Carvedilol hydrophilic molecular dispersed solution

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to carvedilol-containing pharmaceutical composition that is used for treatment and/or prophylaxis of hypertension, cardiac insufficiency or stenocardia. The composition comprises carvedilol or its pharmaceutically acceptable salt and one or some adjuvants. Carvedilol is distributed in adjuvants as a molecular dispersion. Adjuvants are not surface-active substance and/or non-ionogenic surface-active substance. The concentration of adjuvants exceeds 5 wt.-%. Also, invention describes a method for preparing the composition and pharmaceutically acceptable solid formulation for oral administration. Compositions of the present invention provide the enhancing solubility of carvedilol and level of its absorption in lower regions of intestine.

EFFECT: improved and valuable pharmaceutical properties of composition.

17 cl, 9 ex

 

The present invention relates to a concentrated solid or semi-solid hydrophilic molecular dispersed solutions carvedilola and/or its pharmaceutically acceptable salt, pharmaceutical forms of conduct, containing such solutions, and to their use for the treatment or prevention of diseases.

Carvedilol is a β-blocker indiscriminate action type, having a vasodilatory effect which is caused by the antagonism against α1-adrenergic receptors. In addition, carvedilol also has antioxidant properties. Carvedilol (1-(4-carbonyloxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanol) is the subject of a European patent application No. 0004920 and can be obtained as described in this application method.

Used in pharmaceutical practice solid molecular dispersed solutions are a subset of solid dispersions. In the pharmaceutical literature, the term “solid or semi-solid dispersion” refers to the fine distribution of one or more solid substances, for example carvedilola and/or its pharmaceutically acceptable salt, in an inert respectively solid or semi-solid media. The active ingredient may be in the form of a molecular dispersion, i.e. it can be the distribution is in the form of individual molecules, as is true in solid solution, or may be dispersed in the form of small crystals in a glassy amorphous phase. This eutectic mixture, i.e. the crystal structure, consisting of active substances and adjuvants, which are characterized by very fine-grained distribution and certain mixed ratios also fall under the amount specified General concepts. Among them can meet the transitional forms. The sizes of the dispersed substance can vary within wide limits: from atoms or molecules to particles with a size of several millimeters. Therefore, a suitable characteristic for the classification of dispersed systems is the average particle diameter. In General, there are molecular dispersed (<1,0 μm, solid or semi-solid solutions), colloidal dispersed (1-100 µm) and coarse dispersed (<0.5 mm) system. It should be borne in mind that the size ranges in this classification is set quite arbitrarily, since there is no clear definition of boundaries between the individual systems. In a strict physical sense, to the true solid solutions are only single-phase systems formed in the result, the total crystallization of the components with the formation of mixed crystals. Combinations of forms in different for the x state, often lead to the formation of solid dispersions. The most pronounced dominant characteristics can be determined using x-ray diffraction or differential thermal analysis.

The term “pharmaceutically acceptable salt” carvedilola includes alkali metal salts such as salts of sodium or potassium, alkaline earth metals such as calcium salt or magnesium, and salts with organic or inorganic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid or toluensulfonate acid, which are non-toxic to living organisms.

At pH values that are acceptable for pharmaceutical purposes the range 1-8, solubility carvedilola in aqueous media is about 1-100 mg per 100 ml (depending on pH). This leads to problems primarily in the manufacture of highly concentrated compositions for parenteral administration, such as solutions for injection, or other compositions for the preparation of small forms of introduction, designed to be inserted in the eye or oral administration.

When oral introduction the Institute compositions carvedilola with quick release, for example, compositions have been marketed, the levels of absorption (absorption) reach 80%, with a significant portion of the absorbed carvedilola very rapidly metabolized.

In studies of the absorption carvedilola in the gastrointestinal tract was found that the level of absorption carvedilola is reduced during passage through the gastro-intestinal tract, for example in the ileum and colon, the absorption level is only a fraction of that level of absorption, which is typical for the stomach. This causes great difficulties in the development of forms such as “retard”, which are intended for release within a few hours. A lower level of absorption, apparently, entirely or at least partially due to a decrease in solubility carvedilola with increasing pH values. In very acidic conditions (pH approximately 1-2) solubility can also be very small.

To increase absorption primarily in the lower regions of the intestine, research aimed at finding adjuvants and, accordingly, the compositions that can be used to improve the solubility and/or dissolution rate carvedilola.

