Pharmaceutical compositions of rhein or diacerein

FIELD: medicine.

SUBSTANCE: claimed invention relates to granulated from liquid pharmaceutical compositions, which contain rhein or diacerein, or their salts, and pharmaceutically acceptable carrier. Compositions contain from 20 to 45 mg of rhein or diacerein. Invention also relates to methods of producing claimed compositions. Compositions by invention are bioequivalent to preparative form of diacerein in dosage 50 mg, sold under the trade name Art 50®. Compositions do not demonstrate variability in after meal condition and on an empty stomach.

EFFECT: considerable reduction of side effects, such as pulpy stool, in comparison with Art 50®.

13 cl, 37 tbl, 17 ex

 

The scope of the invention

The present invention relates to pharmaceutical compositions Reina or diacerein, or their salts or esters, or prodrugs, which are bio-equivalent preparative form of diacerein at a dose of 50 mg sold under the trade name Art 50®(Art 50®). The compositions do not show the variability in the States after a meal and on an empty stomach. Application of the compositions also leads to a significant reduction of side effects, such as soft stools, compared with Art 50®. The present invention also relates to methods of manufacture of such compositions.

The level of invention

Chemical structure Reina is 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-astratenkova acid, which is represented by formula I, and diacerein is a 4,5-bis(atomic charges)9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-antratsenovoe acid and has the structure of formula II. Diacerein is widely used in the treatment of osteoarthritis and has a unique mechanism of action that distinguishes it from non-steroidal anti-inflammatory drugs (NSAIDs) and other conventional forms of drug therapy. Currently diacerein is available in capsules dosage 50 mg and sold in France by the company Negma under the trade name Art 50®.

The formula I

Formula II

Diacerein is practically insoluble in solvents such as water, alcohols, acetone, dichloromethane and chloroform, which are typically used in the manufacture of pharmaceuticals. Diacerein can be administered orally by, but it is not capable of complete absorption in the digestive tract, and this partial absorption can lead to undesirable side effects such as soft stool.

To solve these problems in the literature proposed various derivative compounds, pharmaceutical compositions and some herbal form. For example, in European patent EP 243968 disclosed potassium salt of diacerein, which dissolves in water and can be used in the manufacture of compositions for parenteral administration.

European patent number EP 904060 discloses pharmaceutical compositions Reina or diacerein, in which the failure to comply or diacerein micronizer together with lauryl sulfate.

European patent number EP 263083, 264989 and 446753 disclose controlled release formulation or composition with delayed release, for example, in the form of a set of beads coated with medication and overlying membrane, or in the form of granules drugs covered by the polymer or filled polymer particles with Nauheim in water of polim the rum, custom made communications with the medicine.

U.S. patent No. 5225192 and 5569469 describe various poorly soluble drugs in a matrix of polymeric particles from nabukelevu in water of the polymer, which made communication with the medication.

U.S. patent No. 5952383 and European patent number EP 862423B1 describe pharmaceutical compositions of diacerein, Reina and their salts with liquid retention systems, such as oil, suspendresume substances, homogenizing agents and other fillers.

It is known that the oral administration in the fasting state preparation of diacerein dose of 50 mg, currently marketed under the trade name Art 50®due to rapid gastric emptying, the basic amount of diacerein remains unabsorbed, and before entering the large intestine unabsorbed diacerein is converted to a failure to comply. When injected into the colon failure to comply up to failure to comply-9-anthrone, which has a pronounced effect of the occurrence of soft stool. Such a soft stool is observed in approximately 50% of patients after the first couple of doses of the Art 50®. In fact, about 30-40% of cases the effect of soft stool is due to the initial pharmacokinetic characteristics of diacerein, namely diacerein undergoes enterohepatic circulation, while failure to comply connects the I in the liver with the formation of the failure to comply-glucuronide, which when reaching the colon turns into failure to comply-9 Andron, and the result of its action occurs upholstered chair.

On the other hand, when the introduction of the Art 50®happening in state after eating, gastric emptying in the presence of food delayed. A longer residence time of diacerein in the upper part of the gastrointestinal tract together with gastric juice increases absorption. When this suction is increased to 25%, which leads to entry into the colon relatively smaller amount of unabsorbed diacerein, and, consequently, to reduce the effect of soft stool. However, this decrease soft stool is insignificant. It was also noted that with the introduction of the formulation of diacerein described in the patent EP 904060, which contained diacerein, micronized together with lauryl sulfate, decreased soft stool only about 18%, which is not significant. This decrease diarrhea is not due to the lower dose, and is associated with increased suction diacerein, which in turn decreases the amount of unabsorbed diacerein coming up in the colon. Recipe of diacerein described in the patent EP 904060, also showed pronounced variability in state after meals and on an empty stomach. Thus, formulations etc is destfolder level techniques differ in the States after a meal and on an empty stomach. Additionally, the formulations of the prior art is also undesirable effect upholstered stool.

The cause of soft stool preparations of the prior art (Art 50®and Art 40) was first administered once a day for about two months, so that came addictive gastrointestinal tract of the patient has the side effect of diacerein. After that, the scheme is the introduction was changed to two times a day for drug Art 50®and Art 40. While this adaptation of the injection mode improves to some extent the adherence to therapeutic recommendations for the patient, but not observed any decrease side effects. There is still a need to develop new formulations or compositions that can achieve higher speed and extent of absorption of diacerein that will lead to improved bioavailability and at the same time show a significant decrease in side effects, such as soft stool.

Despite the efforts of the above-described prior art, the authors of the present invention is not aware of any successful attempts to improve absorption of diacerein and a significant reduction in the soft chair. As described below, the authors of the present invention unexpectedly found that compositions according to izopet is to increase the rate and extent of absorption from the gastrointestinal tract and significantly reduce (by at least 25 %) soft stool. The authors present invention also unexpectedly found that compositions can be administered with food or on an empty stomach, which does not affect the rate and extent of absorption. The authors present invention additionally noted no need to ekranizirovat diacerein in conjunction with any surfactant, to obtain a formula which bioequivalency commercially available solid dosage form of diacerein for oral administration in a dose of 50 mg (Art 50®).

Thus, the composition of the invention usually solve all the problems presented in the prior art. Oral compositions according to the invention diacerein completely absorbed in the upper part of the intestine, and is left unabsorbed of diacerein, which can come in the colon, resulting in a significantly reduced effect stools soft, about 60-70%. In addition, the composition according to the invention are bio-equivalent dose of 50 mg of the formulation of diacerein, currently marketed under the trade name Art 50®and do not show variability with the introduction in the state after meals and on an empty stomach.

The invention

In one General aspect, the present invention relates to granules of the melt pharmaceutical compositions containing the failure to comply or diazene is h, or their salts, or esters, or prodrugs.

In another General aspect, the present invention relates to pharmaceutical compositions containing from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs, in which the failure to comply or diacerein granularit from the melt with pharmaceutically acceptable carriers, and the composition does not show significant differences in the rate and/or extent of absorption Reina or diacerein compared to formulation, 50 mg diacerein sold under the trade name Art 50®.

The composition can be taken with or without food.

Embodiments of the pharmaceutical compositions can include one or more of the following characteristics. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, pharmaceutically acceptable excipients may include one or more fillers, binders, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants, substances that promote the slip, and the like.

The pharmaceutical composition of the present invention may be in the form of tablets, capsules, powder, plates, caplet, granules, beads, encapsulated granules, minitablets, minitablets in the capsule, maintain the new pellets, Sasha and other dosage forms suitable for oral administration. In another General aspect, the present invention relates to a method of manufacturing a pharmaceutical composition Reina or diacerein, or their salts or esters or prodrugs, the method includes mixing Reina or diacerein, or their salts or esters, or prodrugs, with one or more pharmaceutically acceptable carriers, and granulation of the mixture by melting, mixing, freezing, optionally with one or more pharmaceutically acceptable excipients.

In another General aspect, the present invention relates to the immediate release of wet granulated pharmaceutical composition comprising from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs.

In another General aspect, the invention considers the immediate release of wet granulated pharmaceutical composition comprising from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs, and the composition does not show significant differences in the rate and extent of absorption Reina or diacerein, or their salts or esters or prodrugs, in comparison with the formulation of diacerein 50 mg sold in the present remaped trade name Art 50 ®.

The composition can be taken with or without food.

Embodiments of the pharmaceutical compositions can include one or more of the following characteristics. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, pharmaceutically acceptable excipients may include one or more fillers, binders, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants, substances that promote the slip, and the like.

