Pharmaceutical fenofibrate composition possessing high biological potential, and how you can get

 

The pharmaceutical composition of fenofibrate immediate release for oral administration contains granules consisting of isolated or agglomerated between the particles of water-soluble inert basics associated with micronized particles of fenofibrate with a particle size less than 20m in a mixture with a hydrophilic polymer. Hydrophilic polymer deposited on the surface of particles of water-soluble inert base. These granules can have one or more external phases or layers, or may be agglomerated. The method of obtaining the pharmaceutical composition is carried out by preparing a suspension of fenofibrate in micronized form in a solution of hydrophilic polymer and applying the suspension of a water-soluble inert basis. Pharmaceutical composition and method of reception provide an increased biological potential due to improved dissolution profile compared to known compositions. 2 N. and 29 C.p. f-crystals, 2 ill., 1 PL.

The object of the present invention is a new pharmaceutical composition having increased biological potential due to the high dissolution, and str is for oral administration, containing poorly soluble in water, the active principle.

The disadvantage of many active principles is the low solubility in water, i.e. they have insufficient dissolution profile and, consequently, low biological potential in the body when administered orally. Enter therapeutic dose should therefore be higher to overcome this limitation. This applies in particular to the numerous hypolipemic active principles, such as those that belong to the family of fibrates.

Fenofibrate is a well-known hypolipemic collection fibrates, which is sold in different dosages (100 and 300 mg, for example, Secalip), but in a form that leads to low biological potential of the active agent. Indeed, because of its low water solubility of fenofibrate is poorly absorbed from the gastrointestinal tract and therefore is incomplete, irregular and often varies in different individuals of the biological potential.

To improve the dissolution profile of fenofibrate and its biological potential and reducing, thus, the input dose it would be advisable to increase its dissolution so that it could reach the expansion of only one reception per day, which would provide the same effect as the effect achieved by multiple methods.

The way to increase the biological potential of fenofibrate described in the patent EP-A-0 330 532. This patent describes the action of semitransitive fenofibrate with surface-active substance, such as lauryl sulfate, to increase the solubility of fenofibrate and increasing in this way its biological potential. This patent States that tomicronesia fenofibrate with a solid surface-active substance can improve the biological potential of fenofibrate much more effectively than in the case of additives surfactants or micronisation one fenofibrate or thin mixing fenofibrate and surfactants after their separate micronisation. The method of dissolution is the usual way using rotating blades (European Pharmacopoeia): kinetics of dissolution of the substance is measured in a fixed volume of medium dilution, mix using the standard device; testing was also conducted with an alternative method of the European Pharmacopoeia, namely according to the method of the camera with the quartering is sluggish start, semitransitive with a solid surface-active substance, characterized by higher dissolution of fenofibrate, i.e. higher biological potential, which provides for equal efficiency reduction of the daily dose of the drug, respectively, 67 mg and 200 mg instead of 100 mg and 300 mg

However, the method of obtaining this patent does not fully meet the requirements, because it does not provide full biological potential of the active principle, and has several shortcomings. How semitransitive fenofibrate with a solid surface-active substance of course increases the dissolution of the active principle, but this dissolution is incomplete.

Thus, there is a need to increase the biological potential of fenofibrate to achieve in a very short time, close to 100% (or at least above the following limits: 10% for 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes in an environment formed by 1200 ml of water, to which was added 2% of Polysorbate 80, or 1000 ml of water, which added to 0.025 molar sodium lauryl sulfate, when the rotation speed of the blades 75 rpm), even when using environments dissolution with low content of surface-active substances.

The applicant is not the composition by spraying a suspension of the active agent in an inert water-soluble base. The present invention also applies to the thus obtained pharmaceutical compositions.

We already know the use of such a polymer, such as polyvinylpyrrolidone for the manufacture of tablets in the amount of about 0.5-5 weight %, more than 10 weight %. In this case, the polyvinylpyrrolidone is used as the binder. It is also known the use of this polymer as hydroxyethylmethylcellulose as binders for granulation. Thus, in EP-A-0 519 144 described granules of slightly soluble substances of omeprazole, which is produced by spraying in a fluidized bed granulator dispersion or suspension of the active agent in the solution containing the above polymer, inert granules. However, here also the polymer (PMC and PC) used as a binder for granulation in an amount of about 50 weight % of the weight of the active principle that, given the presence of inert granules of large size (about 700 μm) and the total final number of leads to very low final concentrations of the active agent and the polymer, of the order of only a few % of the weight of the final coated granules. Finally, note that the size of the inert granules in this document are high enough that if Fennia.

