Pharmaceutical composition in form of single oral dose containing levodopa, carbidopa and entacapone, or salts thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a group of inventions involving a pharmaceutical composition, a method of preparing it, a method of treating Parkinson's disease and a method of reducing a 'wear' effect in the given patients by administering the same. The pharmaceutical composition in the form of a single oral dose for treating Parkinson's disease consists of a mixture of a) Levodopa or its salt in an amount of 50 mg to 300 mg in the form of prolonged release, b) Carbidopa or its salt in an amount of 10 mg to 100 mg in the form of prolonged release, wherein the prolonged release is ensured by coating or mixing Levodopa and Carbidopa with one or more rate control polymers, and c) Entacapone or its salt in an amount of 100 mg to 1000 mg in the form of prolonged release, optionally with other pharmaceutically acceptable excipients.

EFFECT: group of inventions promotes patient's treatment compliance; using it leads to a stable blood content of active antigens and to reducing administration rate that provides reducing the 'wear' effect in the patients with Parkinson's disease; besides, the additional technical effect ensured by the composition consists in its stability at high temperature and humidity.

9 cl, 15 tbl

 

The technical field to which the invention relates.

Provided a pharmaceutical composition in the form of a single oral dose containing (a) levodopa or a salt thereof in an amount of from about 50 mg to about 300 mg in the form of prolonged release b) carbidopa or a salt thereof in an amount of from about 10 mg to about 100 mg in the form of extended release and (C) entacapone or its salt in an amount of from about 100 mg to about 1000 mg in the form of a continuous release, optionally with other pharmaceutically acceptable excipients. The invention also relates to a method for obtaining such compositions.

The level of technology

Entakapon, an inhibitor of catechin-O-methyltransferase (COMT), is used in the treatment of Parkinson's disease as an adjunct to therapeutic treatment of levodopa/carbidopa. The chemical name of entacapone - (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula C14H15N3O5and the structural formula

Carbidopa, an inhibitor of decarboxylation of aromatic amino acids, is a crystalline compound white, soluble in water. Its chemical name is(-)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxy shall ensol)propionic acid. Its empirical formula C10H14N2O4and its structural formula

Levodopa, an aromatic amino acid, is a white crystalline compound color, soluble in water. Its chemical name is (-)-L-α-amino-β-(3,4-dihydroxybenzyl)propionic acid. Its empirical formula C9H11NO4and its structural formula

In U.S. patent No. 6500867 and 6797732 described oral solid tablet compositions containing entacapone, levodopa and carbidopa or their pharmaceutically acceptable salts or hydrates and pharmaceutically acceptable excipient.

In U.S. patent 7094427 and U.S. patent 20040166159 described composition containing the component immediate release and extended release.

In U.S. patent 20080051459 described method of treating Parkinson's disease comprising the introduction of a pharmaceutically effective amount of a composition containing l-DOPA.

In U.S. patent 20070275060 described tablet prolonged release, including prolonged release composition containing levodopa and composition of immediate or fast release containing carbidopa.

In WO 07/073702 described multi-layered tablet provides three different profile you who are aware.

In U.S. patent 20060173074 described a method of treating restless legs syndrome in a mammal.

Entakapon available in the form of a composition of immediate release under the brand name Comtan®. Sales concentration is 200 mg

The triple combination of levodopa, carbidopa and entacapone available in the form of a composition for the immediate release of various concentrations. For example, Stalevo® 50 (containing 12.5 mg carbidopa, 50 mg of levodopa and 200 mg of entacapone), Stalevo® 75 (containing 18.75 mg carbidopa, 75 mg of levodopa and 200 mg of entacapone), Stalevo® 100 (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone), Stalevo® 125 (containing 31,2575 mg carbidopa, 125 mg of levodopa and 200 mg of entacapone), Stalevo® 150 (containing 37.5 mg carbidopa, 150 mg of levodopa and 200 mg of entacapone) and Stalevo® 200 (containing 50 mg carbidopa, 200 mg of levodopa and 200 mg of entacapone).

Parkinson's disease is a slowly progressive disease, symptoms of which are compounded over time. Therefore, the symptoms will change and develop. The nature of the symptoms can vary for each person. However, after several years, some people may see changes in how their drug control their symptoms. These changes are commonly known as motor fluctuations. Over time the symptoms start to come back, before it's time to take the next dose of Lech is STV levodopa. This change in symptoms referred to as "wear and tear". As soon as the wear becomes noticeable amount of time for a good response to levodopa (known as the "enable") decreases, and the weak response to levodopa (known as the "off"time) may increase.

In the early stages of the disease the brain is able to store a sufficient amount of dopamine. This allows more uniform release of dopamine in the brain. In addition, it provides a more constant control of symptoms. However, as Parkinson's disease aggravated, in the brain becomes smaller cells that can absorb levodopa and to store it in the form of dopamine to release at low concentrations. Due to this reduced ability to store dopamine in the brain the symptoms can return after shorter periods of time (for example, "wear"). If someone with a reduced ability to store dopamine give too much levodopa, it can lead to side effects (eg, psoriasis).

There is an opportunity to better control these symptoms by changing, or modulating treatment. As soon as experiencing these motor fluctuations, there may be other undesirable side effects. They include involuntary movements known as dyskinesia (the example motion twisting/rotation) or dystonia (e.g., prolonged muscle spasm). In patients receiving treatment for Parkinson's disease, can often develop motor fluctuations characterized by failure of the end of treatment, dyskinesia and akinesia at peak dose, and therapeutic treatment of levodopa (wear), in which patients suffer from unpredictable fluctuations from mobility to immobility. More than 50% of patients with Parkinson's disease after therapeutic treatment with levodopa develop motor response fluctuations (the phenomenon of "wear"). Symptoms of wear include bradykinesia, dystonia, tremor, reduced manual dexterity, paresthesia, muscle pain, weakening voice.