The pharmaceutical composition of the present invention may be in the form of tablets, capsules, powder, plates, caplet, granules, pellets, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets, sachets and other dosage forms suitable for oral administration.

In another General aspect, the invention regards a method of manufacturing a pharmaceutical composition with immediate-release formulation containing from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs, the method includes

a) mixing Reina or diacerein, or their salts or esters, or prodrugs with other pharmaceutically acceptable excipients for education Prem the KSA;

b) granulating the premix with one or more suitable solvents; and

c) transforming granules into a suitable dosage form.

In another General aspect, the invention relates to pharmaceutical compositions containing from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs, in which the average particle size is from about 0.1 microns to 30 microns.

In another General aspect, the present invention relates to pharmaceutical compositions containing from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs, in which the average particle size is from about 0.1 micron to about 30 microns, and the composition does not have any significant difference in the rate and extent of absorption Reina or diacerein, or their salts or esters, or prodrugs compared on the specified parameters with the receipt of diacerein 50 mg sold under the trade name Art 50®. The composition can be taken with or without food.

Embodiments of the pharmaceutical compositions can include one or more of the following characteristics. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, pharmaceutically acceptable exci ienty may include one or more fillers, binders, lubricants, sweetening agents, substances promoting sliding, dezintegriruetsja substances and the like.

The pharmaceutical composition of the present invention may be in the form of tablets, capsules, powder, plates, caplet, granules, pastilles, sachets, suspensions, pellets, spheroids, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets, sachets and other dosage forms suitable for oral administration.

In another aspect of the invention regards a method of manufacturing a pharmaceutical composition, and the method contains particles Reina or diacerein, or their salts or esters, or prodrugs, the average particle size is from about 0.1 micron to about 30 microns; the formation of a mixture by mixing particles Reina or diacerein, or their salts, or esters with one or more pharmaceutically acceptable excipients; and molding the mixture into a pharmaceutical dosage form.

In another General aspect, the present invention relates to a pharmaceutical composition with modified release containing the failure to comply or diacerein, or salts or esters or prodrug.

You can get a modified release by one or more functional coating or CME is ywaniem Reina or diacerein, or their salts, or esters, or prodrugs with one or more pharmaceutically acceptable polymers.

In another General aspect, the invention considers the pharmaceutical composition with modified release containing the failure to comply or diacerein, or salts or esters, or the prodrug, when this composition does not show any significant differences in the rate and extent of absorption Reina or diacerein compared with the formulation of diacerein 50 mg sold under the trade name Art 50®and modified-release is achieved by one or more functional coating or mixing Reina or diacerein, or their salts or esters, or prodrugs with one or more pharmaceutically acceptable polymers.

Embodiments of the pharmaceutical compositions can include one or more of the following characteristics. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, pharmaceutically acceptable excipients may include one or more fillers, binders, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants, substances that promote the slip, and the like.

The pharmacist is ical composition of the present invention may be in the form of tablets, capsules, powder, plates, caplet, granules, pastilles, sachets, suspensions, pellets, spheroids, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets and other dosage forms suitable for oral administration.

In another General aspect, the invention regards a method of manufacturing a pharmaceutical composition with modified release containing the failure to comply or diacerein, or salts or esters or prodrug, and the method includes coating or mixing Reina or diacerein, or their salts or esters, or prodrugs with one or more pharmaceutically acceptable polymers, optionally with other pharmaceutical excipients, and converting the mixture into a suitable dosage form.

In another General aspect, the invention relates to a method of treatment of osteoarthritis, and this method provides an introduction to the patient twice a day, starting with the first day of treatment, pharmaceutical dosage forms containing from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs.

Embodiments of the pharmaceutical compositions can include one or more of the following characteristics. The pharmaceutical composition may further include one or more pharmacist who Cesky acceptable excipients. For example, pharmaceutically acceptable excipients may include one or more fillers, binders, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants, substances that promote the slip, and the like.

The pharmaceutical composition of the present invention may be in the form of tablets, capsules, powder, plates, caplet, granules, pastilles, sachets, suspensions, pellets, spheroids, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets, and other dosage forms suitable for oral administration.

In another General aspect, the invention relates to oral pharmaceutical compositions containing from about 20 mg to about 45 mg Reina or diacerein, or their salts or esters, or prodrugs, while this composition has the effect of decreasing the soft chair at least 25% compared with the effect of the formulation of diacerein 50 mg sold under the trade name Art 50®.

In another General aspect, the present invention relates to oral pharmaceutical compositions containing from 20 to 45 mg Reina or diacerein, or their salts or esters, or prodrugs, with one or both of the rate and extent of absorption Reina or diacerein equal to R is capture of diacerein 50 mg, sold under the trade name Art 50®or exceeds these figures. The composition has the effect of decreasing the soft chair at least 25% compared with the effect of the formulation of diacerein 50 mg sold under the trade name Art 50®.

Embodiments of the pharmaceutical compositions can include one or more of the following characteristics. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, pharmaceutically acceptable excipients may include one or more fillers, binders, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants, substances that promote the slip, and the like.

The pharmaceutical composition of the present invention may be in the form of tablets, capsules, powder, plates, caplet, granules, pastilles, sachets, suspensions, pellets, spheroids, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets and other dosage forms suitable for oral administration.

The details of one or more embodiments of the invention are formulated in the description below. Other characteristics, objectives and advantages of the present invention will be PTS what vidrascu come from the description and claims.

Detailed description of the invention

The authors of the present invention have developed different methods of making compositions Reina or diacerein, or which are bioequivalent, or have increased bioavailability compared with the composition of diacerein at a dose of 50 mg, which exists in the commercial market under the trade name Art 50®.

According to one variant of implementation, produced by granulation of the melt Reina or diacerein with one or more pharmaceutically acceptable carriers melts significantly increased the solubility of diacerein and the percentage release of drug of diacerein compared to Art 50®. The release of drug Art 50®approximately 14% of diacerein after 60 minutes, whereas the pharmaceutical composition according to the invention is released 100% of diacerein after 30 minutes. The result is improved bioavailability. Additionally, as a result of increasing bioavailability of a decrease in side effects, that is soft chair. The composition is introduced to a subject person in a state of fasting, is bioequivalent composition introduced the subject in a state after a meal, in particular, according to the calculations of the maximum plasma concentration (Cmaxthe maximum time Tmaxand the area under pharmacokinetics the th curve (AUC), according to the methodical manual control of the food and drug administration (US FDA) and European medicines Agency (EMEA).

In one embodiment, the pharmaceutical composition according to the invention can be produced by fusion of one or more pharmaceutically acceptable carriers and by mixing of diacerein with the molten mass, followed by freezing. Frozen solid can be crushed into granules. Granules can be mixed with other pharmaceutically acceptable excipients and can be molded into a suitable dosage form. Diacerein can be mixed with the molten mass together with one or more surfactants.

Embodiments of the composition may include one or more of the following characteristics. For example, the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients, which are selected from the group of fillers, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants and substances that promote sliding.

Suitable pharmaceutically acceptable carriers include one or more of the following: esters of fatty acids, fatty acids and their salts, fatty alcohols, fatty amines, fatty amides, glycerides, glycol is ibidi, steroids, waxes, natural and synthetic origin, polyethylene glycol or its derivatives, and the like.

Polyethylene glycol (PEG) or its derivatives may include PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, poliglecaprone glycerides, polyethylene glycol-polyoxyethylene, polyethylene glycol-polypropylene, polyethylene glycol-polyoxypropylene.

Suitable esters of fatty acids may include complex triglyceridemia ether, glyceryl distearate, glyceryl tristearate, glyceryl the monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryl dodecanoate, glyceryl tridecanoate, glyceryl Montecasino, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl manneristic, glyceryl demeritt, glyceryl trimyristin, glyceryl nonadecanoic, glyceryl dodecanoate, glyceryl tridecanoate and the like.

Suitable fatty acids may include acids having from 12 to 28 carbon atoms, such as stearic acid, palmitic acid, lauric acid, eleostearic acid, etc. Fatty alcohols may contain compounds containing from 16 to 44 carbon atoms, such as stearic alcohol, Palmitoyl, etc.

The glycerides may include monoglycerides, diglycerides, triglycerides, Glick the lipids, steroids and organic salts of fatty acids containing from 12 to 29 carbon atoms. Examples of such compounds include stearin, palmitin, gidrirovannoe castor oil, lecithin, gidrirovannoe cottonseed oil, gidrirovannoe tall oil, magnesium stearate and calcium and aluminum salts of palmitic and other fatty acids.