In accordance with the foregoing the basis of the invention was used to increase the absorption carvedilola, pre is de only oral introduction and first of all in the lower regions of the intestine, using agents that can be applied in the pharmaceutical field.

If we proceed from the fact that, on the one hand, the solubility depends on the pH value, and, on the other hand, the rate of dissolution of crystals carvedilola is a limiting factor in the absorption carvedilola (or at least one of these factors), should be expected to enhance absorption in the introduction carvedilola in the dissolved form. However, since, as mentioned above, the solubility carvedilola in aqueous media in a pharmaceutically acceptable terms is very small, for practical reasons, it is necessary to exclude the application of the final medicinal product in the form of an aqueous solution.

Attempts were made, aimed specifically at the development of concentrated solid oral compositions in which the active substance is in the form of a molecular dispersion and thus can be absorbed faster.

The literature describes some examples of such “solid” molecular dispersed solutions of slightly soluble drugs, the so-called “solid solutions”. So, for example, by co-deposition of corticosteroids and polyvinylpyrrolidone (PVP) of organic solvents can be obtained transparent supersaturated solution.

As a result the of the waves was established, that carvedilol can be dissolved in solutions of polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) in organic solvents, such as methylene chloride. Then after removal of the solvent receive solid solutions carvedilola in PVP or in GPMC. Upon receipt of the compositions can be used polyvinylpyrrolidone, which is not crosslinked, having a molecular weight of from 8,000 to 630000, preferably 25000.

However, for industrial production preferred are pharmaceutically acceptable compositions which can be obtained without the use of organic solvents.

Alternatively, the above products obtained by co-deposition can be considered as solid solutions in the form of so-called “hardened melts”. However, the results of experiments using several adjuvants, which could be considered as the basis for such melts, suggests that with the introduction carvedilola in such adjuvants or cannot be obtained amorphous state, i.e. after solidification of the solution leads to the formation of molecular variance, so that fully or partially achieved amorphous state can be maintained only for a short period of time or not is the residual of quick hardening solution.

With the invention it has been unexpectedly found that carvedilol in certain conditions can be dissolved in some specially selected adjuvant, the distribution of the active substance in the form of individual molecules is maintained even at room temperature. Thus get a solid or wax-like composition, the so-called solid solutions, in which carvedilol is present in the form of a molecular dispersion, i.e. in amorphous form.

As such adjuvants should be noted first of all adjuvants, non-surfactants, such as polyethylene glycol (PEG) or sugar substitutes, as well as nonionic surfactants, such as the stearates of polyoxyethylene, for example, Myrj® 52 or copolymers of polyoxyethylene and polyoxypropylene, for example, Pluronic® F 68.

The content of hydrophilic polyoxyethylene groups in the above-mentioned copolymers of polyoxyethylene and polyoxypropylene is preferably 70-90%. In the most preferred embodiment, the ratio of hydrophilic polyoxyethylene groups and hydrophobic polyoxypropylene groups is approximately 80:20, and the average molecular weight is preferably approximately 8750.

Above the stearates of polyoxyethylene preferably have the greates is well hydrophilic-lipophilic balance (products HLB) 10-20, preferably 14-20, most preferably 16 to 18.

It was found that among the sweeteners most preferred is isomalt (hydrogenated isomaltose), for example, Palatinit®. Palatinit® represents a hydrogenated isomaltose containing approximately the same number of l-O-α-D-glyukopiranozil-D-sorbitol and dihydrate 1-O-α-D-glyukopiranozil-D-mannitol.

Further, it has been found that for use according to the present invention should be applied glycols having a molecular weight of 1000-20000, preferably 4000-10000, most preferably 6000-8000.

According to a preferred variant embodiment of the invention carvedilol dissolved in nonionic surface-active substance, preferably Pluronic® F 68, or Freund, which is not surface-active agent, preferably polyethylene glycol 6000.

So, carvedilol can be dissolved in polyethylene glycol 6000, which melts at a temperature of about 70°C. Thus obtain a highly concentrated solutions carvedilola (up to 500 mg/ml), in which carvedilol remains in solution in the form of a molecular dispersion. In addition, you can add other excipients, for example, cellulose derivatives such as hydroxypropylmethylcellulose or guide is oxypropylation, in order to be able to control the rate of release of the active substance. In addition, the composition of the invention may contain as substances that prevent adhesion, highly dispersed silicon dioxide.