It is assumed that the effect of wear can be minimized in patients with treatment that provides properties less rapid dissolution and will lead to a more uniform profile of levodopa in the plasma. When introduced in combination with levodopa entakapon increases the bioavailability of levodopa, promoting its passage through the blood-brain barrier. Therefore, entacapone adopted as an aid in the treatment of levodopa Parkinson's disease. However, the dose currently available drug levodopa and entacapone, that is, Stalevo®, on the Ute eight times a day. Frequent dosing of these drugs is associated with more fluctuating concentrations entacapone in the plasma. In addition, this mode is not conducive to the adherence of the patient to treatment.

In addition, it was observed that the patient extremely uncomfortable at the same time to take the tablet Sinemet CR and Comtan several times a day, which leads to nepodvijnosti patient treatment, especially in the case of a patient with Parkinson's disease. In addition, the literature also suggests that if these three ingredients - entacapone, carbidopa and levodopa are together, this leads to reduced bioavailability of entacapone and levodopa. Therefore, in commercially available drug Stalevo a significant part of carbidopa contained separately from levodopa and entacapone. In addition, the literature also reports on the destabilization of the drug with the triple combination in the presence of microcrystalline cellulose.

Therefore, there is a need to promote adherence of the patient to treatment composition entacapone and/or a triple combination comprising levodopa, carbidopa and entacapone, which will dissolve slowly and provide a more uniform profile in plasma of patients with the mode of treatment entacapone or levodopa/entacapone/carbidopa.

The invention

In one aspect of the present invention provided the RA is a new oral dosage pharmaceutical composition, containing a) levodopa or a salt thereof in an amount of from about 50 mg to about 300 mg in the form of prolonged release b) carbidopa or a salt thereof in an amount of from about 10 mg to about 100 mg in the form of extended release and (C) entacapone or its salt in an amount of from about 100 mg to about 1000 mg in the form of immediate release, optionally with other pharmaceutically acceptable excipients.

The following General aspect of the present invention provides a method of treating Parkinson's disease in a mammal, comprising introducing to the needy in the mammal of a single oral dosage pharmaceutical composition comprising (a) levodopa or a salt thereof in an amount of from about 50 mg to about 300 mg in the form of prolonged release b) carbidopa or a salt thereof in an amount of from about 10 mg to about 100 mg in the form of extended release and (C) entacapone or its salt in an amount of from about 100 mg to about 1000 mg in the form of immediate release, optionally with other pharmaceutically acceptable excipients.

The following General aspect of the present invention provides a method of reducing the phenomenon of "wear" in patients with Parkinson's disease, including CE is I introduction to the needy in this patient a single oral dosage pharmaceutical composition, containing a) levodopa or a salt thereof in an amount of from about 50 mg to about 300 mg in the form of prolonged release b) carbidopa or a salt thereof in an amount of from about 10 mg to about 100 mg in the form of extended release and (C) entacapone or its salt in an amount of from about 100 mg to about 1000 mg in the form of immediate release, optionally with other pharmaceutically acceptable excipients.

The following General aspect of the present invention provides a method of receiving a single oral dosage pharmaceutical composition comprising (a) levodopa or a salt thereof in an amount of from about 50 mg to about 300 mg in the form of prolonged release b) carbidopa or a salt thereof in an amount of from about 10 mg to about 100 mg in the form of extended release and (C) entacapone or its salt in an amount of from about 100 mg to about 1000 mg in the form of immediate release, where the method includes: (a) coating or mixing levodopa, carbidopa with pharmaceutically acceptable regulatory speed polymers, (b) entacapone with one or more pharmaceutically acceptable excipients, (C) mixing the mixture from step a) and b) and converting it into a suitable dosage form./p>

Embodiments of this pharmaceutical composition can include one or more of the following characteristics. For example, pharmaceutically acceptable excipients may include one or more of the fillers, bonding agents, lubricants, sweetening agents, coloring and flavoring agents, glidants, dezintegriruetsja substances and so on.

The details of one or more embodiments of the present invention are presented in the description below. Other features, objects and advantages of the invention will be clear from the description and claims.

Detailed description of the invention

Working on the compositions of levodopa, entacapone and carbidopa, the inventors noticed that the compilation of levodopa or carbidopa drug in the form of extended release makes it possible to continuously release levodopa or carbidopa for a long period of time. Thus, the composition of extended release supports extended release of levodopa and carbidopa, leading, thus, to aflocthonous constant concentrations of levodopa and carbidopa in the blood plasma. In addition, it reduces the phenomenon of "wear", which is observed in patients with Parkinson's disease due to fluctuating Konz is ntrace in plasma.

In addition, the inventors have unexpectedly discovered that Sinemet CR and Comtan can be combined in the form of a fixed combination of a single oral dose without affecting the bioavailability of any of the active components in the presence of another. Even microcrystalline cellulose can also be used in the combination with a fixed dose without having any destabilizing effect on the composition of the fixed dose. In addition, the combination of a fixed dose leads to increased commitment to the patient's treatment.

Used in the present description, the term "extended release" refers to a specific release of drugs within a certain period of time, which can last from 4 h to 24 h or more.

Prolonged release pharmaceutical compositions can be achieved by one or more coatings, or embedding in a matrix by using hydrophilic or hydrophobic polymers, or by connecting with ion exchange resins. In addition, sustained release can be achieved also with the help of technology oral osmotic release.

One tablet of the specified composition does not show significant differences in the rate and/or extent of absorption of entacapone compared with 2-4 tablets 200 mg e is Takapuna immediate release commercially available as Comtan®, and levodopa and carbidopa in comparison with one tablet Sineret®CR, administered with an interval of 3-4 hours.

"Bioequivalence" set 90% confidence interval (CI) in the range from 0.80 to 1.25 as for Cmaxand for AUC according to the regulatory standards of Control for sanitary supervision of food and drug administration USA (USFDA) or 90% CI for AUC in the range from 0.80 to 1.25 and 90% CI for Cmaxin the range from 0.70 to 1.43 according to the regulatory standards of the European EMEA.

Used herein, the term "confidence interval" refers to the ordinary meaning known to the person skilled in the art. The confidence interval refers to the statistical interval with a certain probability that a given option will fall in this interval.