Waxes may include paraffin wax, beeswax, Carnauba wax, jojoba wax, microcrystalline, palm, spermaceti, chestney wax and other hydrocarbon waxes, solid at room temperature.

Suitable surfactants may include amphoteric, non-ionic, cationic or anionic surfactants. Suitable surfactants include one or more of the following: sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester polyoxyethylene-sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearyl alcohol, cetosteatil alcohol, cholesterol, polyoxyethylene-ricinulei oil, polyoxyethylene glycerides of fatty acids, poloxamer, cremophor RH 40, and the like.

In another embodiment, the present invention discovered that by granulation Reina or diacerein, or their salts or esters, or prodrugs with a suitable solvent or mixture of solvents is value is to increase the solubility of diacerein and increases the percentage release of drug diacerein compared with performance Art 50 ®. The release of diacerein of the Art 50®made by dry pressing method, measured after 60 minutes, is about 14%, while the pharmaceutical compositions of the present invention manufactured using the technology of wet granulation, after 60 minutes released more than 65% of diacerein. As a result of increased bioavailability and significantly reduced side effects, namely soft stool. The composition is introduced to a man in a state of shock, bioequivalency compositions that introduce a specified subject in the state after a meal, in particular, according to the calculations of Cmax, Tmaxand AUC, under the methodological guidance of the control food and drug administration (US FDA) and European medicines Agency (EMEA).

According to one variant of implementation of the pharmaceutical composition can be produced as follows: by mixing diacerein with other pharmaceutically acceptable excipients to form a premix; granulating the premix with one or more suitable solvent; drying the granules; lubrication of granules and transformations of finite mixture into a suitable dosage form.

Suitable solvents include one or more of the following: water, methanol, ethanol, isopropyl alcohol, acetone, methylene chloride and the like.

The authors present invention also found that when using Reina or diacerein, or their salts or esters, or prodrugs with an average particle size from about 0.1 micron to about 30 microns greatly increases the solubility of diacerein and thus increases the percentage release of diacerein compared to the release of the Art 50®. Drug Art 50®with a particle size of diacerein more than 43 microns releases about 14% of diacerein after 60 minutes, whereas the pharmaceutical composition of the present invention with an average particle size of diacerein from 0.1 microns to 30 microns, in particular from 0.2 microns to 20 microns, releases 100% of diacerein after 15 minutes. The increased bioavailability leads to a significant reduction of side effects, namely soft chair. The composition is introduced to a subject person in a state of fasting, is bioequivalent composition that is administered to the subject in a state after a meal, in particular according to the calculations of Cmax, Tmaxand AUC under the methodological guidance of the U.S. FDA and EMEA.

The authors of the present invention has further revealed the absence of any real need to co-ekranizirovat diacerein with any surfactant with the aim of obtaining recipes, biosimilar commercially available solid dosage forms is diacerein for oral administration at a dosage of 50 mg (Art 50 ®). Additionally, the composition can be taken with or without food. The result of applying the composition according to the invention is a significant reduction in soft stools as a side effect, which is usually observed when using Art 50®.

According to one variant of implementation of the pharmaceutical composition according to the invention can be produced by dispersion of diacerein or its salt, optionally with pharmaceutically acceptable excipients in a suitable liquid dispersion medium and then wet granulating dispersion using a suitable granulator to obtain a suitable size. A dispersion of microparticles of diacerein or its salt can be dried by spraying in the device fluidized bed. The dry mixture can be mixed with other pharmaceutically acceptable excipients and can be converted into a suitable dosage form.

The authors present invention also found that the wet grinding is better reduces the particle size of diacerein or Reina. The use of this technology allows to achieve a smaller particle size of 0.1 micron, it is difficult to implement with the technology of dry grinding. Additionally, the wet grinding prevents smoke dust particles and the loss due to the specified event.

Suitable liquid d is personna environment includes one or more of the following: water, ethanol, isopropyl alcohol, butanol, hexane, glycols, vegetable oils, mineral oils and the like.

Suitable means applied to reduce the particle size Reina or diacerein, or their salts or esters, or prodrugs include one or more of the following: nanogranular, ball mill, disc mill, vibrating mill, a sand mill, bead mill, jet mill, dyno-mill, ultrasonic treatment, high-pressure homogenizer - microfluidizer and the like.

The authors present invention also noted that there is an immediate absorption Reina or diacerein when using forms with immediate-release Reina or diacerein, which leads to achieve rapid phase of elimination and, consequently, to reduction of the area under the time curve in plasma (AUC). Additionally, diacerein is also exposed to the aggressive environment of the stomach, resulting in the splitting of diacerein. The authors of the present invention has solved this problem by developing a pharmaceutical composition with modified release containing the failure to comply or diacerein. Pharmaceutical composition with modified release has a prolonged phase of absorption and increased the area under the time curve in plasma AUC), thus increases the bioavailability. Additionally, it prevents the corrosive environment of the stomach for the whole entered diacerein, therefore, prevents its cleavage. Additionally, the pharmaceutical composition with modified release of the present invention bioequivalent formulation of diacerein at a dose of 50 mg, which exists in the commercial market under the trade name Art 50®.

The term "modified release"as used in the present invention, includes extended release or delayed release, or their combination, in an immediate release interest in any weight ratio. The term "extended release" can be used interchangeably with the term "prolonged release", "controlled release", "slow release" or "perpetual release".

The introduction of compositions with modified release can be performed according to the scheme twice a day.

Modified-release pharmaceutical compositions can be achieved by using one or more functional coating or by mixing Reina or diacerein with one or more pharmaceutically acceptable polymers. The release can also be achieved by attaching reineri of diacerein ion-exchange resins.

Pharmaceutically acceptable polymers may include one or more polymers, which regulates speed, or enteric-soluble polymers.

Suitable polymers regulating the speed may include one or more of the following: polyvinyl acetate, cellulose acetate, acetate butyrate cellulose, acetate propionate, cellulose, ethylcellulose, fatty acid, ester of fatty acid, alkilany alcohol, wax, shellac, resin, Zein (prolamin from corn), poly(meth)acrylate, microcrystalline cellulose or poly(ethylene oxide), salt polihronova acid, cellulose ethers, xanthan gum, tragacantha resin, resin punish, guar gum, gum Arabic, gelling gum beans carob, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, hydroxypropylcellulose, hypromellose, carboxyvinyl polymers and the like.

Suitable enteric-soluble polymers may include one or more of the following: primaryservername gelatin, shellac, methacrylic acid copolymer type C NF, phthalate butyrate cellulose, hydroptila cellulose propionate phthalate cellulose, polyvinyl acetate phthalate (PVAP), acetate cellulose phthalate (CAP), acetate trimellitate cellulose (CAT), hydroxypropylmethylcellulose of ftal is, hydroxypropylmethylcellulose acetate, deoxypyridinoline succinate, karboksimetiltselljuloza (CMEC), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polymers and copolymers of acrylic acid such as methyl acrylate, acrylate, methacrylate and/or ethyl methacrylate with copolymers of esters of acrylic and methacrylic acid (Eudragit NE, Eudragit RL, Eudragit RS), and the like.

Failure to comply or diacerein, or salts or esters or prodrugs may be in the form of powder, granules, pellets, beads, microtablets, minitablets and crystals.

"Bioequivalence" according to the methodological guidelines of the U.S. FDA is installed with a confidence interval (CI) of 90% in the range from 0.80 to 1.25 and Cmaxand for AUC, or DI 90% for AUC in the range from 0.80 to 1.25 and DI 90% for Cmaxin the range from 0.70 to 1.43 according to the European guideline (EMEA).

Used in the present invention, the term "confidence interval" refers to the obvious value that is known to ordinary skilled in the art. The confidence interval refers to the statistical range with a specified probability that a given parameter lies within the range.

Used in the present invention, the term "covariance" refers to the obvious value that is known to ordinary skilled in the field the minute technology. It means a statistical measure of the difference of two random variables that are observed or measured in the same period of time. This measure is equal to the derivative of the deviations of corresponding values of these two variables from their respective values.

Bioequivalence was studied in comparison Art 50®and the composition of the invention, and in state after meals and on an empty stomach. Measurements the study was performed according to the parameters CmaxAUC, Tmaxthat was received with the test substances and consider the substance (Art 50®).