Using the above adjuvants can be obtained concentrated pharmaceutically acceptable solid solutions, in which carvedilol is present in the form of a molecular dispersion.

Thus, an object of the present invention are pharmaceutically acceptable composition comprising carvedilol or its pharmaceutically acceptable salt, which is(Yuexiu) in the form of a molecular dispersion in a concentration of more than 5 wt.%.

The concept of “being in the form of a molecular dispersion” refers to the distribution of the active substance in the form of individual molecules within acceptable carrier.

In a preferred embodiment, the content carvedilola in the compositions according to the invention is from 5 to 60 wt.%, preferably from 5 to 50 wt.%, most preferably from 19 to 40 wt.% in terms of the total weight of the composition (active substance and adjuvant).

Composition based on carvedilola containing such solid solutions according to the invention are characterized by a higher absorption of the active substance and therefore more biologically available to the TEW compared with compositions, which contain crystalline carvedilol, because the active substance in dissolved form, is absorbed faster than the substance in the crystalline state.

The fact that carvedilol allocated on the basis of individual molecules, i.e. in the so-called amorphous state (unlike conventional crystalline state), can be detected and accordingly to control, for example, by x-ray and/or differential scanning calorimetry (DSC).

The most preferred solutions, which are solid at room temperature. In a preferred embodiment, adjuvants according to the invention have a melting point below 120°With, preferably a melting point of 30 to 80°C.

The above adjuvants can be applied individually or in combinations containing two or more adjuvants. Most preferred is a combination containing adjuvant, non-surface-active substance, preferably propylene glycol, and nonionic surfactant, preferably a copolymer of polyoxyethylene and polyoxypropylene, for example, Pluronic® F 68. When using such mixtures, adjuvants can, on the one hand, to obtain a stable solid solutions carvedi the Ola, and, on the other hand, in this case, the presence of surface-active substances can accelerate the release of active substance from solid solutions.

It was found that the most preferred are solid solutions carvedilola that contain adjuvant polyethylene glycol, preferably polyethylene glycol 6000 and 0.1 to 50%, preferably 0.1 to 10% of the copolymers of polyoxyethylene and polyoxypropylene, for example, Pluronic® F 68.

In one of the embodiments of the present invention, the ratio of the above adjuvant that is not surface-active substance, for example, polyethylene glycol 6000, and adjuvant representing a surfactant, for example, Pluronic® F 68, is from 1000:1 to 1:1, preferably from 100:1 to 10:1.

Solid solutions carvedilola according to the invention and medicines obtained on their basis, may contain additional excipients, such as binders, plasticizers, diluents, carriers, substances that improve slip, antistatic agents, antioxidants, adsorbents, separation agents, dispersing agents, substances forming a coating for pills, protivovspenivayushchie agents, film-forming agents, emulsifiers, diluents and fillers.

The above additives can submit, the better an organic or inorganic substance, for example, water, sugar, salts, acids, bases, alcohols, organic polymers, etc. Preferred additives are lactose, sucrose, tablettose, natrocarbonatite, magnesium stearate, various types of cellulose and substituted cellulose such as, for example, methylhydroxypropylcellulose, polymeric compounds based on cellulose, highly dispersed silicon dioxide, corn starch, talc, various polymer compounds based on polyvinylpyrrolidone, and polyvinyl alcohols and their derivatives. A necessary condition is that all used in the production process additives were non-toxic and preferably do not modify the bioavailability of the active substance.

In a preferred embodiment, the composition according to the invention contain carvedilol, polyethylene glycol, a copolymer of polyoxyethylene and polyoxypropylene and highly dispersed silicon dioxide. In the most preferred embodiment, the composition of the invention contains 10-20 wt.% carvedilola, 65-85 wt.% polyethylene glycol, 1-10 mass % of a copolymer of polyoxyethylene and polyoxypropylene and 0.1-10 wt.% highly dispersed silicon dioxide, where the percentages are given in terms of the total mass of these four substances, regardless of whether the composition of the other component is.

If the melt carvedilola in the above adjuvant allow to harden at room temperature, then any component that is present in the melt in crystalline form, can lead to the acceleration of crystallization carvedilola from the amorphous state.

