Pharmaceutical formulations containing nitrocatechol derivatives, and methods for preparing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a storage-stable pharmaceutical composition and a pharmaceutical formulation containing at least one active pharmaceutical ingredient presenting a nitrocatechol derivative, 2,5-dichlor-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, at least one excipients and at least one binding agent, wherein at least one excipient is other than a phosphate derivative, wherein at least one binding ingredient is other than a polyvinylpyrrolidone compound, and wherein the above active pharmaceutical ingredient is present in the granulated form.

EFFECT: compositions and/or formulations according to the invention are stable for a long period of time and show a high stability if stored in the high temperature and moisture environment.

26 cl, 8 tbl, 4 ex

 

The present invention relates to compositions and pharmaceutical formulations comprising at least one active pharmaceutical ingredient selected from derivatives of nitrocatechol and their salts,

Levodopa (L-DOPA) has been used in clinical practice for several decades for symptomatic treatment of various diseases, including Parkinson's Disease. Levodopa is able to penetrate the blood-brain barrier, where it is then converted into dopamine and increases its level. However, the conversion of levodopa into dopamine may also occur in peripheral tissues, sometimes causing adverse effects when prescribing levodopa. Therefore, in standard clinical practice in conjunction with levodopa administered inhibitor of peripheral amino acid decarboxylase (AADC), such as carbidopa or benserazide, which prevents the conversion of levodopa to dopamine in peripheral tissues.

This has led to the need for the development of inhibitors of the enzyme catechol-O-methyltransferase (COMT), based on the hypothesis that the inhibition of the enzyme can provide clinical improvement in patients affected by Parkinson's disease treated with levodopa, starting with the catalysis of the decomposition of COMT levodopa.

It was discovered and formulated in international Publication no WO 2007/013830 and No. WO 2007/11715, what connection are disclosed here for the formula 1 that are derivatives of nitrocatechol, are potent inhibitors of COMT for long periods. These compounds are biologically active and bioavailable. Thus, the compounds of formula 1 have potentially valuable pharmaceutical properties in the treatment of several disorders of the Central and peripheral nervous system, when the inhibition of O-methylation of catecholamines may be therapeutically beneficial, e.g., in mood disorders, diseases and disorders, Parkinson's, restless leg syndrome, gastrointestinal disorders, conditions of the formation of edema and hypertension. In addition, these compounds may also be used in the treatment of other diseases and disorders that are not associated with inhibition of O-methylation of catecholamines.

It was also found that the compounds according to the formula 1 are sensitive to certain excipients (auxiliary substances), which can cause decomposition of the compounds of formula 1 and/or insufficient stability of the compounds and compositions containing these compounds. Compounds of formula 1 can also show low bulk density and/or poor flowability, which can create difficulty for the technology of preparation of medicines and/or sustainable production of medicinal Fort�s, contains the active connection.

The inventors have found a stable compositions and formulations comprising at least one active pharmaceutical ingredient (API) selected from derivatives of nitrocatechol by the formula 1, as defined here, as well as their salts, esters, hydrates, solvates and other derivatives. At least one derivative of nitrocatechol is preferably 2,5-dichloro-3-(5-(3,4-dichlorome-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide or 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2-diol. At least one derivative of nitrocatechol can also be a mixture of 2,5-dichloro-3-(5-(3,4 dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2 diol.

At least in one version of the API is presented in granular form. In some embodiments, compositions and/or formulations may include additional active pharmaceutical ingredient (API). For example, compositions and/or compounds in addition to at least one API selected from derivatives of nitrocatechol by formula 1, may include such further AFI as levodopa, an inhibitor of peripheral amino acid decarboxylase (AADC), such as carbidopa or benserazide. In the following performances, compositions and/or composition� may also include, at least one filler and at least one binder component. Preferably, the filler was not derived phosphate. Preferably, the binder component is a compound derivative of polyvinylpyrrolidone (PVP). In various embodiments, if the API is present in granular form, at least one filler and at least one binder component can be independently from each other vnutrepenialnymi (i.e. granular with API and/or contained within the same granules that and AFI), ehkstragirovanie (i.e. outside of the pellets API) or partially vnutrepenialnymi and partially ehkstragirovanie. In further embodiments of the present disclosure, the composition can have a bulk density greater than one API, and it is in certain performances can be greatly increased. The composition may also have other improved characteristics, such as compressibility. Using the methods described here can lead to improved properties of the granules of the compositions, such as grain size, uniformity of granule size and/or weight of the granules. Compositions and/or formulations are stable over time and under various conditions and in certain versions show increased stability.

For a detailed description.

You need to understand that the preceding General description and the following detailed description are only exemplary and explanatory and do not limit the invention. Other embodiments of the invention will be obvious to specialists when considering the specification and the implementation in practice of the invention disclosed here.

In various embodiments the present invention relates to stable compositions and formulations comprising at least one API selected from derivatives of nitrocatechol by the formula 1, as defined here, as well as salts, esters, hydrates, solvates and other derivatives of nitrocatechol by the formula 1; at least one filler; and at least one binder component. In the next version, at least one filler is not derived phosphate and/or at least one binder component is a compound derived PVP. AFI may be present in granular form.

Used here, the term "pellet", "granulated," "pellets API" and its variations refers to particles obtained by wet or dry granulation of the active pharmaceutical ingredients, selected from derivatives of nitrocatechol by the formula I as defined herein, as well as salts, esters, hydrates, solvates and other derivatives of nitrocatechol by the formula 1. In different incarnations of the existing revealed� API may include two or more derivatives of nitrocatechol by the formula I. For example, the composition may include 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4] oxidiazol-5-yl]-3-nitrobenzene-1,2 diol. Next, the granules may include at least one filler and/or at least one binder component.

As used herein, the term "kompozicija" and its variations is intended to mean a composition comprising at least one API selected from derivatives of nitrocatechol by the formula 1, as defined here, as well as salts, esters, hydrates, solvates and other derivatives thereof and at least one filler, and at least one binder. In certain embodiments, the composition may include two or more derivatives of nitrocatechol by the formula 1 (i.e., APIs), for example, the composition may include 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1, 2 diol, at least one phosphate derivative, and at least one compound derived PVP. The composition may include granules, at least one API; and at least one filler and at least one binder component can be independently vnutrepenialnymi (i.e. granular with API and/�whether contained within the same granules, that and AFI), ehkstragirovanie (i.e. outside of the pellets API) or partially vnutrepenialnymi and partially ehkstragirovanie. For example, the filler can be from 10% to 90% by weight, from 20% to 80% by weight, from 30% to 70% by weight, from 40% to 60% by weight or approximately 50% of the weight vnutrirezonatornym, and the remainder is extraglomerular. The binder component can be from 10% to 90% by weight, from 20% to 80% by weight, from 30% to 70% by weight, from 40% to 60% by weight or approximately 50% of the weight vnutrirezonatornym, and the remainder is extraglomerular. The composition may further include at least one excipient that can be vnutrirezonatornym, extrachromosomally, or partially inside and partially extrachromosomally. It is preferable that the composition was suitable for filling capsules of manufacture of tablets and/or suitable for direct appointments to patients, for example, was packaged in tea bags.