The composition of the invention shows the pharmacokinetic profile with differences in the concentration of Cmaxfrom about 3,15 to 6.0 μg/ml, at time Tmaxfrom about 2.4 to 5.0 hours, and square AUC0-tfrom around 16.4 up to 40 µg / h/ml, AUCφ from about 16.7 to 40 µg / h/ml

In the confidence interval of 90% of the area under the curve of concentration-time (AUC0-tand/or AUCφ) and maximum plasma concentration (Cmax) the composition according to the invention are in the range of from 0.70 to 1.70, compared with obtained values of the formulation of diacerein 50 mg sold under the trade name Art 50®.

Advantages of the compositions of the present invention include, without limitation: (1) the smaller size of the solid dosage form; (2) smaller doses of drug, the mu is necessary to achieve the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the compositions Reina or diacerein, when introduced into the state after a meal compared to fasting state; (5) bioequivalence compositions of diacerein when introduced into the state after a meal compared to fasting state.

Pharmaceutical compositions can include one or more pharmaceutically acceptable excipients selected from the group of fillers, binders, lubricants, dezintegriruetsja substances, sweeteners, dyes, substances that promote the slip, surfactants and the like.

Suitable fillers may include one or more of the following: microcrystalline cellulose, silicatization microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like.

Suitable binders may include one or more of the following: povidone, starch, stearic acid, resin, hypromellose, and the like.

Suitable lubricants may include one or more of the following: magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, gidrirovannoe vegetable oil, glyceryl behenate and the like.

Suitable dezintegriruetsja substances may include one or more of the following: starch, croscarmellose sodium, crosspovidone, sodium starch glycolate, and the like.

Suitable substances promoting sliding, can include one or more of the following: colloidal silicon dioxide, talc or corn starch and the like.

Suitable sweeteners may include sugar, aspartame, saccharin sodium, Acesulfame potassium, neohesperidin, dihydrochalcone, Sucralose, monoammonium the glycyrrhizinate, and mixtures thereof.

The dyes of the present invention can be selected from any of the dyes approved by the FDA for oral use.

The pharmaceutical composition of the present invention may be in the form of granules, pellets, beads, spheroids, tablets, minitablets, microtablets, capsules, encapsulated granules, encapsulated pellets, minitablets in a capsule, or a combination.

The present invention is additionally described in the following examples, which are presented merely to illustrate the invention and do not limit the scope of the invention. Specific modifications and similar variants will be obvious to a person skilled in the art and it is assumed that they are included in the scope of the present invention.

Example 1

Table 1
No.Ingredients% composition
Part I
1PEG 600040-60
Part II
2Diacerein10-60
4Lactose5-40
5Sodium croscarmellose10-25
6Selektsionna microcrystalline cellulose1-25
7Magnesium stearate1-15

Methods: PEG 6000 was melted and mixed at 60-70°C with diacerein for the formation of a homogeneous dispersion, followed by freezing with stirring at room temperature. The frozen solid was passed through a mesh filter to obtain pellets of the same size. Thus obtained granules were mixed with lactose, sodium Crocker what elloso, selektsionnoi microcrystalline cellulose, treated with stearate and filling hard gelatin capsules.

Example 2

Table 2
No.Ingredients% composition
Part I
1PEG 600040-60
2Poloxamer5-40
Part II
2Diacerein10-60
3Sulphate of lauryl sodium1-20
Part III
4Selektsionna microcrystalline cellulose1-25
5Lactose5-40
6Sodium croscarmellose1-40
7Magnesium stearate1-15

Methods: Poloxamer and PEG 6000 were melted and mixed at 60-70°C with diacerein and sulfate lauryl sodium for the formation of a homogeneous dispersion, followed by freezing with stirring at room temperature. The frozen solid was passed through a mesh filter to obtain pellets of the same size. Thus obtained granules were mixed with lactose, selektsionnoi microcrystalline cellulose, sodium croscarmellose, treated with stearate and filling hard gelatin capsules.

Table 3
Data solubility
Time (minutes)% released drugs (Art 50®)% of released drug
(Example 2)
5338
10474
15588
207 97
309100
4511100
6014100

To determine the speed of release of used device United States Pharmacopeia USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Example 3

Table 4
No.IngredientsNumber
(mg per pill)
Inside the granules
1Diacerein44,0
2Povidone11,50
4Lactose220,30
4Sodium croscarmellose11,50
5Colloidal silicon dioxide5,75
6The hypromellose20,00
Pellet outside
7Colloidal silicon dioxideof 5.75
8Magnesium stearate1,20

Methodology: Diacerein was mixed with lactose, sodium croscarmellose, colloidal silicon dioxide and hypromellose and was granulated with an aqueous solution of povidone. The granules were dried, mixed with colloidal silicon dioxide, treated with magnesium stearate and filled hard gelatin capsules of suitable size.

Table 5
Data solubility
Time (minutes)% released drugs (Art 50®)% of released drug
(Example 3)
10417
20728
939
451154
601468
901694
12019100

Table 5 shows the data of solubility for capsules of diacerein made according to the recipe of table 4. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Example 4

Table 6
No.IngredientsNumber
(mg per pill)
Inside the granules
1Diacerein45,00
2Povidone11,50
4Lactose 219,30
4Sodium croscarmellose11,50
5Colloidal silicon dioxideof 5.75
6The hypromellose20,00
Pellet outside
7Colloidal silicon dioxideof 5.75
8Magnesium stearate1,20

Methodology: Diacerein was mixed with lactose, sodium croscarmellose, colloidal silicon dioxide, hypromellose and was granulated with an aqueous solution of povidone. The granules were dried, mixed with colloidal silicon dioxide, treated with magnesium stearate and filled hard gelatin capsules of suitable size.

Table 7
Data solubility
Time (minutes)% released drugs (Art 50®)% visual demogo drugs
(Example 4)
10418
20726
30937
451157
601472
901696
12019100

Table 7 summarizes the data of solubility for capsules of diacerein made according to the recipe of table 6. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Art 50®
Table 8
Data bioequivalence compositions of the present invention in comparison with Art 50®in pharmacokinetic parameters
No.Pharmacokinetic parametersThe composition according to the invention
1Cmax(ág/ml)3,0583,48
2Tmax(h)5,394,80
3AUC0-t(μg h/ml)22,68822,82
4AUCφ (μg h/ml)22,81623,62

Table 9
Comparative data on bioequivalence testing (T-composition according to the invention) and consider the product (R-Art 50®) (ratio T/R) confidence interval (CI) of 90%.
No.Pharmacokinetic parametersRatioDI 90%The coefficient of variation, %
The lower borderThe upper bound
1Cmax(ág/ml)113,7997,56179,0925,23
2AUC0-t(μg h/ml)100,5789,48150,1722,39
3AUCφ (μg h/ml)103,5185,26148,2923,79

Example 5

Table 10
No.Ingredients% ratio wt.
Part I
1Diacereinof 11.26
2Povidone5-40
3Waterq.s.
Part II
4KRA is small 10-50
5Selektsionna microcrystalline cellulose5-70
6Sodium croscarmellose1-15
7Magnesium stearate0,1-3

Methodology: Diacerein and povidone were dispersible in sufficient water to obtain a homogeneous dispersion. In order to obtain the desired particle size of 0.1 μ), variance of diacerein was passed through the homogenizer high pressure one or more times. A dispersion of microparticles was dried in the spray dryer Glatt. The dried mass was mixed with selektsionnoi microcrystalline cellulose, starch, sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Example 6

Table 11
No.Ingredients% ratio wt.
Part I
1Diacerein of 11.26
2Povidone5-40
3Waterq.s.
Part II
4Lactose10-50
5Selektsionna microcrystalline cellulose5-70
6Sodium croscarmellose1-15
7Magnesium stearate0,1-3

Methodology: Diacerein and povidone were dispersible in sufficient water to obtain a homogeneous dispersion. In order to obtain the desired particle size (0,8 μ), variance of diacerein was passed through microfluidizer one or more times. A dispersion of microparticles was dried in the spray dryer Glatt. The dried mass was mixed with selektsionnoi microcrystalline cellulose, lactose, sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Example 7

Table 12
No.Ingredients% ratio wt.
Part I
1Diacerein9,50
2The hypromellose10-50
3Waterq.s.
Part II
4Povidone5-40
5Selektsionna microcrystalline cellulose5-70
6Sodium croscarmellose1-15
7Magnesium stearate0,1-3