It is also known the use of such a polymer, such as polyvinylpyrrolidone for the manufacture of "solid dispersions", usually by co-precipitation, sopravleniya or mixing in the liquid phase, followed by drying. In this case we are talking about fixing the active agent in a separate microparticles on the polyvinylpyrrolidone, which prevents the problems associated with poor wettability of a solid substance and deagglomerate particles. In the article "Stable Solid Dispersion System Against Humidity", Kuchiki and others, Yakuzaigaku, 44, №1, 31-37 (1984) described this method of producing solid dispersions using polyvinylpyrrolidone. The number of PVP is very high, and the ratio of active agent to PVP is from 1/1 to 1/20. In this case, however, there is no inert basis.

Also known from the document WO-A-96 01621 composition of deferred action, including inert core (all examples dvuoksid silicon), coated with a layer containing the active principle mixed with the hydrophilic polymer, with the weight ratio of the active principle/polymer ranges from 10/1 to 1/2, and the weight ratio of the active/inert core is from 5/1 to 1/2, with an outer layer to provide deferred action. Such compositions can be preformed. Guide the second composition; for example, in a fluidized bed granulator sprayed dispersion of the active agent in the polymer solution on an inert core. In this document we are talking only about the songs deferred action. The technical problem to be solved by this document, is in compression without damage to the outer layer, providing for deferred action.

However, nowhere in the level technique is not described in the present invention.

Thus, the present invention provides fenofibrate the composition of the instant release, including:

(a) a water-soluble inert base covered with at least one layer containing fenofibrate in a micronized form with a particle size less than 20 μm, a hydrophilic polymer and, optionally, surfactant, and named the hydrophilic polymer is at least 20 weight % of the weight of element (a);

and

(b) optionally, one or more external phases or layers.

One variant of implementation together with fenofibrate and the hydrophilic polymer is a surfactant.

The invention also provides a composition comprising fenofibrate solubility of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, when measured orenia, formed by water and 2 percent by weight Polysorbate 80 or environment dissolution, formed by water and 0.025 M sodium lauryl.

The subject of the invention is also a method of obtaining a pharmaceutical composition according to the invention, comprising the following stages:

(a) obtaining a suspension of fenofibrate in micronized form with a particle size less than 20 microns in a solution of hydrophilic polymer and, optionally, a surfactant;

(b) applying the suspension stage (a) water-soluble inert;

(C) if necessary, the coating thus obtained granules of one or more phases or layers.

Stage (b) is preferably carried out in a fluidized bed granulator.

The method may include the stage of extrusion products obtained in stage (b) or (C), with additional excipients or without them.

The subject invention is also suspension fenofibrate in micronized form with a particle size less than 20 microns in a solution of hydrophilic polymer and, optionally, surface-active substances.

The present invention is described in more detail in the following description with reference to the accompanying drawings, on which:

- Fig. 1 is a graphical image I Lipantil (Lipantyl®) 200 M;

- Fig. 2 is a graphical depiction of a comparative study of the dissolution profile of the composition of the present invention and dissolution profile of the pharmaceutical products available on the German market.

In the framework of the present invention, the term "micronized" refers to a substance in the form of particles, with a particle size of less than or equal to approximately 20 μm.

Mostly this size is less than or equal to 10 microns.

In the framework of the present invention under the "water-soluble inert substrate" mean any excipient, usually hydrophilic, pharmaceutically inert, crystalline or amorphous, in the form of particles that do not result in chemical reactions used in the working conditions and soluble in aqueous medium, in particular in the environment of gastric juice. Examples of such excipients are derivatives of sugars, such as lactose, sucrose, hydrolyzed starch (maltodextrin), etc. and also Fit mixtures. The size of the individual particles of water-soluble inert bases may be, for example, 50-500 μm.

In the framework of the present invention under the "hydrophilic polymer" refers to any substance with high molecular weight (for example, above 300) with sufficient affinity with water for niloy alcohol, hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, gelatin, etc. are also Suitable mixture of polymers.