With the invention it has been unexpectedly found that in the case of the solidification of the melt adjuvant with the dissolved active substance to carry out as quickly as possible, preferably by setting spray, you can get the most stable solid solutions. Overall, the rapid freezing of the composition containing carvedilol, distributed in the form of a molecular dispersion, apparently, to the greatest extent facilitates maintaining it in an amorphous state. This applies, for example, also to the formation of solid solutions from solutions, which in addition carvedilola also contain as the basis of “solid solutions” cellulose derivatives, primarily hydroxypropylmethylcellulose or hydroxypropylcellulose, if the solid solution is obtained by spray drying. These include spray drying carvedilola and polyvinylpyrrolidone (PVP) of solvent.

In the case of spray drying the product for drying, spray in the form of a solution or suspension in the upper part of the wide cylindrical to which the container through the spray device, receiving consisting of droplets of fog. Formed consisting of droplets of the mist is mixed with hot air (preferably having a temperature of > 100° (C) or inert gas, which is fed to the dryer in an area where they perform sputtering. Arising solvent vapours are absorbed by the drying air and removed, and the resulting powder is removed from the container by means of a separator.

In the case of hardening spray product for hardening, is sprayed in the form of melt in the upper part of the wide cylindrical container means provided with a heating device of the atomizing device, receiving consisting of droplets of fog. Formed consisting of droplets of the mist is mixed with the cooled air (preferably having a temperature < 25° (C)served in the dryer in an area where they perform sputtering. The heat that is released during the curing, is absorbed by the air and is removed, and the resultant solidified powder is removed from the container by means of a separator. As the spray devices can be applied provided with a heating device rotating nozzles, pressure, pneumatic injector (double/triple nozzles or rotary atomizers.

Solid solutions carvedilola can CSS is used to apply in various forms in the pharmaceutical field. For example, carvedilol, included in the media in the form of a molecular dispersion can be subjected to further processing, receiving forms introduction with the rapid release, such as tablets, filmtablette, capsules, granules, pellets, etc. with a high level of absorption. This allows, in certain circumstances, to reduce the magnitude of the dose compared to the dose required in the case of conventional lane oral drugs with quick release, which is obtained using the crystal carvedilola.

Solid solutions carvedilola most preferably can be used for the preparation of drugs, having modified release characteristics. In the context of the present description, the term modified feature release means, for example, that 95% of the active substance is released after a period of time exceeding 2 hours, preferably through 2-24 h, or that the release depends on the pH, resulting in the delay of the release. For this purpose, solid solutions carvedilola can be processed individually or in combination with any of the usual pharmaceutical intended for oral administration of pharmaceutical drugs with modifica ofanim release.

Examples of drugs with modified release characteristics are filmtablette, which are resistant to gastric juices, or form like “retard”, such as hydrocolloid matrix, or drugs of the same type, of which the active substance is released as a result of erosion or diffusion. The composition of the invention can be subjected to processing, receiving composition with modified release of active ingredient, by adding additional adjuvants or film coating or by including them in the usual pharmaceutical system profile release. Thus, the composition of the invention can include, for example, hydrocolloid matrix system, especially in systems based on cellulose derivatives such as hydroxypropylcellulose, hypromellose, methyl cellulose or derivative of a polyacrylate polymer, such as Eudragit RL. The above matrix can contain in addition or as an alternative substance, forming hydrocolloid matrix, the swelling degree of which depends on pH, such as sodium alginate or sodium carboxymethyl cellulose. By adding this adjuvant can be achieved targeted in the osvobojdenie, adapted to the specific conditions. Thus, the use of solid solutions according to the invention allows to significantly increase the level of absorption compared with the level of absorption of the crystalline active ingredient.

So, caulk, spray solid solutions carvedilola according to the invention, preferably solutions containing Pluronic® F 68, polyethylene glycol 6000, highly dispersed silicon dioxide and carvedilol (preferably obtained according to the method described in example 4), can be compressed into tablets, for example, by direct extrusion, granulation and compaction in combination with substances forming the hydrophilic matrix, which allow for controlled release, such as hydroxypropylmethylcellulose 2208, having an average viscosity of about 100 MPa· (Methocel® K100 LV-Premium), and hydroxypropylmethylcellulose 2208, having an average viscosity of about 4000 MPa· (Methocel® K4M Premium), and substances which improve the sliding or agents, caking, such as magnesium stearate and microcrystalline cellulose (Avicel® PH102). In addition, tablets may be coated using conventional varnishes, such as Opadryl® II White Y-30-18037 and Opadryl® II Clear YS-1-7006.