Methodology: Diacerein and povidone were dispersible in sufficient water to obtain a homogeneous dispersion. In order to obtain the desired particle size (5 μ), variance of diacerein was passed through the homogenizer high pressure Odie the time or more. A dispersion of microparticles was dried in the spray dryer Glatt. The dried mass was mixed with selektsionnoi microcrystalline cellulose, sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Example 8

Table 13
No.Ingredients% ratio wt.
Part I
1Diacerein9,50
2Microcrystalline cellulose5-40
3Waterq.s.
Part II
4Starch10-50
5Selektsionna microcrystalline cellulose5-70
6Sodium croscarmellose1-15
7Magnesium stearate0,1-3

Methodology: Diacerein and hypromellose were dispersible in sufficient water to obtain a homogeneous dispersion. In order to obtain the desired particle size (12 μ), variance of diacerein was passed through the homogenizer high pressure one or more times. A dispersion of microparticles was dried in the spray dryer Glatt. The dried mass was mixed with selektsionnoi microcrystalline cellulose, starch, sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Example 9

Table 14
No.Ingredients% ratio wt.
Part I
1Diacerein11,80
2Povidone5-40
3Waterq.s.
Part II
4Sucrose10-50
5Starch10-50
6Selektsionna microcrystalline cellulose5-70
7Sodium croscarmellose1-15
8Magnesium stearate0,1-3

Methodology: Diacerein and hypromellose were dispersible in sufficient water to obtain a homogeneous dispersion. In order to obtain the desired particle size (15 μ), variance of diacerein was passed through the homogenizer high pressure one or more times. A dispersion of microparticles was dried in the spray dryer Glatt. The dried mass was mixed with sucrose, selektsionnoi microcrystalline cellulose, starch, sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Example 10

Table 15
No.Ingredients % ratio wt.
Part I
1Diacerein12,50
2The hypromellose5-40
3Waterq.s.
Part II
4Sucrose10-50
6Starch10-50
5Selektsionna microcrystalline cellulose5-70
6Sodium croscarmellose1-15
7Magnesium stearate0,1-3

Methodology: Diacerein and povidone were dispersible in sufficient water to obtain a homogeneous dispersion. In order to obtain the desired particle size (15 μ), variance of diacerein was passed through microfluidizer one or more times. A dispersion of microparticles is isusually on the spray dryer Glatt. The dried mass was mixed with sucrose, selektsionnoi microcrystalline cellulose, starch, sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Table 16
Data solubility
Time (minutes)% released drugs (Art 50®with a particle size of more than 43 microns)% of released drug
(Composition according to the invention with a particle size of from 0.1 to 30 microns)
5355
10493
155100
207100
309100
4511100
6014100

To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Table 17
Data bioequivalence compositions of the present invention in comparison with Art 50®in pharmacokinetic parameters
No.Pharmacokinetic parametersArt 50®The composition according to the invention
1Cmax(ág/ml)3,0584,050
2Tmax(h)5,394,47
3AUC0-t(μg h/ml)22,68825,559
4AUCφ (μg h/ml)22,81625,675

Table 18
Comparative data on bioequivalence testing (T-composition according to the invention) and consider the product (R-Art 50®) (ratio T/R) confidence interval (CI) of 90%.
No.Pharmacokinetic parametersRatioDI 90%The coefficient of variation, %
The lower borderThe upper boundary
1Cmax(ág/ml)132,4299,59176,0827,73
2AUC0-t(μg h/ml)112,6587,42145,1724,59
3AUCφ (μg h/ml)112,5387,16145,2924,77

Example 11

Table 19
No.Ingredientsmg 1 tablet
Part I
1Diacerein44,00
2Povidone50,00
3Sodium docusinate7,00
4Sodium lauryl sulfate8,00
5Starch160,00
6Selektsionna microcrystalline cellulose30,00
7Waterq.s.
Part II
8Selektsionna microcrystalline cellulose79,00
9Sodium croscarmellose20,00
10Magnesium stearateMethodology: Povidone was dissolved in water to obtain a transparent solution. Diacerein was dispersively in the above-mentioned solution of povidone to form a homogeneous dispersion. In order to obtain the desired particle size (0,9 μ), variance of diacerein was passed through the homogenizer high pressure one or more times. Sodium docusinate was dissolved in water to obtain a clear solution and the clear solution was added to a dispersion of microparticles of diacerein, and then the dispersion was dried in the spray dryer Glatt on the starch and selektsionnoi microcrystalline cellulose. The dried mass was mixed with selektsionnoi microcrystalline cellulose and sodium croscarmellose, treated with magnesium stearate and filled greased with a mixture of hard gelatin capsules of suitable size.

Table 20
Data solubility
Time (minutes)% released drugs (Art 50®with a particle size of more than 43 microns)% of released drug
(Example 11)
10493
20799
309100
4511100
6014100

To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Table 21
Data bioequivalence compositions of the present invention in comparison with Art 50®in pharmacokinetic parameters
No.Pharmacokinetic parametersArt 50®The composition according to the invention
1Cmax(ág/ml)3,0584,250
2Tmax(h)5,394,17
3AC 0-t(μg h/ml)22,68825,659
4AUCφ (μg h/ml)22,81625,778

Table 22
Comparative data on bioequivalence testing (T-composition according to the invention) and consider the product (R-Art 50®) (ratio T/R) confidence interval (CI) of 90%.
No.Pharmacokinetic parametersRatioDI 90%The coefficient of variation, %
The lower borderThe upper boundary
1Cmax(ág/ml)139,9897,56179,0925,23
2AUC0-t(μg h/ml)113,0989,48150,1722,39/td>
3AUCφ (μg h/ml)112,9885,26148,2923,79

Example 12

Table 23
Ingredients% ratio wt.
Part I
Diacerein5-13
Lactose10-50
Povidone5-40
Sodium docusinate1-20
Tocopherol polyethylene glycol succinate TPGS5-30
Starch10-50
ProSolv (prosolv - compound microcrystalline cellulose and silicon dioxide)5-70
Part II
The dried granules from part I
Eudragit7,0
Part III
Pellet outside
Prosolv5-70
Ac-Di-Sol (croscarmellose Sodium)1-15
Magnesium stearate0,1-3

Methods: Sodium docusinate was dissolved in purified water with stirring. To the above solution of sodium docusinate with stirring was added povidone to obtain a clear solution and was additionally added diacerein for homogeneous dispersion. In order to obtain the desired particle size, the dispersion of diacerein was passed through Dino-mill/high-pressure homogenizer/microfluidizer one or more times. A clear solution of tocopherol polyethylene glycol succinate TPGS was added to the above-mentioned fine/nano-dispersion of diacerein. The variance of diacerein was sprayed onto the starch and prosolv way top spray dryers Glatt. Thus obtained dried granules were coated with Eudragit and optionally dried and mixed with prosolv, sodium croscarmellose and treated with stearate. The lubricated blend was filled in capsules of suitable size.

Table 24
Data solubility
Time (minutes)% of released drug
(Example 12)
526
1044
1575
3097
4598
6098

Table 24 shows the solubility capsules of diacerein made according to the formula in table 23. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Example 13

Table 25
Ingredients% ratio wt.
Part I
Diacerein5-13
Povidone5-40
Sodium docusinate 1-20
TPGS5-30
Starch10-50
Prosolv5-70
Part II
The dried granules from part I
Eudragit4,0
Part III
Pellet outside
Prosolv5-70
Ac-Di-Sol1-15
Magnesium stearate0,1-3

Methods: Sodium docusinate was dissolved in purified water with stirring. To the above solution of sodium docusinate with stirring was added polyvinylpyrrolidone (PVP) to obtain a clear solution and was additionally added diacerein for homogeneous dispersion. In order to obtain the desired particle size, the dispersion of diacerein was passed through Dino-mill/high-pressure homogenizer/microfluidizer one or more times. A clear solution TPGS was added to the above-mentioned fine/nano-dispersion of Diaz is Reina. The variance of diacerein was sprayed onto the starch and prosolv way top spray dryers Glatt. Thus obtained dried granules were coated with Eudragit and optionally dried and mixed with prosolv, sodium croscarmellose and treated with stearate. The lubricated blend was filled in capsules of suitable size.