The preferred hydrophilic polymer is polyvinylpyrrolidone (PVP). Used within the present invention PVP has a molecular weight of from 10000 to 100000, preferably, for example, from 20,000 up to 55,000.

Used in the present invention, the term "surfactant" is used in the traditional sense. Can be any surfactant, amphoteric, nonionic, cationic or anionic. Examples of such surfactants are: nutriceuticals, monooleate, monolaurate, monopalmitate, monostearate or another complex polyoxyethylene ether sorbitan, dioctylsulfosuccinate sodium (DOSS), lecithin, octadecylamine alcohol, smoothability alcohol, cholesterol, polyoxyethylene castor oil, polyoxyethylene glycerides of fatty acids, poloxamer®, etc. and also Fit mixtures of surface-active substances.

Preferred surface-active agent is sodium lauryl sulfate, which can semitransverse with fenofibrate.

The composition of the invention can, in addition,proactive, such as binders, fillers, pigments, disintegrators, lubricants, wetting, buffers, etc. as examples of excipients that can be used in the present invention, one can cite: microcrystalline cellulose, lactose, starch, colloidal dvuoksid silicon, talc, complex glycerol esters, sodium fumarate, titanium dioxide, magnesium stearate, stearic acid, reticulated polyvinylpyrrolidone (AC DI SOL®), carboximetilkrahmal (Explotab®, Primojel®), hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, gelatin, etc.

In the framework of the present invention under "outer phase or layer" means any coating on the element (a) with active early (forming the "core"). Indeed, it may be important to have one or more phases or layers over the coated core. Thus, according to the invention a separate core coated with one layer, but also multiple cores in the same phase, as in the case of pellets, derived from the "cores", mixed with the same phase. In the framework of the present invention under "outer phase or layer" does not imply coverage, providing delayed action composition.

This outer layer includes traditional excipients.

is retene outer layer includes a disintegrator and for example, a lubricating substance; covered and mixed so pellets can easily tabletroute and easily disintegrate in water.

The compositions of the present invention include generally, relative to the total weight of the composition without the outer phase or layer, water-soluble inert base, comprising 10-80 weight %, preferably 20-50 weight% with fenofibrate is 5-50 weight %, preferably 20-45 percent by weight, the hydrophilic polymer is 20 to 60 weight %, preferably 25-45 percent by weight, the surfactant is 0-10 weight %, preferably 0.1 to 3 weight %.

The outer layer or phase, if present, may be up to 80 percent by weight of the total weight, preferably up to 50 weight %.

The hydrophilic polymer is preferably more than 25 weight % relative to the weight of the element).

The weight ratio of fenofibrate/hydrophilic polymer may be, for example, from 1/10 to 4/1, preferably, for example, from 1/2 to 2/1.

When using surfactant weight ratio surfactant/hydrophilic polymer may be, for example, from 1/500 to 1/10, preferably, for example, from 1/100 to 5/100.

One option osushestvleniya compression elements (a) in the form of granules with the outer phase.

In another variant implementation of the composition according to the present invention has the form of pellets that are enclosed in a capsule, for example, from gelatin or in a bag.

The compositions of the present invention are particularly suitable for oral administration active principles.

The composition of the present invention receives a new method involving coating on inert cores suspension of the active agent in micronized form in a solution of hydrophilic polymer and, optionally, surface-active substances.

In the presence of surface-active substances, the active principle can semitransverse with surface-active substance. Mostly use the method according to the document EP-A-0 330 532.

The method according to the invention lies in the use of the principle of technology granulation in a fluidized bed, but with a special initial products, in order to obtain improved dissolution profile and, consequently, high biological potential. In particular, the invention uses the suspension of the active principle, micronized in a solution of hydrophilic polymer and optionally a surfactant.

The technology of granulation in a fluidized bed is widely used is the method the powder or mixture of powders (active start + excipient) suspendered fluidized bed in the granulator, and a solution containing a binder and, optionally, surface-active substance is sprayed on the layer for the formation of granules. The granulation in the fluidized bed are well known to the specialist, who can access these sources, for example, to the work "Die Tablette", Ritschel, Ed.Cantor Aulendorf, pages 211-212.