As used herein, the terms "composition" and "pharmaceutical composition" and variations thereof are intended to include the compositions described herein, which are further manufactured or formulated in dosage form. For example, in various exemplary embodiments, the composition may include a composition described herein, usually in the form of granules, in a dosage form appropriate for the purpose� subject such as capsules or extruded dosage form, such as tablets. In the following exemplary implementation, the composition may include a composition described herein, usually in the form of granules, mixed at least one excipients, in a dosage form suitable for the destination entity, such as a capsule or in the form of a molded dosage form, such as tablets.

Used here are derivatives of nitrocatechol by the formula 1 are defined as follows:

where:

R1and R2independently selected from hydrogen or the group, which is a under physiological conditions, optionally substituted lower alkanoyl or Arola;

X is a methylene group;

Y is an oxygen atom, nitrogen or sulfur,

n is selected from 0, 1, 2 and 3;

m is 0 or 1;

R3is a pyridine group selected from the groups of formulae A, b, C, D, E and F, which is connected, as indicated, using unmarked connection:

where:

R4, R5, R6and R7independently selected from hydrogen, C1-C6-alkyl, C1-C6-thioalkyl, C1-C6-alkoxy, sub> 6-C12-aryloxy or group With6-C12-tiary, C1-C6-alkanoyl or group With7-C13-aroyl, Amin, C1-C6-alkyl amine, C1-C6-dialkylamino, S3-C12-cycloalkylation, S3-C12-geteroseksualen, C1-C6-alkylsulfonyl, S6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, such as trifluoromethyl, CYANOGEN, nitro or heteroaryl group; or two or more of the residue R4, R5, R6and R7taken together represent aliphatic or heteroaromatics ring, or an aromatic or heteroaromatic ring; and P is a Central unit, such as a planar unit, such as a unit selected from regioisomeric 1,3,4-oxadiazol-2,5-diyl; 1,2,4-oxadiazol-3,5-diyl; 4-methyl-4H-1,2,4-triazole-3,5-diyl; 1,3,5-triazine-2,4-diyl; 1,2,4-triazine-3,5-diyl; 2H-tetrazol-2,5-diyl; 1,2,3-thiadiazole-4,5-diyl; 1-alkyl-3-(alkoxycarbonyl)-1H-pyrrol-2,5 diyl, where the alkyl represented bromide, ethyl, n-propyl and n-butyl, and where the alkoxy represented by methoxy, ethoxy, n-propoxy and isopropoxy; 1-alkyl-1H-pyrrol-2,5-diyl, where the alkyl represented bromide, ethyl, n-propyl and n-butyl; a thiazole-2,4-diyl; 1H-pyrazole-1,5-diyl; pyrimidine-2,4-diyl; oxazol-2,4-diyl; carbonyl; 1H-imidazole-1,5-diyl; isoxazol-3,5-diyl; furan-2,4-diyl; 3-alkoxycarbonyl-2,4-diyl where and�coxi presents methoxy, ethoxy, n-propoxy and isopropoxy; benzene-1,3-diyl; and (g)-1-CYANOGEN-1,2-diyl. Suitable groups which are a under physiological conditions, known in the technology and include groups that are formed with About atom, ether, ester, carbonic acid or ester bond.

Preferably, R is selected from 1,3,4-oxadiazol-2,5-diyl and 1,2,4-oxadiazol-3,5-diyl.

At least one derivative of nitrocatechol by the formula 1 is preferably 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide or 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2-diol.

At least one derivative of nitrocatechol by the formula I can also be a mixture of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2-diol.

In embodiments where at least one derivative of nitrocatechol is a mixture of two derivatives of nitrocatechol, such as 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2 diol, the ratio of these two components can be approximately 50:50 or any variation of this ratio, approximately 60:40, 70:30, 0:20, 90:10, 95:5, 97:3 or 99:1, or one of the derived nitrocatechols may be present in an amount of not more than and including 5%, up to and including 3% or up to and including 1% of the number of other nitrocatechol; for example, 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2-diol may be present in an amount of not more than and including 5%, up to and including 3% or up to and including 1% of the quantity of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide.

At least one API selected from derivatives of nitrocatechol by the formula 1 disclosed here, and salts, esters, hydrates, solvates and other derivatives thereof, can show low bulk density, thus complicating the technology of preparation of medicines and manufacture of dosage forms. For example, 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1, 2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, nitrocatechol by the formula 1, shows a bulk density less than 0.1 g/ml to granulation and/or preparation of medicines, and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2-diol can show bulk density of about 0.2 g/ml to granulation, and/or preparation of medicines, as defined by the method described here below.

The technology of preparation of API (active pharmaceutical�technical ingredient) low bulk density is complex. For example, the lack of uniformity of content, segregation of particles, small fluidity or lack thereof likely to lead to variability of weight, delamination of tablets and increased brittleness.

At least, in one exemplary implementation, the amount (or dosage), at least one API in the compositions and/or formulations is preferably a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means an amount of therapeutic agent sufficient to treat, alleviate and/or to any extent prevent any disease amenable to treatment and/or prevention of diseases of the appointment of the compositions of this disclosure. The number may, for example, be sufficient to demonstrate a detectable therapeutic, prophylactic or improvement effect. The effect may include, for example, treatment, alleviation and/or prevention of the conditions listed here. In fact, the required number, for example, for the treatment of any particular patient will depend upon a variety of factors including the disorder being treated and/or prevent; its severity; the specific pharmaceutical composition; the age, body weight, General health, gender and diet of the patient; with�persons destination; the destination; the destination; the rate of excretion of therapeutic agent; the duration of the treatment; any drugs used in combination or at the time of reception of therapeutic agent; and other such factors known in the art. In various embodiments, for example, a composition, i.e. a dosage form as capsules or tablets, may contain 1 mg or more APIs, such as 2.5 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 40 mg or more, 50 mg or 100 or more mg or more APIs. The content of the active pharmaceutical ingredients in the mix can vary from 0.02% to 90% by weight, for example from 0.1% to 70% by weight, from 0.2% to 50% by weight or from 0.3% to 45% of the weight.