Table 26
Data solubility
Time (minutes)% of released drug
(Example 13)
532
1056
1575
3085
4590
6094

Table 26 shows the solubility capsules of diacerein made according to the formula in table 25. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Example 14

Table 27
Ingredients% ratio wt.
Part I
Diacerein5-13
Povidone5-40
Sodium docusinate1-20
TPGS5-30
Sodium lauryl sulfate1-20
Starch10-50
Prosolv5-70
Part II
The dried granules from part I
Eudragit4,0
Part III
Pellet outside
Prosolv5-70
Ac-Di-Sol (croscarmellose Sodium)1-15
Magnesium stearate0,1-3

Methods: Sodium docusinate of restore and in purified water with stirring. To the above solution of sodium docusinate was added with stirring PVP to obtain a clear solution and was additionally added diacerein for homogeneous dispersion. In order to obtain the desired particle size, the dispersion of diacerein was passed through Dino-mill/high-pressure homogenizer/microfluidizer one or more times. A clear solution TPGS and sodium lauryl sulphate was added to the above-mentioned fine/nano-dispersion of diacerein. The variance of diacerein was sprayed onto the starch and prosolv way top spray dryers Glatt. Thus obtained dried granules were coated with Eudragit, optionally dried, and mixed with prosolv, sodium croscarmellose and treated with stearate. The lubricated blend was filled in capsules of suitable size.

Table 28
Data bioequivalence compositions of the present invention in comparison with Art 50®in pharmacokinetic parameters
No.Pharmacokinetic parametersArt 50®The composition according to the invention
1 Cmax(ág/ml)3,0585,121
2Tmax(h)5,395,70
3AUC0-t(μg h/ml)22,68824,927
4AUC0-inf(μg h/ml)22,81625,569

Table 29
Comparative data on bioequivalence testing (T-composition according to the invention) and consider the product (R-Art 50®) (ratio T/R) confidence interval (CI) of 90%.
No.Pharmacokinetic parametersRatioDI 90%The coefficient of variation, %
The lower borderThe upper boundary
1Cmax(ág/ml)120,17 107,61134,213,33
2AUC0-t(μg h/ml)94,591,5697,33,80
3AUC0-inf(μg h/ml)94,5591,5697,533,86

Example 15

Table 30
Ingredients% ratio wt.
Part I
Diacerein5-13
Lactose10-50
Povidone5-40
Sodium docusinate1-20
TPGS5-30
Starch10-50
Prosolv5-70
Part a part C instant the m-release)
The dried granules (part contains 65-85 wt.% the total number of diacerein from part I)
Part (part with adjustable release)
The dried granules (part contains 15-35 wt.% the total number of diacerein from part I)
The hypromellose3,75
Prosolv5-70
Magnesium stearate0,1-3
Pellet outside
Pellets of part a
Pellets of parts
Prosolv5-70
Ac-Di-Sol1-15
Magnesium stearate0,1-3

Methods: Sodium docusinate was dissolved in purified water with stirring. To the above solution of sodium docusinate was added with stirring PVP to obtain a clear solution and was additionally added diacerein for homogeneous dispersion. To whom to teach the desired particle size, the variance of diacerein was passed through Dino-mill/high-pressure homogenizer/microfluidizer one or more times. A clear solution TPGS was added to the above-mentioned fine/nano-dispersion of diacerein. The variance of diacerein was sprayed onto the starch and prosolv way top spray dryers Glatt. Thus obtained dried granules were divided into two parts. The first part (A) was retained as part of the immediate-release. The second part was added hypromellose together with prosolv, mixed and treated with stearate. The lubricated granules were condensed rolling in the rolls of the roll and powder preform was grained using a multiple-roll crusher, to obtain pellets of the same size (part B). Granules of part B was mixed with granules of part a together with prosolv, Ac-Di-Sol and stearate and the final mixture was filled in capsules of suitable size.

Table 31
Data solubility
Time (minutes)% of released drug
(Example 15)
1045
2076/td>
3099
45100
60100
90100
120100

Table 31 shows the solubility capsules of diacerein made according to the formula in table 30. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Example 16

Table 32
Ingredients% the ratio of the masses
Part I
Diacerein5-13
Lactose10-50
Povidone5-40
Sodium docusinate1-20
TPGS5-30
Starch10-50
Prosolv5-70
Part a (part of the immediate-release)
The dried granules (part contains 65-85 wt.% the total number of diacerein from part I)
Part (part with adjustable release)
The dried granules (part contains 15-35 wt.% the total number of diacerein from part I
The hypromellose7,5
Prosolv5-70
Magnesium stearate0,1-3
Pellet outside
Pellets of part a
Pellets of parts
Prosolv5-70
Ac-Di-Sol1-15
Magnesium stearate0,1-3

Methods: Sodium docusinate was dissolved in purified water with stirring. To the above solution of sodium docusinate added with paramashiva the receiving PVP to obtain a clear solution and was additionally added diacerein for homogeneous dispersion. In order to obtain the desired particle size, the dispersion of diacerein was passed through Dino-mill/high-pressure homogenizer/microfluidizer one or more times. A clear solution TPGS was added to the above-mentioned fine/nano-dispersion of diacerein. The variance of diacerein was sprayed onto the starch and prosolv way top spray dryers Glatt. Thus obtained dried granules were divided into two parts. The first part (A) was retained as part of the immediate-release. The second part was added hypromellose together with prosolv, mixed and treated with stearate. The lubricated granules were condensed rolling in the rolls of the roll and powder preform was grained using a multiple-roll crusher, to obtain pellets of the same size (part B). Granules of part B was mixed with granules of part a together with prosolv, Ac-Di-Sol and stearate and the final mixture was filled in capsules of suitable size.

Table 33
Data solubility
Time (minutes)% of released drug
(Example 16)
1011
2024
3036
4551
6072
9092
12095

Table 33 lists the data solubility capsules of diacerein made according to the formula in table 32. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Example 17

Table 34
Ingredients% ratio wt.
Part I
Diacerein5-13
Lactose10-50
Povidone5-40
Sodium docusinate1-20
TPGS5-30
Starch 10-50
Prosolv5-70
Part a (part of the immediate-release)
The dried granules (part contains 65-85 wt.% the total number of diacerein from part I)
Part (part with adjustable release)
The dried granules (part contains 15-35 wt.% the total number of diacerein from part I)
The hypromellose6,25
Prosolv5-70
Magnesium stearate0,1-3
Pellet outside
Pellets of part a
Pellets of parts
Prosolv5-70
Ac-Di-Sol1-15
Magnesium stearate0,1-3

Methods: Sodium docusinate was dissolved in purified water with stirring. To the above solution on the model of docusinate was added with stirring PVP to obtain a clear solution and was additionally added diacerein for homogeneous dispersion. In order to obtain the desired particle size, the dispersion of diacerein was passed through Dino-mill/high-pressure homogenizer/microfluidizer one or more times. A clear solution TPGS was added to the above-mentioned fine/nano-dispersion of diacerein. The variance of diacerein was sprayed onto the starch and prosolv way top spray dryers Glatt. Thus obtained dried granules were divided into two parts. The first part (A) was retained as part of the immediate-release. The second part was added hypromellose together with prosolv, mixed and treated with stearate. The lubricated granules were condensed rolling in the rolls of the roll and powder preform was grained using a multiple-roll crusher, to obtain pellets of the same size (part B). Granules of part B was mixed with granules of part a together with prosolv, Ac-Di-Sol and stearate and the final mixture was filled in capsules of suitable size.

Table 35
Data solubility
Time (minutes)% of released drug
(Example 17)
1024
2043
3062
4580
6090
90100
120100

Table 35 shows the solubility capsules of diacerein made according to the formula in table 34. To determine the speed of release used the device a USP type 2 (75 rpm), in which the medium used 1000 ml phosphate buffer with a pH of 5.7 at 37°C ± 0.5°C.

Table 36
Data bioequivalence compositions of the present invention in comparison with Art 50®in pharmacokinetic parameters
No.Pharmacokinetic parametersArt 50®The composition according to the invention
1Cmax(ág/ml)3,0584,773
2Tmax(h) 5,39of 4.44
3AUC0-t(μg h/ml)22,68821,651
4AUC0-inf(μg h/ml)22,81622,192

Table 37
Comparative data on bioequivalence testing (T-composition according to the invention) and consider the product (R-Art 50®) (ratio T/R) confidence interval (CI) of 90%.
No.Pharmacokinetic parametersRatioDI 90%The coefficient of variation, %
The lower borderThe upper boundary
1Cmax(ág/ml)122,63110,76135,78of 11.15
2AUC0-t(m is g in h/ml) 94,8989,71100,366,13
3AUC0-inf(μg h/ml)94,7389,34100,456,41

The present invention is described in terms of specific variants of its implementation, while for professionals in the art it will be apparent that certain modifications and variations are considered within the scope of invention.

