Tablet containing fluvastatin and sodium carboxymethylcellulose of calcium

FIELD: medicine.

SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.

EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.

12 cl, 7 dwg, 6 tbl, 2 ex

 

The present invention relates to a tablet containing fluvastatin, in particular to tablet containing fluvastatin with excellent raspadaemost and good bioavailability.

Fluvastatin has a common (generic) the symbol [R*,S*-(E)]-(±)-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl] - for 3,5-dihydroxy-6-geptanona acid and is known as a compound that prevents the formation of HMG-COA reductase, that is, as an inhibitor of cholesterol biosynthesis. Currently on the market as a medicinal product for the treatment of hyperlipoproteinemias and atherosclerosis offers a sodium salt of this compound, available in capsule form.

Fluvastatin has a bitter taste, high hygroscopicity, low solubility in an acidic medium, low resistance to heat, humidity or light, lack of stability in acidic aqueous solutions, etc. So when selecting a form of pharmaceutical preparation containing fluvastatin as the active substance, it is necessary not only to prevent direct contact of fluvastatin with the environment, for example, by applying to a film shell, but also to take appropriate measures to stabilize fluvastatin. To achieve the latter objective, it is suggested in the drug composition containing fluvastatin, include alkaline substance, pricemat substance shall maintain the pH of an aqueous solution or dispersion of fluvastatin is at least equal to 8 (see patent literature 1).

Patent literature: Japan patent 2774037.

As stated above, fluvastatin commercially available in the form of capsules. From the point of view of industrial production fluvastatin in tablet form is more advantageous compared to the capsule, since the production of tablets is simpler and less expensive than the production of capsules. In addition, the General trend in Japan is the fact that patients medicines in the form of capsules prefer a tablet. Thus, there is a need for tablets containing fluvastatin, but this need to date has not been satisfied. One of the reasons that fluvastatin is so far not available in tablet form, may lie in the fact that currently available for sale drug fluvastatin, available in capsule form, is characterized by a good bioavailability, which can hardly be achieved for the drug in tablet form.

Pharmaceutical preparation such as a capsule or tablet, prescribed orally, divided, dispersed, dissolved or otherwise distributed in the digestive organ (system), by absorption of the mucous membrane of the digestive tract enters the vascular system, and thus the active substance reaches the month is and impacts. For the same active substance bioavailability largely depends on raspadaemosti of the drug. In the General case for tablets is difficult to achieve the decay rate, is equal to capsules and fluvastatin is no exception. The difference in the decay rate thus determines the difference in bioavailability, and capsule and tablet may not be considered equivalent even if the same methods of appointment and the active ingredient. From a clinical point of view this fact is a significant disadvantage.

The objective of the invention

The aim of the present invention to provide a tablet preparation containing fluvastatin, with good bioavailability, at least the same as the bioavailability of commercially available capsule preparation containing fluvastatin, characterized by beautiful raspadaemost.

This goal can be achieved by use in tablet preparation containing fluvastatin, carmellose calcium carboxymethylcellulose calcium) as baking powder.

Carmellose calcium is one of the many leavening agents, which include starch, agar powder, carmellose sodium, crystalline cellulose, hypromellose, hydroxypropylmethyl, amylose, sodium alginate, dialkilsuljfoksidih, Polyak etilenovyi ether of sorbitol and fatty monocellate, calcium carbonate, sodium bicarbonate and other substances that are currently used in pharmaceutical preparations of various active substances. However, what kind of baking powder should be used in each case can only be determined through comparative tests of different leavening agents for each pharmaceutical product of each active substance.

For example, one of the most commonly used leavening agents is carmellose sodium. The possibility of applying this powder was investigated in the work process of the present invention. Carmellose sodium, carmellose calcium have similar structure and physical properties, but carmellose sodium may not provide the required raspadaemost end pills and therefore cannot be used in the present invention. Thus, the use of carmellose calcium is essential for the purpose of the present invention. However, in addition to carmellose calcium is allowed to use other suitable baking powder.

The tablet prepared in accordance with the present invention, provides a fast and almost complete intestinal absorption of active ingredient of fluvastatin. To ensure stabilization of fluvastatin in a long time, preferably in status is in tablets include alkaline substance, such as carbonate.

The practical ways of carrying out the invention

In the tablet prepared in accordance with the present invention, the active substance (i.e. drug) is fluvastatin, which may be present in the drug in free form or in salt form, as far as it is pharmaceutically acceptable. In the form of a salt commonly used salt is an alkali metal, in particular sodium salt. The content of fluvastatin in the tablet is usually from about 0.1 to 60 wt.%, preferably from 0.5 to 40 wt.%.

Tablet in accordance with the present invention can be prepared using essentially known method tableting composition containing fluvastatin and essentially known excipient(CTV) to obtain core tablets, which preferably should use a known method to the core tablet.

Tablet in accordance with the present invention preferably consists of a core tablet and a layer of shell, located on its surface. Education core tablets can also be based on indirect tableting and by direct tableting. The first method is that the pellets containing the active substance obtained by the method of wet or dry granulation, mixing with smatyvayus and components the leavening agents and other auxiliary substances and tabletirujut the mixture. The second method is that, to obtain tablets tabletirujut mixture of the active substance with a diluent(representatives), lubricating component(s), baking powder(s) and other auxiliary substances.

As auxiliary substances(CTV), is added to the current matter, usually apply the filler(s), baking powder(and), connecting components, lubricating components and others. The composition forming the core of the tablet, according the present invention is characterized by the fact that, as the powder is applied carmellose calcium. The number carmellose calcium is from about 1 to 10 wt.%, preferably from 3 to 8 wt.% the total mass of the composition. Another feature of the composition is that the core of the tablet as a stabilizer contains certain alkaline substance in an amount of from about 0.1 to 60 wt.%, preferably from 15 to 50 wt.% the total mass of the composition.