At least one filler of the present disclosure include calcium carbonate, cellulose powder, milifilianjo microcrystalline cellulose, cellulose acetate, compressible sugar, confectionery sugar, dextran, dextrin, dextrose, fructose, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, megatextures, simethicone, sodium alginate, sodium chloride, sorbitol, starches, pregelatinized starch, sucrose, trehalose, and xylitol.

Preferably, at least one filler has not been derived phosphate. As used herein, the term "phosphate derivative" and its variations� is intended to refer to substances, including calcium phosphate, including, but not limited to: calcium phosphate, dibasic anhydrous (e.g., A-TAV™, Di-Cafos A-N™, Emcompress™ Anhydrous, and Fujicalin™); calcium phosphate, dibasic dehydrate (e.g., Cafbs™, Calipharm™, Calstar™, Di-Cafos™, Emcompress™); calcium phosphate tribasic (for example, Tri-Cafos™, TRI-CAL™ WG, TRI-TAB™). In a further implementation, at least one filler may be selected from starches, lactose and cellulose. At least in one version may be present, at least two of the filler, for example a combination of starch, lactose and/or cellulose.

In various embodiments, at least one filler may be from 0.5% to 99.5% by weight of the composition and/or composition, for example from 20% to 95% by weight, from 40% to 95% by weight, from 40% to 85% by weight, from 40% to 70% by weight, from 60% to 95% by weight, or from 80% to 95% of the total weight of the composition and/or composition. The filler may be vnutrirezonatornym, extraglomerular or partially vnutrirezonatornym and partially extrachromosomally. For example, the composition and/or composition can include 85% of the weight of the filler. The amount of at least one filler is replaced, in part, on the desired dosage, bulk density and stability of the composition and/or composition.

At least one binder component of the present disclosure may be selected from acacia, alginic acid, carb�RA, of sodium carboxymethylcellulose, carob, cottonseed oil, dextrin, dextrose, gelatin, the guar resin, hydrogenated vegetable oil type 1, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl cellulose, nitrosamines of hydroxypropyl cellulose, hypromellose, magnesium silicate aluminum, maltodextrin, maltose, methylcellulose, ethyl cellulose, microcrystalline cellulose, megatextures, polyethylene oxide, megamethanol, sodium alginate, starch, pregelatinized starch, stearic acid, sucrose, and Zein.

In various embodiments of the present disclosure, at least one binder component is not derived compounds PVP. As used herein, the term "derivative of compound PVP" and its variations are used to indicate substances comprising polyvinylpyrrolidone (PVP) and its substituted versions, including but not limited to: povidone (e.g., plasdone and kollidon); copovidone (e.g., plasdone S-630™ and kollidon VA-64™); and poperechnyy PVP (e.g., copovidone). In the next version, at least one binder component can be selected from starches, and at least in one version it can be starch 1500™.

In various embodiments, at least one binder component may be from 0.5% �about 40% of the weight of the composition and/or composition, for example, from 1% to 25% by weight, from 5% to 20% by weight, from 8% to 15% by weight, or from 10% to 15% by weight of the total weight of the composition and/or composition. The binder component may be vnutrirezonatornym, extraglomerular or partially vnutrirezonatornym and partially extrachromosomally. For example, the composition and/or composition can include between 6 wt% and 8 wt%, such as 7 wt%, or 6.3 per cent of the weight of the binder components. The amount of at least one binder will vary depending, in part, on the desirable dosage, bulk density and stability of the resulting composition and/or composition.

In one exemplary performance composition and/or composition includes APIs from 0.2 to 50 weight -%, binder is from 5 to 10% by weight, the filler is from 33 to 85% by weight, as in the following compositions and/or formulations:

Active pharmaceutical ingredient (API) 0.2 to 50 weight - %

Filler 35,0-85,0% weight

Binder 1,0-15,0% weight

Grease 1,0-15,0% weight

Disintegrant 1,0-15,0% weight

Active pharmaceutical ingredient (API) 30,0-50,0% of the weight

The filler is 35.0-60.0% of weight

Binder 3,0-10,0% of the weight

Of grease of 1.0-10.0% of the weight

Disintegrant 3,0-10,0% of the weight

Active pharmaceutical ingredient (API) 0.2 to 35 weight - %

Filler 50,0-85,0% weight

Binder 3,0-10,0% of the weight

Grease of 1.0-10.0% of the weight

Disintegrant 3,0-10,0% of the weight

Invented�e also relates to compositions, including the composition of the invention. Such compositions can be in various dosage form such as capsules or extruded form, such as tablets.

The invention also includes a method of creating the composition or the composition of the invention comprising the steps:

- crushing, at least one active pharmaceutical ingredient selected from 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-3-nitrobenzene-1,2 diol and its salts to form granules;

- mixing at least one filler, at least one active pharmaceutical ingredient before, during or after granulation;

- mixing at least one binder component, at least one active pharmaceutical ingredient before, during or after granulation; and

- preparation of pharmaceutical composition in the form of dosage forms.

Preferably, the filler was not derived phosphate. Preferably, the binder component is a compound derivative of polyvinylpyrrolidone (PVP).

At least one API, at least one filler and at least one binder component can be combined by mixing (also referred to here as doba�tion). The instruments, the mixing time and the ratio can easily be determined by experts, based, for example, on the number of submitted material, the type of mixing process and other parameters known in the art. For example, in different versions of the product can be mixed by hand, using a mixer, a V-type mixer, a high shear rate, or any other device for mixing and/or process known in the art. Further components can be mixed within any relevant time period, such as from 1 to 20 minutes, or from 2 to 10 minutes.

In various exemplary embodiments, the mixture can be dry or wet granulation. Preferably, the pellets were wet-granulated, and has been used in at least one granulating liquid. For example, at least one granulating liquid can be selected from water, ethyl alcohol, isopropyl alcohol and/or acetone. Preferably, the granulating liquid was water. Suitable device, the mixing time and speed granulating can be determined by specialists based on, for example, the amount of material and the amount of granulating liquid. For example, in various embodiments, the components can granulomatosa manually using mixture�tel high shear rate, planetary mixer or any other device for granulating and/or process known in the art. Further, for example in different versions of the product can split any appropriate interval, such as from 1 to 60 minutes or from 2 to 30 minutes. The end point of granulation is determined by the expert, and it can be determined by observing the stabilization of the grain size and the cohesion of the particles, which reduces the amount of air captured by the granule, or a steady state is reached when the rheological or korrelirovana the definition of voltage, torque, electrical conductivity, power, or near IR techniques. The speed of granulation may vary from 5% to 100% speed mixing granulator, and from 25% to 100%.