Used herein, the term "covariance" refers to the ordinary meaning known to the person skilled in the art. It is a statistical measure of variation of two random variables that are observed or measured in the same average time. This measure is equal to the product of the deviations of corresponding values of two variables from their respective mean values.

The pharmaceutical composition sustained release may include one or more of the tablets,bilayer tablets, three-layer tablet, tablet in tablet, capsule, powder, plates, tablets in the form of capsules, granules, beads, pellets in capsule, minitablets, minitablets capsule beads in a capsule, sachet, and so on.

Levodopa, carbidopa or entacapone can be in the form of powder, pellets, pills, beads, microtablets, minitablets and crystals.

The number of entacapone in these pharmaceutical compositions varies from approximately 100 to approximately 1000 mg. Amount of levodopa in these pharmaceutical compositions varies from approximately 50 to approximately 300 mg. Amount of carbidopa in these pharmaceutical compositions varies from approximately 10 to approximately 100 mg

Suitable regulating the speed of hydrophilic or hydrophobic polymers include one or more of the polyvinyl acetate, acetate cellulose, acetate-butyrate cellulose, acetate-propionate cellulose, ethyl cellulose, fatty acids, fatty acid ester, alkylboron alcohol, wax, shellac, resin, Zein (prolamine corn), povidone, kollidon SR, poly(meth)acrylate, microcrystalline cellulose or poly(ethylene oxide), salt polihronova acid, ethers of cellulose, xanthan gums, tragacanth gum, karaya, guar gum, Arabia gum, Gellan gum, carob gum D. the roar, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, carboxyvinyl polymers, polymerized gelatin, shellac, copolymers of methacrylic acid type With NF, butyrate-cellulose phthalate, hydrofolate cellulose propionate-cellulose phthalate, polyvinyl acetate phthalate (PVAP), acetate-cellulose phthalate (CAP), acetate-trimellitate cellulose (CAT), phthalate of hydroxypropylmethylcellulose, acetate hydroxypropylmethylcellulose, succinate of deoxypyridinoline, karboksimetiltselljulozy (MIXTURE), acetate-succinate of hydroxypropylmethylcellulose (HMPCAS) and polymers and copolymers of acrylic acid type, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic esters and methacrylic acid (Eudragit NE, Eudragit RL, Eudragit RS), and so on. The polymer can be used in an amount of from 0.1 to 50% by weight of the composition.

The pharmaceutical composition sustained release may include one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can include diluents, binders, dezintegriruetsja substances, surfactants, lubricants is, glidant and so on.

A suitable binder may be one or more of the number of povidone, starch, stearic acid, gums, hydroxypropylmethylcellulose and so on. Binder can be used in amounts of from 0.1% to 40% by weight of the composition.

Suitable diluent may be one or more of the microcrystalline cellulose, mannitol, calcium phosphate, calcium sulphate, kaolin, dry starch, powdered sugar, and so forth. The diluent can be used in an amount of from 1 to 50% by weight of the composition.

Suitable disintegrity agent may be one or more of the starch, croscarmellose sodium, crosspovidone, glycolate, starch sodium, and so forth. Disintegrity agent can be used in an amount of 2-20% by weight of the composition.

Suitable lubricating substance may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium fumarate, hydrogenated vegetable oil, glycerinated and so on. The lubricating substance can be used in amounts of from 0.1-5% by weight of the composition.

Suitable glidant can represent one or more of the colloidal silica, talc, corn starch and so on. Glean which can be used in amounts of from 0.1-5% by weight of the composition.

This pharmaceutical composition can be obtained by mixing entacapone with pharmaceutically acceptable excipients to obtain a mixture of entacapone. Levodopa and carbidopa can be mixed with one or more pharmaceutically acceptable polymers and excipients to obtain a mixture of levodopa-carbidopa. A mixture of entacapone and a mixture of levodopa-carbidopa can be mixed with pharmaceutically acceptable excipients and transfer into a suitable dosage form.

Further, the invention is illustrated by the following examples, which are provided only to illustrate the invention and do not limit the framework of the invention. Some modifications and equivalents will be apparent to experts in this field, and it is implied that they are included in the scope of this invention.

Examples

The composition of the portions shown in tables 1 to 23. The following compounds are representative of the preferred compositions of the invention. Getting the example described in detail later.

Example I

Table 1. The pharmaceutical composition of the invention.

Table 1
Ingredients% wt./wt.
IR layer/portion of entacapone
Entakapon38,41
Mannitolof 6.73
The glycolate, starch sodium3,85
Corn starch9,42
Croscarmellose sodiumto 4.62
Povidone1,51
Purified waterAs needed
Extraglandular ingredients
Magnesium stearate0,77
CR layer/portion of levodopa and carbidopa
Levodopa19, 22 the
Carbidopa5,19
Microcrystalline celluloseto 4.62
Povidoneof 3.46
Purified waterAs needed
Extraglandular ingredients
Polyvinylpyrrolidone1,73
Magnesium stearate0,38

The method

Layer/portion of entacapone

Entakapon and mannitol together crushed and sieved. Corn starch, croscarmellose sodium and glycolate, starch sodium jointly screened separately. Substances were placed in a granulator and mixed. Povidone was dissolved in purified water and was grained with a mixed substance. Granular contents were dried. Magnesium stearate was sifted and mixed with the dried granules.

Layer/portion of levodopa and carbidopa

Levodopa carbidopa and microcrystalline cellulose were co-sifted and mixed. Povidone was dissolved in purified water and granulated with the above-mentioned mixed content. Granular contents were dried. Magnesium stearate was screened with polyvinylpyrrolidone and mixed with the dried granules.

Pressing

And layer/portion of entacapone, and layer/portion of levodopa and carbidopa extruded in a double-layered tablet or a tablet in a tablet with entacapone surrounding nested tablet levodopa-carbidopa.

Table 2. Data regarding the dissolution of the composition obtained in accordance with example I.

