect, containing Trimetazidine a dihydrochloride in an effective amount, prolonging the polymer and pharmaceutically acceptable excipients suitable for use in extended compositions that distinguish the fact that as prolonging polymer contains ionic or donor-acceptor interpolymer complexes of complementary macromolecules (CIT) in an amount of 5.0 to 50.0 wt.%.

2. Prolonged pharmaceutical composition according to claim 1, characterized in that it contains as CPN complex polyacrylic (poly (methacrylic) acid with glycol.

3. Prolonged pharmaceutical composition according to claim 1, characterized in that as auxiliary substances, provides a sufficient mass of tablets (filler), it contains at least one substance selected from the group of calcium phosphate, calcium dihydrophosphate, calcium hidratos is at the dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, calcium carbonate, basically.

4. Prolonged pharmaceutical composition according to claim 1, characterized in that as auxiliary substances, which is moving, it contains at least one substance selected from the group of stearic acid and/or its salts.

5. Prolonged pharmaceutical composition according to claim 1, characterized in that it contains Trimetazidine a dihydrochloride and excipients in the following ratio of ingredients, wt.%:

Trimetazidine a dihydrochloride10,0-25,0
CIT5,0-50,0
Moving0.5 to 1.5
Filler5,0-75,0

6. Prolonged pharmaceutical composition according to claim 5, characterized in that as the CPN it contains a complex of poly (acrylic (poly (methacrylic) acid with glycol.

7. Prolonged pharmaceutical composition according to claim 1, characterized in that it is made in the form of a coated solid dosage forms.

8. Solid dosage form, made on the basis of prolonged farmaceuticas the second composition, described in claims 1 to 7, containing Trimetazidine a dihydrochloride dose 35-70 mg and at least one auxiliary substance selected from the group of calcium phosphate, calcium dihydrophosphate, calcium hydrogen phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, calcium carbonate basically as a filler; and stearic acid and/or its salt as moving matter, in the following ratio of ingredients, wt.%:

Trimetazidine a dihydrochloride10,0-25,0
Composite polymeric carrier (CAT)5,0-50,0
Filler5,0-75,0
Moving0.5 to 1.5

9. Solid dosage form of claim 8, characterized in that it further comprises a protective shell.

10. Solid dosage form of claim 8, wherein said protective coating contains hypromellose (HPMC) or a copolymer of methacrylic acid.

11. A method of manufacturing solid dosage forms with antianginal effect, characterized in PP-10, which receive the first granulate, this mix is Trimetazidine a dihydrochloride, dibasic calcium phosphate, moisten the mixture with an alkaline solution CPN, granularit her moist granulate is dried, perform a dry granulation; to obtain a second granulate is mixed with calcium phosphate, calcium dihydrophosphate, calcium hydrogen phosphate dihydrate, calcium sulfate dihydrate, CAS, the resulting mixture is moistened with water, granularit her moist granulate is dried, carry out dry granulation, and then both of the obtained granulate is mixed, optivault stearic acid and/or its salts and tabletirujut.

12. The method according to claim 11, characterized in that the tablet is applied polymer protective membrane from the aqueous suspension.

13. A method of manufacturing solid dosage forms with antianginal effect, characterized in PP-10, which consists in the fact that mixed Trimetazidine a dihydrochloride and at least one component from the group comprising calcium phosphate, calcium dihydrophosphate, calcium hydrogen phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, calcium carbonate, basic, and CIT, the mixture bitteroot, and then granularit her, the obtained granulate optivault stearic acid and/or its salts and tabletirujut.

14. The method according to item 13, wherein the tablet is applied polymer protective membrane from the aqueous suspension.

15. Way to slurry the solid dosage forms, with antianginal effect, characterized in PP-10, which consists in the fact that mixed Trimetazidine a dihydrochloride, at least one component from the group comprising calcium phosphate, calcium dihydrophosphate, calcium hydrogen phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, calcium carbonate, basic, and composite polymeric carrier, the resulting mixture is moistened alcohol solution of composite polymer carrier, granularit her moist granulate is dried, carry out dry granulation, and then the obtained granules are mixed, optivault stearic acid and/or its salts and tabletirujut.

16. The method according to item 15, wherein the tablet is applied polymer protective membrane from the aqueous suspension.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

, where R and R1 independently denote a link selected from: i) hydrogen; ii) substituted or unsubstituted phenyl and iii) substituted or unsubstituted 5- or 6-member heteroaryl in which heteroatoms are selected from nitrogen, oxygen, sulphur or combinations thereof; said substitutes are selected from: i) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkoxy; iii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic halogenalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) 5- or 6-member heteroaryl in which heteroatoms are selected from nitrogen, oxygen, sulphur or combinations thereof; or ix) two substitutes may be taken together to form a condensed ring containing 5-7 atoms; R4 is C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; R5a and R5b each independently denotes: 1) hydrogen; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring containing 3-7 atoms; R2 is selected from: i) -OR6; or ii) -NR7aR7b; R6 is hydrogen or C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; R7a and R7b each independently denotes: i) hydrogen; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; or iii) R7a and R7b may be taken together to form a ring containing 3-7 atoms; R3 is hydrogen, methyl or ethyl; L is a binding link of formula -[C(R8aR8b)]n -R8a and R8b each independently denotes hydrogen, methyl or ethyl; n ranges from 1 to 3; R9 is hydrogen or methyl; or pharmaceutically acceptable salt thereof; provided that R and R1 both denote hydrogen. The invention also relates to compositions based on the described compounds for treating anaemia or assisting wound healing and use of said compounds to prepare a composition for treating anaemia or wounds.