After the process of wet granulation is complete, the granules can be dried. Pellets can be dried until the loss in mass on drying (LOD) is less than 6%, preferably below 5% and even more preferably between 1-3%. A suitable method to calculate the loss on drying is described below. A suitable device for drying, drying time and temperature can be determined by specialists based on, for example, the amount of material, moisture content of material, and a granulating fluid. As neogranichivatsya, can be used a fluidized bed dryer or tray-drying rack, drying the granules at a temperature of e.g. 25°C or above 40°C or higher, or 70°C or higher. For example, the pellets can be dried at a temperature of 66°C.

Granules can be sieved. Sieving of the granules allocates granules with defined particle sizes and is used to select particles of the size required for the preparation of dosage forms. In various embodiments, the granules may be sieved through a sieve or a sieve of 0.5 mm or larger, for example 0.6 mm, 0.8 mm, 1.0 mm and 1.6 mm.

The composition may further include at least one additional excipient, which may be mixed with at least one API, at least one filler and at least one binder component before, during or after granulation. For example, in at least one implementation, at least one additional excipient can be selected from such excipients as disintegrant, Gldani and lubrication.

Suitable disintegrant of the present disclosure include agar-agar, calcium carbonate, alginic acid, calcium phosphate (triatomic), carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, copovidone, docusate sodium, guar resin, nitrosamino hydroc�ypropyl cellulose, aluminum silicate of magnesium, methylcellulose, microcrystalline cellulose, sodium alginate, glycolate sodium starch, polacrilin potassium, milifilianjo microcrystalline cellulose, starch and predelineation starch and mixtures thereof. Disintegrate can be a combination of disintegrant and/or at least two presents disintegrant, for example the combination of glycolate sodium starch and carboxymethyl sodium starch, such as manufactured under the trademark Explotab™.

Disintegrant may be from 0.5% by weight to 40% by weight of the composition and/or composition, for example from 1% by weight to 25% by weight, from 5% weight to 20% by weight, from 10% by weight to 15% by weight, or from 5 weight - % to 15 weight -%. For example, the composition and/or composition can include between 6 wt% and 9% of the weight of disintegrant, for example, 6.8% of the weight of disintegrant. The amount of at least one disintegrant depends in part on the desired dose, bulk density and stability of the resulting composition and/or composition.

Suitable glidant (regulators flowability) of the present disclosure include calcium silicate, cellulose, powdered colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch, talc, and mixtures thereof.

Glidant may be from 0.1 weight - % to 15 weight - % of the composition and/or composition, for example from 0.5% by weight to 15% by weight, from 1 weight - % to 10 weight - % or from 2% to 6 weight% of the weight. �number of glidant would in part depend on the desired dose, bulk density and stability of the resulting composition and/or composition.

Lubricants of the present disclosure include calcium stearate, glycerol monostearate, glycerol behenate, the glycerol palmitostearate, hydrogenated castor oil, hydrogenated castor oil type I, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearyl sodium fumarate, stearic acid, talc, sucrose stearate and zinc stearate, and mixtures thereof.

Lubrication can be from 0.1 weight - % to 15 weight - % of the composition and/or composition, for example from 0.5% by weight to 15% by weight, from 1% by weight to 10% by weight, from 1% by weight to 2% by weight or 2% by weight to 8% by weight. The amount of lubricant varies partially to the desired dose, bulk density and stability of the resulting composition and/or composition.

At least one excipient can be added before, during or after mixing with at least one API, and before or during the granulation and, thus, can be vnutrirezonatornym of ecipients. Alternatively, at least one excipient can be added to the composition after granulation, for example, mixing with the granules, and thus may be present as extrachromosomally exipient. In various versions�, at least one first excipient can be added before or during the granulation, and at least one second excipient and/or more than one excipient can be added to the composition after granulation. For example, disintegrant can be added before or during the granulation, while lubricants and glidant can be added after granulation.

Composition comprising at least one API, at least one filler and at least one binder component, can be used to obtain a composition, for example, for filling capsules or pill arrangement.

Capsules for use in the present disclosure include, but are not limited to, capsules, gelatin capsules and hydroxypropylmethyl cellulose (polymer). Appropriate ways of filling such capsules composition according to the embodiment of the disclosure.

Tablets of the present disclosure can be formed by any method known in the art, for example by compression. At least one execution of the present disclosure tablets can be coated, for example, a film water-based coatings, film coatings, based on the solution, and/or sugar shells.

The compositions of the invention may also be colored, for example, the inclusion of the dye in the composition is invented�I and/or coating compositions and/or composition.

At least one execution of the present disclosure, a composition is a capsule comprising at least one API, at least one filler and at least one binder component, preferably in granular form, and may further include at least one glidant and/or at least one disintegrant. At least one execution of the present disclosure, a composition is a tablet comprising at least one API, at least one filler and at least one binder component, preferably in granular form, and may further include at least one glidant, at least one lubricant and/or at least one disintegrant.

The compositions may have increased bulk density and/or fluidity compared to one API. As used herein, the terms "high bulk density", "a significantly higher bulk density" and variations thereof mean that the bulk density of the composition is approximately at least twice, three times, at least four times, or, at least, five times more than one API. An expert can determine the bulk density of the composition or of the composition, using well known methods. Suitable methods include, for example, the European Pharmacopeia edition 6, Test 2.9.15 "apparent volume" pages 285-286, EQM, 2007, and USP 31, vol.1, test <616> page 231-232, The United States Pharmacopeia Convention, 2008. A suitable method is described below:

Device:

device for deposition, can get in 1 minute 250±15 from a height of 3±0.2 mm. Support a graduated cylinder with tripod has a mass of 450±5 g

- 250 ml graduated cylinder (intervals 2 ml) weighing 220±40 g

Method: In a dry cylinder type without seal 100,0 g (t) of the test substance. The cylinder is in the tripod. Measure the apparent volume (Vo) with accuracy to one milliliter. Performed 10, 500 and 1250 measurements and record the corresponding volumes V10V500V1250accurate to milliliters. If the difference between V500and V1250more than 2 ml, still running 1250 measurements.

If it is not possible to take 100,0 g, take any test sample mass, but with a volume of between 50 ml and 250 ml, measure its volume Voas described above, weigh the sample and determine the mass. Volume/bulk density can be determined in g/ml according to the formula:

m/Vo

where m is the mass in grams and Vo- unknown the apparent volume.

Density after abrasion can be determined in g/ml according to the formula:

M/V1250,

where m is the mass in grams and V1250- the apparent volume after 1250 measurements.