Pharmaceutical to the position according to the invention can be used to obtain the usual pharmaceutical forms of administration, preferably oral forms of administration, for the treatment and/or prevention of heart disease and diseases associated with the circulatory disorders such as hypertension, heart failure and angina.

Dose, which is administered pharmaceutical composition according to the invention depend on the age and individual needs of the patient and route of administration. In General, it can be applied dose carvedilola comprising about 1-50 mg per day. For this purpose, the composition containing as active substance 1-50 mg carvedilola.

The present invention relates also to a method for obtaining concentrated solid or semi-solid solutions, where carvedilol is in the form of a molecular dispersion, which contain a mixture of carvedilola with hydrophilic adjuvants, such as polyethylene glycol, and/or surfactants such as Pluronic® F 68. In a preferred embodiment, the composition thus obtained, and then subjected to curing by spraying.

In addition, an object of the present invention is a method of treatment of diseases, such as hypertension, heart failure, or angina, which provides for the introduction of medicines containing the above in pharmaceutical preparations is practical composition.

The following examples serve to describe the preferred embodiments of the present invention and are not intended to limit its scope.

Example 1

Solid solution carvedilola:

Carvedilol 50.0 g

Polyethylene glycol 6000 250,0 g

Total weight: 300,0 g

Polyethylene glycol 6000 melted at 70°C. Carvedilol mixed with the formed melt and dissolve to a homogeneous state. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly.

Example 2

Solid solution carvedilola:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene of 250.0 g

Total weight: 300,0 g

The copolymer of polyoxyethylene and polyoxypropylene 6000 melted at 70°C. Carvedilol mixed with the obtained melt and dissolve to a homogeneous state. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly.

Example 3

Solid solution carvedilola:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene 15.0 g

Polyethylene glycol 6000 235,0 g

Total weight: 300,0 g

Polyethylene glycol 6000 melted at 70°C. then obtained by melt mixing a copolymer of polyoxyethylene and polyoxypropylene, melted in a similar manner to obtain a homogeneous solution. Carvedilol is mixed with the obtained melt and homogenize. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly.

If necessary characteristics of a technical process, such as the fluidity of solid solutions can be improved by adding additional adjuvants (see example 4).

Example 4

Solid solution carvedilola:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene 15.0 g

Polyethylene glycol 6000 232,0 g

Silicon dioxide, highly dispersed 3.0 g

Total weight: 300,0 g

Polyethylene glycol 6000 melted at 70°C. then obtained by melt mixing a copolymer of polyoxyethylene and polyoxypropylene, melted in the same way and homogenize the melt. Carvedilol is mixed with the formed melt and dissolve to a homogeneous state. Then the melt is subjected to curing by spraying, p is the beam solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly. Solid solution carvedilola handle high disperse silica and stirred until a homogeneous state.

The use of high concentrations of adjuvant representing a surface-active substance, also allows to obtain stable amorphous products.

Example 5

Solid solution carvedilola:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene 125.0 g

Polyethylene glycol 6000 125.0 g

Total weight: 300,0 g

Polyethylene glycol 6000 melted at 70°C. then obtained by melt mixing a copolymer of polyoxyethylene and polyoxypropylene, melted in the same way and homogenize the melt. Carvedilol is mixed with the formed melt and dissolve to a homogeneous state. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly.

Example 6

Solid solution carvedilola:

Carvedilol 50.0 g

Isomalt to 450.0 g

Total weight: 500.0 g

Isomalt is melted at a temperature above its melting point. The village is E. this with the formed melt mixed carvedilol and dissolve to a homogeneous state. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly.

Example 7

Tablets with quick release obtained with the use of solid solution carvedilola:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene 15.0 g

Polyethylene glycol 6000 232,0 g

Silicon dioxide, highly dispersed 3.0 g

Tablettose 146,0 g

Natrocarbonatite 15.0 g

Silicon dioxide, highly dispersed 4.0 g

Magnesium stearate 10.0 g

Total weight: 475,0 g

Polyethylene glycol 6000 melted at 70°C. then obtained by melt mixing a copolymer of polyoxyethylene and polyoxypropylene, melted in the same way and homogenize the melt. Carvedilol is mixed with the obtained melt to obtain a homogeneous solution. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly. After this solid solution carvedilola handle high disperse silica and stirred until a homogeneous state. The resulting mixture of srabatyvayut tablettose and mix. To the obtained mixture is added to the external phase (sizing agent, which improves the fluidity of the separating agent and filler), consisting of natrocarbonatite, highly dispersed silicon dioxide and magnesium stearate, and mixed to a homogeneous state. Then the resulting mixture standard method pressed, obtaining the appropriate pharmaceutical form, or it is filled capsules containing the required amount of the active substance.