The term "alkaline substance" (or "base") in this context means one or more pharmaceutically acceptable substances, which can provide a pH of the aqueous solution or dispersion of the composition forming the core of the tablet, is equal to at least 8, preferably from about 9 to 10. The pH value can the be determined by dispersing or dissolving a unit dosage of the composition, containing 20 mg of fluvastatin, the volume of water from 10 to 100 ml in order to provide a higher stabilizing effect of the alkaline component, fluvastatin and alkaline component must be mixed to obtain good contact of fluvastatin and alkaline substances. Obviously, the alkaline substance should be inert with respect to fluvastatin as applicable to the substance.

The alkaline substance used to create an alkaline environment may be either water soluble or insoluble, or substantially insoluble in water. Examples of water-soluble alkaline substances are inorganic carbonates (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate), dibasic phosphates of alkaline or alkaline-earth metals (for example, dibasic sodium phosphate, dibasic potassium phosphate, dibasic calcium phosphate), trinacria phosphate and others, as well as mixtures thereof.

Examples of insoluble or practically insoluble in water, alkaline substances are magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, rejonowy calcium phosphate and others and mixtures thereof.

Among alkaline substances that are listed as examples, preferred are inorganic carbonates and reorgan the economic bicarbonates, in particular sodium carbonate, sodium bicarbonate, calcium carbonate and other substances and their mixtures. Particularly preferred is a mixture containing an alkaline substance(VA), soluble in water, and the substance(VA), insoluble or practically insoluble in water, in particular a mixture of carbonate, soluble in water, and carbonate is practically insoluble in water, such as a mixture of sodium bicarbonate and/or sodium carbonate with calcium carbonate.

Alkaline substance should be contained in the composition of the core tablets in sufficient amount to provide a pH of the aqueous solution or dispersion system at least 8, preferably at least about 10. In General, the content of the alkaline substance in the composition is from about 0.1 to 60 wt.%, in particular from 15 to 50 wt.%. For example, the content of water-soluble carbonate(s), such as a carbonate or sodium bicarbonate, may be from about 0.1 to 35 wt.%, preferably from 1 to 15 wt.%. The mass ratio of water-soluble and essentially insoluble carbonate(s) typically ranges from about 2:1 to 1:40, for example, the mass ratio of sodium bicarbonate and calcium carbonate is from about 2:1 to 1:2.

The composition for the preparation of tablets may contain fluvastatin as the active substance, carmellose in the quality of the ve baking powder, the alkaline substance as a stabilizer and optional known additives used to facilitate the preparation of tablets.

Examples of diluents are carbohydrates (such as cellulose), klasterizovannykh starch (for example 1500R, Use Corp.), corn starch, dicalcium phosphate, cellulose, microcrystalline cellulose, sugar, sodium chloride and others. Among them, preferred are lactose, microcrystalline cellulose, klasterizovannykh starch and mixtures thereof, microcrystalline cellulose are particularly preferred.

Application carmellose calcium as baking powder to ensure raspadaemosti and pressuemosti tablet is an essential characteristic of the present invention. For this purpose you can also optionally add crystalline cellulose (AvicelR, High-flow Corp.), klasterizovannykh starch and other components.

In the General case, to provide the necessary binding composition for the preparation of tablets using a binder components. Examples of binders include starch, dextrin, Arabic gum, sodium alginate, gelatin, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, policyprovider, lactose, mannitol, microcrystalline cellulose, calcium lactate, and others. For the present invention Ave is the application of the binder(s) is not required because the necessary binding is achieved by other components.

As component(s)that increase the fluidity, it is possible to use synthetic silicon dioxide, talc and similar substances in quantities of from about 0.1 to 10 wt.%, preferably from 0.5 to 6 wt.%. As the lubricating component may be any component, optionally selected from among conventional lubricating components such as starch, magnesium stearate, calcium stearate, sucrose, salt, and others, and the use of magnesium stearate is most preferable in the present invention. The amount of the lubricating component is usually from about 0.1 to 3 wt.%, preferably from 0.5 to 1.5 wt.%.

Applying a composition containing fluvastatin and additives, provides the core tablets with standard single-dose, such as 5 mg, 10 mg, 20 mg, 30 mg, and others.

The core of the tablet, preferably with a suitable shell. For example, to prevent decomposition of fluvastatin gastric juice on the way to the place of absorption in the small intestine can be used enteric-soluble shell. Examples of materials that can be used as an enteric-soluble membranes are phthalate of hydroxypropylmethylcellulose, acatitla cellulose, polyvinylacetate, phthalate methyl is ellulose, copolymer of methacrylic acid/methyl methacrylate (EudragitR, Rohm Pharma). Enteric-soluble shell may be of such thickness that the resulting increase in the mass of the tablet is from about 5 to 12 wt.%, preferably from 8 to 12 wt.% weight of the core tablet.

To protect the tablets prepared in accordance with the present invention, the color change caused by humidity or light, and also to mask the bitter taste of the active substance, surface tablets should be covered with a sheath. For this purpose, the composition of the intestinal-soluble shell may further comprise a stabilizer turbidity or dye. Or plain opaque film may be deposited on the pill after applying enteric-soluble shell.

The composition of the film sheath covering the tablet in accordance with the present invention, may include a component selected from polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and others. Preferred is the use of hydroxypropylmethylcellulose (OpadryR, Use Corp.). Examples of hydrophilic components, forming a film that can be applied when using organic solvents, are ethically is for, the cellulose acetate, a copolymer of polyvinyl alcohol and maleic anhydride, and others. The amount of the composition of the membrane may be such that the increase in mass due to its application ranges from about 1 to 10 wt.%, preferably from 2 to 6 wt.%, weight of the core tablet.