For example, as stated earlier, 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-46-dimethylpyridine 1-oxide, nitrocatechol by formula I, has a bulk density less than 0.1 g/ml to pelletizing. The compositions according to the present disclosure that includes 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1, 2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, have a bulk density of 0.2 g/ml or more, for example 0.4 g/ml or more, or 0.5 g/ml or more. The compositions of the present disclosure for use as final mixes for filling capsules or tablets, comprising 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1, 2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, may also have a bulk density of 0.2 g/ml or more, for example 0.4 g/ml or more, 0.5 g/ml or more and 0.6 g/ ml or more.

In certain embodiments of the disclosure the compressed compositions of the disclosure, such as tablets, have a bulk density of 0.5 g/ml to 1.5 g/ml, such as from 0.6 g/ml to 1.4 g/ml 0.7 g/ml to 1.3 g/ml, or from 0.8 g/ml to 1.2 g/ml.

The bulk density of extruded composition is measured in terms of mass and volume composition and known to experts.

Also well-known among the specialists of methods for determining the yield/volume rate of flow of the composition or composition. However, suitable methods include, for example, checking the volumetric flow rate through the hole, described in USP 31, vol. 1, test <1174>, The United States Pharmacopeia Convention, 2008. Fluidity can be measured as mass flowing che�from the opening of the glass pipe with a diameter of 10 mm. The value of the flow velocity greater than 10 g/sec is considered good, whereas a value of the flow rate less than 10 g/h is considered insufficient.

The coefficient of compressibility and the rate of which was also appropriate ways to rate a song or composition. For example, the coefficient of compressibility and the rate of which was can be evaluated using USP 31, vol.1, the test <1174>, The United States Pharmacopeia Convention, 2008, and volume measurement of bulk material (Vo) and the amount of abrasion (Vf) granules. The compressibility index (CI) can then be calculated by the formula:

CI(%)=100×[(V0-Vf)/V0]

Indicator of which was (HR) can be calculated by the formula:

HR=V0/Vf

The coefficient of compressibility is considered good when its calculated value is less than 15%. The index value of which was (a measure of yield) is considered good when its calculated value is less than 1.25.

Compositions and/or formulations are stable and/or show increased stability. As used herein, the terms "stability", "stability" and variations thereof are intended to indicate that less than 15% by weight, of at least one API in the composition and/or the composition is split more than 6 months under the test conditions: 40°C and a relative humidity of 75%, or more than 3 years in testing conditions: temperature 25�C or 30°C and 60% relative humidity, or more than 15-30 days under the test conditions: a temperature of 70°C and unregulated humidity. In various embodiments, for example, less than 10% by weight, less than 8% by weight, less than 6% by weight, less than 5% by weight, less than 4 wt%, less than 3% by weight, less than 2% weight or less than 1% by weight, of at least one API may break down under these conditions. An expert can determine the stability of the compounds, composition or compositions using methods generally accepted in the technology. For example, the number of the at least one API may be measured by any suitable method, such as HPLC (liquid chromatography). For example, in various embodiments the assay analysis sustained composition or the composition (i.e. the number of APIs) can show from 85% to 115% of the API after a probationary conditions, such as 95-105% of the API.

Decomposition is a chemical process consisting of at least one reaction, such as oxidation, reduction or hydrolysis, which causes a chemical change in decaying matter, leading to the generation of one or more new chemical compounds. These new connections (or impurities) can result in a decrease and/or change in the amount of API in the composition and/or composition, reducing its effectiveness, and may have undesirable and/or harmful side effects for patients. As used herein, the term "impurity" means any new connection�s, which is present in the composition and/or the composition in an amount of less than 10% by weight of the API, for example less than 5% by weight, less than 3% by weight, less than 1% by weight or less than 0.5% by weight of the API. Thus, the change in the total amount of impurities in the composition and/or composition under conditions and for specified periods of time set forth herein, may also be indicative of stable compounds or composition and can be measured using a suitable method, such as HPLC. In different versions the total number of impurities in APIs in stable compositions and/or composition after the probation conditions may increase by less than 5% by weight, less than 2% by weight, less than 1% weight or less than 0.5% of the weight.

Stability can also be checked under the influence of the various other test conditions, including, for example:

- temperature 40°C at 75% relative humidity for 6 months;

- the temperature of 25°C or 30°C at 60% relative humidity after 3-5 years (long term conditions); and

- temperature 70°C with uncontrolled humidity after 15-30 days (stressful conditions).

Stability can also be defined appearance. As used herein, the term "visual stability" and its variations are intended to refer to visible color changes, the integrity of the molded dosage form (e.g., not broken), forms �/or size of the granules of the composition and/or composition.

As used herein, the terms "enhanced stability", "increased stability" and variations thereof mean that the magnitude of destruction, at least of the API in the composition and/or composition, and/or the increase of impurities in the composition and/or structure is less than in compound and/or composition that has been subjected to the test conditions.

Unless otherwise indicated, all numbers used in the specification and claims, should be considered, as modified in all samples by the term "approximately". It should also be understood that the precise numerical values used in the specification and claims form additional embodiments of the disclosure. Efforts have been made to ensure the accuracy of the numerical values disclosed in the Examples. Any measured numerical value, however, the integral may contain certain errors resulting from the standard deviation in the corresponding measurement method.

Used here represent "the same", "somewhat" or "at least one" should not be limited to "only one" unless explicitly specified to the contrary. Thus, for example, the use of the words "certain" or "some part" is intended to denote at least one composition.

Other embodiments of the disclosure will be apparent to those skilled in p�smotreniya specification and practice of the present disclosure. The specification and examples should be considered only as exemplary, and in accordance with the scope and spirit of the invention, denoted in formulas.

Examples.

The following examples do not limit the invention.

Example 1

Four small dosing the capsules were made in the scale of the experiment as a result of the first mixing AFI, starch and lactose in amounts shown in Table 1 below (download A-D). APIs used in these examples was 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide. Each mixture was then added purified water, and the mixture was granulated by mixing.

The granules were then dried using a fluidized bed dryer until the loss of volume in the dried granules had not been below 6%. The dried granules were sieved and then mixed with the remaining ingredients formulated in Table 1. Gelatin capsules were filled with the composition, using a machine for filling capsules InCAP HS.

For granules and final compositions were evaluated volume and bulk density using the methods described above. Was also rated flow/volumetric flow rate by measuring the volume rate of flow through the hole as described in USP 31, vol. 1, test <1174>, The United States Pharmacopeia Convention, 2008. Fluidity was measured as the mass flowing per time suosituista glass tube with a diameter of 10 mm. The value of the volumetric flow rate greater than 10 g/sec is considered good, whereas a value less than 10 g/h is considered insufficient.

