Novel composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and deals with pharmaceutical composition, which includes dipeptidyl peptidase IV (DPPIV) inhibitor, preferably vildagliptin in amount from 1.5 to 20% and metformin in amount from 80 to 98.5%. Active ingredients constitute from 60 to 98% of composition. Cellulose or its derivatives in amount from 1 to 20% is used as binding agent. Also described is method of obtaining said composition.

EFFECT: novel composition is claimed.

47 cl, 7 ex, 8 tbl

 

The present invention relates to a composition containing an inhibitor of dipeptidylpeptidase IV (DPP-IV), preferably vildagliptin and Metformin, tablets containing these compounds, and to methods for their preparation.

Metformin is a widely used tool for reducing the level of glucose in the blood of patients suffering from non-insulin-dependent diabetes mellitus, and issued in the form of dosage forms with the content of the active component 500, 750, 850 and 1000 mg. However, because Metformin is the drug of short-term actions, it is necessary to enter two or three times a day (tablets containing the active ingredient 500-850 mg 2-3 times per day or 1000 mg 2 times a day during meals). Biguanides protivogipergonichesky agent Metformin, described in U.S. patent No. 3174901, currently available in the U.S. in the form of hydrochloride (product Glucophage@ company Bristol-Myers Squibb Company). Receiving Metformin (dimethylbiguanide) is well known in the contemporary art and was first described in article Emil A.Werner and James Bell, J. Chem. Soc., t, s-1794 (1922). Metformin you can enter, for example, in the form of product GLUCOPHAGE™.

Metformin increases the sensitivity of peripheral tissues of the host organism to insulin. Metformin is also involved in the inhibition of absorption of glucose from the intestine, suppression of hepatic what about gluconeogenesis and inhibition of fatty acid oxidation. Suitable dose of Metformin include 500 mg 2 to 3 times per day, and up to 5 times per day or 850 mg once or twice per day (see Martindale, The Complete Drug Reference).

The term "Metformin"used in this context, means Metformin or its pharmaceutically acceptable salt, such as hydrochloride, fumarate Metformin (2:1) and succinate Metformin (2:1), as described in U.S. application No. 09/262526 filed March 4, 1999, hydrobromide, para-chlorophenoxyacetic or embonate, as well as other known salts of Metformin and mono - and dibasic carboxylic acids, examples of which are described in U.S. patent No. 3174901. Currently preferred is the use as his Metformin hydrochloride, namely products GLUCOPHAGE-D or GLUCOPHAGE XR (company Bristol-Myers Squibb Company).

The terms "inhibitor of DPP-IV", "Metformin", "glitazone" or any other of glitazone, such as pioglitazone, rosiglitazone, used in this context, also means any pharmaceutically acceptable salt, crystalline form, hydrate, solvate, diastereoisomers or enantiomers.

Preferred inhibitors of DPP-IV according to the present invention are described below.

The term "inhibitor of DPP-IV"as used in this context also means active metabolites and prodrugs, such as active metabolites and prodrugs of inhibitors of DPP-IV. The term "metabolite" oznake the active derived inhibitor of DPP-IV, which is formed in the metabolism of the inhibitor of DPP-IV. The term "prodrug" means a compound, from which the metabolism is formed inhibitor of DPP-IV or metabolite(s), similar to(e) the inhibitor of DPP-IV.

Inhibitors of DPP-IV are described in the present level of technology. For example, inhibitors of DPP-IV in General or in detail described in the following documents: WO 98/19998, DE 19616486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO 01/52825, WO 9310127, WO 9925719, WO 9938501, WO 9946272, WO 9967278 and WO 9967279.

Preferred inhibitors of DPP-IV are described in the following documents: WO 02053548, primarily compounds 1001-1293 and examples 1-124, WO 02067918, primarily compounds 1000-1278 and 2001-2159, WO 02066627 primarily examples, WO 02/068420, first of all compounds described in examples I-LXIII, and their respective analogues, more preferred are compounds 2(28), 2(88), 2(119), 2(136), listed in the following table, which shows the value of the IC50WO 02083128 primarily examples 1-13, US 2003096846 primarily described compounds, WO 2004/037181, especially examples 1 and 33 and the compounds described in paragraphs 3-5, WO 0168603, first of all compounds described in the examples 1-109, EP 1258480, primarily compounds described in the examples 1-60, WO 0181337 primarily examples 1-118, WO 02083109 primarily examples 1A-1D, WO 030003250, primarily compounds described in the examples 1-166, most preferably 1-8, WO 03035067, primarily compounds described in the reamers, WO 03/035057, primarily compounds described in the examples, US 2003216450 primarily examples 1-450, WO 99/46272, primarily compounds described in paragraphs 12, 14, 15 and 17, WO 0197808, primarily compounds described in paragraph 2, WO 03002553, primarily compounds described in examples 1-33, WO 01/34594, primarily compounds described in examples 1-4, WO 02051836 primarily examples 1-712, EP 1245568 primarily examples 1-7, EP 1258476 primarily examples 1-32, US 2003087950, first of all the examples, WO 02/076450 primarily examples 1-128, WO 03000180 primarily examples 1-162, WO 03000181 primarily examples 1-66, WO 03004498 primarily examples 1-33, WO 0302942 primarily examples 1-68, US 6482844 primarily examples, WO 0155105, primarily compounds described in examples 1 and 2, WO 0202560 primarily examples 1-166, WO 03004496 primarily examples 1-103, WO 03/024965 primarily examples 1-54, WO 0303727 primarily examples 1-209, WO 0368757, first of all the examples 1-88, WO 03074500 primarily examples 1-72, examples 4.1-4.23, examples 5.1-5.10, examples 6.1-6.30, examples 7.1-7.23, examples 8.1-8.10, examples 9.1-9.30, WO 02038541 primarily examples 1-53, WO 02062764 primarily examples 1-293, preferably the compound described in example 95, hydrochloride (2-{{3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-ethenolysis}oxy}ndimethylacetamide), WO 02308090 primarily examples 1-1-1-109, examples 2-1 - 2-9, example 3, examples 4-1 - 4-19 examples 5-1 - 5-39, examples 6-1 - 6-4, examples 7-1 - 7-10, examples 8-1 - 8-8, examples 71 - 7-7, p.90, examples 8-1-8-59, p.91-95, examples 9-1 - 9-33, examples 10-1 - 10-20, US 2003225102, primarily compounds 1-115, the compounds described in the examples 1-121, primarily compounds (a) - z), AA) - az), ba) - bz), ca) - cz) and da - dk), WO 0214271 primarily examples 1-320, US 2003096857, WO 2004/052850, primarily compounds, as described in the examples 1-42, and compounds described in paragraph 1 DE 10256264 A1, first of all compounds, such as described in the examples 1-181, and compounds described in paragraph 5, WO 04/076433, first of all compounds listed in table, preferably compounds listed in tablw, preferred compounds I-XXXXVII, or compounds described in paragraphs 6 - 49, WO 04/071454 primarily described compounds, for example, compounds 1-53, or compounds listed in table-If, or compounds described in paragraphs 2-55, WO 02/068420 primarily described compounds, for example, compounds I-LXIII, or the compound described in example I, and its analogs 1-140, or the compound described in example 2, and its analogs 1-174, or the compound described in example 3, and its counterpart 1, or the compound described in examples 4-5, or the compound described in example 6, and its analogues 1-5, or the compound described in example 7, and its analogues 1-3, or the compound described in example 8, and its counterpart 1, or the compound described in example 9, or the compound described in example 10, and its analogs 1-531, even more preferred is sustained fashion are compounds described in paragraph 13, WO 03/000250 primarily described connections, such as connections 1-166, preferably, the compounds described in examples 1-9, WO 03/024942 primarily described compounds, such as compound 1-59, compounds listed in table 1(1-68), compounds described in paragraphs 6, 7, 8, 9, WO 03024965 primarily described compounds, such as compound 1-54, WO 03002593 primarily described compounds, such as compounds listed in table 1 or in paragraphs 2-15, WO 03037327 primarily described compounds, such as compounds described in the examples 1-209, WO 03/000250 primarily described connections, such as connections 1-166, preferably compounds described in examples 1-9, WO 03/024942 primarily described compounds, such as compound 1-59, compounds listed in table 1(1-68), compounds described in paragraphs 6, 7, 8, 9, WO 03024965 primarily described compounds, such as compound 1-54, WO 03002593 first all described compounds, such as compounds listed in table 1 or in paragraphs 2-15, WO 03037327 primarily described compounds, such as compounds described in the examples 1-209, WO 0238541, WO 0230890, U.S. application No. 09/788173, subject, February 16, 2001(file LA50), primarily examples, WO 99/38501 primarily examples, WO 99/46272, first Avenue the measure, and DE 19616486 A1, first of all val-pyr, val-thiazolidin, isoleucyl-thiazolidin, isoleucyl-pyrrolidide and salts of fumaric acid and isoleucyl-thiazolidine and isoleucyl-pyrrolidide, WO 0238541 primarily described compounds, such as compounds described in the examples 1-53, WO 03/002531 primarily described compounds, such as compounds listed on page 9 to 13, more preferably compounds described in the examples 1-46, and most preferably the compound described in example 9, U.S. No. 6395767, preferably compounds described in the examples 1-109, most preferably the compound described in example 60.

Additional preferred examples of inhibitors of DPP-IV include compounds described in US patents No. 6124305 and No. 6107317, applications WO 9819998, WO 9515309 and WO 9818763, such as 1-[2-[(5-cyano-2-yl)aminoethylamino]acetyl-2-cyano-(S)-pyrrolidine and (2S)-I-[(2S)-2-amino-3,3-dimethylbutanol]-2-pyrrolidinecarbonyl.

In the application WO 9819998 described N-(N'-substituted glycyl)-2-cyanopyrrolidine, especially 1-[2-[5-cyano-2-yl]amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidin. The preferred compounds described in the application WO 03/002553 on p.9-11, which is included in the present invention as a reference. In the application WO 0034241 and published patent US 6110949 described N-substituted adamantylamine-2-cyanopyrrolidine and N-(substituted glycyl)-cyanopyrrolidine respectively. Preferred inhibitors of DPP-IV are compounds described in claims 1 to 4. First of all, these applications are described compound 1-[[(3-hydroxy-1-substituted)amino]acetyl]-2-cyano-(S)-pyrrolidin (also known as LAF237).

In the application WO 9515309 described 2-cyanopyrrolidine amino acids as inhibitors of DPP-IV, and in the application WO 9529691 described peptidyltransferase diesters of α-aminoalkylphosphonic acids, primarily comprising a Proline residue or a similar structure. Preferred inhibitors of DPP-IV are compounds listed in table 1-8. In the application WO 01/72290 described preferred inhibitors of DPP-IV (example 1 and claims 1, 4 and 6). In the application WO 9310127 described esters Bronevoy acid and Proline, are suitable as inhibitorof DPP-IV. Preferred inhibitors of DPP-IV are compounds described in examples 1-19. In the application WO 9925719 described surfactin, which is an inhibitor of DPP-IV, obtained from a strain of Streptomyces. In the application WO 9938501 described N-substituted 4-8 membered heterocyclic ring. Preferred inhibitors of DPP-IV are compounds described in PP-20.

In the application WO 9946272 described phosphorus-containing compounds as inhibitors of DPP-IV. Preferred inhibitors of DPP-IV are compounds described in claims 1 to 23.

Other preferred inhibitors of DPP-IV are compounds of formulas I, II or III described the application WO 03/057200 on p.14-27. The most preferred inhibitors of DPP-IV are compounds described on page 28 and 29.

In applications WO 9967278 and WO 9967279 described prodrugs and inhibitors of DPP-IV in the form a-b-C, where C means a stable or unstable inhibitor of DPP-IV.

Preferred N-peptidyl-O-aroylhydrazines is a compound of formula VII

where

j is 0, 1 or 2,

Rε1means a side chain of natural amino acids and

Rε2means (ness.)alkoxy, (ness.)alkyl, halogen or nitro,

or its pharmaceutically acceptable salt.

In an even more preferred embodiment of the present invention N-peptidyl-O-aroylhydrazines is a compound of formula VIIa

or its pharmaceutically acceptable salt.

N-Peptidyl-O-aroylhydrazines, for example, of formula VII or VIIa, as well as obtaining them are described in the article H.U.Demuth etc., J. Enzyme Inhibition, vol. 2, SC-142, first of all SS-132 (1988).

The preferred inhibitors are N-(substituted glycyl)-2-cyanopyrrolidine formula (I)

where

R is substituted and substituted

n is from 0 to 3, in free form or in the form of an acid additive salt.

The term "substituted substituted" means, for example, 1 - or 2-substituted, containing one or more, for example, the VA's Deputy, which is selected from the group comprising alkyl, -OR1or-NR2R3where R1, R2and R3independently mean hydrogen, alkyl, C1-C8alkanoyl, carbamyl or-CO-NR4R5where R4and R5independently signify alkyl, unsubstituted or substituted aryl, and where one of R4and R5means hydrogen or R4and R5together mean With2-C7alkylen.

The term "aryl" preferably means phenyl. The term "substituted phenyl" preferably means phenyl containing one or more, for example, two deputies, chosen from the group comprising, for example, alkyl, alkoxy, halogen or trifluoromethyl.

The term "alkoxy" means alkyl-O-.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "alkylene" means a bridge group with a straight chain containing from 2 to 7 carbon atoms, preferably from 3 to 6 carbon atoms and most preferably 5 carbon atoms.

A preferred group of compounds of the present invention are the compounds of formula (I)where the Deputy as part of adamantyl attached to the end atom of the bridging group or a methylene group adjacent to the terminal atom of the bridging group. In the compounds of formula (I), where the remainder of glycyl-2-cyanopyrrolidine associated with magnetic atom bridging group, the " R " in the part of adamantyl means preferably 3-hydroxy. In the compounds of formula (I), where the remainder of glycyl-2-cyanopyrrolidine is linked to a methylene group adjacent to the terminal atom of the bridging group, the substituent R' in the remainder of adamantyl means preferably 5-hydroxy.