Table 2
Time (h)% Of released drug substance
LevodopaCarbidopa
0,54545
15858
2,59492
49695

Table 3
Time (min)% Of released drug substance (entacapone)
1051
2070
3079
4585

Table 2 shows data on the dissolution of part of levodopa and carbidopa from the composition obtained according to the composition shown in table 1. Table 3 shows data on the dissolution of the Asti entacapone from the composition, obtained according to the composition shown in table 1. To determine the speed of release of medicinal substances entacapone used the USP apparatus type 2 (50 rpm)in which the medium used 900 ml phosphate buffer pH 5.5 at 37°C±0,5°C. in Addition, to determine the speed of releasing the drug levodopa and carbidopa used the USP apparatus type 2 (50 rpm)in which the medium used 900 ml of 0.1 N Hcl at 37°C±0,5°C.

Example II

Table 4. The pharmaceutical composition of the invention.

Table 4
Ingredients% wt./wt.
IR layer/portion of entacapone
Entakaponto 28.57
Mannitol5,00
The glycolate, starch sodium2,86
Corn starch7,00
Croscarmellose sodium3,43
Povidone1,14
Purified waterAs needed
Extraglandular ingredients
Magnesium stearate0,57
CR layer/portion of levodopa and carbidopa
Levodopato 28.57
Carbidopa7,71
Microcrystalline cellulose6,86
Povidone5,14
Purified waterAs needed
Extraglandular ingredients
PVPto 2.57
Magnesium stearate0,57

The method

Layer/portion of entacapone

Entakapon and mannitol together crushed and p is useualy. Corn starch, croscarmellose sodium and glycolate, starch sodium jointly screened separately. Substances were placed in a granulator and mixed. Povidone was dissolved in purified water and was grained with a mixed substance. Granular contents were dried. Magnesium stearate was sifted and mixed with the dried granules.

Layer/portion of levodopa and carbidopa

Levodopa carbidopa and microcrystalline cellulose were co-sifted and mixed. Povidone was dissolved in purified water and granulated with the above-mentioned mixed content. Granular contents were dried. Magnesium stearate was screened with polyvinylpyrrolidone and mixed with the dried granules.

Pressing

And layer/portion of entacapone, and layer/portion of levodopa and carbidopa extruded in a double-layered tablet or a tablet in a tablet with entacapone surrounding nested tablet levodopa-carbidopa.

Data regarding the dissolution of the composition obtained in accordance with example II.

Table 5
Time (h)% Of released drug substance
Levodopa Carbidopa
0,54343
15858
2,58889
49898

Table 6
Time (min)% Of released drug substance (entacapone)
1059
2076
3082
4587

Table 5 shows data on the dissolution of the composition obtained in accordance with the composition shown in table 4. Table 6 shows data on the dissolution of part of entacapone from the composition obtained according to the composition shown in table 4.

To determine the speed of release of medicinal substances entacapone used the USP apparatus type 2 (50 rpm)in which the medium used 900 ml f is statnogo buffer pH 5.5 at 37°C±0,5°C. In addition, to determine the speed of releasing the drug levodopa and carbidopa used the USP apparatus type 2 (50 rpm)in which the medium used 900 ml of 0.1 N Hcl at 37°C±0,5°C.

Example III

Table 7. The pharmaceutical composition of the invention.

Table 7
Ingredients% wt./wt.
IR layer/portion of entacapone
Entakapon36,36
Mannitol21,27
Povidonewith 3.27
Crosspovidone4,36
Magnesium stearate0,54
Extraglandular ingredients
Talc0,90
Magnesium stearate0,54
CR layer/portion of levodopa and carbidopa
Levodopa18,18
Carbidopa4,90
Microcrystalline cellulose4,36
Povidonewith 3.27
Purified waterAs needed
Extraglandular ingredients
PVP0,16
Magnesium stearate0,03

The method

Layer/portion of entacapone

Entakapon and mannitol together crushed and sieved. Povidone, crosspovidone and mannitol were co-sifted separately. Substances were mixed, gaining mass. Magnesium stearate was sifted and mixed with the above-mentioned mass. The mass is extruded and crushed. Magnesium stearate and talc were sifted separately and mixed with the crushed substance.

Layer/portion of levodopa and carbidopa

Levodopa carbidopa and microcrystalline cellulose were co-sifted and mixed. Povidone was dissolved in purified water and granulated with the above-mentioned mixed content. Granular contents were dried. Magnesium stearate was screened with polyvinylpyrrolidone and mixed with dried gr is a research and educational laboratories have.

Pressing

And layer/portion of entacapone, and layer/portion of levodopa and carbidopa extruded in a double-layered tablet or a tablet in a tablet with entacapone surrounding nested tablet levodopa-carbidopa.

Example IV

Table 8. The pharmaceutical composition of the invention.

Table 8
Ingredients% wt./wt.
IR layer/portion of entacapone
Entakapon27,39
Mannitol21,27
Povidone2,47
Crosspovidone3,29
Magnesium stearate0,41
Extraglandular ingredients
Talc0,68
Magnesium stearate0,41
CR layer/portion of levodopa and carbidopa
Levodopa 27,39
Carbidopa7,39
Microcrystalline celluloseto 6.58
Povidoneis 4.93
Purified waterAs needed
Extraglandular ingredients
PVP2,46
Magnesium stearate0,54

The method

Layer/portion of entacapone

Entakapon and mannitol together crushed and sieved. Povidone, crosspovidone and mannitol were co-sifted separately. Substances were mixed, gaining mass. Magnesium stearate was sifted and mixed with the above-mentioned mass. The mass is extruded and crushed. Magnesium stearate and talc were sifted separately and mixed with the crushed substance.

Layer/portion of levodopa and carbidopa

Levodopa carbidopa and microcrystalline cellulose were co-sifted and mixed. Povidone was dissolved in purified water and granulated with the above-mentioned mixed content. Granular contents were dried. Magnesium stearate was screened with polyvinylpyrrolidone and mixed with wyssen the mi granules.

Pressing

And layer/portion of entacapone, and layer/portion of levodopa and carbidopa extruded in a double-layered tablet or a tablet in a tablet with entacapone surrounding nested tablet levodopa-carbidopa.