Examples of other components used in the composition of intestinal-soluble membrane or film membrane, are plasticizers such as polyethylene glycol (e.g. polyethylene glycol 6000), triethylcitrate, diethylphthalate, propylene glycol and glycerin, butylphthalate, stabilizer clouding agents such as titanium dioxide, colorants such as iron oxide and aluminum flakes and other. These components can be used in conventional amounts.

The application of the enteric-soluble membrane or film membranes can be essentially carried out using a known method in the corresponding apparatus for applying a sheath or pseudoviruses installation (fluidizer), use water and/or organic solvents, such as alcohols (e.g. methanol, ethanol, isopropanol), ketones (e.g. acetone, methyl ethyl ketone), chlorinated hydrocarbons (e.g. methylene chloride, dichloroethane) and other substances.

The composition used for the preparation of core tablets can typically contain the following materials (in wt.% weight is the composition): fluvastatin as the active substance, from about 0.1 to 60 wt.% (preferably from 0.5 to 40 wt.%), carmellose as affinity from about 1 to 10 wt.% (preferably from 3 to 8 wt.%); the carbonate(s) (e.g., sodium bicarbonate + precipitated calcium carbonate) as a stabilizer, from about 0.1 to 60 wt.% (preferably from 10 to 40 wt.%); microcrystalline cellulose as a solvent from about 1 to 65 wt.% (preferably 50 to 60 wt.%), the talc as the component that increases the fluidity of from about 0.1 to 10 wt.% (preferably from 0.5 to 6 wt.%); magnesium stearate as a lubricant and from about 0.1 to 3 wt.% (preferably from 0.5 to 1.5 wt.%).

For preparation of a composition intended for receiving tablets, fluvastatin and alkaline substance is first mixed together with the dry or wet method (using a small amount of water or other liquid). The resulting mixture is mixed with other additives to produce a homogeneous mixture. A homogeneous mixture is subjected to pelletizing direct or indirect method. In the tabletting process, if necessary, can be drying.

In one example embodiment of the invention the active substance, an alkaline component, and optionally other additives are mixed with a small amount of water to obtain pellets, followed by drying. Visos the nnye pellets mixed with other additives, stored separately, or remain, in particular with diluent to obtain a mixture, suitable for tableting.

In another example embodiment of the invention when carrying out drying in the fluidized bed using solvent, the active substance and the alkaline component is mixed wet in accordance with essentially known method and is subjected to wet granulation with a certain amount of solvent. Thus prepared granules are dried, mixed with the remaining diluent and other components, such as lubricating components and tabletirujut.

Drying carried out with known methods on a tray dryer or fluidized bed, the latter method is preferred. Typically, drying is carried out at a temperature at the inlet to about 50°C and relative humidity not more than 50%.

In the preparation of the composition, preferably before wet granulation sift the active substance and additives, except for lubricating components, using the sieve of 30 to 40 mesh. Preferably, the active substance is first sieved and then mixed with the diluent. The dried granules are sieved through a sieve of from 18 to 20 mesh and mixed with additives, which were kept separate.

Composition for tableting usually sift through a fine filter, such as 24 mesh, mixed with mazaudon component and pressed. The above-mentioned stage screening usually requires additional drying, at which the wet granules obtained by granulating, dried to L.O.D. from 6 to 8%. The resulting granules are sieved from 12 to 14 mesh and again dried to L.O.D. from 2 to 3%.

A separate process specified method of wet granulation is a joint drying by freezing of the active substance and an alkaline component from the aqueous solution.

As mentioned above, in dosage form can be applied enteric-soluble shell and/or plastic shell.

Drawing on the core tablets containing microcrystalline cellulose, enteric-soluble film or membrane having a composition based on water, should be performed at a temperature from 30 to 50°C, the inlet temperature of 50 to 80°C and relative humidity not more than 50%. For optimum stability of the tablets, as the final product, it is important that dosage form after applying the enteric-soluble film or membrane has dried to a water content of no more than 4%, preferably not more than 3%.

Prepared dosage form tablets should be protected from oxidation by the action of heat or light and discoloration of moisture during storage.

The tablet is prepared using the m composition in accordance with the present invention, has good storage stability.

The tablet film-coated in accordance with the present invention has a disintegration time of from about 10 to 30 minutes. Tablet with enteric-soluble shell is characterized by a disintegration time of from about 60 minutes to 6 hours.

The practical implementation of the present invention is further demonstrated by the examples, which, as it is obvious, do not limit the technical scope of the invention.

Examples

Example 1

(1) Preparation of core tablets containing fluvastatin

a) For the preparation of approximately 600,000 tablets containing fluvastatin (each tablet contains 30 mg of fluvastatin), sodium salt of fluvastatin, precipitated calcium carbonate, sodium hydrogen carbonate, crystalline cellulose (Avicel PH101) and carmellose calcium (ECG-505) weighed in amounts specified in table 1A or table 1B, and mix. The resulting mixture is crushed to powder.