The present invention primarily relates to the compound of formula (IA) or (IB)

or

where

R' represents hydroxy, C1-C7alkoxy, C1-C8alkanoyloxy or R5R4N-CO-O-, where R4and R5independently mean C1-C7alkyl or phenyl, unsubstituted or contain substituents which are selected from the group including C1-C7alkyl, C1-C7alkoxy, halogen or trifluoromethyl, and R4means hydrogen, or R4and R5together mean With3-C6alkylen, and

R means hydrogen, or

R' and R” independently denote With1-C7alkyl,

in free form or in the form of a pharmaceutically acceptable acid additive salt.

Such inhibitors of DPP-IV formulas (I), (IA) or (IB) described in U.S. patent No. 6166063, issued December 26, 2000, and in the application WO 01/52825. Examples of such inhibitors include (8)-1-{2-[5-cyano-2-yl)amino]acylaminoacyl)-2-cyanopyrrolidine or (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (product LAF237). They exist in a free the Orme or in the form of an acid additive salt. Preferred are pharmaceutically acceptable, i.e. non-toxic and physiologically acceptable salts, although it is possible to use other salts, for example, when selecting or clearing the compounds of the present invention. Although the preferred acid additive salts are hydrochloride, you can also use salt methansulfonate, sulfuric, phosphoric, citric, lactic and acetic acids.

Preferred inhibitors of DPP-IV are the inhibitors described in article Mona Patel and other Expert Opinion Investig Drugs., vol.12, No. 4, s.623-633 (April 2003), paragraph 5, first of all the products R/98, K-364, FE-999011, BDPX, NVP-DDP-728 and others, the content of which is primarily a description of inhibitors of DPP-IV, included in the present invention by reference.

Product FE-999011 described in the application WO 95/15309, p.14, as the connection 18.

Another preferred inhibitor is a compound BMS-477118, described in U.S. patent No. 6395767 (compound described in example 60), i.e. benzoate (1S,3S,5S)-2-[(28)-2-amino-2-(3-hydroxytriazine[3.3.1.13,7]Oct-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (1:1) of formula M as described in the application WO 2004/052850, page 2, and the corresponding free base (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytriazine[3.3.1.13,7}Oct-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (M') and the monohydrate (M) of formula M as described in the application WO 2004/052850, p. 3. Other n the title compound BMS-477118 is saxagliptin.

Another preferred inhibitor is a compound GSK23A described in the application WO 03/002531 (example 9, that is, hydrochloride, (2S,4S)-1-((2R)-2-amino-3-[(4-methoxybenzyl)sulfonyl]-3-methylbutanoyl)-4-ftorpirimidinu-2-carbonitrile).

Other preferred inhibitors of DPP-IV according to the present invention described in the application WO 02/076450 (primarily in the examples 1-128), and also in the article, Wallace T. Ashton, Bioorganic & Medicinal Chemistry Letters, t, s-863 (2004), especially compound 1 and compounds listed in table 1 and table 2. The preferred connection is the connection a (table 1) formula

Product R/98 or R (CAS number 251572-86-8, that is, 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidin) can be used in the form of a mixture of 3-[(2S,3S)-2-amino-3-methyl-1-oxobutyl]thiazolidine and (2E)-2-butenedioate (2:1), as shown below

and described in the application WO 99/61431 and article Diabetes, t, SS. 1253-1258 (1998), under the name of the company Probiodrug and connection of the P 93/01 the same company.

Other preferred inhibitors of DPP-IV are compounds described in the application WO 02/083128, such as compounds described in claims 1 to 5.

The most preferred inhibitors of DPP-IV are compounds described in examples 1-13 and PP-10.

Other preferred inhibitors of DPP-IV are the inhibitors described in applications WO 2004/037169 first of all would enable in examples 1-48, and WO 02/062764, primarily in the examples 1-293, more preferred are the compounds 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}acetamide", she described on page 7, as well as in the application WO 2004/024184, primarily in the comparison examples 1-4.

Other preferred inhibitors of DPP-IV as described in the application WO 03/004498, primarily in examples 1-33, and the most preferred compound of the formula

described in example 7 (a product of MK-0431 or sitagliptin).

Preferred inhibitors of DPP-IV is also described in the application WO 2004/037181, primarily in examples 1-33, the most preferred compound is described in PP-5.

The preferred hibitory DPP-IV are N-substituted adamantylamine-2-cyanopyrrolidines, N-(substituted glycyl)-4-cyanopyrrolidine, N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoethylethanolamine, N-AMINOETHYLPIPERAZINE, L-allisonallison, L-treeselectionmodel and L-allopolyploidy, 1-[2-[(5-cyano-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidin and their pharmaceutically acceptable salts.

First of all, preferred is the dihydrochloride of 1-{2-[(5-cyano-2-yl)amino]ethylamino} acetyl-2-(S)-cyanopyrrolidine (product DPP728) formula

first of all would enable its dihydrochloride,

and (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (product LAF237) formula

and L-treeselectionmodel (code connection directory Probiodrug P32/98, as described above), MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethyl)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}ndimethylacetamide and optional pharmaceutically acceptable salts of such compounds.

DPP728 and LAF237 are the most preferred compounds described in the application WO 98/19998, example 3, and in the application WO 00/34241, example 1, respectively. Inhibitor of DPP-IV P32/98 (see above) is described in detail in Diabetes, t, s-1258 (1998). DPP728 and LAF237 receive, as described on p.20 application WO 98/19998 or in the application WO 00/34241. Preferred compounds designed for product introduction LAF237, described in the provisional application US No. 60/604274.

First of all, preferred are inhibitors of DPP-IV, which are active when ingested by the way.

In all cases, especially for compounds described in the claims and the final products described in the working examples, the subject of the final products, the pharmaceutical compositions and claims included in the present description as reference to such publication or application.

Inhibitors of DPP-IV, such as the er, the compounds of formula (I), and their corresponding pharmaceutically acceptable acid salt additive can be used in a mixture with one or more pharmaceutically acceptable carriers and, optionally, with one or more standard pharmaceutical adjuvants and enter enteric way, for example, by oral way, in the form of tablets, capsules, mini-tablets and the like, or parenteral way, for example, intravenously, in the form of sterile solutions or suspensions for injection. Compositions for administration of enteral and parenteral method are the standard ways.

Inhibitors of DPP-IV, for example, the compounds of formula (I), and their corresponding pharmaceutically acceptable acid additive salts can be converted into pharmaceutical compositions for administration of enteral and parenteral way, contains the amount of active agent that is effective for treating conditions mediated by inhibition of DPP-IV, and in these compositions in the form of a standard dosage form and such compositions comprising a pharmaceutically acceptable carrier.

Inhibitors of DPP-IV, for example, the compounds of formula (I), including those described in the present description and in each example, you can type in enantiomerically pure form, for example, contains more than 98%, preferably more than 99% in evaluating enantiomer, or in combination with the R enantiomer, for example, in the form of a racemate. The above dose is given in the calculation of the compounds of formula (I) and excluding the amount of enantiomer R.

In connection with inhibitory activity against DPP-IV inhibitors of DPP-IV, for example, connection of the formula (I) and their corresponding pharmaceutically acceptable acid salt additive can be used for treating conditions mediated by inhibition of DPP-IV. Taking into account the above, as well as literature data, it can be expected that the compounds described in this context, are suitable for treating conditions such as non-insulin-dependent diabetes mellitus, arthritis, obesity, transplantation of allografts and chalcedonianism osteoporosis. In addition, taking into account the role of peptides glucagonoma type, such as GLP-1 and GLP-2 and their relationship to inhibition of DPP-IV, it can be expected that the compounds described in this context, it is possible to use, for example, to provide a calming effect to reduce postoperative catabolic changes or hormonal responses to stress, or to reduce the mortality and incidence of myocardial infarction, or for the treatment of conditions associated with the above actions, which are mediated by changes in the levels of GLP-1 and/or GLP-2 in the body.

In more detail, in the example, inhibitors of DPP-IV, for example, connection of the formula (I) and their corresponding pharmaceutically acceptable acid salt additive improves initial response to insulin with the introduction of the provocative dose of glucose by oral way, and are therefore suitable for the treatment of non-insulin-dependent diabetes mellitus.

Inhibitors of DPP-IV, primarily compounds of formula I, IA or IB according to the present invention are hygroscopic, which leads to problems with sustainability and, in addition, by themselves, are not amenable to compaction. Thus, there is a need to develop a cohesive composition with a sufficiently high fluidity, which can be pressed into tablets with an acceptable dissolution profile in vitro and relatively high stability of the active ingredients. The term "tablet" means a solid dosage form that contains medicinal agent in the presence or in the absence of suitable fillers. Tablets obtained by compressing or compacting the composition containing the active ingredient and certain excipients that choose to simplify processing and improve the properties of the product. Use of tablets, coated or uncoated, which is obtained from a powder of crystalline materials. Tablets may include various diluents, binders AG is, for example, dezintegriruetsja agents, sizing, glidant and in many cases colorings. Used excipients are classified according to their functions. For example, glidant used to improve the fluidity of the powder mixture in the hopper and the mold machine for tableting.

Tablets have been widely used since the late 19th century, and now the main part of the dosage forms produced in the form of tablets. The main reasons for such popularity of tablets are ease of administration, low cost and high performance. Other causes include drug resistance, simple packaging, transportation and distribution. For patients and consumers pill use is associated with a simple method of administration, accurate dosage, compactness, portability, neutral taste, ease of administration and beautiful appearance.

Tablets receive in the form of a flat tablets with a film or sugar coating, with a notch, in the form of a convex, multi-layered tablets and delayed release. The size, shape and color of the tablets vary in a wide range. Tablets are intended for ingestion, grinding or dissolving in the mouth or under the tongue. The tablets are also dissolved in water for injection local way. Article is realnye tablets are usually used to obtain solutions for the introduction of parenteral and method for implantation under the skin.

In addition to active or medicinal agents, tablets can contain a number of inert materials, known as excipients. They are classified depending on the function they are in the final tablet. The primary composition includes a filler, binder, lubricant and glidant. Other excipients, which impart certain physical properties of the final tablet, are the colors and flavors in the case of chewable tablets. In the absence of excipients most medicines and pharmaceutical components cannot be directly pressed into tablets mainly because of the low fluidity and cohesion properties of most drugs. Usually excipients added to the composition to give the material intended for pressing, a sufficiently high yield strength and compressive characteristics. Such properties get at the stages of pre-processing, such as wet granulation, aggregation, spheronization or crystallization with a spray dryer.

The oil is usually added to eliminate sticking of the material in the pelletizing to the punch, to minimize friction during tablet pressing and removal of compressed tablet from the die. Such sizing is usually included in the final mixture to obtain tabla is OK in the amount of about 1 wt.%.

Here are some other required properties of excipients:

- High ability to pressing to ensure durable tablets at low forces pressing.

- Giving a powdery material cohesive properties.

- An acceptable rate of disintegration.

Is quite a high turnover, which can improve the fluidity of other excipients in the composition and

- Cohesive ability (to prevent the crushed pills in the handling, transport and use).

There are three commercially important method of obtaining a compressed tablet: wet granulation, direct pressing and dry granulation (aggregation or rotary pressing). The method of obtaining and type of excipients chosen to give a composition intended for tabletting, the required physical properties, providing a quick pressing of tablets. After pressing the tablet should have a number of additional features, such as appearance, hardness, ability to disintegration and acceptable dissolution profile. The choice of fillers and other excipients depends on the chemical and physical properties of drugs, behavior of the mixture during processing and properties of the finished tablets. To determine the chemical and physical compatibility of the active component with predpolagaemyy and the excipients were carried out preliminary studies.

The properties of the drug, its dosage form and economical method of producing determine the most suitable method of tableting. In most cases, to obtain tablets using wet granulation and pressing.

Dry granulation is used, if one of the components, drug or diluent, characterized cohesive properties sufficient for tableting. The method involves mixing, aggregation ingredients, dry screening, the addition of sizing and pressing.

Wet granulation is used for processing the powder mixture into granules with suitable for tabletting fluidity and cohesion properties. The method consists in mixing the powders in a suitable mixer with a shift and then adding to the mixed powder granulating solution, thus there is granulation. Then the wet mass is sieved through a suitable sieve and dried in a drying trays or in the fluidized bed. In another embodiment, the wet mass is dried first, and then crushed in a mill. The whole process includes weighing, mixing of dry powders, wet granulation, drying, grinding, mixing with lubricant and pressing.

In most cases, the powders do not have adhesive or cohesive properties, sufficient DL the formation of solid, durable pellets. Usually due to low cohesive properties of most powders for aggregation of the powder particles is required binder. Drugs that are sensitive to heat and moisture, it is impossible to process wet granulation. Many stages of processing and processing time lead to the problem due to the high cost of processing. It is known that wet granulation reduces the ability to pressing some pharmaceutical excipients, such as microcrystalline cellulose.

Extrusion is a relatively fast process in which powders are pressed directly without changing the physical and chemical properties of the drug. Before pressing into tablets active ingredient(s), excipients for direct compression, and other excipients, such as glidant and the sizing is mixed in the mixer with double hulls or similar device with low shift. This type of mixing is important to obtain pharmaceutically acceptable dosage forms. Some pharmacists believe that it is necessary to strictly control the method of adding lubricant in the composition. Therefore, the oil is usually added to the composition with weak stirring. I also believe that continuous mixing Zama is levatala with a solution for granulation may significantly affect the hardness and disintegration time of the resulting tablets. Excessive mixing of the lubricant with the ingredients of the granules leads to the formation of water-repellent granules and reduces the hardness or strength of the tablets. In such cases, to obtain dosage forms direct pressing, you cannot use a mixer with high shear.

The advantage of direct compression is the homogeneity of the mixture, reducing the number of processing stages, i.e. the whole process includes weighing powders, mixing and extrusion, which leads to cost reduction, elimination of heat and moisture, the primary dissociation of particles and physical stability.