The invention, as indicated, includes a coating on an inert base suspension of the active principle, micronized with a hydrophilic polymer. After completion of the granulation, the resulting granules consists of isolated (or possibly agglomerated to each other via a solution for spraying) crystals, for example lactose, and particles of the active agent and PVP deposited on the surface of the crystals. The pellet can also be formed is covered with a sintered between crystals or even so agglomerate, in turn covered.

The composition of the invention can also be obtained by other methods, for example, by evaporation of a solution of micronized active agent to water-soluble inert basis.

Thus obtained granules can, if necessary, be covered with an outer layer or tablets or to form agglomerates.

The outer layer or layers are applied is received granule (later covered or not) is pressed to form tablets, this stage can be performed by any suitable conventional method, for example, using a tablet press machine of the reciprocating or rotary type.

An important starting product is a suspension of the active principle. This suspension is produced by suspendirovanie micronized active agent in the solution containing the hydrophilic polymer and, optionally, surface-active agent dissolved in the solvent. When using a surfactant dissolves in the solvent (chemical glass + magnetic mixer or paddle mixer). After that, the hydrophilic polymer (PVP) is dispersed with stirring in is received before this solution. Depending on the solubility of the polymer it is dissolved in solution or forms a more or less thick gel or suspension. While continuing the stirring, micronized active principle is dispersed from the top in is received before this solution or suspension to form a homogeneous suspension. It is possible to change the order of these stages. The used solvent can be aqueous or organic (e.g., ethanol). Use, for example, demineralized water.

The concentration of an asset is limera suspension is 5-40 weight %, preferably 10-25%.

The concentration of surfactant in the suspension is 0-10 weight %, preferably less than 5%.

The subject invention is also this new suspension.

Not wishing to be bound by theory, the applicant believes that this new way through the use of a suspension of the active principle, micronized in a solution of hydrophilic polymer, allows to obtain a new composition in which the active principle is refereegagelmann.

The examples given below illustrate the invention without limiting it.

EXAMPLE 1

Obtaining a pharmaceutical composition fenofibrate according to the invention

Get composition comprising as an element of a) micronized fenofibrate, Plasdone®, Capsulac® and sodium lauryl sulfate.

Micronized fenofibrate has a particle size of about 5 microns as measured with the counter Cultura (Coulter).

Plasdone K25® meets the polyvinylpyrrolidone PVP COI, a Capsulac 60 (MEGGLE) corresponds to the monohydrate lactose with large crystals (particle size from 100 to 400 μm).

Sodium dodecyl sulfate (7 g) was dissolved in water (demineralized water, 1750), micronized fenofibrate (350 g) is translated in suspension in the mixture (for example, with the TEW 10 000 rpm, within 10 minutes). Then add with stirring PVP (350 g), with stirring (propeller mixer) continued until the dissolution of the latter (30 minutes). All passed through a sieve (350 μm) to remove possible agglomerates.

Separately lactose (400 g) was transferred to a suspension of the pellet air fluidized bed (type Glatt GPCG1 - Top Spray or similar) and heated to 40C.

The suspension fenofibrate sprayed on lactose. This stage is carried out under the following conditions: spray pressure of 2.1 bar; air consumption 70 m3/h; the temperature of the air supply 45C; the temperature of the outlet 33C; product temperature 34°C; the duration of the spraying 3 o'clock

Thus obtained pellets can be placed in gelatin capsules or tablets. Can be used in any suitable conventional way of obtaining such galenical forms.

For tabletting add to 191 g of the obtained granules (for example, using a mixer type mixing unit, a planetary mixer or rotary mixer) an outer phase having the following structure:

- 56 g of Polyplasdone XL® (reticulated polyvinylpyrrolidone, COI, as described farmacopea US "USP fumarata sodium (Mendell, USA); and

2 g Aerosil® 200 (colloidal dvuoksid silicon).

Reticulated polyvinylpyrrolidone, microcrystalline cellulose, sodium fumarate and colloidal dvuoksid silicon are respectively the disintegrator, binder, lubricant and regulator fluidity.

Getting a tablet can be done on a tablet press machines, reciprocating (for example, Korsch Eko) or rotary tablet press machine (for example, Fette Perfecta 2).