The coefficient of compressibility and the rate of which was were evaluated using USP 31, vol. 1, the test <1174>, The United States Pharmacopeia Convention, 2008, and measuring volume and bulk material (Voand the amount of abrasion (Vf) granules. Then was calculated the coefficient of compressibility (CI), using the formula:

CI(%)=100×[(Vo-Vf)/V0]

Indicator of which was (HR) can be calculated by the formula:

HR=V0/Vf

The coefficient of compressibility is considered good when its value is less than 15%. The index value of which was (a measure of yield) is considered good when its value is less than 1.25.

Humidity or dryness were determined by loss on drying, as described in USP 31, vol.1, the test <731>, The United States Pharmacopeia Convention, 2008. The test involves accurate weighing of the test substance (I), (for example, the use of model number 1-2 g). Then the test sample was dried at 105°C until it reached constant weight (mf). Humidity can be calculated using the expression:

LOD(%)=[(mo-mf)/mo]*100

The capsules were evaluated for uniformity of weight and impurities. Uniformity of mass was estimated by weighing each of 20 capsules; were then calculated average weight and signicade�ary deviation. The full amount of impurities was obtained using HPLC method with a limit of determination of the quantity less than 0.05%.

The results are formulated in Table 2 below. All download showed good characteristics of granules and capsules.

Example 2

Had four capsules dosing in laboratory scale mixing in the first mixer V-type APIs, starch and lactose in amounts formulated in Table 1 (download the E-H). APIs used in these examples was 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide. To each mixture was added purified water and the mixture was mixed manually. Then, the thus obtained wet mass was granulated in an oscillating granulator.

Then the granules were dried in the dryer chute, while the loss of the granules during drying does not become lower than 6%. The dried granules were sieved. The granules were blended in a mixer, V-type with the remaining ingredients formulated in Table 1. The gelatin capsules were filled with the composition, using a device for filling capsules InCAP HS.

Each of the columns E-H were evaluated as described in Example 1 above, and the results are presented in Table 3 below. All download showed good characteristics of granules and capsules.

Table 1
The compositions downloads
Ingredient (per capsule)Download
AndInDEFGN
AFI 9-10670,40,40,40,440404040
Corn starch082,0Of 40.826,0042,4Of 21.214,0
Lactose 20082,0041,256,042,40Of 21.228,4
Starch15006,86,8 6,86,86,86,86,86,8
Explotab™6,86.86,86,86,86,86.86.8
Purified waterand.to.and.to.and.to.and.to.and.to.and.to.and.to.and.to.
Silica, colloidal2,02,02,02,02,02,02,02,0
hydrated
(Syloid™)
Talc2,02,02,02,02,02,02,02,0
Capsule size 11 un1 un1 un1 un1 un1 un1 un1 un
S. T. - as required
and.to. - adapted quantity

Table 2
Analytical results for downloads A-D
DownloadAndInD
The resulting granules
Bulk density (g/ml)0,620,590,600,64
The density of abrasion 1250 (g/ml)0,750,730,700,74
Compressibility factorGoodGoodGoodGood
Indicator of which wasGoodGoodGoodGood
Flow rateGoodGoodGoodGood
The resulting granules
Homogeneous mass (RSD %)2,391,771,26To 1.14
�remesi (%) 3,343,303,233,38

Table 3
Analytical results for downloads E-N
DownloadEFGN
The resulting granules
Bulk density (g/ml)0,600,570,550,56
The density of abrasion 1250 (g/ml)0,680,620,600,64
Compressibility factorGoodGoodGoodGood
Indicator of which wasGoodGoodGoodGood
Flow rateGoodLowLowLow
The resulting granules
Homogeneous mass
(relative standard
deviation (RSD)%)
2,862,342,082,89
Impurities (%)2,95Of 3.072,982,97

Example 3

All downloads of examples 1 and 2 were investigated on the influence of stressful conditions to determine their stability. Each of the eight downloads was incubated for 15 days at room temperature and when exposed to stressful conditions (temperature 70°C without control of relative humidity). All downloads have been checked for impurities for both storage conditions, the results are formulated in Tables 4 and 5. The amount of impurities was obtained using HPLC method with a limit of determination of the quantity less than 0.05%.

APIs used in these downloads, contained approximately 3% of impurities before introduction into the composition (impurity 8).

BUT
Table 4
The results of stability testing for downloads A-D
AndBD
DosageSmallSmallSmallSmall
StorageCTSUCTSUCTSUCTSU
The total number of impurities (%)3,343,893,305,043,23Of 5.363,394,03
Impurity 83,343,033,302,90 3,233,293,393,17
Admixture 1<0,050,76<0,051,37NP1,38NP0,68
Impurity 2BUT0,06BUT0,05BUT0,19BUT0,11
Impurity 3BUTBUTBUT0,07BUT0,14BUTBUT
Impurity 4BUTBUTBUT0,20BUT0,100,050,05
Impurity 5BUTBUT0,18BUT0,15BUTBUT
Impurity 6BUT0,07BUT0,14BUT0,14BUT0,07
Impurity 7BUT<0,05BUT0,12BUT0,13BUTBUT
CT - room temperature
SU - stressful conditions
BUT - not detected (below limit of detection)

Table 5
The results of stability testing for downloads E-N
EF GN
DosageLargeLargeLargeLarge
StorageCTSUCTSUCTSUCTSU
The total number of impurities (%)2,962,86Of 3.073,032,982,782,972,78
Impurity 82,962,78Of 3.07To 2.942,982,712,972,75
Admixture 10,060,08NP0,10 NP0,07NP0,06
Impurity 2BUT0,05BUT<0,05BUTBUTBUTBUT
Impurity 3BUTBUTBUTBUTBUTBUTBUTBUT
Impurity 40,050,050,050,05BUTBUTBUTBUT
Impurity 5BUTBUTBUTBUTBUTBUTBUTBUT
Impurity 6BUTBUT BUTBUTBUTBUTBUTBUT
Impurity 7BUTBUTBUTBUTBUTBUTBUTBUT
CT - room temperature
SU - stressful conditions
BUT - not detected (below limit of detection)

Example 4

Download E in Example 2 was taken for the long-term stability studies. In one study, the load was maintained for 6 months at 25°C and a relative humidity (RH) 60%, in the second study, the load was maintained for 6 months at 40°C and relative humidity of 75%. After each test the load was tested for impurities, the results are formulated in Table 6. Fire assay and impurities were obtained using HPLC method with a limit of determination of the quantity less than 0.05%.