The pharmaceutical manufacturers prefer to use direct pressing instead of wet or dry granulation due to the reduction of processing time and low cost. However, direct pressing can be used only in cases where the medicinal product or active ingredient has the physical properties required to obtain pharmaceutically acceptable tablets. However, it is necessary to mix one or more of the excipients with the active component before direct pressing, since most components do not have the required properties. Because the addition of each excipient in the composition leads to an increase in the size of the final tablet, manufacturers often limited in applications to the Institute of direct pressing only for compositions with a low content of active ingredient in the tablet.

Solid dosage form with a high content of the medicinal product, i.e. if the drug is the bulk of the molded tablets can be subjected to direct pressing only if the medicinal product has physical properties, such as cohesion, sufficient for direct compression of ingredients, and if the drug is characterized by a suitable composition.

For example, the inhibitor of DPP-IV, for example, the compound of formula (I), is considered to be a medicinal product with a high dose. Most of the compositions of the tablets contain 70-85 wt.% an inhibitor of DPP-IV in a single tablet. Such drugs with a high content of the active component and physical properties unsuitable for direct compression, it is impossible to process direct pressing in the finished tablet. In addition, the active ingredients are unstable in the presence of water, which eliminates the use of wet granulation.

Another limitation of applying direct pressure to obtain tablets is the size of CT. If the amount of the active ingredient is high, then you should choose a wet granulation of the active ingredient in a mixture with other excipients to obtain pellets of the appropriate size with the required amount of the active ingredient. Wet is ranolazine require smaller amounts of filler, a bonding agent or other excipients in comparison with direct pressing, because the wet granulation gives the required properties of the tablets.

Despite the advantages of direct compression, for example, a shorter period of processing and low cost, to obtain solid dosage forms in the industry widely used wet granulation. Wet granulation is often used instead of direct pressing, since the first method allows you more likely to eliminate the problems associated with the physical properties of the various ingredients of the composition, and allows to obtain a material having the desired fluidity and cohesion properties required for the production of solid dosage forms.

The popularity of wet granulation in comparison with direct extrusion associated with at least three advantages. First, in wet granulation get the material for pressing with better wetting properties, especially in the case of hydrophobic drugs. The addition of hydrophilic excipients leads to hydrophilization surface hydrophobic drugs, eliminating the problems associated with the disintegration and dissolution. Secondly, in wet granulation improves the uniformity of the composition of solid dosage forms, since all of the granules is usual contain the same number of medicines. Finally, you can eliminate the segregation of drugs from excipients.

Segregation is a potential problem with direct pressing. The size and shape of particles containing granular and designed for pressing, optimize wet granulation, because in the process of granulation binder glues the particles with each other and they form the agglomerate in the form of sfericheskie granules.

Because the composition of the present invention has a significant amount of Metformin, the size and shape of the finished tablets may cause problems with the introduction of their oral means to the patient, and in case of simple pelletizing, satisfying all the requirements. In this regard, in industry there is a need to develop methods and pharmaceutical compositions, which will allow you to obtain on an industrial scale tablet with a high dose combination of an inhibitor of DPP-IV and Metformin tablets with high content drug). Tablets with a high dose of an inhibitor of DPP-IV and Metformin must meet all these requirements, at the same time to reduce the size of the tablets, it is preferable to reduce the number and quantity of pharmaceutical excipients.

The object of the present invention is to provide a composition containing an inhibitor of DPP-IV and metform is h, in the form of a cohesive powder for tableting with a fairly high turnover, which can be subjected to granulation or pressed into tablets.

Another object of the present invention is a tablet with a high content of drug in dosage form, comprising an inhibitor of DPP-IV and Metformin, characterized fit the dissolution profile of acceptable levels of hardness, tensile strength and resistance to delamination, and suitable time of disintegration and high stability of the active ingredients in the tablet.

Vildagliptin is sensitive to moisture and, therefore, is unstable, i.e. the active ingredient decomposes. To overcome this problem in the present invention the composition (containing certain excipients) and a method of directly pressing (excluding wet granulation) to provide the desired properties of the tablet, for example, hardness, tensile strength, resistance to delamination and improved stability of the active component, while the tablet contains only 25% of the medicinal product.

Metformin usually get wet granulation with a high content drug that is very difficult. It is also known that rotary pressing cannot be applied due to unsatisfactory SP is the ability to pressing, and it is not recommended to use direct pressing to obtain compositions with a high content of medicines. Known problems are low ability to pressing and high brittleness tablets, and therefore, in the present invention, when designing, special attention was paid to these characteristics. Other problems are:

- A large number of Metformin, which results in larger tablets with low content of drug LAF237.

- Metformin almost defies processing.

- Metformin processed by wet granulation and moisture has a negative effect on LAF.

Thus there is a need to provide patsientov suffering from diabetes, pressed tablets, containing from 25 to 100 mg Villepin and up to 1000 mg of Metformin, an acceptable size, with improved properties, such as hardness, brittleness and stability of active components.

Another object of the present invention is a tablet in the form of standard dosage forms, including inhibitor of DPP-IV and Metformin, with a high content of drugs in tablet form small size, preserving the stability of the active components.

Another object of the present invention is a method of obtaining a composition or tablet, the content is General inhibitor of DPP-IV and Metformin, or their salts.

The present invention features a composition containing an inhibitor of DPP-IV and Metformin, in the form of a powder for tableting, capable of compressing into tablets of suitable size with the appropriate hardness, stability, low disintegration time and suitable dissolution profile.

In addition to active ingredients, powder for tableting contains a number of inert materials such as excipients. They are classified depending on their destination. The primary composition comprises fillers, binders or diluents, sizing, dezintegriruetsja agents and glidant. Other excipients, which impart certain physical properties of the final tablet, include dyes and flavorings in the case of chewable tablets. In most cases, excipients added to the compositions to provide material intended for pressing, high yield strength and compressive characteristics.

The preferred composition of the present invention includes the active ingredients, namely inhibitor of DPP-IV and Metformin, and a binder agent.

Examples of pharmaceutically acceptable binding agents include, without limitation, starches, cellulose and derivatives thereof, for example, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxyprop is methylcellulose, sucrose, dextrose, corn syrup, polysaccharides and gelatin. Binding agent, for example, may be present in amounts of from about 1 to about 40 wt.% based on the weight of the composition, preferably from 1 to 30 wt.%, or from 1 to 25 wt.%, or from 1 to 20 wt.%.

Not necessarily in the compositions of the present invention add 1, 2, 3 or more diluents. Examples of pharmaceutically acceptable excipients and pharmaceutically acceptable diluents include, without limitation, confectionery sugar, pressed sugar, dextrans, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, for example, may be present in an amount from about 15 wt.% up to 40 wt.% based on the weight of the composition. Preferred diluents include microcrystalline cellulose, which is obtained by controlled hydrolysis of α-cellulose, obtained from the pulp of fibrous cellulosic material in the presence of dilute solutions of mineral acids. After hydrolysis hydroxyalkyl purified by filtration and the aqueous slurry is dried by spray, you get a dry porous particles with a wide size distribution. The average particle size suitable microcrystalline cellulose composition is employed, from about 20 nm to about 200 nm. Microcrystalline cellulose are produced by several manufacturers. Examples of suitable microcrystalline cellulose include product Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200 company FMC Corporation. The most preferred of the present invention is the product Avicel PH 102, characterized by a smaller surface area and porous structure. Preferably microcrystalline cellulose is present in the composition for tableting in the amount of from about 25 to 70 wt.%. Another preferred interval content of the specified material is from about 30 to 35 wt.%, another preferred range is from about 30 to 32 wt.%. Other diluent is lactose. Preferably lactose crushed while before adding to the composition of the average size of its particles is from about 50 to about 500 microns. Lactose is present in the composition for tableting in the amount of from about 5 to 40 wt.%, preferably from about 18 to 35 wt.% and most preferably from about 20 to 25 wt.%.

In the composition of the present invention do not necessarily add 1, 2, 3 or more dezintegriruetsja agents. Examples of pharmaceutically acceptable dezintegriruetsja agents include, without limitation, starches, clays, cellulose, algae is Nata, gums, crosslinked polymers, for example, crosslinked polyvinylpyrrolidone, crosslinked calcium salt of carboxymethylcellulose and crosslinked sodium carboxymethyl cellulose, polysaccharides of soybean and guar gum. Disintegrity agent, for example, is present in amounts of from about 2 to about 20 wt.%, for example, from about 5 to about 10 wt.%, for example, approximately mass% based on the weight of the composition. Disintegrity agent is optional, but an acceptable component of the composition for tableting. Dezintegriruetsja agents included in the composition to ensure an acceptable rate of disintegration. Typical dezintegriruetsja agents include starch derivatives and salts of carboxymethylcellulose. Preferred dezintegriraat agent is the sodium salt of starch glycolate. Preferably disintegrity agent present in the composition for tableting in the amount of from about 0 to about 10 wt.%, from about 1 to about 4 wt.% and most preferably from about 1.5 to about 2.5 wt.%.

In the composition of the present invention do not necessarily add 1, 2, 3 or more sizing. Examples of pharmaceutically acceptable oil and pharmaceutically acceptable glidants include, without limitation, colloidal d is the oxide of silicon, the magnesium trisilicate, starch, talc, rejonowy calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The sizing, for example, is present in amounts of from about 0.1 to about 5 wt.% based on the weight of the composition, glidant, for example, is present in amounts of from about 0.1 to about 10 wt.%. The oil is usually added to prevent adhesion of the material for tabletting to punches, to minimize friction in the compaction process and to accelerate the removal of the compressed tablet from the die. Such sizing is usually included in the composition of the final mixture for tableting in the amount less than 1 wt.%. The sizing is hydrophobic or hydrophilic. Examples of such oiling agents include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction between the walls of the matrix and mixture for tableting in the process of pressing and accelerates the destruction of the tablets. It also helps to prevent adhesion of the tablets to the punch and matrix. Magnesium stearate increases the fluidity of the powder in the hopper and in the matrix. The particle size of the magnesium stearate is from 450 to 550 μm, and a density of from 1.00 to 1.80 g/ml. It is stable and no polymer is used in the composition of the mixture for tabletting. The preferred lubricant, magnesium stearate, are also added to the composition. Preferably the lubricant is present in the composition for tableting in the amount of from about 0.25 to 6 wt.%, more preferably from about 0.5 to about 4 wt.% and most preferably from about 0.1 to about 2 wt.%. Other possible oiling agents include talc, polyethylene glycol, silica and hardened vegetable oils. In a preferred embodiment of the present invention, the lubricant is not added to the composition and dispersed in the matrix, or punches.

Use other standard excipients or carriers such as corn starch, calcium phosphate, calcium sulfate, calcium stearate, magnesium stearate, stearic acid, mono - and distearate glycerin, sorbitol, mannitol, gelatin, natural or synthetic gums, such as carboxymethyl cellulose, methylcellulose, alginate, dextran, Arabian gum, gum karaya, gum carob, tragakant etc., diluents, binders, sizing, dezintegriruetsja agents, dyes and fragrances.

Other examples of suitable excipients which do not necessarily add to the composition of the present invention, described in the books Handbook of pharmaceutical excipients, 3-e Izd., edited A.H.Kibbe, ed. American Pharaceutical Association, Washington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4th ed.), edited With Raymond Rowe, ed. Science and Practice, which are included in the present description as a reference.

Thus, in the first embodiment of the present invention features a pharmaceutical composition with a high content of drugs, comprising from 50 to 98 wt.%, from 50 wt.% up to 96 wt.%, from 60 wt.% up to 98 wt.%, from 60 wt.% up to 96 wt.% or from 70 to 98 wt.%, from 70 wt.% up to 96 wt.%, from 80 to 98 wt.% or from 80 to 96 wt.% based on the weight of active ingredients, the active ingredients include an inhibitor of DPP-IV, preferably vildagliptin, and Metformin or its pharmaceutically acceptable salt.

In the second embodiment of the present invention features a tablet with a high content drug or a pill that you receive direct pressing, containing 50 wt.% up to 98 wt.%, from 50 wt.% up to 96 wt.%, from 60 wt.% up to 98 wt.%, from 60 wt.% up to 96 wt.% or from 70 to 98 wt.%, from 70 wt.% up to 96 wt.%, preferably from 80 to 98 wt.% or from 80 to 96 wt.% based on the weight of active ingredients, the active ingredients include an inhibitor of DPP-IV, preferably vildagliptin, and Metformin or its pharmaceutically acceptable salt.

In the present invention it is also proposed composition or tablet, as described above, in which Metformin is present in the form of granules.

In this image the attachment also serves composition or tablet as described above, in which Metformin is present in the form of granules, which contain at least one pharmaceutically acceptable excipient.

In the present invention it is also proposed composition or tablet, as described above, in which Metformin is present in the form of granules, which contain binder.

In the present invention it is also proposed composition or tablet, as described above, in which Metformin is present in the form of granules, which contain from 1 to 25 wt.% a bonding agent (based on the dry weight of the granules).

In the present invention it is also proposed tablet, as described above, obtained by direct pressing of the granules of Metformin in mixture with vildagliptin and neobyazatelno one pharmaceutically acceptable excipient.

In the present invention it is also proposed composition or tablet as described above containing from 1 to 25 wt.% a bonding agent, preferably from 1 to 20 wt.%, preferably from 1 to 12 wt.%, from 2.9 to 11 wt.%, or from 6.5 to 9.5 wt.%, or from 7.5 to 17.5 wt.%, or from 12.5 to 17.5 wt.% based on the weight of pharmaceutically acceptable binding agent.

In the present invention it is also proposed composition or tablet, as described above, comprising at least one pharmaceutically acceptable excipient, which is a lubricant, preferably a number of from 0.1 wt.% up to 5 wt.%, from 0.1 wt.% up to 2 wt.%, or from 0.1 wt.% up to 1.5 wt.% based on the weight of the composition or tablet, or from 0.1 wt.% up to 1 wt.% based on the weight of the composition or tablet. In the present invention it is also proposed composition or tablet, as described above, in which the lubricant is magnesium stearate.

In the present invention it is also proposed pharmaceutical composition or tablet, as described in this context in which the binding agent is chosen from the group comprising starches, cellulose and derivatives thereof, for example, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose and hypromellose, sucrose, dextrose, corn syrup, polysaccharides and gelatin.