So, get a tablet having the following composition mg:

element:

Micronized fenofibrate 100,0

PVP 100,0

Lactose 114,3

Sodium lauryl sulfate 2,0

- outer phase (or layer):

Net of 92.7 PVP

Microcrystalline cellulose to 145.7

Fumarate sodium 5,8

Colloidal dvuoksid silicon 3,3

EXAMPLE 2

The dissolution of the compositions according to the invention and known compositions

a) Environment dilution and Protocol for measuring dissolution.

Choose the environment dissolution, which is a discriminant, i.e., two products with very different profiles of dissolution in the gastric juice, will have different curves of dissolution.

For this purpose, use aqueous medium containing a surfactant, namely Polysorbate ikov, it is the subject of monographs in pharmacopoeias and easy to use (liquid water-soluble product). Other surfactants, such as sodium lauryl sulfate, may also be used.

Use the method of rotating blades (European Pharmacopoeia) in the following conditions: the volume of the environment 1200 ml; temperature 37With the speed of rotation of the blades 75 rpm; probatory - every 2.5 minutes. The determination of the dissolved amount is realized by means of spectrophotometry. The test is repeated six times.

b) Results

The composition according to the invention contains two tablets with a dose of about 100 mg fenofibrate obtained in accordance with example 1.

Known composition consists of Lipantil (Lipanthyl®) 200 M (Laboratoires Fournier) with a dose of 200 mg fenofibrate (corresponding gelatin capsules 200 mg fenofibrate, semitransitive with lauryl sulfate and lactose, pregelatinized starch, reticulated polyvinylpyrrolidone and magnesium stearate, in accordance with patent EP-A-0 330 532).

The obtained results are presented graphically in Fig.1, on which a specified percentage of dissolution, and in brackets mark the standard deviation.

These results clearly show the shaft compositions.

These results also clearly show that the compositions according to the invention are celebrating the standard deviation is significantly lower than in the known compositions.

EXAMPLE 3

The study of the biological potential of the compositions of the present invention and known compositions

Conducted testing on the biological potential in healthy volunteers.

Tested the following songs:

the composition according to the invention: gelatin capsules containing granules obtained in example 1 and containing a dose of 200 mg fenofibrate,

the first known composition: Lipanthyl® 200 M (Laboratoires Fournier) with a dose of 200 mg fenofibrate, as in the previous example,

the second known composition: Secalip® gelatin capsules (300 mg fenofibrate in the form of 3 gelatin capsules with 100 mg).

The study was carried out on 6 healthy volunteers who received the same dose of fenofibrate with an interval of at least 6 days between meals. Samples for pharmacokinetic analysis are collected after each round for time: 0,5; 1 h; 2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h, 36 h, 48 h, 72 h and 96 h after administration of the drugs. Content fenofibrate acid in plasma is measured on each sample.

The results are shown in the table below:

EXAMPLE 4

Comparison of dissolution profile of the compositions according to the invention with the dissolution profile of the products currently available on the German market

In Germany you can find forms of fenofibrate instantaneous or prolonged action. As in France, forms with 100 and 300 mg (traditional) coexist with forms 67 and 200 mg (with increased bitapaka according to patent EP-A-0 330 532).

These are the following products:

Fenofibrat - Ratiopharm; Ratiopharm - Ulm;

Gelatin capsules;

Composition: Fenofibrate 100 mg;

Excipients: lactose, corn starch, magnesium stearate, dye E 171, gelatin.

.Duravent; Brahimi - Wolfratshausen;

Gelatin capsules;

Composition: Fenofibrate 100 mg;

Excipient: lactose, corn starch, magnesium stearate, dye E 171, gelatin.

.Normaly about; knoll - Ludwigshafen;

Gelatin capsules;

Composition: Fenofibrate 200 mg;

Excipients: Crosspovidone, gelatin, lactose monohydrate, magnesium stearate, corn starch, sodium lauryl sulfate, dyes E 132, E 171.

Conduct a comparison between:

the tablet according to the invention, poruchenoprorabotatj Ratiopharm® (2100 mg);

- Durateston® (2100 mg).

The tests are conducted under the same conditions as in the previous examples. The results are shown in Fig.2.

These results clearly show that the compositions according to the invention have significantly higher dissolution compared to known compositions.

Naturally, the present invention is not limited to the described variants of implementation, and suitable for many options readily available specialist.