EFFECT: novel compounds which are HIF-16 prolyl hydroxylase inhibitors are obtained.

14 cl, 18 ex, 15 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: for treatment of patients with ischemic heart disease in addition to basic therapy introduced is cudesan in dose 25 drops simultaneously with preductal MB 35 mg 2 times per day during meal for 3 months, with further parenteral introduction of essentiale H in dose 0.5-1 g for 10 days, after that, enterally in dose 1 capsule 3 times per day for 20 days. Course of treatment is repeated 3 times per year.

EFFECT: expressed anti-ischemic effect and normalisation of processes of lipid peroxidation, including in patients with severe affection of coronary channel and expressed diastolic dysfunction of left ventricle.

2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: claimed are method of reducing in circulating blood of LDL-cholesterol, triglycerides, total cholesterol and their mixtures, including introduction of efficient amount of one or more phosphate derivatives of one or more electron-transfer agents, which represent monotocopheryl phosphate, dotocopheryl phosphate, monotocotrienyl phosphate, ditocotrienyl phosphate and their mixtures, their application for relief of symptoms, treatment and/or prevention of disease, selected from group which consists of chronic renal failure, primary and secondary hyperemias and dislipemia, retinopathy, enlargement of liver and spleen, xanthomas and their combinations by reduction of lipid content in circulating blood.

EFFECT: reduction under action of claimed tocopherylphosphates of levels of total cholesterol, LDL in mice and reduction in them of atherosclerotic lesions, in people - improvement of dislipidemia state and increase of HDL cholesterol in comparison with tocopherol acetate.

5 cl, 3 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) given below or pharmaceutically acceptable salts thereof:

[where: each of X, Y, Z and W independently denotes a methane group which optionally contains substitutes selected from a group of substitutes α, or a nitrogen atom (except when all elements X, Y, Z and W denote a methane group which optionally contain substitutes selected from the group of substitutes α); A denotes -(C(R3)(R4))m1-; B denotes -O-; D denotes -C(O)-; m1 equals 0; Q denotes a methane group or a nitrogen atom; R denotes a group of formula (II)

, where R6 denotes a lower alkyl group; R7 and R8, together with the nitrogen atom with which they are bonded, form a 5-6-member nitrogen-containing aliphatic heterocyclic group; and where the group of substitutes α includes the following substitutes. Group of substitutes α: halogen atom, hydroxyl group, lower alkyl group, alkoxyl group (said group can be substituted with a cycloalkyl group), amino group, mono- or disubstituted lower alkylamino group, aryl group (said group can be substituted with a halogen atom, a -SO2CH3 group), aryloxy group (said group can be substituted with a halogen atom), heteroaryl group, where 'heteroaryl group' denotes a 5- or 6-member monocyclic saturated or unsaturated group containing 1-2 heteroatoms selected from an oxygen atom or a nitrogen atom (said group can be substituted with an alkoxyl group, alkyl group). The invention also relates to a histamine 3 receptor antagonist, histamine 3 receptor inverse agonist, a prophylactic or medicinal agent, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having histamine H3 receptor antagonist or inverse agonist action.

15 cl, 57 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application relates to composition for application of sugar coatings by method of spraying directly on core material with obtaining of hard drug form. According to invention, composition includes water and hard component, representing mixture of sugar, binding agent, hydroxyalkylcellulose, water-soluble polymer, therapeutic agent, second polymer, which is water-soluble or dispersible in water and plasticiser. Invention also relates to hard drug form, in particular, tablet for peroral introduction, which has described above coating, and as therapeutic agent, in core material contains conjugated estrogens. Invention also relates to method of said sugar coating application, which includes core obtaining, application of coating composition on core material and in case of necessity application of colour and glossy coatings.

EFFECT: invention ensures obtaining coatings which demonstrate good mechanical strength and elasticity when applied on substrate, thus reducing probability of cracks development; in addition, application of water-soluble system in coating composition makes it possible to minimise application of organic solvents in process of film coating application.

110 cl, 1 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: offered is a new modified release dosage form of trimetazidine dihydrochloride in the form of an oral tablet which contains an active substance in amount 3.5 - 70.0 wt %, mixed povidone and polyvinyl acetate as a release modifier in amount 20.0 - 70.0 wt % and pharmaceutically acceptable pharmaceutical aids. Preferentially, the dosage form of trimetazidine dihydrochloride as mixed povidone and polyvinyl acetate contains Collidon SR.