In the present invention it is also proposed pharmaceutical composition or tablet, as described in this context in which the binding agent is chosen from the group comprising cellulose and derivatives thereof, preferably hydroxypropylcellulose (LDCs).

The ratio of the components described in this context, is determined when calculating the mass of inhibitors of DPP-IV, Metformin and excipients, for example, a bonding agent.

In the present invention it is also proposed pharmaceutical composition, as described in this context in the form of a standard dosage forms. The term "standard dosage form which means any pharmaceutical dosage forms, such as capsules, tablets (preferably, the tablets obtained by direct pressing), granules, chewable tablets, etc.

In another embodiment, the present invention features a tablet or pharmaceutical composition, which includes, as active ingredients include:

1) from 0.5 to 35% or from 1.5%to 35%, preferably from 0.5 to 20% or from 1.5% to 20% of the inhibitor of DPP-IV, preferably vildagliptin or its pharmaceutically acceptable salt,

2) from 65 to 98.5%, preferably from 80 to 98.5% of the Metformin or its pharmaceutically acceptable salt,

and in which Metformin is in the form of pellets, containing from 1 to 25% of a coupling agent (based on the dry weight of the granules), or

features described in this context, the tablet with a high content of a drug or pharmaceutical composition, which as active components include:

1) from 0.5 to 35% or from 1.5%to 35%, preferably from 0.5 to 20% or from 1.5% to 20% of the inhibitor of DPP-IV, preferably vildagliptin or its pharmaceutically acceptable salt,

2) from 65 to 98.5%, preferably from 80 to 98.5% of the Metformin or its pharmaceutically acceptable salt and in which Metformin is in the form of pellets, containing from 1 to 25% of a coupling agent (based on the dry weight of the granules).

In the present invention it is also proposed tablet or pharmaceutical the song, as described in this context in which the granules contain from 1 to 20%, preferably from 3 to 13 wt.%, from 4.9 to 12 wt.%, or from 7.5 to 10.5 wt.%, or from 7.5 to 17.5 wt.%, or from 12.5 to 17.5 wt.% based on the weight of pharmaceutically acceptable binding agent.

In the present invention it is also proposed tablet or pharmaceutical composition as described in this context in which the binding agent is chosen from the group comprising starches, cellulose and derivatives thereof, for example, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose and hypromellose, sucrose, dextrose, corn syrup, polisher IDA and gelatin.

In the present invention it is also proposed tablet or pharmaceutical composition as described in this context in which the binding agent is chosen from the group comprising cellulose and derivatives thereof, preferably hydroxypropylcellulose (LDCs).

Compositions and tablets that are described in this context, preferably contain at least one pharmaceutically acceptable excipient.

As described, in this context, the compositions optionally add other conventional pharmaceutically acceptable excipients, at least one, e.g. 1, 2, 3 or 4, such as a standard binding agents, diluents, dezintegriruetsja agents, solid Napo is the distributors or carriers, described in this context. Preferred compositions contain no more than 25 or 20 wt.%, or preferably of 17.5 or 15 wt.%, or 11 wt.% pharmaceutically acceptable excipient, including binder (calculated on the weight of dry excipient).

In the present invention it is also proposed tablet or pharmaceutical composition as described above containing from 1 to 12 wt.%, from 2.9 to 11 wt.%, or from 6.5 to 9.5 wt.%, or from 7.5 to 17.5 wt.%, or from 12.5 to 17.5 wt.% pharmaceutically acceptable binding agent, or optionally from 0.1 to 10 wt.% other pharmaceutically acceptable excipient (1, 2 or more), for example, from 0.1 wt.% up to 2 wt.% lubricant (e.g. magnesium stearate) in the calculation of the mass composition/tablets. Preferred granules contain from 3 to 13 wt.%, from 4.9 to 12 wt.%, or from 7.5 to 10.5 wt.%, or from 7.5 to 17.5 wt.%, or from 12.5 to 17.5 wt.% based on the weight of pharmaceutically acceptable binding agent.

Tablet or pharmaceutical composition as described above, contains from 50 to 98 wt.%, from 70 to 98 wt.%, preferably from 80 to 98 wt.% or from 80 to 96 wt.% active ingredients, based on the weight of active ingredients, active ingredients preferably include vildagliptin and Metformin, or in each case their pharmaceutically acceptable salts.

In the present invention it is also proposed tablet or headlamp is aseptically composition, as described above, containing at least one pharmaceutically acceptable excipient.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which additional pharmaceutically acceptable excipients include fillers, binders or diluents, sizing, dezintegriruetsja agents and glidant. Other excipients, which impart certain physical properties of the final tablet, include dyes and flavorings in the case of chewable tablets.

In the present invention it is also proposed tablet or pharmaceutical composition as described above containing at least one additional pharmaceutically acceptable excipient, such as sizing, preferably in quantities of from 0.1 to 5 wt.% or from 0.1 to 2 wt.% based on the weight of the composition, most preferably from 0.5 to 1.5 wt.% based on the weight of the composition/tablets.

In the present invention it is also proposed tablet or pharmaceutical composition as described above containing from 0.1 to 5 wt.%, preferably from 0.1 to 2 wt.% or from 0.5 to 1.5 wt.% the stearate.

In the present invention it is also proposed tablet or pharmaceutical compostie, as described above, in which the lubricant is magnesium stearate.

In this izaberete the AI also invited to a tablet or pharmaceutical composition, as described above, in which granules of Metformin get wet granulation or by granulation of the melt in the presence of a coupling agent.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which granules of Metformin get wet granulation in the presence of water or solvent, which is selected from organic solvents such as ethanol, isopropanol, ethyl acetate, glycoluril and propylene glycol.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which granules of Metformin is obtained by granulation of the melt. Methods of granulation of the melt is described in several publications, such as Rina Chokshi and others, "Hot-melt extrusion Technique: A Review, Iranian Journal of Pharmaceutical Research, Vol.3, p.3-16 (2004) or in a review article Jörg Breitenbach "Melt extrusion: from process to drug delivery technology", European Journal of Pharmaceutics and Biopharmaceutics, t, s-117 (2002), which are included in the present description as a reference.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which vildagliptin is present in the form of medicines.

In the present invention it is also proposed tablet or composition, as described above, in which the quantity of inhibitor of DPP-IV, preferably vildagliptin is from 0.5 to 35 wt.% the sludge is from 1.5 to 35 wt.% based on the weight of active ingredients, i.e. an inhibitor of DPP-IV and Metformin.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which vildagliptin is present in the form of particles in which at least 40% vildagliptin, preferably 60%, more preferably 80% and most preferably 90% is present in the form of particles, the distribution of which size is less than 250 μm or preferably between 10 to 250 μm, or preferably in which at least 25% or at least 35% vildagliptin is present in the form of particles which are distributed in size ranges from 50 to 150 microns.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which vildagliptin is present in the form of particles.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which the particles vildagliptin obtained by granulation of a solution.

In the present invention it is also proposed tablet or pharmaceutical composition as described above, in which the solvent for granulation is preferably chosen from the group comprising ethanol, isopropanol, ethyl acetate, glycoluril or propylene glycol.

In the present invention it is also proposed pharmaceutical composition, as described in this Contex is e, which is contained in a capsule or receive it in the form of tablets, preferably molded tablets or tablets obtained by direct compression. The tablet may also contain a film coating, for example, obtained from a preliminary mixture of Opadry.

In the present invention it is also proposed pharmaceutical composition, as described in this context, in which the composition forms one of the layers of two-layer or three-layer tablets. The preferred two-layer tablet according to the present invention contains a first layer comprising the composition according to the present invention, and as the second layer composition on the basis of Metformin or glitazone (e.g., pioglitazone or rosiglitazone or in each case their pharmaceutically acceptable salts).

In the present invention it is also proposed composition of the present invention, which, in addition, includes an additional active component of glitazone, for example pioglitazone or rosiglitazone, or stimulants of insulin secretion, such as the sulfonylureas, e.g., products, Glipizide, gliburid and amaryl, insulinotropic ligands of the receptor sulfonylureas, such as meglitinide, for example, nateglinide and Repaglinide. Glitazone or sulfonylureas introduced into the granules of Metformin (Metformin + binder+glitazone or Metformin + binder + sulf is nimodipine) or in a mixture with the drug LAF237.

In the present invention it is also proposed two-layer or three-layer tablet in which the compositions of the present invention comprise a single layer, and glitazone, for example pioglitazone or rosiglitazone or sulfonylurea form a second layer.

As described, in this context, the compositions optionally add other standard pharmaceutically acceptable excipients (at least one, e.g. 1, 2, 3 or 4 excipient), such as standard thinners, dezintegriruetsja agents, particulate fillers or carriers described in this context. The preferred composition contains not more than 25, 20, 17,5 or 13 wt.% based on the weight of pharmaceutically acceptable excipient, including a binding agent, i.e. the binder included in the granules of Metformin.

The most preferred pharmaceutical composition comprises from 0.1 to 5 wt.%, preferably from 0.5 to 3 wt.% or from 0.5 to 1.5 wt.% pharmaceutically acceptable lubricant, preferably magnesium stearate.

The above compositions can include one or two of diluent which is selected from microcrystalline cellulose, such as product Avicel PH 102, and lactose.

The term "pharmaceutically acceptable disintegrity agent"used in this context means at least one disintegrity agent, a mixture of, for example, 2 is 3, dezintegriruetsja agents.

The term "pharmaceutically acceptable lubricant"used in this context means at least one sizing mixture, for example, 2 or 3, oiling agents.

A preferred inhibitor of DPP-IV is the product LAF237, preferred diluents are microcrystalline cellulose or lactose, or preferably a combination of microcrystalline cellulose and lactose, preferred dezintegriraat agent is the sodium salt of starch glycolate, preferred binding agent is a binding agent of the type of cellulose (cellulose and its derivatives), for example, LDCs, and the preferred lubricant is magnesium stearate.

The above compositions are intended primarily for pharmaceutical tablets, for example, CT or tablets obtained by direct pressing, and microtablets or capsules, and are characterized by the desired physical properties, profiles dissolution and release of drugs, as is known in the art. Thus, in another embodiment, the present invention features the use of any of the above compositions for preparation of pharmaceutical tablets, microtablets or capsules granulation, direct pressing and dry granulation (and reagirovanie or rotary seal).

The above compositions are primarily suitable for the production of tablets, especially CT or tablets obtained by direct compression.

The tablets obtained from the above compositions, primarily characterized by extremely low brittleness, high tensile strength, superior resistance, optimal ratios of thickness pills/weight pills (tablets obtained by direct pressing), a lower content of water in the composition, particularly in tablets prepared by direct pressing, suitable disintegration time DT (according to the instructions of the British Pharmacopoeia (1988)), a sufficiently high dispersion properties.

In the present invention are described mixing, granulation and pressing. When choosing the type of excipient whereas the size of particles in the interval, which ensures the homogeneity of the powder mixture and the uniformity of the active ingredients in the composition. This prevents segregation of powders in the hopper during pressing. The advantage of using the compositions of the present invention is that the powder mixture can be pressed and is characterized by cohesion and fluidity. In addition, extrusion provides a competitive cost, shelf life, eliminates the use of heat and moisture, provide the rest of the primary dissociation of particles, physical stability and uniformity of particle size.

Describes the advantages of the compositions of the present invention can be effectively used, for example, when the rotary seal or wet granulation, extrusion or direct compression or filling capsules.

In the development process described in this context, the pharmaceutical compositions has been unexpectedly found that extruded tablets, especially tablets obtained by direct pressing, characterized by a particular advantage, if the following conditions are true:

1) size distribution of the particles comprising the inhibitor of DPP-IV is less than 250 μm, preferably from 10 to 250 μm, and/or

2) the water content of the tablet is less than 10% after storage for 1 week at 25°C. and 60% room humidity (RH).

Thus, in another embodiment (a) of the present invention features a pharmaceutical composition or molded tablet, as described in this context in which the dispersion contains particles comprising the inhibitor of DPP-IV, preferably a product LAF237, in free form or in the form of an acid additive salt, and size distribution of at least 60%, preferably 80% and most preferably 90% of the particles which is less than 250 μm or preferably between 10 to 250 μm.

In this image hetenyi features a pharmaceutical composition or molded tablet, as described in this context in which the dispersion contains particles comprising the inhibitor of DPP-IV, preferably a product LAF237, in free form or in the form of an acid additive salt, and size distribution of at least 60%, preferably 80% and most preferably 90% of the particles which is more than 10 μm.

The term "Metformin is in the form of pellets" means that the inhibitor of DPP-IV is not included in the composition of granules containing Metformin.

The term "at least 60%, preferably 80% and most predpodtitelno 90%" means at least 60%, preferably at least 80% and most preferably at least 90%.

The term "at least 25%, preferably 35% and most predpodtitelno 45%" means at least 25%, preferably at least 35% and most preferably at least 45%.

First of all, the present invention features a pharmaceutical composition or molded tablet, as described in this context in which the dispersion contains particles comprising the inhibitor of DPP-IV, preferably a product LAF237, in free form or in the form of an acid additive salt, and size distribution of at least 25%, preferably 35% and most preferably 45% of the particles in the tablet is between 50 to 150 microns.

In the second embodiment of the present invention offer the W of the pharmaceutical composition or molded tablet, as described in this context in which the dispersion contains particles comprising the inhibitor of DPP-IV, preferably a product LAF237, in free form or in the form of an acid additive salt, and for which the following conditions are true:

1) size distribution of at least 60%, preferably 80% and most preferably 90% of the particles are less than 250 μm or preferably between 10 to 250 μm,

2) the water content of the tablet is less than 10% after storage for 1 week at 25°C. and 60% RH.

Preferably in the present invention features a pharmaceutical composition or molded tablet, as described in this context in which the dispersion contains particles comprising the inhibitor of DPP-IV, preferably a product LAF237, in free form or in the form of an acid additive salt, and for which the following conditions are true:

1) size distribution of at least 25%, preferably 35% and most preferably 45% of the particles ranges from 50 to 150 μm,

2) the water content of the tablet is less than 10% after storage for 1 week at 25°C. and 60% RH, preferably the water content of the tablet is less than 5% after storage for 1 week at 25°C. and 60% RH.