Claims

1. The pharmaceutical composition of fenofibrate immediate release for oral administration, containing granules, consisting of isolated or agglomerated between the particles of water-soluble inert basics associated with micronized particles of fenofibrate with a particle size less than 20 microns in a mixture with a hydrophilic polymer, deposited on the surface of particles of water-soluble inert basis, and these granules can have one or more external phases or layers, or may be agglomerated.

2. The composition according to p. 1, wherein the micronized fenofibrate dispersed in the hydrophilic polymer to form one or more layers on the particles Nisim or equal to 10 microns.

4. Composition according to one of paragraphs.1-3, in which the fenofibrate is present in an amount of 5 to 50 wt.%.

5. The composition according to p. 4, in which the fenofibrate is present in an amount of from 20 to 45 wt.%.

6. Composition according to one of paragraphs.1-5, in which the hydrophilic polymer is selected from polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin and mixtures thereof.

7. The composition according to p. 6, in which the hydrophilic polymer is polyvinylpyrrolidone.

8. Composition under item 6 or 7, in which the hydrophilic polymer is from 20 to 60 wt.%.

9. Composition under item 6 or 7, in which the hydrophilic polymer is present in more than 25 wt.%.

10. The composition according to p. 8 or 9, in which the hydrophilic polymer is from 25 to 45 wt.%.

11. Composition according to one of paragraphs.1-10, in which the weight ratio of fenofibrate/hydrophilic polymer is in the range from 1/10 to 4/1.

12. The composition according to p. 11, in which the weight ratio of fenofibrate/hydrophilic polymer is in the range from 1/2 to 2/1.

13. Composition according to one of paragraphs.1-12, in which the water-soluble inert base is gidrolizovannogo derived sugar or starch, or mixtures thereof.

14. Composition according to one of paragraphs.1-13, in which the water-soluble inernal size of individual particles in the range from 50 to 500 μm.

16. The composition according to p. 15, in which the water-soluble inert base is lactose with the size of the individual particles in the range from 100 to 400 microns.

17. Composition according to one of paragraphs.1-16, in which a water-soluble inert base ranges from 10 to 75 wt.%.

18. The composition according to p. 17, in which the water-soluble inert base ranges from 20 to 50 wt.%.

19. Composition according to one of paragraphs.1-18, additionally containing surfactant.

20. The composition according to p. 19, in which the surfactant is selected from the following substances: sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another polyoxyethylenated ester of sorbitol, dioctylsulfosuccinate sodium (SDOS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylenated castor oil, polyoxyethylene glycerides of fatty acids, poloxamer and mixtures thereof.

21. The composition according to p. 19 or 20, in which the surface-active agent is sodium lauryl sulfate.

22. Composition according to one of paragraphs.19-21, in which the fenofibrate and surfactant semitransitive.

23. Composition according to one of paragraphs.19-22, in which the surfactant comprises up to 10 wt.%.

MW of PP.19-24, in which the weight ratio of surfactant/hydrophilic polymer is in the range from 1/500 to 1/10.

26. The composition according to p. 25, in which the weight ratio of surfactant/hydrophilic polymer is in the range from 1/100 to 5/100.

27. Composition according to one of paragraphs.1-26 in tablet form.

28. Composition according to one of paragraphs.1-26 in the form of granules in a gelatin capsule.

29. The method of preparation of the pharmaceutical composition according to any one of the preceding paragraphs, including the stage (a) preparation of a suspension of fenofibrate in micronized form with a particle size less than 20 microns in a solution of hydrophilic polymer may contain a surfactant; (b) applying the suspension stage (a) water-soluble inert basis; (c) coating, if necessary, the thus obtained granules of one or more phases or layers.

30. The method according to p. 29, in which stage (b) is carried out in the granulator, fluidized bed.

31. The method according to p. 29 or 30, comprising the stage of extrusion products, obtained in stage (b) or (C).

 

Same patents:

The invention relates to a new crystalline hydrated form of the calcium salt of bis[(E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-ene acid] of the formula I:

having a powder x-rays with characteristic peaks at values of angle 2-theta (2)=4,92; 11,50; 6,93; 9,35; 23,12 and 18,76for the manufacture of a medicinal product having the properties of an inhibitor of HMG-COA-reductase