1. Granulated from the melt pharmaceutical composition comprising a failure to comply or diacerein, or salts and one or more pharmaceutically acceptable carriers.

2. The composition according to claim 1, in which the pharmaceutically acceptable carriers include one or more of: esters of fatty acids, fatty acids, fatty alcohols, fatty amines, fatty amides, glycerides, glycolipids, steroids, natural or synthetic waxes, and polyethylene glycol or its derivatives.

3. The composition according to claim 1, which further comprises one or more pharmaceutically acceptable excipients, contain fillers, binders, lubricants, sweeteners, dyes, dezintegriruetsja substances, surfactants and substances, with substudies slip.

4. The composition according to claim 1, with the specified composition comprises one or more of: tablets, capsules, powder, plates, caplet, granules, pellets, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets, sachets, beads, spheroids, suspensions and tablets in the tablet.

5. The composition according to claim 1, with the specified composition has the following profile solubility: more than 85% of diacerein released within 20 min, and the rate of release is measured in apparatus 2 (USP, dissolution, paddle stirrer, 75 rpm) using 1000 ml of phosphate buffer with a pH of 5.7 at 37°C±0,5°C.

6. The composition according to claim 1, the composition can be taken with or without food.

7. A method of manufacturing a pharmaceutical composition Reina or diacerein, or their salts, including mixing Reina or diacerein, or their salts, with one or more pharmaceutically acceptable carriers and granulating the mixture by melting optionally with one or more pharmaceutically acceptable excipients.

8. The method according to claim 7, in which the pharmaceutically acceptable carriers include one or more of: esters of fatty acids, fatty acids and their salts, fatty alcohols, fatty amines, fatty amides, glycerides, glycolipids, steroids, natural or synthetic waxes, and polyethylene glycol or E. what about the derivative.

9. Granulated from the melt oral pharmaceutical composition comprising from about 20 mg to about 45 mg Reina or diacerein or their salts and one or more pharmaceutically acceptable carriers, this composition exhibits the effect of reducing the soft chair at least about 25% compared with the preparative form of diacerein 50 mg sold under the trade name Art 50®.

10. The pharmaceutical composition according to claim 9, which has the effect of decreasing the soft chair at least about 35%.

11. The composition according to claim 9, which contains about 44 mg Reina or diacerein or their salts.

12. The composition according to claim 9, the composition can be taken with or without food.

13. The composition according to claim 9, with the specified composition includes one or more of: tablets, capsules, powder, plates, caplet, granules, pellets, encapsulated granules, minitablets, minitablets in the capsule encapsulated pellets, sachets, beads, spheroids, suspensions and tablets in the tablet.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: method comprises the following steps: (1) dissolving 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol in a mixed solvent which contains a solvent in which a compound in form of its hydrochloride has high solubility and a solvent in which the hydrochloride is less soluble, so as to obtain a solution of 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol; (2) adding hydrochloric acid to the obtained solution while stirring so as to crystallise 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride.

EFFECT: invention relates to a method for highly efficient production of crystals of 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride.

11 cl, 4 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely - to dermatology, physiotherapy. The method includes taking mineral baths with mineral water of Annensk deposit of the Khabarovsk Territory and joint mud therapy. Additional, the patient intakes mineral water 100 - 200 ml, 3 times a day 30 minutes before meals. The baths are taken once a day at temperature 37 - 38°C, for 10-20 minutes. The therapeutic course includes 10-14 baths. The joint mud therapy is performed by applying low-mineralised low-sulphide silt mud on the affected joints. The mud therapy is performed two days running with a one-day pause. The therapeutic course is 6-10 procedures. After the therapeutic course is completed, the affected joints are coated with Relyct gel for 1.0 - 1.5 months dissolved in mineral water.

EFFECT: method prolongs the length of the intercurrent period.

3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically preparing a tumour necrosis factor receptor and may be used in medicine. Genetic engineering technique is used to produce mutant TNFRp75 bound to a tumour necrosis factor and lymphotoxins substantially consisting of N-terminal 257 amino acid residues TNFRp75 wherein the N-terminal residue Glu92 is substituted by Asn, His, Ser or Ala and wherein the N-terminal residue Trp89 is optionally substituted by Tyr or Phe. The produced mutant is used to construct a fused protein with an additional amino acid fragment specified in a constant area of human immunoglobulin and one of five functional areas of albumin found on C-terminal of the soluble mutant TNFRp75. The produced mutant TNFRp75 and the fused protein is used as a part of a pharmaceutical composition for treating the diseases associated with TNFα overexpression which involve rheumatoid arthritis, psoriasis, sclerodermatitis, Sjogren syndrome, Strumpell-Marie disease, lupus erythematosus, acute disseminated myositis and syndrome similar to systemic lupus erythematosus.

EFFECT: invention enables producing soluble TNFRp75 mutant able to be bound to tumour necrosis factor and lymphotoxins at a high affinity degree.

9 cl, 12 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to pharmaceutical composition for treating diseases of joints. Pharmaceutical composition for treating diseases of joints is characterised by the fact that it contains methylsulfonylmethane, glucosamine sulfate, docosahexaenoic acid of vegetative origin with definite ingredient ratio.

EFFECT: pharmaceutical composition possesses expressed effect in treatment of joint diseases.

5 cl, 1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula 1a:

, wherein: A means CH=CH orS; R23 means hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkyloxy or (C1-C4)-alkyl-S-; R24 means hydrogen or halogen when A means CH=CH or hydrogen, halogen, (C1-C4)-alkyl when A means S; X means N(H)C=O, N(H)S(O)2, C=ON(H) or S(O)2N(H); Y means C(R12)=C(R13), N=C(R14) or C(R15)=N, or condensed optionally substituted 5-7-member carbocyclyl; R12 means hydrogen, halogen, (C1-C10)-alkyl, (C2-C10)-alkenyl, (C3-C6)-cycloalkyloxy, (C3-C10)-cycloalkenyloxy, (C3-C6)-cycloalkyl, (C3-C10)-cycloalkenyl, (C3-C6)-cycloalkyl[(C1-C4)-alkyl or (C2-C4)-alkenyl], (C3-C6)-cycloalkyl (C1-C4)-alkyloxy, (C1-C10)-alkyloxy, (C3-C10)-alkenyloxy, (C1-C10)-alkyl-S-, cyano, (C1-C10)-alkylcarbonyl- or phenyl; R13 means hydrogen, halogen or (C1)-alkyl; R14 means hydrogen or (C1-C3)-alkyl-S(O)m; R15 means hydrogen, halogen, (C1-C10)-alkyl, amino, [(C1-C10)-alkyl or (C2-C10)-alkenyl] amino, [(C1-C10)-alkyl or (C2-C10)-alkenyl]((C1-C10)-alkyl)amino or nitro; R21 means hydrogen; R22 means hydrogen, halogen, (C1)-alkyl, while Y means C(R12)=C(R13), N=C(R14) or C(R15)=N; R51 means COOH or CONH(R53); R53 means R55-SO2- or tetrazolyl; R55 means (C1-C4)-alkly; and m is equal to 0; wherein all specified phenyl groups may be independently substituted by one or more halogen atoms; wherein all specified alkyl groups may be independently substituted by one or more fluorine atoms; or its stereoisomer form, a mixture of stereoisomer forms in any ratio or its physiologically acceptable salt, provided the following compounds are excluded: 2-benzoylamino-2,3-dihydro-2-indencarboxylic acid; 2-(naphthalin-2-ylsulphonylamino)indane-2-carboxylic acid. Also, the invention refers to a pharmaceutical composition possessing CXCR5 receptor inhibitory activity on the basis of the compounds described above, as well as a method of treating a patient, involving introducing said compounds into the patient.

EFFECT: there are prepared and described the new compounds which possess CXCR5 inhibitory action and may be used for treating and preventing various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, lupus, and Crohn's disease.

17 cl, 397 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an agent for neutralising toxic action of tumour necrosis factor on the basis of hydrated pyrido(4,3-b)indoles of formula (1), a pharmaceutical agent on the basis thereof, and a method of treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

EFFECT: preparing the agent for treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

13 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to orthopedics, and can be used for surgical treatment of knee joint osteoarthrosis. For this purpose subchondral spongiosotomy is carried out. After that, channel is formed in zone of its performance to internal cortical layer. After that, biocomposite glass crystalline material "Biosit Sr-Elkor" is introduced into formed channel in form of granules.