Example V

Table 9. The pharmaceutical composition of the invention.

Table 9
Ingredient% wt./wt.
Internal LC-ER tablet core
Levodopa30,77
Carbidopa8,31
Hydroxypropylcelluloseto 4.62
Mannitol1,54
Povidone K0,46
Isopropyl alcohol0,00
Methylene chloride0,00
Magnesium stearate0,46
The mass of the inner ER kernel tablets
External IR granules e is Takapuna
Entakapon30,77
Mannitol 255,38
The glycolate, starch sodiumis 3.08
Croscarmellose sodium3,69
Corn starch7,54
Povidone K1,23
Water0,00
The glycolate, starch sodium1,54
Magnesium stearate0,62
Weight external IR granules entacapone
Total weight pills

The method

Layer/portion of entacapone

Levodopa carbidopa, hydroxypropylcellulose and mannitol were co-sifted and mixed. Povidone K was dissolved in isopropyl alcohol and methylene chloride. Mass from step 1 was granulated using a solution from stage 2 and was dried granules. To the obtained granules was added magnesium stearate and extruded lubricated granules, receiving core is Ableton.

External granules IR entacapone

Entakapon and mannitol were co-sifted. The glycolate, starch sodium, croscarmellose sodium, corn starch together sifted. Povidone K was dissolved in purified water and used for granulating mass with stage 1. The granules were dried. The glycolate, starch sodium was proseware through a suitable sieve and added to the above-described granules. To the above mixture was added magnesium stearate.

Pressing

The tablet in the tablet comprising an inner core tablets LC ER and external granules IR entacapone, extruded by means of a suitable apparatus for pressing.

16
Table 10
TimeLevodopaCarbidopa
Sinemet CRExample ISinemet CRExample I
00000
15201523
3037403840
4552575258
6066706570
7577797579
9085868186
12095969095
15010010294101
18010210397103

Table 11
For entacapone
TimeComtanExample V
000
51717
104739
208872
309882
4510190

Table 11 provides data on the dissolution of the composition obtained in accordance with the composition, s in table 9. To determine the speed of release of medicinal substances entacapone used the USP apparatus type 2 (50 rpm)in which the medium used 900 ml phosphate buffer pH 5.5 at 37°C±0,5°C. in Addition, to determine the speed of releasing the drug levodopa and carbidopa used the USP apparatus type 2 (50 rpm)in which the medium used 900 ml of 0.1 N Hcl at 37°C±0,5°C.

Bio data (fasting)

p> For entacapone -

Table 12
The parameters RKRatio % (T/R)90% CIInside-CV (%)
The lower borderThe upper boundary
Cmax105,4275,03148,1156,28
AUCt106,9291,78124,5623,89
AUV INF106,1491,39123,2723,89

For carbidopa -

Table 13
The parameters RKRatio % (T/R)90% CIInside-CV (%)
The lower border The upper boundary
Cmax142,51120,86168,0525,84
AUCt142,04120,91166,8625,23
AUV INF141,54120,78165,87to 24.84

For levodopa -

Table 14
The parameters RKRatio % (T/R)90% CIInside-CV (%)
The lower borderThe upper boundary
Cmax125,57109,25144,3221,73
AUCt112,57 97,92129,4121,76
AUV INF112,5897,88129,4921,84

Table 12 presents bioprofile of entacapone IR; table 13 presents bioprofile carbidopa ER; table 14 presents bioprofile levodopa ER, obtained according to example V in conditions of starvation compared with the control product Comtan® 200 mg + one tablet of Sinemet CR (manufacturer: Merck; levodopa 200 + carbidopa 50 mg ER tablet). Study design includes double crossover bioequivalence study of 15 normal adult subjects in terms of obtaining food.

Example VI

Table 15. The pharmaceutical composition of the invention.

Table 15
Ingredient% wt./wt.
Internal LC ER tablet core
Levodopa30,30
Carbidopa8,18
Hydroxypropylcellulose4,55
Mannitol1,97
Copolymer of methacrylic acid1,52
Isopropyl alcohol--
Methylene chloride--
Magnesium stearate0,45
External granules IR entacapone
Entakapon30,30
Mannitol 25and 5.30
The glycolate, starch sodium3,03
Croscarmellose sodiumof 3.64
Corn starch7,42
Povidone K1,21
Water--
The glycolate, starch sodium1,52
Magnesium stearate0,61
Total weight pills

Method

Internal LC-ER core tablets

Levodopa carbidopa, hydroxypropylcellulose and mannitol were co-sifted and mixed. Copolymer of methacrylic acid was dissolved in isopropyl alcohol and methylene chloride. Mass from step 1 was granulated using a solution from stage 2 and was dried granules. To the obtained granules was added magnesium stearate and mixed. Mass with stage 4 was grained using suitable dies, receiving core tablets.

External granules IR entacapone

Entakapon and mannitol were mixed and crushed. The glycolate, starch sodium, croscarmellose sodium, corn starch together sifted and mixed. Povidone K was dissolved in purified water. Mass with stage 7 was granulated using a solution from stage 8 and the granules were dried. The glycolate, starch sodium was added to the mass with stage 9 and stirred. Magnesium stearate was added to the mass with the stage 10 and stirred.

Pressing

Dosage form tablets in the tablet received when using the internal cores LC ER pill is to and external granules IR entacapone using an appropriate apparatus for pressing.

1. Pharmaceutical composition in the form of a single oral dose for the treatment of Parkinson's disease, where the composition consists of a mixture of (a) levodopa or a salt thereof in an amount of from about 50 mg to about 300 mg in the form of prolonged release b) carbidopa or a salt thereof in an amount of from about 10 mg to about 100 mg in the form of extended release, where prolonged release is achieved by coating or mixing levodopa and carbidopa with one or more regulatory speed hydrophilic or hydrophobic polymers, and (C) entacapone or its salt in an amount of approximately 100 mg to approximately 1000 mg in the form of an immediate release with other pharmaceutically acceptable excipients, where the composition optionally contains one or more pharmaceutically acceptable excipients.