Table 6
These stability to Download E
DownloadE
Time06 months6 months
Storage25°C/60% RH40°C/75% RH
Study (%)969998
The change in total impurity Content(%)<0,05<0,05<0,05

Comparative Example

Three intermediate dosing capsules were made by first mixing the active pharmaceutical ingredients, excipient (s), binder and disintegrant (a smaller portion in the comparative example and the total number in downloads I and J) in the amounts set forth in the Table 7 below, for 3 minutes in a mixer with high shear rate. APIs used in these examples was 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide. To each mixture was added purified water in the first 3 minutes, then the mixture of granulates�was ovalis mixing in the next 3 minutes.

The granules were then dried in a fluidized bed dryer until then, until the loss in weight of the pellets during drying does not become lower than 6%. The dried granules were sieved and then mixed with the remaining ingredients formulated in Table 7, in a biconic mixer. Gelatin capsules were filled with the composition, using the mechanism for filling capsules InCAP HS.

Table 7
The compositions for comparative Example 1
DownloadRef.IJ
Ingredient (per capsule)
API222
Dicalcium phosphate (filler)33
Lactose (filler)8054
Microcrystalline cellulose (filler) 46
Sodium croscarmellose (filler)2
Corn starch (filler)27
Povidone (binder)7
Purified waterS. T.and.to.and.to.
Modified starch (binder)77
Sodium amido glycolate (disintegrant)77
Sodium croscarmellose (disintegrant)4
Hydrate colloidal silica (lubricant)422
Tal�to (lubricant) 222
Magnesium stearate (lubricant)2
S. T. - as required
and.to. - adapted quantity

Granules and capsules were evaluated, the results shown in Table 8 below. After two studies on the stability for 6 months at 25°C and a relative humidity (RH) of 60% and the second at a temperature of 40°C and relative humidity (RH) of 75% was observed, which download I and J have increased stability compared to the composition of the comparator.

Table 8
Stability formula after 6 months of testing at 40 C and a relative humidity (RH) 75%
DownloadComparativeIJ
(composition)Time066066066
(months)
25°C/40°C/25°C/40°C/25°C/40°C/
Storage60% RH75% RH 60% RH75% RH60%75% RH
RH
Study (%)999992981001029798100
Changes0,072,34He is determined0,15He is determined0,15
the amount of total impurities

1. Pharmaceutical composition, stable in storage, comprising:
as active pharmaceutical ingredient (API) of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide,
at least one filler; and
at least one binder component;
where at least one filler is not derived phosphate;
where at least one binder component is a compound of polyvinylpyrrolidone; and
where the specified active pharmaceutical ingredient is present in granular form.

2. Pharmaceutical composition according to claim 1, where less than 10% of the API is degraded more than 15 days of storage at 70°C and unregulated humidity.

3. Pharmaceutical composition according to claim 2, where less than 5% of the API is degraded more than 15 days of storage at 70°C and unregulated humidity.

4. Pharmaceutical composition according to claim 3, wherein less than 3% of the API is degraded more than 15 days of storage at 70°C and unregulated humidity.

5. Pharmaceutical composition according to claim 4, where less than 1% of the API is degraded more than 15 days of storage at 70°C and unregulated humidity.

6. Pharmaceutical composition according to claim 5, where the increase in the total amount of impurities is less than 5% more than 15 days of storage at tempera�ur 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

7. Pharmaceutical composition according to claim 6, where the increase in the total amount of impurities is less than 2% more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

8. Pharmaceutical composition according to claim 7, where the increase in the total amount of impurities is less than 1% more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

9. Pharmaceutical composition according to claim 8, wherein the increase in the total amount of impurities is less than 0.5% more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

10. Pharmaceutical composition according to any one of claims.1-9, where the granules further include, p� least one filler and/or at least one binder component.

11. Pharmaceutical composition according to claims.1-9, where the composition has a bulk density greater than 0.1 g/ml.

12. Pharmaceutical composition according to claim 11, where the composition has a bulk density greater than 0.5 g/ml.

13. Pharmaceutical composition according to any one of claims.1-9, where the composition further includes additional APIs.

14. Pharmaceutical composition comprising stable during storage of the composition according to any one of claims.1-13.

15. The pharmaceutical composition according to claim 14, where the composition is in a dosage form of tablets or capsules.

16. The pharmaceutical composition according to claim 15, where the composition has a bulk density greater than 0.1 g/ml.

17. The pharmaceutical composition according to claim 16, where the composition has a bulk density greater than 0.5 g/ml.

18. Pharmaceutical composition according to any one of claims.15-17, where the pharmaceutical composition is stable.

19. The pharmaceutical composition according to claim 18, where less than 10% AFI destroyed more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

20. The pharmaceutical composition according to claim 19, where less than 5% AFI destroyed more than 15 days storage at a temperature of 70°C nereguliruemoy humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

21. The pharmaceutical composition according to claim 20, wherein less than 3% AFI destroyed more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

22. The pharmaceutical composition according to claim 21, where less than 1% API dissolved more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

23. Pharmaceutical composition according to any one of claims.19-22, where the increase in the total amount of impurities is less than 5% more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

24. The pharmaceutical composition according to claim 23, where the increase in the total amount of impurities is less than 2% more than 15 days of storage at temperatures� 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

25. The pharmaceutical composition according to claim 24, where the increase in the total amount of impurities is less than 1% more than 15 days storage at a temperature of 70°C and unregulated humidity, more than 6 months storage at 40°C and a relative humidity of 75% and/or more than 3 years of storage at 60% relative humidity and a temperature of 30°C or 25°C.

26. The pharmaceutical composition according to claim 25, where the increase in the total amount of impurities is less than 0.5% more than 15 days storage at a temperature of 70°C and unregulated humidity.



 

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FIELD: medicine.

SUBSTANCE: group relates to peptides or polypeptides inducing the anti-alpha-synuclein antibody production in vivo for producing medicaments for preventing and/or treating synucleinopathies.

EFFECT: producing the peptides or polypeptides, which induce the antibodies responsible for the removal of the alpha-synuclein involved in the production of alpha-synuclein aggregates, the Lewy bodies, or for the dissolution of alpha-synuclein aggregates, the Lewy bodies in the individual suffering from synucleinopathies.

22 cl, 3 ex, 5 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and presents a pharmaceutical composition for injections for acute forms of parkinsonian syndrome characterised by the fact that an active substance is presented by a therapeutically effective amount of N-(2-adamantyl)-hexamethylenimine hydrochloride (hymantan), and additive substances are presented by water for injections or a physiological solution. The invention also concerns a method for preparing the pharmaceutical composition.

EFFECT: pharmaceutical composition possesses storage stability, releases the active substance easily that provides its high bioavailability and efficacy.