EFFECT: method ensures elongation of remission terms due to elimination of venous congestion of subchondral zone and normalisation of intraosseous pressure, as well as reduction of surgery traumare.

2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a therapy of the patients suffering rheumatoid arthritis accompanied by secondary osteoarthrosis. The presented method for integrated treatment involves: Methotrexate 7-15 mg per os 1 time a week, non-steroid anti-inflammatory preparations, diacerein 50 mg - 2 times a day in a combination with the exposure to low-intensity laser light, including the exposure of knee joints to skin infrared pulse laser light along a projection of a joint space, and the exposure of blood to supravenous red laser light.

EFFECT: implementing the method ensures an evident analgesic, anti-inflammatory effect, a reduced length of morning stiffness, improved functional capacity and expanded range of motion in the injured joints, as well as lower consumption of non-steroid anti-inflammatory preparations thereby reducing a rate of related side effects.

3 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to solid fast-disintegrating dosage form of medication with antiparkinsonian action, which contains as active pharmaceutical ingredient memantine and/or memantine hydrochloride and cellulose II with the following ingredient ratio, wt %: memantine and/or memantine hydrochloride - 5-10, cellulose II - 90-95. Dosage form can represent pellet, created by method of direct pelletting.

EFFECT: obtaining fast-disintegrating in oral cavity dosage form, its distribution throughout oral cavity and delay of its transport to stomach, in order to provide medication delivery, not entering gastrointestinal tract and eliminating metabolism of medication in liver.

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition with controlled release. Claimed composition includes one or more multiple particles with modified release with dimensions 50-800 mcm, which have effective quantity of one or more therapeutic compounds. Said multiple particles possess known profile of medication release and are subjected to thermal processing into extrudate in thermoplastic polymer matrix or lipid material. Invention also relates to method of obtaining pharmaceutical composition with controlled release and to pharmaceutical hard dosage form, which includes said composition.

EFFECT: invention ensures preservation of predominance of known profile of release of multiple particle medication when it is released from thermoplastic polymer matrix or lipid material.

35 cl, 6 dwg, 12 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with solid pharmaceutical composition, possessing high physical strength. Claimed invention also presents method of manufacturing solid pharmaceutical composition. Claimed pharmaceutical composition contains 7 varicoloured types of granules in form of capsule. Granules contain, wt %: nikotinamide 1-35; pyridoxine 0.1-8; calcium pantitenate 0.1-15, thiamin 0.1-30; tryptophan 1-30; tocoferol 0.5-5; ascorbic acid 0.1-50; 5-hydroxyanthranyl acid 0.01-10; Riboflavin 0.1-10; folic acid 0.1-6; cyanocobalomin 0.001-6; isoleucin 0.5-10; leucin 0.5-15; lysine 0.5-20; phenylalanine 0.1-5; threonine 0.1-5.0; valin 0.1-8.0; methionine 0.1-15; lactose 1-4.0; ergocalcioferol 1-95.0 and auxiliary substances for obtaining granules.

EFFECT: claimed composition possesses excellent properties of medication release and digectionin application composition possesses hepatoprotective hypolipidemic immunostimulating and normalising kidney activity action.

2 cl. 2 ex. 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to materials based on silicon oxides. Ordered mesoporous silicon oxide material with uniform in size pores in range from 4 to 30 nm is characterised by ratio Q3 to Q4 for silicon atoms smaller than 0.65. Material is synthesised in weakly acidic or neutral conditions with application of alkali metal silicate, amphiphilic blockcopolymer, buffer with pH within the interval from 5 to 7 and, possibly, compound ammonium tetraalkyl. Material has two-dimensional hexagonal structure of ordered mesoporous silicon oxide materials, designated SOK-12. Size of mezopores is preferably in the range from 4 to 12 nm. Size of pores can be precisely regulated by varying synthesis conditions.

EFFECT: obtained ordered mesoporous silicon oxide materials are efficient in their application as materials-carriers for molecules of poorly soluble drugs and for peroral drug forms with immediate release.

13 cl, 48 dwg, 2 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical compositions for preparing infusion solutions of antibacterial and antimycotic preparations, and to methods for preparing them. The declared pharmaceutical compositions are presented in the form of powder, contain sodium chloride and dextrose and particles of colloidal silicone dioxide among which a portion of particles of 5 mcm and less makes less than 35%, in certain weight proportions. A method for preparing said pharmaceutical compositions consists in the fact that sodium chloride in the form of powder and dextrose in the form of powder are mixed with powdered colloidal silicone dioxide in certain proportions; the prepared mixture is mechanically treated by impact abrasion to increase a weight portion of fine particles of silicone dioxide of 5 mcm or less to min. 35%.

EFFECT: group of inventions provides the intensified therapeutic effectiveness of parenteral forms of the antibacterial and antimycotic preparations.

4 cl, 4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of manufacturing compositions, containing potassium bicarbonate and sodium picosulfate, which includes stage of application by spraying sodium picosulfate solution on potassium bicarbonate and drying of said salts with formation of granules, containing sodium picosulfate layer on potassium bicarbonate core. Invention also relates to composition, suitable for obtaining composition, which possesses laxative action, which contains granules, including sodium picosulfate layer, applied on potassium bicarbonate core. Invention also relates to composition, possessing laxative action, and to method of its obtaining, which contains granules of homogeneous mixture of citric acid, magnesium oxide, potassium bicarbonate and sodium picosulfate, and possibly sodium saccharin and/or orange flavouring agent, with granules containing sodium picosulfate, applied on potassium bicarbonate core.

EFFECT: invention is aimed at obtaining composition, which can be used for emptying of bowels before X-ray examination, endoscopy or surgery, which is homogeneous and possesses improved characteristics.

34 cl, 2 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention includes compositions and methods for obtaining activated polymer nanoparticles for targeted delivery of medication. Nanoparticle includes biocompatible polymer and amphiphilic stabilising agent, non-covalently bound with linker, which includes, at least, one elecrophile, selectively reacting with any nucleophile on targeting substance, and places targeting substance on external surface of biodegradable nanoenvelope, active substance being loaded into nanoenvelope. Biocompatible po;ymer includes one or several polyesters, selected from group, containing polylactic acid, polyglycolic acid, copolymer of lactic and glycolic acids and their combinations. Amphiphilic stabilising agent includes polyol. Active substance represents anti-cancer medication, preferably, curcumin.

EFFECT: invention ensures delivery of therapeutic substance to the place of its action.

27 cl, 11 dwg, 2 tbl

Pressed tablets // 2472491

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pressed tablet containing a pressed non-chewable base and a volatile active agent, preferentially menthol or eucalyptol included in a spray-dried granule additionally containing a starch carrier and a polyol granulating agent. The pressed tablet may be a two-layer tablet containing a sparkling layer and a non-sparkling layer with the spray-dried granule included in the sparkling layer. The tablets in the present application are effective to provide decongestant effects in a nasal cavity.

EFFECT: invention additionally refers to the use of starch for increasing release rate of the volatile active agent from the pressed tablet and improving its disintegration smoothness.

12 cl, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and describes pharmaceutical compositions in the form of a capsule consisting of granules containing a therapeutic agent in the form of a homogenous mixture with at least one pharmaceutically acceptable excipient wherein said therapeutic agent means pyrimidylaminobenzamide agent as 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide (nilotinib) or its pharmaceutically acceptable salt, preferentially wherein said nilotinib is hydrochloride monohydrate, and whereon said granule additionally means a surfactant wherein the surfactant concentration additionally means 0 to 1% at weight of said pharmaceutical composition, and wherein said pharmaceutical composition contains a lubricant does not exceed 1% at weight of said pharmaceutical composition. What is also described is a method for preparing pharmaceutical compositions.

EFFECT: compositions provide bioavailability of the therapeutic agents in the oral introduction.

12 cl, 2 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition with controlled release. Claimed composition includes one or more multiple particles with modified release with dimensions 50-800 mcm, which have effective quantity of one or more therapeutic compounds. Said multiple particles possess known profile of medication release and are subjected to thermal processing into extrudate in thermoplastic polymer matrix or lipid material. Invention also relates to method of obtaining pharmaceutical composition with controlled release and to pharmaceutical hard dosage form, which includes said composition.

EFFECT: invention ensures preservation of predominance of known profile of release of multiple particle medication when it is released from thermoplastic polymer matrix or lipid material.

35 cl, 6 dwg, 12 tbl, 10 ex

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