Example 8

Pill retard containing carvedilol:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene 15.0 g

Polyethylene glycol 6000 232,0 g

Silicon dioxide, highly dispersed 3.0 g

Tablettose 146,0 g

The hypromellose 2208 240,0 g

Silicon dioxide, highly dispersed 4.0 g

Magnesium stearate 10.0 g

Total weight: 700,0 g

Polyethylene glycol 6000 melted at 70°C. then obtained by melt mixing a copolymer of polyoxyethylene and polyoxypropylene, melted in the same way and homogenize the melt. Carvedilol is mixed with the obtained melt and dissolve to a homogeneous state. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that otwarte what W happens quickly. After this solid solution carvedilola handle high disperse silica and stirred until a homogeneous state. The resulting mixture is treated with tablettose and mix. To the obtained mixture is added to the external phase (sizing agent, which improves the fluidity of the separating agent and filler), consisting of hydroxypropylmethylcellulose 2208, highly dispersed silicon dioxide and magnesium stearate, and mixed to a homogeneous state. Then the resulting mixture standard method pressed, obtaining the appropriate pharmaceutical form, or it is filled capsules containing the required amount of the active substance.

Example 9

Pill retard containing carvedilol:

Carvedilol 50.0 g

The copolymer of polyoxyethylene and polyoxypropylene 15.0 g

Polyethylene glycol 6000 232,0 g

Silicon dioxide, highly dispersed 3.0 g

Tablettose 96,0 g

The hypromellose 2208 240,0 g

Sodium alginate 50.0 g

Silicon dioxide, highly dispersed 4.0 g

Magnesium stearate 10.0 g

Total weight: 700,0 g

Polyethylene glycol 6000 melted at 70°C. then obtained by melt mixing a copolymer of polyoxyethylene and polyoxypropylene, melted in the same way and homogenize the melt. Carvedilol is mixed with the obtained melt and dissolve to nd ogandaga state. Then the melt is subjected to thickening spray, getting solid solution carvedilola. Alternatively, the melt can be subjected to curing by other means, provided that curing occurs rapidly. After this solid solution carvedilola handle high disperse silica and stirred until a homogeneous state. The resulting mixture is treated with tablettose and mix. To the obtained mixture is added to the external phase (sizing agent, which improves the fluidity of the separating agent and a filler consisting of sodium alginate, highly dispersed silicon dioxide and magnesium stearate, and mixed to a homogeneous state. Then the resulting mixture is pressed to give the corresponding pharmaceutical form, or make it a standard method in capsules in an amount which is determined on the basis of the required amount of the active ingredient.

1. Pharmaceutically acceptable composition for the treatment and/or prevention of hypertension, heart failure, or angina, containing carvedilol or its pharmaceutically acceptable salt, distributed in the form of a molecular dispersion in one or more adjuvant that are not surface-active substance and/or are non-ionic surface-active agent, concentration, etc which exceeds 5 wt.%.

2. The composition according to claim 1, which are solid or semi-solid solution.

3. The composition according to claim 1, where the adjuvant, which is not surface-active substance used glycol.

4. The composition according to claim 3, where the polyethylene glycol has a molecular weight of 1000-20000, preferably 4000-10000.

5. Composition according to any one of claims 1 to 4, where adjuvant, which is not surface-active substance, use a sugar substitute.

6. The composition according to claim 5, where as a sugar substitute used isomalt.

7. The composition according to claim 1, where the solution contains as the nonionic surfactant is a copolymer of polyoxyethylene and polyoxypropylene.

8. The composition according to claim 7, where the solution contains as non-ionic surfactants of the polyoxyethylene stearate.

9. Composition according to any one of PP 8, wherein the ratio of adjuvants, which are not surfactants, and nonionic surfactants is from 1000:1 to 1:1, preferably from 100:1 to 10:1.

10. Composition according to any one of claims 1 to 9, where the concentration carvedilola is from 5 to 60 wt.%.

11. Composition according to any one of claims 1 to 10, where the concentration carvedilola is from 10 to 40 wt.%.

12. Composition according to any one of claims 1 to 11, containing highly dispersed silicon dioxide.

13. To the position according to any one of claims 1 to 12, containing 10-20 wt.% carvedilola, 65-85 wt.% polyethylene glycol, 1-10 wt.% copolymer of polyoxyethylene and polyoxypropylene and 0.1-10 wt.% highly dispersed silicon dioxide.