2. A method of treating Parkinson's disease in a mammal, comprising introducing to the needy in the mammal of a single oral dosage pharmaceutical composition according to claim 1.

3. A method of reducing the phenomenon of "wear" in patients with Parkinson's disease, including an introduction to the needy in this patient a single oral dosage pharmaceutical composition according to claim 1.

4. The way to get a lump of oral dozirovanno the second pharmaceutical composition according to claim 1, where the method includes: (a) coating or mixing levodopa, carbidopa with one or more pharmaceutically acceptable regulatory speed hydrophilic or hydrophobic polymers, (b) mixing entacapone with one or more pharmaceutically acceptable excipients; (c) stirring the mixture from step a) and b) and converting it into a suitable dosage form.

5. The composition according to claim 1, where the composition is one or more of the tablets, bilayer tablets, three-layer tablets, capsules, powder, plates, tablets in the form of capsules, granules, beads, pellets in capsule, minitablets, minitablets capsule beads in the capsule and sachet.

6. The composition according to claim 1, in which the pharmaceutically acceptable regulatory speed hydrophilic or hydrophobic polymers include one or more of the polyvinyl acetate, acetate cellulose, acetate-butyrate cellulose, acetate-propionate cellulose, ethyl cellulose, fatty acids, fatty acid ester, alkylboron alcohol, wax, shellac, resin, Zein (prolamine corn), povidone, kollidon SR, poly(meth)acrylate or poly(ethylene oxide), salt polihronova acid, ethers of cellulose, xanthan gums, tragacanth gum, karaya, guar gum, Arabia gum, Gellan gum, gum carob, with whom she alkali metal alginic acid or pectic acid, of sodium alginate, potassium alginate, ammonium alginate, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, carboxyvinyl polymers, polymerized gelatin, shellac, copolymers of methacrylic acid type C NF, butyrate-cellulose phthalate, hydrofolate cellulose propionate-cellulose phthalate, polyvinyl acetate phthalate (PVAP), acetate-cellulose phthalate (CAP), acetate-trimellitate cellulose (CAT), phthalate of hydroxypropylmethylcellulose, acetate hydroxypropylmethylcellulose, succinate of deoxypyridinoline, karboksimetiltselljulozy (MIXTURE), acetate-succinate of hydroxypropylmethylcellulose (HMPCAS) and polymers and copolymers of acrylic acid type methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic esters and methacrylic acid (Eudragit NE, Eudragit RL, Eudragit RS).

7. The pharmaceutical composition according to claim 1, in which one tablet a specified composition does not show significant differences in the rate and/or extent of absorption of entacapone compared with 2-4 tablets 200 mg entacapone immediate release, commercially available as Comtan® CR, and there is no significant difference in rate and/or extent of absorption of levodopa and carbidopa in comparison with one tablet of Sinemet®, administered with an interval of 3-4 hours.

8. The method of treatment according to claim 2, where o is on the tablet of the specified composition does not show significant differences in the rate and/or extent of absorption of entacapone compared with 2-4 tablets 200 mg entacapone immediate release commercially available as Comtan® CR, and there is no significant difference in rate and/or extent of absorption of levodopa and carbidopa in comparison with one tablet of Sinemet®, administered with an interval of 3-4 hours.

9. A method of reducing the phenomenon of "wear" according to claim 3, where one tablet a specified composition does not show significant differences in the rate and/or extent of absorption of entacapone compared with 2-4 tablets 200 mg entacapone immediate release, commercially available as Comtan® CR, and there is no significant difference in rate and/or extent of absorption of levodopa and carbidopa in comparison with one tablet of Sinemet®, administered with an interval of 3-4 hours.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using an oxadiazolyl compound of the formula I

,

wherein R1 and R2 mean hydrogen; X means a methylene group; Y represents an oxygen atom; n represents an integer of 0, 1, 2 or 3, and m represents an integer of 0 or 1; R3 means a group of N-oxide pyridine according to the formula B which is attached as shown by an unmarked bond: ,

wherein R4, R5, R6 and R7 are the same or different and mean hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl; the term "alkyl" means carbon chains, unbranched or branched, containing one to six carbon atoms; the term "halogen" means fluorine, chlorine, bromine or iodine; or its pharmacologically acceptable salt for preparing a drug for preventing or treating diseases related to the central and peripheral nervous system, wherein the above drug is administered according to a dosage regimen characterised by a dosage rate within approximately twice a day to approximately once every two days.

EFFECT: optimising the dosage regimen.

84 cl, 3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and presents using (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethinyloctahydroindole-1-carboxylic acid methyl ester for treating, preventing or arresting the development of dyskinesia caused by levodopa (L-dopa) in treating Parkinson's disease.

EFFECT: invention refers to a pharmaceutical composition, a kit and a foodstuff containing (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethinyloctahydroindole-1-carboxylic acid methyl ester.

5 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel imidazopyridine or imidazopyrimidine derivatives of formula (I) and to pharmaceutically acceptable salts and esters thereof, where A is N or C(R6); R1 is hydrogen, lower alkyl; R2 is halogen, C(O)NR7R8 or C(O)OR9; R3 is hydrogen, NR10R11; R4 is hydrogen, lower alkyl; R5 is phenyl or thiazolyl or pyridine, which can be substituted with one substitute independently selected from a group consisting of halogen; R6 is hydrogen, halogen, CN, C3-C6cycloalkyl; R7 and R8 are independently selected from a group consisting of hydrogen, lower alkyl, lower alkoxy-lower alkyl, fluoro-lower alkyl, C3-C6cycloalkyl, N(H,lower alkyl)-lower alkyl, hydroxy- lower alkyl, hydroxy-lower alkoxy- lower alkyl, N(lower alkyl2)C(O)- lower alkyl, lower alkoxy, hydroxy-lower alkyl-oxetanyl- lower alkyl, oxo-tetrahydrofuranyl, tetrahydrofuranyl-lower alkyl, hydroxy-fluoro-lower alkyl, tetrahydrofuranyl, phenyl and thiazolyl or pyridine, or R7 and R8 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of pyrrolidinyl, azetidinyl, morpholinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, 3,4-dihydro- 1H-pyrrolo[1,2-a]pyrazinyl, 2-oxa-6-aza-spiro[3.3]heptyl, 5,6-dihydro- 8H-imidazo[1,2-a]pyrazinyl, [1,4]oxazepanyl, piperazinyl, thiomorpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl, where the heterocyclyl is optionally substituted with 1 or 2 substitutes independently selected from a group consisting of halogen, lower alkyl, lower alkyl-C(O), lower alkoxy-lower alkyl, oxo, hydroxy, hydroxy-lower alkyl, N(lower alkyl2); R9 is lower alkyl; R10 and R11 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of piperidinyl, morpholinyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel imidazopyridine or imidazopyrimidine derivatives which are PDE10A inhibitors.