Table 1A
ComponentsMass per tablet mgWeigh quantity, kg
Sodium salt of fluvastatin31,5918,594
Precipitated calcium carbonate42,0025,200
Sodium bicarbonate19,80019,800
Crystalline cellulose36,54036,540
Carmellose calcium5,4005,400

Table 1B
ComponentsMass per tablet mg
Sodium salt of fluvastatin31,59
Precipitated calcium carbonate42,00
Sodium bicarbonate33,00
Crystalline cellulose60,90
Carmellose calcium9,00

b) the Obtained powder mixture plumage is eshivot for 1 minute with shaking in a vertical granulator, after 3 minutes, add purified water (16 kg) and shaken for mixing for 1 minute. The stirred mixture was ground in an electric mill, and the crushed material by suction is moved to a drier, representing a fluidized bed furnace, followed by drying until then, until the activity of the water shall not be less than 0.2 (the drying is carried out at a temperature of supplied air 60°C for about 50 minutes and the temperature of supplied air 55°C for about 30 minutes). The dried granules are sieved through a vibratory screening machine (30 mesh), the material remaining on the sieve, ground in an electric mill (30 mesh), and then again sift through vibrating sieve unit (30 mesh). The material remaining on the sieve advanced ground in an electric mill (30 mesh), and the crushed material is screened (30 mesh) to obtain a granulated product.

C) a Granulated product obtained in stage b), talc and magnesium stearate are weighed in amounts specified in table 2 (which corresponds to 580000 tablets). Then to talc and magnesium stearate, sifted through a sieve of 42 mesh, add 5 kg of the granulated product and pre-mixed in the package made of polyethylene. The resulting mixture and the remainder of the granulated product is loaded into a double cone will smusic the eh (570 l) and stirred at a speed of 21 rpm for 3 minutes to obtain granules, which tabletirujut using a rotary tablet press machine to obtain core tablets containing sodium salt of fluvastatin and having the characteristics shown in table 3.

Table 2
ComponentsMass per tablet mgWeigh quantity
Granules for tableting176,49102,36 kg
Talc2,551479,0 g
Magnesium stearate0,96556,8 g

Table 3
Typical properties pills
Diameter7.5 mm
The radius of curvature15 mm
Weight pills180 mg
Hardness35 N or more
Disintegration timeWithin 10 minutes

(2) Film sheath core tablets

a) Hypromellose 2910, polyethylene glycol (Macrogol 6000, titanium oxide, talc and yellow iron oxide (III) weighed in amounts shown in table 4.

Table 4
ComponentsMass per tablet mgWeighted number, g
The hypromellose 29107,25760
Macrogol 60000,8640
The titanium oxide1,41120
Talc1,2960
Yellow iron oxide (III)0,2160

b) Hypromellose 2910 and Macrogol 6000 added to purified water (60.8 kg) and stirred for dissolution. To the resulting solution add talc and mix before formation of a suspension (primary suspension), which placed the Ute in the container. The titanium oxide and yellow iron oxide (III) is dispersed in purified water (4.8 kg), the resulting suspension (impervious to the sun's rays) pass through a sieve with a mesh size of 200 mesh and add to the main suspension to obtain a mixture. The container and the sieve was washed with purified water (6.4 kg), the solution obtained by washing, add to this mixture, then the mixture is stirred to obtain a film-forming liquid to the inner layer.

C) Hypromellose 2910, polyethylene glycol (Macrogol 6000, titanium oxide, talc and yellow iron oxide (III) weighed in amounts specified in table 5. The hypromellose 2910 and Macrogol 6000 added to purified water (20,0 kg) and dissolved by stirring to obtain fluid for the outer layer.

Table 5
ComponentsMass per tablet mgWeighted number, g
The hypromellose 29101,0800
Macrogol 60000,2160

d) Core tablets obtained in stage (1)) is placed in condition is the time for coating (Hicoater NA-130) and pre-heated by means of pulsed excitation to achieve at the output of the temperature, equal to 50°C. the film-Forming liquid to the inner layer, obtained in stage b), sprayed on the core tablets (the number for the application is 10.8 mg per tablet) under the conditions below. After the drawing of the tablet with the first coating layer is dried in a machine for applying wrappers for 15 hours. After drying under the same conditions, which are listed below, but if the temperature of the air supplied to the drying equal to 45°C., the feed rate of the liquid for spraying shell 75 ml/min (×2) and the number for the deposition of 1.2 mg pills cause fluid forming the outer layer. After applying the shell to retrieve the target tablets containing 30 mg of fluvastatin in the tablet, for 15 hours to perform the dewatering apparatus for applying a shell.

Conditions coating

The pressure of atomizing air at 5 kg/m

The feed rate of the liquid 75 ml/min (×2)

The temperature of the air supply 70°C (for spraying), 45°C (for drying)

Outlet temperature 45°C

Example 2

Tablets containing 10 mg or 20 mg of fluvastatin, receive, as described in example 1, in accordance with the formulation shown in table 6.

Table 6
The component is Tablet (20 mg), mgTablet (10 mg), mg
CoreSodium salt of fluvastatin21,0610,53
tabletsPrecipitated calcium carbonate22,0011,00
Sodium bicarbonate28,0014,00
Crystalline cellulose40,6020,30
Carmellose calcium6,003,00
Talc1,700,85
Magnesium stearate0,640,32
Film shellThe hypromellose 29106,154,10/td>
Macrogol 60000,750,50
The titanium oxide1,050,70
Talc0,900,60
Yellow iron oxide (III)0,150,10
Only129,00of 66.00

Experience 1

The bioequivalence test for tablets and capsules in the human body

One tablet prepared in accordance with the present invention (example 1; containing 30 mg of fluvastatin), or one capsule LocholRcontaining 30 mg of fluvastatin (commercially available product sold by Novartis Pharma), appointed for a single oral administration on an empty stomach each of the 24 volunteers - adult men using double blind method with suspension treatment for one week.

Then compared the behavior of fluvastatin in plasma.