The invention relates to organic chemistry, in particular to new compounds of the formula (I)

in which U represents O or a lone pair of electrons; V represents O, S, - CH2-, - CH=CH - or - C-; W represents CO, COO, CONR1CSO , CSNR1, SO2or SO2NR1; m and n independently of one another each represents a number from 0 to 7, and the sum of m+n is from 0 to 7, provided that m represents 0, if V denotes O or S; AND1represents H, lower alkyl, hydroxy(ness.)alkyl or (ness.)alkenyl; AND2means (ness.)alkyl, cycloalkyl, cycloalkyl(lower)alkyl or (ness.)alkenyl, optionally substituted by a group R2;3and4each denotes a hydrogen atom or (ness.)alkyl; AND5denotes H, (ness.)alkyl, (ness.)alkenyl or aryl(ness.)alkyl; AND6means (ness.)alkyl, cycloalkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl; R2denotes hydroxy, hydroxy(ness.)alkyl, (ness.)alkoxy, (ness.)alkoxycarbonyl, N(R4,R5) or thio(ness.)alkoxy; R1, R3, R4and R5each independent is asepticheski acceptable esters

The invention relates to derivatives of 5,6-dihydrobenzo[a,g]chinoline formula (I), where R1and R2represent hydroxy or alkoxygroup having from 1 to 4 carbon atoms, or R1and R2together represent methylenedioxy; R3represents hydroxy or alkoxygroup having from 1 to 4 carbon atoms; R4represents an alkyl group having from 1 to 8 carbon atoms; X represents an ion of an inorganic acid ion, organic acid or halide, in particular nitrate, sulfate, acetate, tartras, maleate, succinate, citrate, fumarate, aspartate, salicylate, glycerin, ascorbate, fluoride, chloride, iodide or bromide; Z represents an alkyl group having from 5 to 12 carbon atoms, or alkenylphenol group having from 4 to 6 carbon atoms, N-benzotriazolyl, chinoline, furyl with Deputy NO2or a group represented by the formula (II), where Z1, Z2, Z3, Z4, Z5And In such, as defined in the claims

The invention relates to 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione hydrochloride

The invention relates to medicine

The invention relates to the field of medicine and relates to the application of metabolite of sibutramine as a new drug to treat attention deficit or attention deficit hyperactivity disorder

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

A therapeutic agent // 2234917
The invention relates to medicine, to a method of treating obesity in a human in need of such treatment, by appointing such a person a therapeutically effective amount of the compounds of formula I, including enantiomers and pharmaceutically acceptable salts, where R1and R2independently mean hydrogen or methyl, and therapeutically effective amounts of compounds of formula II, in which the compound of formula I and the compound of formula II appointed simultaneously, separately or sequentially, and farbkomposition, including the compounds of formula I and II

The invention relates to medicine, in particular to endocrinology and therapy, and for the treatment of pathological conditions associated with obesity

Inovative polymers // 2222335
The invention relates to medicine, in particular to the treatment of obesity, reducing the absorption of dietary fat and hypertriglyceridemia

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to the agonist Area-I, comprising the peptide or peptide analogue containing from 15 to 29 amino acid residues, which forms amphipatic-helix in the presence of lipids and which is characterized by the following formula: Z1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-Z2,

or its pharmaceutically acceptable salt, values radicals cm

The invention relates to medicine, in particular to therapy and endocrinology, and for the treatment of obesity

The invention relates to new cyclic peptides of General formula 1

< / BR>
where is a bridging group; E=H, halogen, -NO2, -NR8R8'or or13, R8and R8'each independently represents hydrogen or methyl; R13represents hydrogen or methyl; X - substituents on the phenyl ring, selected from hydrogen, halogen, -NR2or8; Z is one or more substituents on the phenyl ring, independently selected from hydrogen, halogen, -OR9or two groups Z may be taken together with the formation of a condensed aryl ring; R9is hydrogen or methyl; D

< / BR>
< / BR>
substituted or unsubstituted, imidazolyl; R2, R3, R4and R5each represents hydrogen, methyl, or any two radicals of R2, R3, R4and R5can be connected to form heterocyclic or heteroaryl ring; R = 1 to 3; and to a pharmaceutical composition having a selectivity for receptors MC-3 and/or MC-4 compared with other receptors melanocarcinoma

The invention relates to the field of medicine and relates to means for the prevention and treatment of colds and flu
Up!