Preferably the particles DPPIV, first of all particles of the product LAF237, contain more than 70% of the DPPIV inhibitor, more preferably more than 90% of the sludge is 95% and most preferably more than 98% of the DPPIV inhibitor.

Preferably the particles of the product LAF237 contain more than 70% of the product LAF237, more preferably more than 90% or 95% and most preferably more than 98% of the product LAF237.

Unexpectedly, it was found that the selected distribution of particle size of DPPIV inhibitor, primarily product LAF237 is extremely important to ensure improved ability for pressing tablets.

Preferred excipients selected distribution of particle size are described, for example, in the book Handbook of Pharmaceutical Excipients (4th ed.), edited With Raymond Rowe, Science and Practice.

The particle size of drugs, for example, the particle size of the product LAF237, can be controlled using crystallization, drying and/or grinding/sifting (examples, without limitation, below). The particle size can be reduced using a rotary seal and the grinding/sifting. Obtain particles of the desired size is known and described, for example, in the book " Pharmaceutical dosage forms", Vol.2, 2nd ed., edited H.A.Lieberman, L.Lachman, J.B.Schwartz (Chapter 3: SIZE REDUCTION)".

The method of obtaining the relevant product particles LAF237 desired size is also described in the application WO 2005/067976 included in the present description by reference.

Were investigated particles of various size and unexpectedly it was found that the particle size is described in di the range provides improved ability to pressing.

Estimate of the distribution of particle size by the method of sieve analysis

The distribution of particle size was evaluated using standard sieve analysis, photon correlation spectroscopy or laser diffraction (international standard ISO 13320-1), electron-sensitive areas, light scattering, sedimentation or microscopy. Screening is one of the oldest methods of classification of powders on the distribution of particle sizes. Such methods are known and described in the art, for example, in any textbook on analytical chemistry or in the US Pharmacopoeia (USP) USP-NF (2004 - Chapter 786 - (The United States Pharmacopeial Convention, Inc., Rockville, MD), which describes the standards approved by the monitoring Committee food and drug administration (FDA). The used methods are described, for example, in the book of Pharmaceutical dosage forms: volume 2, 2nd ed., edited H.A.Lieberman, L.Lachman, J.B.Schwartz. On str also described other methods: electron-sensitive areas, light scattering, breathability, sedimentation in gaseous or liquid phase.

When measuring particle size using the air flow, the air flows upward through the sieve of the rotating slit, while the material on the sieve enters pseudouridine state. At the same time to the bottom of the sieve is applied negative pressure, which leads to the destruction of small frequent the C from the sieve into a collecting device. Size analysis and determination of the average size of the particles occurs at the cut-off of particles with smaller sizes on the curve of raspredeleniya size using separate screens in sequential screening (for a detailed description of this method are also given in the book by Allen, Chapman and Hall, T., "Particle Size Measurement", 5th ed., vol. 1, pp.178, London, UK (1997). Thus, for specialists in the art known methods of measuring particle sizes.

The water content of the tablet was measured by the method of water loss during drying or by the method of Karl Fischer, which are standard methods for professionals in the art (for example, the water content can be measured by the method loss on drying according to thermogravimetry). Such methods are known and described in the art, for example, in any textbook on analytical chemistry (J.A. Dean, Analytical Chemistry Handbook, section 19, McGraw-Hill, New York (1995)) or in the US Pharmacopoeia (USP) USP-NF (2004), which describes the standards approved by the Committee of the FDA ((2004 - USP - Chapter 921).

In the present invention primarily serves pressed tablet or tablet obtained by direct pressing, which can dispergirujutsja in water for 15 to 50 minutes, or from 20 to 45 minutes with the formation of the dispersion, which passes through a sieve with a mesh size of 710 μm in accordance with the procedure outlined in this to the text test method dispersible tablets as described in the British Pharmacopoeia.

The tablet of the present invention, is capable of rapidly dispergirujutsja in water, characterized by additional advantage, because it meets the requirements described in the British Pharmacopoeia (V.R.) for dispersible tablets against time dispersion and the quality of dispersion (for example, passage through a sieve with a mesh size of 710 μm).

Preferred time dispersion tablets of the present invention is less than 15 minutes, more preferably less than 12 min, and most preferably less than 10 minutes

Another advantage of the tablets of the present invention is as follows: due to the formation of a relatively thin dispersion tablet has a smaller time of dissolution, which leads to reduction in time of absorption of the drug in the bloodstream. Moreover, an advantage of the present invention is to reduce the time of formation of a relatively thin dispersion of the tablets of the present invention, which are intended for ingestion. Thus, the tablets of the present invention is intended to obtain dispersions in water, and for direct ingestion. These tablets according to the present invention, intended for ingestion, preferably cover planon the m floor, which promotes swallowed.

In another embodiment, the present invention features a pharmaceutical composition or molded tablet, as described in this context, satisfying the following conditions:

1) from 90 to 99.5% product LAF237 is released within from 0 to 45 min and

2) from 70 to 99% of the Metformin is released within 10 to 45 minutes

To determine the dissolution rate of a drug (% release) used the paddle method using 1000 ml of 0.01 N. HCl. Such methods are known and described in the art, for example, in any textbook on analytical chemistry or in the US Pharmacopoeia (USP) USP - NF (2004 - Chapter 711 - (The United States Pharmacopeial Convention, Inc., Rockville, MD), which describes the standards approved by the FDA.

In the present invention it is also proposed a method of obtaining a pharmaceutical composition comprising an inhibitor of DPP-IV, preferably a product LAF237, or their pharmaceutically acceptable salts and Metformin or its pharmaceutically acceptable salts, which consists in the fact that they are carrying out the following stages:

1) granulation of Metformin and a bonding agent,

2) drying of granules containing Metformin and a binder agent,

3) mixing the drug substance is an inhibitor of DPP-IV, product preferably LAF237, with granules containing Metformin and a binder agent,

4) it is interesting mixing sizing for example, magnesium stearate, the mixture obtained in stage 3).

In the present invention it is also proposed a method of obtaining a pharmaceutical tablet containing inhibitor of DPP-IV, preferably a product LAF237, or their pharmaceutically acceptable salts, and Metformin or its pharmaceutically acceptable salts, which consists in the fact that they are carrying out the following stages:

1) granulation of Metformin and a bonding agent,

2) drying of granules containing Metformin and a binder agent,

3) mixing the drug substance is an inhibitor of DPP-IV, product preferably LAF237, with granules containing Metformin and a binder agent,

4) optional mixing of the lubricant, e.g. magnesium stearate, the mixture obtained in stage 3),

5) pressing the mixture into a tablet, you get a standard dosage form.

The resulting mixture is obtained in the form of a powder for tableting, is able to be pressed into a pill.

The final level of moisture in the granules after drying (LOD) is also an important criterion that determines the appropriate properties of pressing and fluidity of Metformin in wet granulation (low LOD ability to pressing decreases and increases brittleness, while at high LOD when granulation is observed adhesion and/or established the e units, impairing the fluidity of the powder). The required value of the LOD is approximately 2% (range from 0.5 to 3.5, preferably in the range from 1.5 to 2.4%).

Thus, in a preferred embodiment, in stage 2) are dried granules to a value of LOD equal to from 0.5 to 3.5%, preferably from 1.5 to 2.4% (LOD: method for the determination of water loss on drying according to the instructions of the United States Pharmacopeia).

The preferred granulation stage 1) is wet granulation or dry granulation of the melt.

Unexpectedly positive results were obtained by granulation of Metformin and a bonding agent from the melt (stage 1). The finished composition or tablets are characterized is described in the context of benefits, such as improved hardness, low breakage, high enough ability to pressing, dissolution and stability.

Thus, in a preferred object of the present invention Metformin and binder are mixed and the resulting mixture is passed through the extruder for granulation of the melt.

The preferred temperature in the extruder in the mixing zone ranges from 140 to 220°C., or from 155 to 205°C. or from 170 to 190°C.

The preferred stage pressing 5) is directly compressing the mixture obtained in stage 3) or (4).

In other embodiments, the above method may include the following stages:

- stage 1), so that at the completion of stage 2) to get Metformin in the form of pellets, containing from 1 to 25 wt.%, or from 1 to 20 wt.%, preferably from 1 to 20 wt.%, more preferably from 3 to 13 wt.%, from 4.9 to 12 wt.%, or 7.5% to 10.5 wt.%, or from 7.5 to 17.5 wt.%, or from 12.5 to 17.5 wt.% per mass of dry pharmaceutically acceptable carrier,

- stage 1), on which at least one pharmaceutically acceptability excipient, such as a diluent or pharmaceutically acceptable disintegrity agent, is added to the mixture, intended for mixing, the preferred content of the additional pharmaceutically acceptable excipient(s) is less than 25 wt.%, preferably less than 17.5 wt.% or 15 wt.% per mass of dry granules

- stage 3), on which at least one additional pharmaceutically acceptable excipient, such as thinner or desintegrasii agent, is added to the mixture, intended for mixing,

- stage coating obtained extruded core (pill),

extruded cores before coating optional dried to a value of LOD is less than 1%, preferably less than 0.5%.

A preferred inhibitor of DPP-IV is the product LAF237, preferred diluents are microcrystalline cellulose or lactose, or preferably the combination is microcrystalline cellulose and lactose, preferred dezintegriraat agent is the sodium salt of starch glycolate and the preferred lubricant is magnesium stearate.

Before stage 1) is preferably carried out stage screening composition for primary crushing, i.e. to remove any agglomerates/large particles. Before stage 3) is preferably carried out screening product LAF237 before adding it into granules of Metformin.

In another embodiment, the present invention proposes a capsule containing the above-described pharmaceutical compositions.

The final product is obtained in the form of tablets, microtablets, capsules, etc. using standard methods, as pellets or similar machines.

The hardness of the tablets obtained one of the above methods, is 14 to 30 thousand when pressing force of 15 kN, and brittleness is from 0.5 to 0.18% at force pressing from 15 to 20 kN.

The most preferred inhibitor of DPP-IV are described in this context, compositions, CT or ways of opting out of the dihydrochloride of 1-{2-[(5-cyano-2-yl)amino]ethylamino}acetyl-2-(S)-cyanopyrrolidine, (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine, L-treeselectionlistener, products, MK-0431, GSK23A, BMS-477118, 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-ethanolinduced and 2-{[3-(aminomethy is)-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-ethanolic]oxy}ndimethylacetamide and not necessarily their pharmaceutically acceptable salts.

The most preferred inhibitor of DPP-IV is 1-[3-gidroksilamin-1 ylamino)acetyl]pyrrolidin-2(S)-carbonitrile (LAF237 or vildagliptin) or its pharmaceutically acceptable salt.

Dose (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (vildagliptin) is preferably from 10 to 150 mg per day, most preferably from 25 to 150 mg, or 50 to 100 mg, or from 25 to 100 mg per day. Preferred examples of daily doses for the introduction of the oral method is 25, 30, 35, 45, 50, 55, 60, 70, 80, 90 or 100 mg of Active ingredient can be entered up to 3 times per day, preferably 1 or 2 times per day.

Glitazone, which can be mixed with the compositions of the present invention in the form of a triple combination, known in the art and described in many publications.

Glitazone under development include products AZ242 (firm AstraZeneca), phase 2, KRP-297 (Kyorin company, licensed by Merck) phase 1-2, MCC-555 (Mitsubishi Chemicals, licensed firm J&J), phase 2, JTT-501 (company Japan Tobacco, a licensed firm Pharmacia), phase 2.

Glitazone 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]methyl}thiazolidine-2,4-dione (pioglitazone, EP 0193256 A1), 5-{[4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl]methyl}thiazolidine-2,4-dione (rosiglitazone, EP 0306228 A1), 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl]methyl}thiazolidine-2,4-dione (troglitazone, EP 039421), (S)-((3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl)methylthiazolidine-2,4-dione (englitazone, EP 0207605 B1), 5-(2,4-dioxothiazolidine-5-ylmethyl)-2-methoxy-N-(4-trifloromethyl)benzamide (KRP297, JP 10087641-A)5-[6-(2-forbindelse)naphthalene-2-ylmethyl]thiazolidine-2,4-dione (MS, EP 0604983 B1), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)phenyl]methyl} thiazolidine-2,4-dione (darglitazone, EP 0332332), 5-(2-naphthylmethyl)thiazolidin-2,4-dione (AY-31637, US 4997948), 5-{[4-(1-methylcyclohexyl)methoxy)phenyl]methyl}thiazolidine-2,4-dione (ciglitazone, US 4287200) in General terms and is described in detail in the documents specified in parentheses after each of the compounds, in each case in the claims, in the examples, the objects of the final products, the pharmaceutical compositions and claims included in the present invention as references. Product DRF2189 and 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}thiazolidine-2,4-dione described in article V. Lohray, etc., J. Med. Chem., v.41, SS-1630 (1998), examples of 2d and 3g on str and 1628. Getting 5-[3-(4-chlorophenyl])-2-PROPYNYL]-5-phenylsulfonyl)thiazolidine-2,4-dione and other compounds in which a represents phenylethynyl and mentioned in this context, carried out by the method described in the article by J. Wrobel, etc., J. Med. Chem., v.41, SC-1091 (1998).

First of all MSS receive, as described on page 49, line 30 to 45, in the patent EP 0604983 B1, englitazone receive, as is written on page 6, line 52 - page 7, line 6, or in the same way as described in examples 27 or 28 on page 24 in the patent EP 0207605 B1, and darglitazone and 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)]benzyl}thiazolidine-2,4-dione (VM-13.1246) receive, as described on page 8, lines 42-54 in the patent EP 0332332 B1. Product AY-31637 impose, as described in column 4, line 32-51 in patent US 4997948 and get rosiglitazone, as described on page 9, lines 32-40 in patent EP 0306228 A1, preferably in the form of maleate. Rosiglitazone is introduced as a commercial product, for example, under the trade name AVANDIA™. Troglitazone impose a commercial product, for example, under the trade names ReZulin™, PRELAY™, ROMOZIN™ (in the UK) or NOSCAL™ (in Japan). Pioglitazone is administered as described in example 2 in patent EP 0193256 A1, preferably in the form of monohydrochloride. Depending on the requirements of a particular patient pioglitazone is administered in the form of a commercial product, for example, under the trade name ACTOS™. Ciglitazone enter, for example, as described in example 13 in the patent US 4287200.