For 90% confidence interval of the difference in average AUCo-sh (logarithm of the magnitude of transformation) n is erated between the values of log(0,88821) and log(1,18200), that corresponds to the standard interval (log(0,8)~log(1,25)). The value ofmaxmuch has changed and, in accordance with the method of the 90% confidence interval was within the bounds of the specified standard range. The difference in averagemaxwas log(1,09089)that lies within a predefined interval (log(0,90)~log(1,11)). Indicated significant variation Withmaxmay be due to the strong influence of the initial distribution of fluvastatin and may be caused not by the preparation and properties of the fluvastatin. Based on the results of this test and the test results of the decomposition obtained previously, was the conclusion on bioequivalence tablets and capsules.

Experience 2

Test the bioequivalence of tablets and capsules in the process of disintegration

In accordance with the "Guide for testing bioequivalence store brand product (the"Guideline for examination of biological equivalency of generic product"), annexed to the Notification No. 487, issued Deliberative Council of Medicine on December 22, 1997, the tests were carried out under the following conditions: 50 rpm (in case 2), optionally at 100 rpm; 1) pH 1,2 (1-I fluid test decay); 2) pH 5.5 (diluted buffer solution McIIvaine); 3) pH 6.8 (2-I fluid when the test of decay), and 4) water.

(1) pH 1,2

Tests showed that at pH 1.2 fluvastatin is low and insufficient stability. The poet is mu the degree of decomposition of the test drug (pills, prepared in accordance with the present invention, containing 30 mg of fluvastatin) and standard drug (capsules "Lochol", containing 30 mg of fluvastatin) remain equal to about 30%, and the difference between the averaged curve decay is absent. Also was not observed impact sinkers. The average degree of disintegration testing of the drug after 5 minutes and after 120 minutes coincided with degrees of collapse of the standard of the drug within the error of ±8%, and in accordance with the standard Guide both drugs were considered equivalent (see figure 1).

(2) pH 5.5 (50 rpm)

I) were compared with standard drug using weights and test preparation without the use of weights after 5 minutes and after 60 minutes the average degree of decomposition of the standard drug was, respectively, 40 and 85%. These drugs were considered equivalent, since the average degree of disintegration test solution after 60 minutes differed from the average of the degree of disintegration of a standard solution by more than ±15%.

II) were compared to the standard solution, from which he removed the sinker in the process of testing and test preparation, for which the sinker is not used. These drugs have been identified as equivalent because within 15 minutes of the observed decay for each of them was not me is it 85%.

III) were compared to the standard solution using the weights and the test solution using sinkers. These drugs were considered equivalent, since the average degree of decomposition of the test solution after 5 minutes and after 60 minutes coincided with those for the standard preparation is not more than ±15% and 40% and 85%, respectively.

In accordance with the above results raspadaemosti standard preparation and the test preparation can be considered as equivalent, because the correct comparison of the results obtained under the same conditions, including the use or absence of weights (see figure 2).

(3) pH 6.8, water (50 rpm), pH 5.5 (100 rpm)

The standard drug and test drug were considered equivalent, since both drugs decay within 15 minutes was not less than 85% (see figure 3-5).

Experience 3

Using the method described in example 1 was prepared core tablets (each weighing 180 mg), in the preparation used sodium salt of fluvastatin (containing 30 mg of fluvastatin) and carmellose calcium (ECG505) or croscarmellose sodium (AcDiSol; FMC BioPolymer Corp.) the quantities listed in table 7. For each core tablets were testing solubility in water (37°C)using the method of mixing the lo is astoi stirrer (speed of rotation of 50 rpm).

Core tablets (A), (B), (C) and (D) were treated with moisture in the desiccator (for 1.5 hours at room temperature and 100% relative humidity). Then under the conditions specified above, were tested for solubility.

Table 7
Disintegrant-
tel
The core of the tablet in accordance with the inventionThe core tablets to control (control)
(A)(B)(In)(G)
ECG505 (wt.%)*5.4 mg (3%)9.0 mg (5%)--
AcDiSol (wt.%)*--5.4 mg (3%)9.0 mg (5%)
* the number one core tablets

Results

As can be seen from the dissolution curve, shown in Fig.6, the core tablets (a) and (B)prepared in accordance with the present invention (before processing moisture is) have a good dissolution rate (the degree of dissolution within 15 minutes after the start of the test is not less than 85%). As can be seen from the dissolution curve, shown in Fig.7, the control core tablets (In) (before treatment with moisture) is characterized by the same rate of dissolution as the core of the tablets prepared in accordance with the present invention, whereas, for the control of core tablets (G) the time to reach 85% degree of dissolution is at least 30 minutes or more.

As can be seen from Fig.6, the core tablets (a) and (B)prepared in accordance with the present invention retain a high dissolution rate after treatment moisture (degree of dissolution is not less than 85% within 15 minutes after the start of the test). The dissolution rate of the control core tablets (C) and (D) slowed significantly after treatment with moisture compared with the velocities obtained prior to this treatment (see Fig.7).

Technical effect

The use of the present invention allows to obtain tablets containing fluvastatin, with good bioavailability equivalent to the bioavailability of commercially available capsules containing fluvastatin. In General, the production of tablets is more efficient and cost-effective in comparison with the production of capsules. In addition, preparations in the form of tablets more popular with patients than drugs in capsule form. Accordingly, the present application makes peror the aspects of the application of fluvastatin cost-effective and more convenient for patients.

Brief description of drawings

Figure 1 shows the averaged decay curves of the drug "Lochol (standard drug in the form of a capsule containing 30 mg of fluvastatin) and tablets made in accordance with the present invention (test preparation in the form of tablets containing 30 mg of fluvastatin) (method of mixing paddle stirrer at 50 rpm; test preparation: the pH is 1,2; 900 ml, n=12).