EFFECT: invention shall allow to enlarge the range of high quality, available domestic modified release drugs.

18 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: pH-controlled pulse delivery system according to the invention, contains a nucleus enclosed by an external coating. Said nucleus contains an active substance which is preferentially a pharmaceutically active substance. Said external coating contains a pH-sensitive coating material embedding a swelling ingredient of water swell equal to at least 1.1 in relation to own weight. Said swelling ingredient is present in aforesaid coating in an amount which depending on particle size and structure of the coating forms a coating with a leakless system. The pH-controlled pulse delivery system aims at pH-related place-specific delivery of an active substance preferentially to a large intestine or a duodenum.

EFFECT: invention allows fast release of the active substance owing to the presence of the swelling ingredient in the external coating.

15 cl, 6 dwg, 8 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: application describes a method for preparing and administering pancreatine micropellet nuclei and such pancreatine micropellet nuclei prepared by said method which do not contain synthetic oils. Also, the application describes the entero-soluble coated pancreatine micropellets.

EFFECT: invention provides the improved method for preparing entero-soluble coated pancreatine micropellets which can be delivered to an optimum area of digestive system wherein a digestive enzyme action is required, particularly to upper intestines, for pancreatine release.

17 cl, 3 tbl

Sugar-coated drug // 2407515

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry and concerns a drug which contains a portion containing an oxygen-intolerant active ingredient wherein the oxygen-intolerant active ingredient is (R)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline and a sugar coating containing (1) sugar alcohol as a base material of the sugar coating where sugar alcohol is erythrite and (2) a binding agent where the binding agent is gum arabic wherein a portion is sugar-coated. Also, the invention concerns a method for preparing the declared drug.

EFFECT: agent exhibits high storage stability and oxygen tolerance.

8 cl, 18 ex, 15 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and pharmaceutics, namely to medication for treatment or prevention of cardiovascular system and/or nervous system diseases. Medication contains ethylmethylhydroxypyridine succinate, pyridoxine hydrochloride, pharmaceutically acceptable salt of magnesium and auxiliary substances in quantities given in invention formula. Method of cardiovascular and/or nervous system diseases treatment includes peroral introduction of medication by invention in efficient quantity. Also described is method of obtaining claimed medication.

EFFECT: obtaining highly technological medication characterised by low cost and high therapeutic effect.

13 cl, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to solid dosed compositions containing conjugated estrogens and bazedoxifene or bazedoxifene acetate. In accordance with some versions of invention realisation, said compositions contain core, which contains conjugated estrogens, and at least one envelope, which contains bazedoxifene or bazedoxifene acetate.

EFFECT: solid dosed composition in accordance with invention is intended for treatment of postmenopause symptoms and states with minimisation of proliferative effects in uterus and mammary gland.

52 cl, 6 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to field of medications, in particular to tablet, manufactured by method of building-up coating, in composition of which included are core, containing medication, and core-surrounding coat from non-soluble or badly water-soluble material, core being located inside said coat in such way that coat on axis (X-Y) has greater thickness and lower density than on axis (A-B), orthogonal to axis (X-Y), coat porosity on axis (X-Y) being sufficient for ensuring penetration of water medium, so that when immersed into water medium after period from 2 to 6 hours destruction of coat and release of medication takes place. Invention also relates to method of said tablet manufacturing, pharmaceutical package containing it and treatment method. Said tablet form ensures fast release and delivery of active component after period of delay, which can be set with great accuracy.

EFFECT: system will ensure directed delivery of active component to place of absorption or action.

19 cl, 2 dwg, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: oral controlled-release dosage form includes granules of therapeutically effective amount of pharmacologically high water-soluble active substance, and at least one nonpolymeric release inhibitor. Said granules are combined at least with one pH-independent nonswelling release inhibitor representing a polymer. Nonpolymeric release inhibitor represents glyceryl behenate. Polymeric pH-independent release inhibitor preferentially represents mixed polyvinyl acetate and polyvinyl pyrrolidone (Collidone SR). The active substance preferentially represents vitamin C.

EFFECT: dosage form provides controlled release of an active component with the reduced initial "explosive" release.

34 cl, 4 dwg, 19 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry. Trimetazidine preparation as a matrix tablet of prolonged action contains an active substance, montanic glycolic wax, polymer of methacrylic acid, hydrophilic polymer representing hydroxypropyl methylcellulose, microcrystalline cellulose, mannitol and adjuvants, in amounts specified in the patent claim. There is also disclosed method for making Trimetazidine preparation as a matrix tablet.

EFFECT: invention provides controlled prolonged release of Trimetazidine that leads to stable concentration level of the active substance.

10 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are dosed forms of guanfacine for per oral application, suitable for single intake per day, which has acceptable general size of pills.

EFFECT: dosed form by invention ensures satisfactory pharmacological profile for prolonged delivery of guanfacine during period of time up to 24 hours with regulated total weight of dosed form.

79 cl, 1 dwg, 2 tbl, 5 ex

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