With the introduction of glitazone adult patient suffering from diabetes (body weight 50 kg), for example, the daily dose is usually from 0.01 to 1000 mg, preferably from 0.1 to 500 mg of the Indicated dose can be administered from one to several times per day. First of all, with the introduction of pioglitazone hydrochloride as insulin sensibilization dose of pioglitazone hydrochloride is usually from 7.5 to 60 mg, predpochtene from 15 to 45 mg. With the introduction of troglitazone as an insulin sensitizer daily dose of troglitazone is usually from 100 to 1000 mg, preferably from 200 to 600 mg. With the introduction of rosiglitazone (or maleate) as an insulin sensitizer daily dose of rosiglitazone is usually from 1 to 12 mg, predpochtene from 2 to 12 mg.

Predpochteniem glitazone is pioglitazone, pioglitazone hydrochloride, troglitazone or rosiglitazone or its maleate), particularly preferably hydrochloride pioglitazone.

The dose of the product ACTOS® (pioglitazone) should not exceed 45 mg 1 time per day in monotherapy or in combination with sulfonylurea, Metformin or insulin. The initial dose of the product ACTOS in combination with Metformin is 15 or 30 mg 1 time per day. The introduction of a daily dose of Metformin should be continued after the initiation of treatment product ACTOS. Unfortunately, the dose of Metformin should be adjusted due to the potential for hypoglycemia in the combined treatment in combination with the product ACTOS. The product is ACTOS available in the form of tablets weighing 15 mg, 30 mg and 45 mg

Product AVANDIA® (rosiglitazone) as the initial dose is administered once in the amount of 4 mg 1 time per day or as multiple doses morning and evening. If inadequate response of the organism of patients within 8 to 12 weeks is ü treatment (at lower levels of plasma glucose fasting (FPG)), increase the dose to 8 mg in monotherapy or in combination with Metformin. The dose of the product AVANDIA should not exceed 8 mg per day as single dose or 2 times per day. Product AVANDIA produced in the form of tablets, 2 mg, 4 mg and 8 mg of active agent.

In the treatment of diabetes, the dose of Metformin should be chosen individually depending on efficacy and tolerability, without exceeding the maximum recommended daily dose of Metformin 2000 mg Metformin reduces glucose levels in the blood of patients diagnosed with non-insulin-dependent sagarnaga diabetes, and it comes in the form of tablets of 500, 750, 850 and 1000 mg of active agent. However, because Metformin is a fast-acting drug, it should be administered 2 or 3 times a day (tablets of 500-850 mg 2-3 times per day or 1000 mg 2 times a day during meals). The preferred dose of the present invention ranges from 250 to 2000 mg, preferably from 250 to 1000 mg In the present invention it is also proposed pharmaceutical composition, the tablet or capsule of the present invention, containing 250 mg, 500 mg, 850 or 1000 mg of Metformin or its pharmaceutically acceptable salt.

Thus, in another embodiment, the present invention features a tablet or a composition containing the following active ingredients:

1) from 50 to 2000 mg of Metformin, preferably from 250 to 1000 mg of Metformin,

2) from 25 to 100 mg of inhibitor of DPP-4, preferably of vildagliptin the A.

In the present invention it is also proposed standard pharmaceutical dosage form, preferably a tablet or capsule comprising a composition of the present invention, containing the following active ingredients:

1) from 50 to 2000 mg of Metformin, preferably from 250 to 1000 mg of Metformin,

2) from 25 to 100 mg of inhibitor of DPP-4, preferably vildagliptin, preferably from 25 to 50 mg vildagliptin.

In the present invention it is also proposed standard pharmaceutical dosage form, preferably a tablet or capsule comprising a composition of the present invention, comprising the following active ingredients:

1) 25 mg vildagliptin and 250 mg of Metformin, or in each case their pharmaceutically acceptable salts,

2) 25 mg vildagliptin and 500 mg of Metformin, or in each case their pharmaceutically acceptable salts,

3) 25 mg vildagliptin and 850 mg of Metformin, or in each case their pharmaceutically acceptable salts,

4) 25 mg vildagliptin and 1000 mg of Metformin, or in each case their pharmaceutically acceptable salts,

5) 50 mg vildagliptin and 500 mg of Metformin, or in each case their pharmaceutically acceptable salts,

6) 50 mg vildagliptin and 850 mg of Metformin, or in each case their pharmaceutically acceptable salts or

7) 50 mg vildagliptin and 1000 mg of Metformin, or in each case and the pharmaceutically acceptable salts.

The present invention also proposes the composition or tablet of the present invention, containing:

a) active ingredients, including:

1) 25 mg vildagliptin and 250 mg of Metformin, or in each case their pharmaceutically acceptable salts,

2) 25 mg vildagliptin and 500 mg of Metformin, or in each case their pharmaceutically acceptable salts,

3) 25 mg vildagliptin and 850 mg of Metformin, or in each case their pharmaceutically acceptable salts,

4) 25 mg vildagliptin and 1000 mg of Metformin, or in each case their pharmaceutically acceptable salts,

5) 50 mg vildagliptin and 500 mg of Metformin, or in each case their pharmaceutically acceptable salts,

6) 50 mg vildagliptin and 850 mg of Metformin, or in each case their pharmaceutically acceptable salts or

7) 50 mg vildagliptin and 1000 mg of Metformin, or in each case their pharmaceutically acceptable salts, and

b) Metformin in the form of granules comprising from 1 to 25 wt.% a bonding agent (based on the dry weight of the granules), 1 to 20 wt.% a bonding agent, or from 7.5 to 17.5 wt.% a bonding agent,

C) the composition or tablet comprising from 50 to 98 wt.%, from 50 to 96 wt.%, from 60 to 98 wt.%, from 60 to 96 wt.% or from 70 to 98 wt.%, from 70 to 96 wt.%, from 80 to 98 wt.% or from 80 to 96 wt.% active ingredients

d) the composition, optionally comprising at least one additional excipient, is for example, from 0.1 to 2 wt.% the stearate.

In the present invention it is also proposed standard pharmaceutical dosage form, preferably a tablet or capsule comprising a composition of the present invention, containing the following active ingredients:

1) from 50 to 2000 mg of Metformin, preferably from 250 to 1000 mg of Metformin,

2) from 25 to 100 mg of inhibitor of DPP-4, preferably vildagliptin, preferably from 25 to 50 mg vildagliptin, and

3) from 2 to 50 mg glitazone, preferably from 2 to 8 mg rosiglitazone or from 15 to 45 mg of pioglitazone.

Thus, in another embodiment, the present invention features a tablet of the present invention, which is characterized by the following parameters:

the hardness ranges from 60 to 340 H,

- fragility is less than 0.8%

the thickness of the tablet is from 4.5 to 8.3 mm

Thus, in another embodiment, the present invention features a tablet of the present invention, which is characterized by the following parameters:

the hardness ranges from 60 to 340 H,

- fragility is less than 0.8%,

the thickness of the tablets ranges from 4.5 to 8.3 mm,

at least 70% vildagliptin dissolves within 30 minutes,

at least 80% of the Metformin hydrochloride is dissolved within 45 minutes

according to the paddle method.

In other variations which those present invention features a tablet or composition of the present invention, in whom Metformin is present in the form of hydrochloride.

The present invention features any of these songs or tablets containing from 50 to 98 wt.%, from 50 to 96 wt.%, from 60 to 98 wt.%, from 60 to 96 wt.% or from 70 to 98 wt.%, from 70 to 96 wt.%, from 80 to 98 wt.% or from 80 to 96 wt.% active ingredients, the active components are vildagliptin and Metformin, or in each case their pharmaceutically acceptable salts.

Another object of the present invention features the use of the above described formulations, capsules, tablets, compressed tablets, tablets prepared by direct pressing, to treat conditions such as non-insulin-dependent diabetes mellitus, arthritis, obesity, transplantation of allografts, chalcedonianism osteoporosis, heart failure, impaired glucose metabolism, IGT (impaired glucose tolerance), neurodegenerative diseases such as Alzheimer's and Parkinson's, modulated hyperlipidemia, modulated conditions associated with hyperlipidemia or with reduced levels GPON, GPNP and LP(a), cardiovascular or renal diseases, for example, diabetic cardiomyopathy, hypertrophy of the left or right ventricles, hypertrophic median thickening of arteries and/or large vessels, hypertrophy of the mesenteric vessels, hypertro the Oia mesangial vessels, neurodegenerative disorders and disorders of cognitive functions, to provide a calming or sedative action, to facilitate postoperative catabolic changes and hormonal responses to stress, to reduce mortality and incidence of myocardial infarction, for the treatment of conditions associated with the above-described effects, mediated by altering the levels of GLP-1 and/or GLP-2.

In all cases, especially in the case of compounds described in the claims, the final products described in the examples, the subject of the final products, analytical methods and measurement techniques (e.g., documents, USP), the ways to obtain particles of the desired size, pharmaceutical formulations, excipients and the claims of the invention included in the present invention as references to the said publication or application.

The following examples illustrate the present invention.

Example 1

The way to obtain

Because the drug Metformin is solidified during storage, the required grinding using oscillatory mill (Frewitt)equipped with a sieve with mesh size 1,68 mm Then Metformin mixed with HPC-EXF (Aqualon company, EXF means the classification of the product of viscosity and particle size, x means xtrafine, HF means the viscosity compared with other values elm is Ooty LDCs, HF, GF, LF, EF) for 1-2 minutes under stirring with a high shear. 9 wt.% the solution LDCs was pumped into the tank for granulation high shear at constant speed (for 4 min) before the formation of the desired granules (total water content of about 7%). Then the granules were dried in the dryer with pseudovirions layer to the end felcini LOD (loss on drying) of approximately 2% (from 1.5 to 2.4%). The dried granulate was passed through the oscillator Fitzmill (equipped with a sieve with mesh size 0,078” or 2 mm) or oscillator Frewitt (equipped with a sieve with mesh size 1,68 mm). Drug LAF237 was passed through the hand sieve with mesh size of 1 mm and mixed with the crushed granules of Metformin in the mixer with hopper for 300 turns. Magnesium stearate is also passed through the hand sieve with mesh size of 1 mm and mixed with a mixture of Metformin/LAF for 60 turns. The mixture is then extruded on a rotary press for tableting. Before coating extruded cores were dried to a value of LOD less than 0.5%. At the core was coated with a density of approximately 5 mg/see

Operational characteristics of the process of obtaining a series of the described compositions containing the core Metformin/LAF237 in the ratio 5:1, 10:1, 20:1 and 40:1

Volume series

Usually production series costal is l less than 1.0 kg In the process of getting wet granulation was carried out in the mixer in demand include Collette Gral volume of 25 l, the mass series ranged from 3.0 to 6.0 kg

The scalability and reliability of the process

All methods associated with wet granulation and drying of Metformin, as well as with mixing, pressing and coating are standard and performed on standard equipment. The target value of the LOD at drying in pseudovirions layer (FBD) is 1.5 to 2.4% LOD.

Since the moisture level in the dried granulate significantly affects the properties when pelletizing, all the granules preferably received with use of a mixer K.G5 and dried in a drying Cabinet to a value of LOD approximately 2% (preferred range from 1.5 to 2.4%).

Another option way to obtain

Step 1: Sift the Metformin and LDCs through a sieve with mesh size of 1700 μm. Endured the sifted ingredients in a diffusion mixer and predvaritelno was mixed at 20 rpm for 200 turns.

Stage 2: Missed the mixture through a twin screw extruder at 180°C (zone mix) - granulation of the melt.

Stage 3: Sieved granules through a sieve with a mesh size of 500 μm using a Frewitt mill (stage grinding).

Stage 4: Sift LAF237 through a sieve with a mesh size of 500 μm and mixed with the granules, the floor is obtained at stage 3, at 20 rpm for 300 rpm.

Stage 5: Sift magnesium stearate through a sieve with a mesh size of 1000 microns and mixed at 20 rpm for 60 turns.

Step 6: Pressing the obtained composition

Stage 7: Application of film coating

Primers

Obtaining granules of Metformin granulation of the melt

IngredientContent (wt.%/wt.%)Quantity per tablet (mg)
Internal phase
Metformin HCl1000
Hydroxypropylcellulose99
External phase
Magnesium stearate11
Vildagliptin50
Total1160

The ingredients of the internal phase, i.e. hydrochloride Metformin and hydroxypropylcellulose, product KLUCEL EXF company Hercules Chemical Co. (Wilmington, Delaware) was mixed in a mixer with bunker is within 200 rpm. The mixture was applied to the feed section or hopper of twin screw extruder. Suitable twin screw extruder is a pharmaceutical co-rotating twin screw extruder PRISM (16 mm) Thermo Electron Corp.(Waltham, Massachusetts).

At the end of the twin screw extruder is filler with a hole of 3 mm Twin screw extruder consists of 5 zones or sections, each of which can be set independently. Starting from the hopper to the die zone, respectively, were heated to the following temperatures: 40°C, 110°C, 130°C, 170°C and 185°C. the temperature of the heated zone should not exceed the melting point of the hydrochloride Metformin (approximately 232°C). Screw rotation speed was 150 rpm, but most can be 400 rpm, the volumetric feed rate was approximately 30 to 45 grams of material per minute Performance ranged from 4 g/min to 80 g/min

The extrudate or pellet obtained from the extruder, cooled to room temperature within 15 to 20 minutes the Cooled granules were then sieved through a sieve with a mesh size of 500 μm (i.e. a sieve of 1 mm).