6 cl, 15 tbl, 4 ex

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

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic biologically active substances of the heterocyclic series, having anticholinesterase activity, and is a product of modification of pyrodoxine acetals, specifically 1,5-dihydro-3-R1-3-R2-7,8-dimethyl-9-dimethylcarbamoyloxy-[1,3]dioxepino[5,6-c]pyridinium bromide of general formula I, where R1 is a hydrogen atom or a methyl, R2 is selected from: methyl, ethyl, propyl, iso-propyl, tert-butyl, heptyl, octyl or (1-methyldecyl). The compounds of formula (I) have high anticholinesterase activity and can be used in medicine and veterinary.

EFFECT: high activity of the compounds.

2 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a pharmaceutical composition, which contains formula compound as an active pharmaceutical ingredient or its pharmaceutically acceptable salt; and at least pharmaceutically acceptable filler, where the active pharmaceutical ingredient is present in an amount of at least 80% of the total dry weight of the composition.

EFFECT: composition possesses the good rate of release independently on the pH value.

8 cl, 4 dwg, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to biotechnology and represents anti-nerve growth factor (NGF) antibodies. The present invention also discloses a pharmaceutical composition for relieving pain associated with a disease or a condition, wherein pain progression or persistence is mediated by NGF, containing the above antibodies, as well as a kit for treating a HGF-related disease, such as e.g. osteoarthritis, nucleic acids coding a heavy or light chain of the antibody, an expression vector, a host cell for preparing the above antibodies, a method for expressing the above anti-NGF antibodies, as well as using the above antibodies in managing pain and for preparing a therapeutic agent for managing pain associated with the disease or condition, wherein pain progression or persistence is mediated by NGF.

EFFECT: present invention enables producing the anti-NGF antibodies characterised by high stability in vivo.

16 cl, 7 dwg, 13 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula (I), X means CH2 or C=O; R means hydrogen, Ar1, Ar2-Ar3, -(CH2)qAr3, -C(O)Ar3, C(O) - (CRxRy)q-Ar3, -C(O) - (CRxRy)q-O-Ar3 or -C (O)-Ar2-AR3; each of the fragments Ar1, Ar2 and Ar3 means C6-10aryl or 5-13-merous heteroaryl containing 1, 2 or 3 heteroatoms specified in N, O or S; q means 1, 2 or 3; Rx and Ry independently mean hydrogen or alkyl; wherein each aryl or heteroaryl are independently unsubstituted or substituted by 1, 2 or 3 substitutes specified in a group of alkyl, halogen, cyano, -OR1a, -O-(CR4aR5a)p-O-, -C(O)R1a, -H(Rb)(R3a), -H(Ra)C(O)R1a and halogenalkyl; wherein R1a and R3a independently mean hydrogen or alkyl; and R4a and R5a mean hydrogen; Ra and Rb independently mean hydrogen or alkyl; p means 1 or 2.

EFFECT: invention refers to the compounds of formula (I) possessing an activity modulating α7 nicotinic acetylcholine receptors, α4β2 nicotinic acetylcholine receptors or both subtypes of α7 and α4β2 nicotinic acetylcholine receptors, the based pharmaceutical composition and methods of treating with using them.

18 cl, 1 tbl, 113 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: general formula I involves both new, and known compounds. The compounds can be used for treating neuropathic pain mediated by Ih channel modulation and related inflammatory pain. In a compound of formula I. Ar means phenyl or a 6-merous heteroaryl group containing 1 or 2 nitrogen atoms, each of which can be optionally substituted by one or more substitute(s) specified in a group consisting of a halogen, (C1-4)alkyl, halogen(C1-4)alkyl, (C1-4)alkyloxy, halogen(C1-4)alkyloxy and (C1-4)alkylthio; X means O, S or NR1; R1 means H; R2 means (C1-4)alkyl, halogen(C1-4)alkyl or (C1-4)alkyloxy(C1-4)alkyl; R3 means H, (C1-4)alkyl, halogen(C1-4)alkyl or (C1-4)alkyloxy(C1-4)alkyl; Y1 means N; and Y2 and Y3 mean N or Y3 means CH, and Y2 independently means CH or N; R4 and R5 independently mean H, (C1-4)alkyl, halogen(C1-4)alkyl or (C1-4)alkyloxy(C1-4)alkyl; or R4 and R5 form a 3-7-merous saturated cycle together with a nitrogen atom which they are attached to.

EFFECT: invention refers to aminoheteroaryl derivatives having the general formula I, or their pharmaceutically acceptable salts.

12 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition applicable for treating Down syndrome mediated by Dyrkla activity. The composition contains a compound of formula I in an effective amount and a pharmaceutically acceptable carrier. In Formula I, each R1 is independently specified in a group consisting of 3 and F; R2 represents S; R3 represents (CH2)m, wherein m is equal to 3; R4 represents H; R6 represents H; each R8 is independently -OR9 and each R9 independently represents 3 or C1-6alkyl.

EFFECT: invention refers to a method of treating Down syndrome mediated by Dyrkla activity.

7 cl, 1 dwg, 4 ex

FIELD: veterinary medicine.

SUBSTANCE: method comprises administering a homeopathic agent. The agent "Liarsin" is used, which is administered subcutaneously before calving into the biologically active points in the centre of the front and rear udder parts.

EFFECT: invention is highly effective for prevention of parturient paresis in cows.

4 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: analgesic preparations caused the onset of abuse headache are withdrawn; detoxification therapy, alternative anaesthesia, preventive and behavioural therapy follow. The detoxification therapy represents a 10-day therapeutic course according to the schedule: Cytoflavin 10 ml dissolved in 0.9% NaCl 200 ml is administered intravenously drop-by-drop daily in the morning and evening. Additionally, Milgamma 2.0 ml is injected intramuscularly daily in the morning; Reamberin 200-400 ml is administered intravenously drop-by-drop every second day.

EFFECT: treating the patients with abuse headache and reducing the number of recurrences.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine. What is described is a pharmaceutical composition containing licarbazepine acetate, preferentially eslicarbazepine acetate, in a combination with acceptable excipients, particularly a binding agent and a disintegrating agent. What is also described is a method for wet granulation for preparing the pharmaceutical composition.

EFFECT: composition is compacted as a tablet, which has reduced size and volume density.

79 cl, 10 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains anastrozole, poly(lactic-co-glycolic acid), polyvinyl alcohol and D-mannitol. The therapeutic agent represents sub-micron particles and can be presented in the form of capsules, granules, powder, as well as a suspension for injections.

EFFECT: using the developed therapeutic agent enables achieving the therapeutic effect with lower therapeutic doses and making the antitumour therapy more comfortable for the patient.

2 cl, 1 tbl, 2 dwg, 3 ex

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