14. Pharmaceutically acceptable form of introduction, representing a solid form for oral administration containing composition according to any one of claims 1 to 13.

15. Pharmaceutically acceptable form is entered at 14, characterized by the release of the active substance, where 95% of the active substance is released within 2-24 hours

16. A method of obtaining a composition according to any one of claims 1 to 13, providing a mixture carvedilola with adjuvant that is not surface-active substance and/or nonionic surface-active agent.

17. The method according to clause 16, in which the composite mixture utverjdayut spray.



 

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22 cl, 2 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; R2 and R3 mean independently of one another F, Cl, Br, J, CO-R(6) or O-R(7); R(6) means hydrogen atom; R(7) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R4 means S(O)p-R(16); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also. Also, invention relates to pharmaceutical composition used for inhibition of cellular Na+-dependent bicarbonate/chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; or R2 and R3 mean independently of one another CO-R(6), O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17) wherein R(17) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(6) means hydrogen atom; R4 and R5 mean independently of one another hydrogen atom, F, Cl, Br, J, S(O)p-R(16) or O-(alkylene with 2, 3 or 4 carbon atoms)-OR(33); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(33) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also under condition that at least one of residues R2 or R3 means O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17). Also, invention relates to pharmaceutical composition used for inhibition of Na+-dependent bicarbonate-chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation with the constant rate for releasing a medicinal substance, core of medicinal formulation and to a method for providing relieved release of medicinal substance. Medicinal formulation comprises medicinal substance-containing layer and semi-permeable wall and expanding layer. A layer promoting to moving forward is placed between semi-permeable wall and medicinal substance-containing layer and the content of medicinal substance is at least 20% of the total layer mass containing a medicinal substance. Invention provides releasing practically all amount of medicinal substance from medicinal formulation to medium for it applying.

EFFECT: improved and valuable medicinal and pharmaceutical properties of medicinal formulation.

12 cl, 13 dwg, 8 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises internal lipophilic matrix and external hydrophilic matrix in the mass ratio of lipophilic and hydrophilic matrices from 100:0.5 to 100:20. The internal lipophilic matrix consists of substances with melting point below 90oC and comprises at least partially an active component as globules. As an active component the composition comprises mesalazine - 5-aminosalicylic acid in the concentration up to 95 wt.-%. Lipophilic matrix is dispersed in external hydrophilic matrix. The composition can comprise optionally other excipients. Also, invention describes a method for preparing the composition. Invention provides sustained-release of mesalazine from first phases after administration and more homogenous pattern of release as compared with conventional systems.

EFFECT: improved properties of composition.

11 cl, 5 ex

FIELD: medicine, in particular composition for quick-disposable in buccal cavern tablets.

SUBSTANCE: claimed composition contains granulated product of fine dispersed long releasing particles, comprising drug and fillers selected from group including sugars and sugar alcohols together with binder, wherein content of non-granulated fine dispersed long releasing particles is 0-15 %. Method for production of such tablets is also disclosed.

EFFECT: pharmaceutical composition with accelerated degradation.

24 cl, 9 ex, 3 dwg

The invention relates to the field of pharmaceutical industry, namely pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions

The invention relates to a solid molded dosage form for controlled release of nimesulide for oral administration

The invention relates to medicine, in particular to pharmaceutical preparations containing peptides

The invention relates to solid pharmaceutical preparative forms with controlled release based on sulfoalkyl ether cyclodextrin (SAE-CD)

The invention relates to the field of pharmaceutical chemistry and relates to a composition extended release, containing a physiologically active substance or its salt, oximately acid or its salt and a biodegradable polymer or its salt with improved bioavailability

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a composition eliciting an antibacterial effect. Composition comprises hydrophilic conglomerate of immunoglobulins consortium adsorbed with polyethylene glycol 4000-6000 and a special additive taken among the following substances: glycine, glucose, maltose, sodium chloride taken in the definite ratio of components. Invention provides sufficient desorption of biologically active substances in resuspending the composition eliciting an antibacterial effect and comprising consortium of immunoglobulins.

EFFECT: valuable medicinal properties of composition.

5 ex

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