To receive the external phase magnesium stearate was sifted through a sieve with a mesh size of 1000 microns, and drug vildagliptin first passed via a sieve with a mesh size of 500 ám. Then vildagliptin was mixed with the obtained granules in a suitable mixer with hopper is for about 150 or 300 spins. Magnesium stearate was mixed with the mixture for 50 or 70 spins. The final mixture was pressed into tablets using standard rotary for tabletting press (Manesty Beta Press) when pressing force of 6 kN to 25 kN. The obtained tablets were monolithic, and their hardness ranged from 5 thousand to 35 thousand. Tablets with the specified hardness characterized by a suitable value of the tensile strength less than 1 wt.% after 500 shots. Moreover, these tablets are characterized by a disintegration time of less than or equal to 20 min when using discs at 37°C in 0.1 G. of HCl.

Example 2

A. Brief description of the extended testing for compatibility

Evaluated the compatibility is described in this context, compounds with standard excipients at 50°C/75% (open) for 4 weeks. The received test data compatibility indicate a lower degree of degradation of Metformin or LAF237 in compositions and tablets of the present invention.

C. Method of determining stability

Stability was determined at 25°C/60% RH, 30°/65% RH and 40°C/75% RH in closed vessels made of HDPE (polyethylene wiscoy density) in the presence of drying agent and at 40°C/75% RH in the absence of drying agent in the clear. The results of tests at different time intervals indicate improved the stability is described in the context of the compositions and tablets.

RH means relative humidity

The results of the study indicate a rather high stability of the compositions and tablets of the present invention.

The stability of the compositions with low humidity, the ratio Metformin/LAF. 40:1

The total degradation of LAF237 (Metformin, obtained by direct pressing) (pre-granulated material intended for direct compression into tablets, available under the brand name "new product") + LAF237 (granulation of solution) was 2.9% at 40°C/75% RH during storage for 6 weeks in the closed state.

The total degradation of LAF237 (Metformin, obtained by granulation in water in the presence of 6.6% LDCs) + LAF237 (granulation of a solution, the composition of the present invention) was 0.9% at 40°C/75% 0 In storage for 6 weeks in the closed state.

The total degradation of LAF237 co-granulation (Metformin + LAF237) in the presence of 6.6% LDCs) was 6.6% at 40°C/75% RH during storage for 6 weeks in the closed state.

Moreover, explored a variety of other compounds and found that, for example, the tablet is in the form of standard dosage forms containing an inhibitor of DPP-IV and Metformin, with a high content of drugs characterized by a higher stability, especially in the Pris is under a bonding agent, preferably LDCs.

C. Conditions determine the rate of dissolution

The selected method is based on the preliminary results of the testing method, which showed similar release profiles of Metformin and LAF237 at different pH (in 0.01 N. HCl, pH 4.5 and buffer solution with pH 6.8) under stirring (50 or 100 rpm).

The USP apparatus I (basket centrifuge)

Rotation speed: 100 rpm

Environment for dissolution: 0,01 N. degassed HCl

Volume: 900 ml

Dissolution (n=3) was performed only for the original samples. There were obtained satisfactory results in the dissolution of stable samples of compositions and tablets of the present invention. The compositions meet the criteria for the dissolution rate.

3. Composition

Examples of compositions with all the values of the doses given in table 3-1 - 3-6

Example 4

The tablets obtained as described above in the description and examples

Methods of assessment tablets

1. The average weight of the tablets. 20 tablets were weighed on an analytical balance, and calculated the average weight of the tablets.

2. The tensile strength of tablets on the gap (thousand). Each tablet was investigated in the device for determining the tensile strength of Lanigera and R is scitable average tensile strength.

3. Brittle (weight loss in %). 10 accurately weighed tablets were tested for the brittleness of using the device to determine the fragility Roche for 10 minutes Then tablets were obespylivanie, re-weighed and the mass loss due to breakage was calculated in percent of the initial mass.

4. The time of disintegration of the variance DT (test Method dispersible tablets described in the British Pharmacopoeia (BP), t.ii, s (1988)). Tablets were tested according to the method described above BP (without disks) for dispersible tablets using water at a temperature of 19-21°C.

5. The quality of the dispersions. According to the method of testing the homogeneity of variances for dispersible tablets BP (BP, t.ii, S. 895 (1988)), 2 tablets were placed in 100 ml of water at 19-21°C and dispersively.

Assessment methods granules

1. Loss on drying (LOD). The residual moisture content in the pellet (LOD) was determined for sample weighing 3-4 g using Computrac moisture analyzer at 90°C according to the instructions of the manufacturer.

2. The mass median diameter (WMD). The sample pellets weighing 10 g of sieved for 2 min with suitable amplitudes of the pulses and screening ultrasound sieve Alien Bradley according to the instructions of the manufacturer. Used a sieve with a mesh size of 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, 53 μm and 40 μm. The value of WMD expected in view of the percentage distribution of particle sizes, passed through the sieve using a computer program.

Example 5

Improved reliability of way to obtain

A preliminary assessment of the ability to extrusion was performed on a Carver press using a variety of structures.

The data obtained indicate that the compositions of the present invention during pressing at high pressure (pressing force) is characterized by extremely high strength. First of all, for example, the compositions of the present invention are characterized by high strength and compressibility during pelletizing. At high pressure (pressing force) of the compositions according to the present invention are characterized by significantly higher strength tablets.

Research on the ability to pressing (D.Becker, unpublished data) was performed on single-station press Korsch, equipped with motion sensors on the upper and lower punches.

The data obtained clearly indicate that tablets LAF237 are characterized by low values of strength/tensile strength in the absence of a filler with a high degree of pressuemosti. However, the compositions of the present invention are characterized by the desired compressibility primarily for LAF237/Metformin at a ratio of 1:5.

The results obtained indicate that the desired hardness is of Ableton can be obtained when the content in the granules of Metformin, for example, from 1 to 20%, preferably from 3 to 13%, from 3 to 17.5% of a coupling agent, such as LDCs.

Example 6

Brittle

The evaluation was performed with use of a press Manesty Betapress with 6 different parameters: the speed 66-90 rpm (63000-86000 tons per h) and a pressure of 7.5-15 kN. Testing used a device with a flat surface and a beveled edge (FFBE) with a diameter of 9 mm for tablets weighing 250 mg and a diameter of 10 mm for tablets weighing 310 mg (depending on the mass of the investigated tablets used devices with other diameters). Measured the ability to breakage, profile extrusion, profile, speed, and weight change. Test conditions and results for the study of fragility used to determine the influence on strength parameters (distribution of particle composition, size, thickness and weight of the tablets, the water content in the tablets and the like). The compositions of the present invention are characterized by the desired brittleness.

Example - Tablets containing Metformin/LAF237 in a ratio of 20:1:

The results obtained indicate that the tablets containing LAF237 + (granules of Metformin in the absence of a binding agent) are characterized by fragility of 0.8%, while tablets containing LAF237 + (granules of Metformin containing 12% LDCs), are characterized by brittleness of less than 0.2% (when pressing force 15 kN).

p> Example 7 Mechanical impact (distribution of particle sizes)

The material with the desired distribution of particle sizes can be obtained from vildagliptin of any shape, for example, amorphous vildagliptin, under the action of mechanical forces. Such action can be provide upon impact, shear or compression. Most commercial devices for grinding combines all three principles. For vildagliptin preferably used shock (mechanical shock) or jet mill. The most preferred shock meltina equipped with various blades, screens, liners or plate for column guides. In the method according to the present invention preferably use impact mill, equipped with flat blades and a sieve with a flat mesh size of 5×2,5 see the Speed of impact ranged from 20 to 100 m/sec (peripheral speed) depending on the batch. In the present invention used peripheral speed of the blades is approximately 40-50 m/S.

1. Pharmaceutical composition, which includes, as active ingredients includes:
1) from 1.5 to 20% vildagliptin or its pharmaceutically acceptable salt, or
2) from 80 to 98.5% of the Metformin or its pharmaceutically acceptable salt, while the active ingredients are 60 to 98% of the composition, and in which Metformin is in fermignano, containing from 1 to 20 wt.% calculated on the dry weight of pharmaceutically acceptable binding agent selected from cellulose and its derivatives.

2. The pharmaceutical composition according to claim 1, which is a tablet.

3. The pharmaceutical composition according to claim 1, which is a tablet obtained by direct compression.

4. The pharmaceutical composition according to any one of claims 1 to 3, in which the granules contain from 3 to 13 wt.% calculated on the dry weight of pharmaceutically acceptable binding agent.

5. The pharmaceutical composition according to any one of claims 1 to 3, in which the granules contain from 4.9 to 12 wt.% calculated on the dry weight of pharmaceutically acceptable binding agent.

6. The pharmaceutical composition according to any one of claims 1 to 3, in which the granules contain from 7.5 to 10.5 wt.% calculated on the dry weight of pharmaceutically acceptable binding agent.

7. The pharmaceutical composition according to any one of claims 1 to 3, in which the granules contain from 7.5 to 17.5 wt.% calculated on the dry weight of pharmaceutically acceptable binding agent.

8. The pharmaceutical composition according to any one of claims 1 to 3, in which the granules contain from 12.5 to 17.5 wt.% calculated on the dry weight of pharmaceutically acceptable binding agent.

9. The pharmaceutical composition according to any one of claims 1 to 3, in which the binder is chosen from the group comprising microcrystalline, cellulo is, hydroxypropylcellulose, hydroxyethyl cellulose and hypromellose.

10. The pharmaceutical composition according to any one of claims 1 to 3, in which add at least one standard pharmaceutical acceptable excipient.

11. The pharmaceutical composition according to claim 9, in which add at least one standard pharmaceutical acceptable excipient.

12. The pharmaceutical composition according to any one of claims 1 to 3, in which the pharmaceutical acceptable excipient chosen from the group comprising binders, diluents, dezintegriruetsja agents, sizing, solid fillers and carriers.

13. The pharmaceutical composition according to any one of claims 1 to 3, in the form of tablets obtained by direct pressing of the granules of Metformin in combination with vildagliptin and optionally at least one pharmaceutically acceptable excipient.

14. The pharmaceutical composition according to any one of claims 1 to 3, containing not more than 25 or 20 wt.% pharmaceutically acceptable excipient, including binder based on the dry weight of excipient.

15. The pharmaceutical composition according to any one of claims 1 to 3, containing not more than 15 wt.% pharmaceutically acceptable excipient, including binder based on the dry weight of excipient.

16. The pharmaceutical composition according to any one of claims 1 to 3, including:
1) from 1 to 12 wt.% Pharm is citiesi acceptable binding agent based on the dry weight of pharmaceutically acceptable binding agent and optionally from 0.1 to 10 wt.% additional pharmaceutically acceptable excipient, or
2) from 7.5 to 17.5 wt.% or from 12.5 to 17.5 wt.% pharmaceutically acceptable binding agent based on the dry weight of pharmaceutically acceptable binding agent and optionally from 0.1 to 10 wt.% additional pharmaceutically acceptable excipient calculated on the dry weight of the additional pharmaceutical excipient.

17. The pharmaceutical composition according to any one of claims 1 to 3, comprising from 7.5 to 17.5 wt.% pharmaceutically acceptable binding agent based on the dry weight of pharmaceutically acceptable binding agent and optionally from 0.1 to 10 wt.% additional pharmaceutically acceptable excipient calculated on the dry weight of the additional pharmaceutical excipient.

18. The pharmaceutical composition according to claim 11 in the form of tablets, in which other pharmaceutically acceptable excipients is the sizing.

19. The pharmaceutical composition according to any one of claims 1 to 3 in the form of a tablet comprising from 0.1 wt.% up to 5 wt.% pharmaceutically acceptable lubricant based on the weight of the composition.

20. The pharmaceutical composition according p, comprising from 0.5 wt.% up to 1.5 wt.% pharmaceutically acceptable lubricant based on the weight of the composition.

21. The pharmaceutical composition according to claim 19, in which the lubricant is magnesium stearate.

22. The pharmaceutical composition according to any one of claims 1 to 3,in which granules of Metformin get wet granulation or by granulation of the melt in a mixture with a binder agent.

23. The pharmaceutical composition according to any one of claims 1 to 3, in which granules of Metformin get wet granulation of water or solvent chosen from the group comprising ethanol, isopropanol, ethyl acetate, glycoluril or propylene glycol.

24. The pharmaceutical composition according to any one of claims 1 to 3, in which vildagliptin is present in the form of particles.

25. The pharmaceutical composition according to any one of claims 1 to 3, in which vildagliptin is present in the form of particles, in which at least 40% vildagliptin is present in the form of particles, the distribution of which size is less than 250 microns.

26. The pharmaceutical composition according A.25, in which at least 40% vildagliptin is present in the form of particles, the distribution of which size is from 10 to 250 microns.

27. The pharmaceutical composition according to any one of claims 1 to 3, which is filled capsule or which is obtained in the form of tablets, compressed tablets or tablets obtained by direct compression.

28. The pharmaceutical composition according to claim 1, 2 or 3 in the form of tablets obtained by direct pressing of the granules of Metformin in mixture with vildagliptin and optionally at least one pharmaceutically acceptable excipient.

29. The pharmaceutical composition according to claim 1, where the composition is in one of the layers of two-layer or three-layer tablets.

30. Pharmaceutical compo is ice according to any one of claims 1 to 3, including:
1) from 25 to 100 mg vildagliptin or its pharmaceutically acceptable salt, or
2) 25 mg, 50 mg or 100 mg vildagliptin or its pharmaceutically acceptable salt.

31. The pharmaceutical composition according to any one of claims 1 to 3, including: 1) from 50 to 2000 mg of Metformin or its pharmaceutically acceptable salt.

32. The pharmaceutical composition according to any one of claims 1 to 3, including:
1) 25 mg vildagliptin and 250 mg of Metformin, or in each case their pharmaceutically acceptable salts,
2) 25 mg vildagliptin and 500 mg of Metformin, or in each case their pharmaceutically acceptable salts,
3) 25 mg vildagliptin and 850 mg of Metformin, or in each case their pharmaceutically acceptable salts,
4) 25 mg vildagliptin and 1000 mg of Metformin, or in each case their pharmaceutically acceptable salts,
5) 50 mg vildagliptin and 500 mg of Metformin, or in each case their pharmaceutically acceptable salts,
6) 50 mg vildagliptin and 850 mg of Metformin, or in each case their pharmaceutically acceptable salts, or
7) 50 mg vildagliptin and 1000 mg of Metformin, or in each case their pharmaceutically acceptable salts.