Figure 2 shows the averaged decay curves of the drug "Lochol (standard drug in the form of a capsule containing 30 mg of fluvastatin) and tablets made in accordance with the present invention (test preparation in the form of tablets containing 30 mg of fluvastatin) (method of mixing paddle stirrer at 50 rpm; test solution: pH 5.5; 900 ml, n=12).

Figure 3 shows the averaged decay curves of the drug "Lochol (standard drug in the form of a capsule containing 30 mg of fluvastatin) and tablets made in accordance with the present invention (test preparation in the form of tablets containing 30 mg of fluvastatin) (method of mixing paddle stirrer at 50 rpm; test solution: pH 6.8; 900 ml, n=12).

Figure 4 shows the averaged decay curves of the drug "Lochol (standard drug in the form of a capsule containing 30 mg of fluvastatin) and tablets made in accordance with the present invention (test report in the form of tablets, containing 30 mg of fluvastatin) (method of mixing paddle stirrer at 50 rpm; test liquid: water; 900 ml, n=12).

Figure 5 shows the averaged decay curves of the drug "Lochol (standard drug in the form of a capsule containing 30 mg of fluvastatin) and tablets made in accordance with the present invention (test preparation in the form of tablets containing 30 mg of fluvastatin) (method of mixing paddle stirrer at 100 rpm; test solution: pH 5.5; 900 ml, n=12).

Figure 6 shows the results of dissolution testing of core tablets prepared in accordance with the present invention, as described in example 1, before (1) and after (2) treatment with moisture.

Figure 7 shows the test results of the disintegration of the control core tablets prepared as described in example 1, before (1) and after (2) treatment with moisture.

1. Tablet containing fluvastatin, in which the baking powder represented by carmellose calcium.

2. The tablet according to claim 1, which further comprises a pharmaceutically acceptable alkaline agent, providing the pH of an aqueous solution or dispersion of the specified tablet at least 8.

3. The tablet according to claim 2, in which the alkaline substance is a carbonate.

4. The tablet according to one of claims 1 to 3, which is applied to the shell.

5. The tablet according to one of claims 1 to 3, containing a crystalline Zell the RAM as a diluent.

6. The tablet according to claim 5, which is applied to the shell.

7. Tablet fluvastatin according to claim 1, containing:

sodium salt of fluvastatinabout 31,59 (mg)
precipitated calcium carbonateabout 42,00 (mg)
sodium bicarbonateapproximately 19,800 (mg)
crystalline celluloseabout 36,540 (mg)
carmellose calciumapproximately 5,400 (mg)

8. Tablet fluvastatin according to claim 1, containing:

sodium salt of fluvastatinabout 31,59 (mg)
precipitated calcium carbonateabout 42,00 (mg)
sodium bicarbonateapproximately 19,800 (mg)
crystalline celluloseabout 36,540 (mg)
carmellose calciumapproximately 5,400 (mg)
talc about 2,55 (mg)
magnesium stearateabout 0,96 (mg)

9. Tablet fluvastatin according to claim 1, containing:

sodium salt of fluvastatinabout 21,06 (mg)
precipitated calcium carbonateabout 22,00 (mg)
sodium bicarbonateabout 28,00 (mg)
crystalline celluloseabout 40,60 (mg)
carmellose calciumapproximately 6,00 (mg)
talcabout 1,70 (mg)
magnesium stearateabout 0,64 (mg)
the hypromellose 2910about 6,15 (mg)
Macrogol 6000about 0.75 (mg)
the titanium oxideapproximately 1,05 (mg)
talcapproximately 0.90 (mg)
yellow iron oxide (II) approximately 0.15 (mg)

10. Tablet fluvastatin according to claim 1, containing:
the core tablets

sodium salt of fluvastatinabout 10,53 (mg)
precipitated calcium carbonateapproximately 11,00 (mg)
sodium bicarbonateabout 14,00 (mg)
crystalline celluloseabout 20,30 (mg)
carmellose calciumapproximately 3,00 (mg)
talcapproximately 0,85 (mg)
magnesium stearateabout 0,32 (mg)
in the film the shell
the hypromellose 2910about 4,10 (mg)
Macrogol 6000approximately 0,50 (mg)
the titanium oxideabout 0,70 (mg)
talcapproximately 0,60 (mg)
yellow iron oxide (III)approximately 0,10 (mg)

11. Tablet fluvastatin according to claims 7 to 10, characterized in that the time of its disintegration is from about 10 to 30 minutes

12. The tablet according to one of claims 7 to 10, which is applied to the shell.



 

Same patents:

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the method for modulation of the CRTh2-receptor activity with usage of the compounds of formula (I) or their pharmaceutically acceptable salts where: W is O, S(O)n (where n is equal 0, 1 or 2), NR15, CR1OR2 or CR1R2; X is hydrogen, halogen or C1-6 alkyl which can be substituted with one or more halogen atom; Y is hydrogen, halogen; Z is phenyl, pyridyl, pyrimidyl or quinolyl possibly substituted with one or more substituting group independently selected from following groups: halogen, CN, nitro, SO2R9, SO2NR10R11, CONR10R11, NHSO2R9 or C1-3 alkyl substituted with one or more halogen atom; R1 and R2 are independently hydrogen atom or C1-6 alkyl; R9 is C1-6 alkyl; R10 and R11 are independently hydrogen atom or C1-6 alkyl; R15 is hydrogen atom or C1-6 alkyl.

EFFECT: improvement of the method.

19 cl, 68 ex

FIELD: medicine.