24 cl, 94 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition for treating β-amyloid diseases and synucleinopathies, based on said compound.

EFFECT: obtaining a novel compound and a pharmaceutical composition based thereon, which can be used in medicine to treat such diseases as Alzheimer's disease and Parkinson's disease.

17 cl, 38 dwg, 14 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and aims at treating, preventing or relieving a disease or a condition which is to be treated, prevented or relieved by NMDA receptor inhibition. The method involves administering a total daily dose of approximately 2 to approximately 50 mg of a compound of formula

or a pharmaceutically acceptable salt thereof into the patient in need thereof. What is also declared is using the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating, preventing or relieving the course of a cognitive disorders, a neurodegenerative disorder, pain, depression, attention deficient hyperactivity disorder or an addiction, and for treating, preventing or relieving the course of a disease or a disorder by inhibition of NMDA receptors containing an NR2B subunit wherein a total daily dose of the compound makes from approximately 2 to approximately 50 mg.

EFFECT: group of the inventions is high effective in treating, preventing or relieving the course of a disease or a disorder which is to be treated, prevented or relieved by NMDA receptor inhibition.

10 cl, 6 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using a metabotropic glutamate receptor modulator (mGluR5 modulator) (-)-(3aR, 4S, 7aR)-4-hydroxy-4-meta-tolylethinyl-octahydro-indole-1-methyl carboxylate in a combination with at least one of: L-dopa or a dopa-decarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, or a dopamine agonist, or in each case their pharmaceutically acceptable salt for preparing a therapeutic agent for treating, preventing or delaying the development of Parkinson's disease and/or a disorder related to Parkinson's disease, and a pharmaceutical composition with the above ingredients for the same application.

EFFECT: what is shown is a synergetic effect of the combination as compared with the response caused by administering L-dopa separately, and relieving dyskinesia.

8 cl, 7 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carboxyl- or hydroxyl-substituted benzimidazole derivatives of formula (I), or pharmaceutically acceptable salts thereof, where R1 is selected from and , R2 is hydrogen; R3 is cyclohexyl or bicyclo[2.2.1]heptyl; R4 is phenyl, which is substituted in the 4th position with a halogen or a lower fluoroalkyl, or a pyridyl, which is substituted with 1 or 2 substitutes independently selected from halogen and a lower alkoxy group; R5 and R6 independently denote hydrogen or fluorine; R7 and R9 are independently selected from a group consisting of hydrogen, lower alkyl, halogen, lower alkoxy group, lower fluoroalkyl, lower fluoroalkoxy group and cyano group; R8 is -(CR12R13)n-COOH, where n equals 0, 1 or 2, and R12 and R13 are independently hydrogen or lower alkyl, or -O-(CR14R15)p-COOH, where p equals 1 or 2, and R14 and R15 are independently hydrogen or lower alkyl, or R14 and R15 together with the carbon atom with which they are bonded form a cycloalkyl ring, or R8 is tetrazole; R10 is a hydroxy group or -(CH2)p-COOH, where p equals 0 or 1; m equals 0 or 1; R11 is -COOH. The invention also relates to specific carboxyl- or hydroxyl-substituted benzimidazole derivatives and a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel carboxyl- or hydroxyl-substituted benzimidazole derivatives, having selective activity with respect to farnesoid X receptor, are obtained.

26 cl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with application of mimotopes for treatment of β-amyloidosis, including Alzheimer's disease, where said mimotopes, are polypeptides, which contain from 4 to 20 amino-acid residues and are able to induce in vivo formation of antibodies to complete Ap 1-40/42 and short-cut from N-end forms AβpE3-40/42, Aβ3-40/42, Aβ11-40/42, AβpEl 1-40/42 and Aβ14-40/42 without impairment of physiological function of FHT.

EFFECT: group of inventions ensures reduction of risk of autoimmune diseases when introduced to subject.

29 cl, 3 ex, 4 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: dry powder composition for pulmonary inhalation Parkinson's disease contains apomorphine and magnesium stearate with a nominal dose of apomorphine being 3 to 10 mg and providing a dose of fine particle fraction (FPF) making 2 to 6 mg when administered. A method for preparing the composition involves the stages of combining the apomorphine particles with the magnesium stearate particles by mixing and milling, milling including compression.

EFFECT: composition under the invention contains apomorphine in a stable dry powder form suitable for the direct administration of low doses of the drug with minimal adverse side effects.

15 cl, 12 dwg, 13 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: claimed is application of levodopa and carbidopa for preparation of medication, intended for treatment of Parkinson's disease; or for treatment of sleep malfunction in patients with Parkinson's disease, for treatment of motive activity malfunction in patients with Parkinson's disease (versions), where medication contains levodopa and carbidopa in pharmaceutically effective quantity for continuous introduction into intestine for time period, which constitutes 24 h per day or more than one day. Sleep rating scale of patients with Parkinson's disease increased by 130% on the second night after starting twenty-four-hour introduction and remained within two following years.

EFFECT: twenty-four-hour introduction of medication replaces frequent per oral intake of medications, makes it possible to reach claimed prescriptions, with preservation of stable response to on medication introduction, which is not accompanied by development of clinically significant tolerance or side effects.