SUBSTANCE: there is offered application of the substance representing enzyme-processed fish protein hydrolyzate able to inhibit activity of acyl-CoA cholesterole acyltransferase and to intensify mitochondrial β-oxidation for making a pharmaceutical or food composition applied for treatment and/or prevention of hepatic adipose degeneration in animals, for treatment and/or prevention of hypercholesterolemia and for treatment and/or prevention of hyperhomocysteinemia, and also for treatment and/or prevention of atherosclerosis, coronary heart disease, stenosis, thrombosis, myocardial infarction and stroke in an animal. There is offered method for making enzyme-processed fish protein hydrolyzate able to inhibit activity of acyl-CoA cholesterole acyltransferase, to reduce triglyceride concentration in liver, to reduce homocysteine concentration in plasma and/or to intensify mitochondrial β-oxidation. The preferential embodiment of the invention concerns FPH application as an antiatherogenic and cardioprotective agent presented either as a pharmaceutical agent, or as a functional food.

EFFECT: improved properties of the substance.

14 cl, 7 ex, 5 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, and concerns atherosclerosis nutritive prevention and treatment ensured by introduction of BAAs "Pharmanex": LifePak dosed 1 pill in the morning and in the evening, MarineOmega® dosed 1 capsule in the morning; Tegreen97 dosed 1 capsule in the morning every second day within 8 weeks.

EFFECT: scheduled introduction of said specific BAAs provides mutual potentiation of their anti-oxidant, hypolipidemic and hypotensive properties.

3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a pharmaceutical industry, in particular to a medicinal preparation for treatment of cardiovascular and cerebrovascular diseases. A medicinal preparation for treatment of the cardiovascular and cerebrovascular diseases, containing iso lithis sperm acids A and B which are characterised in mass spectra by certain peaks. The way of manufacturing of a medicinal preparation including weighing of Radix Salviae Miltiorrhizae and Radix Notoginseng; addition of a hydroxide of sodium, Sodium hydrogenum, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate or their admixture in certain quantity; boiling of admixtures in 3-6-time quantity of water 2-4 times; filtration of an admixture and concentration of incorporated filtrates; addition of ethanol infusion of an admixture and separation of the supernatant liquid; allocation of ethanol from the supernatant liquid and concentration of the rest with reception of extract Radix Salviae Miltiorrhizae - Radix Notoginseng, mixing of the received extract with borneol or oil Lignum Dalbergie Odoriferae (rosewood); and excipient addition.

EFFECT: development of a preparation, effective for treatment of cardiovascular and cerebrovascular diseases.

11 cl, 6 dwg, 7 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: application of the oxidised ATF form (o-ATF) as the antiangiogenic pharmacological agent, a therapeutic preparation for treatment of the tumours, including o-ATF with antitumoral substance and a therapeutic preparation for treatment of the atherosclerotic processes, containing o-ATF with antiatherosclerotic substances is offered. The agent is applicable for treatment of diseases, in whose beginning or advance the angiogenesis, such as diseases of eyes, atherosclerotic processes or tumours is involved.

EFFECT: maintenance of suppression of a proliferation of endothelial cells, or anti-angiogenic effect even in the presence of the endothelial factor of growth of vessels.

6 cl, 2 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine, in particular to experimental cardiology and pharmacology, and concerns correction of endothelial dysfunction. For this purpose in experiment endothelial dysfunction is modeled to male laboratory rats of Wistar line by intraperitoneal daily injection of the N-nitro-L-arginine of methyl ether in a dose of 25 mg/kg, within 7 days. Simultaneously a Phosphogliv preparation is entered daily intragastrically in a dose 2.2g/kg. The way provides effective correction of endothelial dysfunction at the expense of Phosphogliv ability to raise production and bioavailability of nitrogen oxide.

EFFECT: effective correction of endothelial dysfunction.

1 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and pharmaceutics and concerns angiatherosclerotic composition including intestine-soluble coating and core, which contains 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)tio-5,6-trimethylenepyrimidin-4-one and one or several additives, selected from loosing agent, thinner and binding agent.

EFFECT: elaboration of composition with high bioavailability.

10 cl, 9 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to a composition containing Candesartan and Rosuvastatin used to prevent and treat atherosclerosis and cardiovascular diseases, as well as to method of prevention or treatment of atherosclerosis or cardiovascular diseases.

EFFECT: composition shows synergetic effect.

10 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: atherosclerotic plaques are stabilised by introduction of effective amount of 2-[4-[2-(benzimidazole-2-ylthio)ethyl]piperazine-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide, or the pharmaceutical composition containing effective amount of this compound as an active principle.

EFFECT: effective prevention of plaque destruction, their stabilisation ensured by reduced amount of macrophages and increased collagen fibres in atherosclerotic plaques.

12 cl, 7 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new antioxidant, antihyperglycemic, hypolipidemic and antishock compound, as well as to production process and application for making corrective agent for metabolic syndrome and vascular disorders in pancreatic diabetes type II, atherosclerosis and coronary heart disease.

EFFECT: compound can be applied in endocrinology, cardiology, emergency medicine and other fields.

3 cl, 4 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: there is offered application of the substance representing enzyme-processed fish protein hydrolyzate able to inhibit activity of acyl-CoA cholesterole acyltransferase and to intensify mitochondrial β-oxidation for making a pharmaceutical or food composition applied for treatment and/or prevention of hepatic adipose degeneration in animals, for treatment and/or prevention of hypercholesterolemia and for treatment and/or prevention of hyperhomocysteinemia, and also for treatment and/or prevention of atherosclerosis, coronary heart disease, stenosis, thrombosis, myocardial infarction and stroke in an animal. There is offered method for making enzyme-processed fish protein hydrolyzate able to inhibit activity of acyl-CoA cholesterole acyltransferase, to reduce triglyceride concentration in liver, to reduce homocysteine concentration in plasma and/or to intensify mitochondrial β-oxidation. The preferential embodiment of the invention concerns FPH application as an antiatherogenic and cardioprotective agent presented either as a pharmaceutical agent, or as a functional food.

EFFECT: improved properties of the substance.

14 cl, 7 ex, 5 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: method involves products of submerged cultivation of xylotrophic fungi Trametes hirsuta TI-14 or Trametes ochracea TI-15, or Panus conchatiis TI-16, or Cerrena unicolor TI-9, or Ganoderma lucidum TI-7, or Flammulina velutipes TI-3 as a biomass contained in the higher basidiomycetes culture collection of microbiological synthesis department of St.-Petersburg state technical university. The biomass is introduced into the dietary intake in minimal amount 2% of the whole dietary intake.

EFFECT: lower blood level of total cholesterol and triglycerides and lower liver lever of total cholesterol.

2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical preparation for treatment of hypercholesterolemia and hyperlipemia containing an amorphous active material in inert gas medium. There are disclosed stabilisation method of the pharmaceutical preparation containing pharmaceutical composition with the amorphous active material, stabilisation process of the pharmaceutical composition containing the amorphous active method, and stabilisation method of the amorphous active material. The amorphous active substance may represent amorphous calcium atorvastatin.

EFFECT: improved effectiveness.

25 cl, 3 ex, 4 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to compounds with formula I, active towards receptors, activated by peroxisome proliferators (PPAR), and can be used in medicine, formula I, where U, W, X and Y represent CH, V represents CR8; R1 represents-C(O)OR or a carboxylic acid isoster, where R is a hydrogen atom, substituted alkyl, aryl or heteroaryl; R2 represents -S(O)2R21; R6 and R7 represent a hydrogen atom, substituted alkyl or cycloalkyl; R8 represents a hydrogen atom, halogen, -OR9, substituted inferior alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, heteroaryl or heteroaralkyl; R9 represents a substituted alkyl or cycloalkyl; R21 represents a substituted heteroaryl or phenyl; n equals 1.

EFFECT: obtaining new biologically active compounds and pharmaceutically active compositions based on these compounds.

46 cl, 134 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: it is offered a cholesterol-regulating medical product intended for normalisation of level of cholesterol. The agent contains a formaldehyde solution and sodium chloride, thereat formaldehyde content makes 0.07-0.24%.

EFFECT: agent for 35 and 65 days of treatment authentically normalised cholesterol level in blood at the moderate and expressed hypercholesterinemia.

3 tbl

FIELD: medicine.

SUBSTANCE: methods provide that composition, containing compound selected from flavanol of cacao and its oligomer, which have definite structure, is introduced to subject. Said compositions and products can also be used for treatment, prevention, reducing risk or retarding progress of any state, associated with pathology of gap junction contact between cells, such as malignant tumor, cardiac arrhythmia and other diseases, associated with defective intercellular communication by means of gap junction contacts.

EFFECT: treatment of subject suffering from cognition impairment, as well as to method of cognition improvement in subject suffering from neurodegenerative disease.

32 cl, 5 dwg, 7 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention claims bioactive agent in the form of compound of formula (I) , where n is 1 or 2, m is 0, q is 0, t is 0, R9 is hydrogen, A is phenyl substituted by 1 or 2 groups selected out of alkyl with 1 or 2 carbon atoms, X is -CH2CR12R13- group where each of R12 and R13 is hydrogen, Q is OR1, R1 is hydrogen or alkyl with 1 to 7 carbon atoms, and agent application in medicine manufacturing for treatment of state selected out of group including resistance syndrome and diabetes.

EFFECT: method of treatment for mammal subject with state selected out of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, adiposity, atherosclerosis, and arteriosclerosis, involving daily oral administration of 1 to 400 mg of bioactive agent, and pharmaceutical composition based on the bioactive agent.

12 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical industry, particularly means of cerebral cardiovascular disease treatment and prevention. Pharmaceutical composition for cerebral cardiovascular disease treatment and prevention includes definite steroid saponins in definie amount. Method of pharmaceutical composition preparation involves weighing furostanol saponin and spyrostanol saponin, mixing them at definite ratio, adding pharmaceutically acceptable adjuvants. Method of obtaining pharmaceutical composition involves cutting or breaking of rhizome of definite plants, extraction, extract filtering and passing through a column with absorbing resin, eluate disposal, column flushing with water, flush water disposal, column elution, eluate collection and concentration, adding alcohol to concentrated solution, filtrate collection after filtration, filtrate concentration and drying, adding pharmaceutically acceptable adjuvates. Pharmaceutical composition is applied in pharmaceutical medicine production for cerebral cardiovascular disease treatment and prevention.

EFFECT: highly stable composition efficient for cerebral cardiovascular disease treatment and prevention.

17 cl, 4 dwg, 8 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: hyperlipidemia relief in organism is enabled with submerged cultivation products of Panus conchatus fungi as a biomass or extract within dietary intake. Biomass or extract are introduced into dietary intake in minimum amount 2% or 0.002% of dietary intake respectively.

EFFECT: reduced level of total cholesterol, triglycerides, higher blood level of high density lipoproteids and activated liver cholesterol metabolism.

3 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical chemistry, namely to the method of obtaining of a medical product with a covering from a Pioglitazone hydrochloride which can be used as a therapeutic agent for treatment of diabetes, lipidemias, and also can be an antihypertensive agent, an antiobesity agent, diuretic or an antithrombotic agent.

EFFECT: medical product covered with a hydrochloride pioglitazon, possesses larger stability of an agent at storage, and also improved properties, such as solubility of a Pioglitazone hydrochloride.

11 cl, 30 ex, 3 tbl

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