17 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to using a polyurethane polymer as a drug delivery system to provide the biologically active risperidone delivery at a constant speed for a relatively long period of time, as well as to methods for using it.

EFFECT: system provides high biological compatibility and biological stability and is applicable as an implant in patients (humans and animals) for the risperidone delivery to tissues and organs.

25 cl, 13 dwg, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: group concerns a prolonged delivery of a compstatin analogue, as well as an optional additional active agent when released from a microscopic gel-like inclusion formed if a liquid composition containing the compstatin analogue is introduced into an extravascular space, such as a vitreous chamber of eye in a mammalian body. The invention also refers to a method of treating an individual suffering age-related macular degeneration (ARMD).

EFFECT: improving the compstatin delivery system for the complement system inhibition required for treating ARMD.

58 cl, 4 ex, 6 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical compositions containing (2-hydroxyethoxy)amide 6-(4-brom-2-chlorophenylamino)-7-fluor-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrosulphate and solvates, crystalline forms and amorphous forms thereof, to using the above compositions as a drug; and to methods for preparing the above compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 7 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for outpatient treatment and prevention of the cardiovascular diseases, containing therapeutic amounts of a vasodilator, a renin-angiotensin system inhibitor, a thrombocyte aggregation inhibitor, a cholesterol-lowering agent, and an antihypoxic agent. As a vasodilator, the declared composition contains an agent possessing α-adrenergic receptor antagonist action, and a thrombocyte aggregation inhibitor is presented by an ADP-dependent thrombocyte activation mechanism blocking agent.

EFFECT: invention provides the integrated therapeutic effect on the cardiovascular system after acute administration that improves the compliance with treatment regimen by the patient.

20 cl, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: microparticle contains an agglomerate of particles containing a hydrophilic active substance, wherein the particle contains an amphiphilic polymer composed of a hydrophobic segment of polyhydroxy acid and a hydrophilic segment of polysaccharide or polyethylene glycol, and a hydrophilic active substance. What is also disclosed is a method of producing the agglomerated microparticles, which involves (a) a stage of preparing a reverse phase emulsion, (b) a stage of preparing a solid residue containing the hydrophilic active substance, and (c) a stage of introducing the solid residue into a liquid phase containing a surface modifier.

EFFECT: agglomerated microparticles provide the effective encapsulation of the hydrophilic active substance and the release of the hydrophilic active substance at an appropriate speed.

14 cl, 22 dwg, 4 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents gel-forming mixed dextran esters containing phosphate and carbamate groups of general formula: {C6H7O2(OH)3-x-y{[(OP(O)ONa)mONa)]xl[(O2P(O)ONa)k]x2}x(OCONH2)y}n, wherein x=x1+x2 is a degree of substitution in phosphate groups (mono- and diesters), x=0.47-1.09; X1 is a degree of substitution in monoesters, X1=0.01-0.48; m is a number of phosphates in monoesters, m=1-2; x2 is a degree of substitution in diesters, x2=0.01-1.09; k is a number of phosphates in diesters, k=1-2; y is a degree of substitution in carbamate groups, y=0.39-1.23; n is a degree of polymerisation, 20≥n≤1000.

EFFECT: invention provides producing low-toxic low- and high-substituted dextran phosphates in the form of hydrogels containing additionally carbamate groups and possessing antiproliferative activity with respect to cancer cells.

2 cl, 3 dwg, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmacy and represents microsphere with controlled release, which has covering layer and contains core, which contains exendin as active ingredient and biodegradable polymer, and covering layer, which covers core with covering material, exendin being exendin-4 (SEQ ID NO:2), biodegradable polymer represents polymer, selected from group, consisting of polylactide (PLA), polyglycolide (PGA), lactide and glycolide copolymer (PLGA), polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and polyalkylcarbonate; copolymer or simple mixture of two or more polymers, selected from said group of polymers; copolymer of said polymer and polyethylene glycol (PEG); or polymer-sugar complex, in which sugar is bound with said polymer or said copolymer, covering material is selected from group, consisting of essential amino acids, polypeptides and organic nitrogenous compounds, essential amino acid being one or more, selected from group, consisting of arginine, lysine and histidine; polypeptide represents L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and organic nitrogenous compound is selected from group, consisting of creatine, creatinine and urea, content of covering layer constitutes from 0.01 to 5 wt fractions in terms per 100 wt fractions of microsphere.

EFFECT: invention ensures increase of bioaccessability and reduction of initial peak of exendin for prevention of such side effects as vomiting, nausea, headache.

10 cl, 7 ex, 5 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form contains oxycodone hydrochloride as a physiologically active substance (A), optionally one or more physiologically combined excipients (B), a synthetic or natural polymer (C) and optionally natural, semisynthetic or synthetic wax (D).

EFFECT: dosage form of oxycodone hydrochloride possess degradation resistance of at least 400 N to less than 500 N, and releases max 99% of oxycodone hydrochloride in the physiological conditions after 5 h.

14 cl, 7 dwg, 17 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to medicine. What is declared is a delayed release complex pharmaceutical composition containing a delayed release part and an immediate release part. The delayed release part contains AII-receptor blocker as an 'active ingredient'. The immediate release part contains HMG-CoA reductase inhibitor as an active ingredient.

EFFECT: declared composition is effective for treating hypertension and preventing complications in the patients suffering metabolic syndromes, such as diabetes, obesity, hyperlipidemia, coronary vessel disease, etc.

10 dwg, 13 bl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical preparation for controlled release of a contained active ingredient, differing by the fact that said pharmaceutical preparation contains medically acceptable yeast able for alcoholic fermentation.

EFFECT: invention provides release of the active ingredient from the pharmaceutical preparation regardless of the environmental conditions.

13 cl, 4 ex, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to using a polyurethane polymer as a drug delivery system to provide the biologically active risperidone delivery at a constant speed for a relatively long period of time, as well as to methods for using it.

EFFECT: system provides high biological compatibility and biological stability and is applicable as an implant in patients (humans and animals) for the risperidone delivery to tissues and organs.

25 cl, 13 dwg, 3 tbl, 5 ex

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