33. The pharmaceutical composition according to any one of claims 1 to 3, comprising an additional active ingredient, which are sulfonylureas or glitazone, such as pioglitazone or rosiglitazone.

34. A method of obtaining a pharmaceutical composition, tereasa inhibitor of DPP-IV, which is vildagliptin or its pharmaceutically acceptable salt and Metformin, or in each case their pharmaceutically acceptable salts according to any one of claims 1 to 3, including:
1) granulation of Metformin and a bonding agent,
2) drying of granules containing Metformin and a binder agent,
3) mixing the drug substance is an inhibitor of DPP-IV with granules containing Metformin and a binder agent,
4) optional mixing of the lubricant, for example magnesium stearate with the mixture obtained in stage 3).

35. The method according to clause 34 of pharmaceutical tablets, containing an inhibitor of DPP-IV and Metformin, or in each case their pharmaceutically acceptable salts, including:
1) granulation of Metformin and a bonding agent,
2) drying of granules containing Metformin and a binder agent,
3) mixing the drug substance is an inhibitor of DPP-IV with granules containing Metformin and a binder agent,
4) optional mixing of the lubricant, for example magnesium stearate with the mixture obtained in stage 3),
5) pressing the mixture into a tablet with obtaining a standard dosage forms.

36. The method according to clause 34, the implementation of which in stage 2) the granules are dried until the amount of water loss on drying (LOD) of 0.5-3.5%, preferably 1.5 to 2.4 per cent.

37. The method according to p, where stir the mixture at the stage or stage 3) add at least one additional pharmaceutically acceptable excipient.

38. The method according to clause 37, where additional pharmaceutically acceptable excipients is thinner or disintegrity agent.

39. The method according to p, which offers the additional step of coating the tablet obtained in stage 5).

40. The method according to p, at which stage granulation 1) is from the melt granulation or wet granulation.

41. The method according to p, which includes a step of granulation 1), which mix Metformin and a binder agent, and the mixture is passed through the extruder for granulation of the melt.

42. The method according to paragraph 41, in the exercise of which the temperature in the extruder in the mixing zone ranges from 140°C to 220°C or 155°C to 205°C or 170°C to 190°C.

43. The method according to p, in the exercise of which as a binder agent for use cellulose or its derivative selected from the group comprising microcrystalline cellulose, hydroxypropylcellulose, hydroxyethyl cellulose and hypromellose.

44. The pharmaceutical composition according to any one of claims 1 to 3, which as of Metformin use of Metformin hydrochloride, and as an inhibitor of DPP-IV use vildagliptin or its pharmaceutically acceptable salt.

45. The pharmaceutical composition according to any one of claims 1 to 3 in the form of tablets, which is characterized by the following parameters:
- solid is the terrain ranges from 60 to 340 H,
- fragility is less than 0.8%, and
the thickness of the tablet is from 4.5 to 8.3 mm

46. Tablet § 45, which is characterized by the following parameters:
the hardness ranges from 60 to 340 H,
- fragility is less than 0.8%, and
the thickness of the tablets ranges from 4.5 to 8.3 mm, and
at least 70% vildagliptin dissolves within 30 min according to the paddle method of analysis, and
at least 80% of the Metformin hydrochloride is dissolved within 45 minutes according to the paddle method of analysis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to DGAT inhibitor of formula (I), its N-oxide, pharmaceutically acceptable salt and solvate, based on it pharmaceutical composition and its application for treatment of diseases, mediated by DGAT activity, such as obesity and diabetes. In general formula (I) A represents CH or N; X represents -C (=O)-C(=O); -O-C(=O)-; -NRX-C(=O)-; -Z1-C(O)-; -Z1-NRx-C(O)-; -C(O)-Z1-; -NRx-C(O)-Z1-; -S(=O)p-; -NRX-C(=S) -; Y represents NRx-C(=O)-Z2-; -NRx-C(=O)-Z2-NRy-; -NR*-C(=O)-Z2-NRy-C(=O)-; -NRx-C(=O)-Z2-NRy-C(=O)-O-; -NRx-C(O)-Z2-O-; -NRx-C(=O)-Z2-O-C(=O)-; -NRx-C(=O)-Z2-C(=O)-O-; -NRx-C(=O)-Z2-C(=O)-NRy-; -NRx-C(=O)-Z2-NRy-C(=O)-NRy-, -C(<))-Z2-; -C(=O)-NRx-Z2-; -C(=O)-NRx-Z2-O-; R1 represents C1-12alkyl, optionally substituted with cyano, C1-4alkyloxy, C1-4alkyloxy C1-4alkyloxy, C3-6cycloalkyl or aryl; C2-6alkenyl, C2-6alkinyl; C3-6cycloalkyl; adamantanyl; aryl1; aryl1C1-6alkyl; Het1; or HetC1-6alkyl, on condition that when Y represents -NRxC(=O)-Z2-; -NRx-C(=O)-Z2-NRy; -NRx-C(=O)-Z2-C(=O)-NRy-, -C(=O)Z2-; -NRx-C(=O)-Z2-NRy-C(=O)-NRy-; -C(=O)-NRx-Z2-; -C(=O)-NRx-O-Z2- or -C(=O)-NRx-Z2-NRy-; then R1 can also represent hydrogen; R2 represents R3; R3 represents phenyl, naphthalenyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle, containing 1 or 2 N atoms, where each of said cycles can optionally be substituted with, at least, one substituent, in particular, one-five substituents, said substituents represent halogen, C1-6alkyl, optionally substituted with hydroxy, polyhalogen C1-6alkyl, C1-6alkylthio, polyhalogen-C1-6alkyloxy, carboxyl, hydroxyl, C1-6alkylcarbonyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, nitro, R5R4N-C(=O)-; R5R4N-C1-6alkyl; HetC1-4alkyl, Het-C(=O)-C1-4alkyl, Het-C(=O)-; R8 represents hydrogen, halogen, C1-4alkyl, substituted with hydroxyl Values of other radicals are given in invention formula.

EFFECT: obtaining pharmaceutical composition for treatment of diseases, mediated by DGAT activity, such as obesity and diabetes.

31 cl, 5 tbl, 352 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a product containing an insulin response. A method for producing the product containing the insulin response involving mixing at least one polyphenol-containing herbal material specified in a group consisting of fruit, vegetables, tea, green tea, coffee, cocoa, chocolate and bark, and at least aqueous edible solvent for making the mixture; heating said mixture; adding at least one lactic acid bacilli strain specified in Lactobacillus plantarum, and optionally at least one protein source specified in a group including peptones, tryptones, yeast extracts and their combinations to said heated mixture for making the fermented mixture; and exposing said fermented mixture to the conditions suitable for fermentation for making the product reducing the insulin response, and optionally eliminating the Lactobacillus plantarum strain. The use of the product reducing the insulin response for preparing a composition for preventing or treating diabetes, metabolic syndrome, obesity and cardiovascular diseases.

EFFECT: product prepared by the method described above effectively reduces the insulin response.

15 cl, 7 dwg, 11 tbl

FIELD: chemistry.

SUBSTANCE: compounds activate glucokinase and can be used to prepare medicine for treating of metabolic disorders, for lowering blood glucose level, for treating hyperglycemia, for treating IGT, for treating Syndrome X, for treating impaired fasting glucose (IFG), for treating type 2 diabetes, for treating type 1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for appetite regulation, for for treating obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. In compounds of formula , A denotes , R3 is selected from a group consisting of phenoxy and benzyloxy, each possibly substituted with one or more substitutes independently selected from R12; R12 is F, CI, Br, -CF3, -CN methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH3 or -S(O)2-CH3; R30 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy or cyclopropyl-methoxy, each possibly substituted with one or more substitutes independently selected from R12; R8 is methylthio, isopropylthio, ethylthio or 2-methylpropylthio, each substituted with one or more substitutes independently selected from R34; R34 is carboxy.

EFFECT: improved properties of the compound.

13 cl, 1 tbl, 242 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology and can be used for reduction of hypoglycemia acute exacerbation or severe hypoglycemia exacerbation in patients with type II diabetes after treatment with insulin. For this purpose vildagliptin or its salt is introduces to patient in combination with insulin.

EFFECT: invention ensures reduction of risk of hypoglycemia development, as well as necessity to apply several antihyperglycemic medications.

12 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical industry and concerns a composition for glucose delivery through an oral mucosa for increasing of glucose (sugar) blood level of an individual. The composition contains: a. effective amount of glucose, b. effective amount of sodium glycocholate, c. effective amount of a pharmaceutically acceptable carrier; the composition it is free from additional active pharmaceutical agents.

EFFECT: development of the effective method for increasing glucose (sugar) blood level.

13 cl, 9 ex, 4 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: medicine.

SUBSTANCE: present invention concerns new, selectable hybrid polypeptides expressing at least two hormonal activities containing a first biologically active module of a peptide hormone covalently bonded with at least one additional biologically active module of the peptide hormone.

EFFECT: polypeptides can be used as agents for treatment and prevention of metabolic diseases and disorders associated with overweight.

19 cl, 6 dwg, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 2-alkylsufanyl-3-arylsufonyl-cycloalkano[e]pyrazolol[1,5-a]pyrimidines of general formula 1 or 2-alkylsufanyl-3-arylsufonyl-cycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2, which are antagonist of 5-HT6 receptors. In compounds of formula 1

and 2 ,

R1 is a hydrogen atom or C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is a hydrogen atom, one or two optionally identical halogen atoms, C1-C3 alkyl or hydroxyl, optionally substituted with C1-C3 alkyl; n is an integer equal to 1, 2 or 3.

EFFECT: compounds can be used in preventing and treating diseases of the central nervous system, anxiolytics and as compounds with nootropic effect and suitable for enhancing memory.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: medicine, pharmaceutics.

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

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

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

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

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

35 cl, 6 dwg, 12 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely, to antidiabetic composition. Method of obtaining antidiabetic pharmaceutical composition includes preparation of trituracio mixture of active substance repaglinide, taken in therapeutically efficient quantity, with complex-forming substance, solubiliser and colloid silicon dioxide, further addition of filling agent, disintegrant and lubricant, and tabletting by method of direct pressing.

EFFECT: pharmaceutical composition in form of tablet, obtained by claimed method, is characterised by high degree of active substance release, satisfactory strength and has storage term longer than 2 years.

10 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of pharmaceutics. Claimed is method of obtaining drug form, which include: a) placement inside depression of friable material, including at least approximately 5 wt % of at least one hydrated salt and pharmaceutically active agent, and where at least one hydrated salt is characterised by temperature of dehydration from 20 to 120°C; b) heating friable material in depression to temperature higher than said temperature of dehydration of at least one hydrated salt for time period sufficient for fusion of material with formation of aggregate, and heating is performed by radio-frequency or microwave heating; and c) cooling aggregate in depression until aggregate hardens in dosed form. Friable material can additionally contain carbohydrate. Claimed is drug form, obtained by said method. In order to obtain drug form, which includes external edible part and internal part, disintegrating in oral cavity, said friable material is placed inside depression in preliminarily created external edible form, with depression having required shape and volume, sufficient for placement of part of drug form, disintegrating in oral cavity.

EFFECT: method makes it possible to create dosed drug forms avoiding production stage of pressing, which in its turn improves integrity of particles, which contain pharmaceutically active agent and are sensitive to forces of compression.

16 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an oral solid dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt wherein an active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet, and contains an internal phase containting aliskiren or its pharmaceutically acceptable salt, an excipient, a binding agent and a disintegrant, and an external phase containing a disintegrant, an excipient, a glidant and a lubricant.

EFFECT: invention provides administration of the active ingredient aliskiren in the small oral dosage form; it is characterised by an acceptable disintegration time.

32 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent to be used for treating arterial hypertension and congestive cardiac failure. A pharmaceutical composition contains ramipril, a combination of sodium bicarbonate and arginine as a stabiliser, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium croscarmellose, glidant and a lubricant and optionally a dying agent. A method for preparing the pharmaceutical composition involves moisturising of a mixture of ramipril, lactose monohydrate, microcrystalline cellulose, sodium bicarbonate, and optionally the dying agent in a solution of hypromellose and arginine, granulation, drying, dry granulation, addition of sodium croscarmellose, glidant and the lubricant, and tableting of the prepared mixture. The pharmaceutical composition in the form of a solid dosage form is characterised by decreased formation of all impurities, including ramiprilate and diketopiperazine ramipril, fast release of the active substance, high strength and storage stability of the quality characteristics guaranteed within more than 2 years of shelf life.

EFFECT: preparing the agent for treating arterial hypertension and congestive cardiac failure.

11 cl, 2 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with combined pharmaceutical composition, which possesses anti-tuberculosis action. Composition is made in form of solid drug form, which contains combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride ad active ingredient, and pharmaceutically acceptable auxiliary substances.

EFFECT: composition is characterised by high therapeutic activity.

10 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to tablet, which is decomposed in mouth, containing D-mannite, active ingredient, disintegrating preparation, selected from crospovidone and carmellose, lubricant, selected from sodium stearylfumarate and sucrose esters of fatty acids, binding agent and starch. D-mannite has average size of particles larger than 30 mcm and specific surface larger than 0.40 m2/g.

EFFECT: claimed tablet has time of decomposition in oral cavity within 30 seconds, excellent sensation in oral cavity and sufficient strength, as a result of which tablet is not decomposed in the process of distribution.

28 cl, 1 dwg, 12 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of silibinin component of general formula (I) for obtaining medication for parenteral introduction for trweatment of viral hepatitis, with medication optionally containing cyclodextrin and/or phospholipid, and set of similar purpose, which includes said silibinin component and other medication, representing one or several pharmaceutical agents from: arginine, glutamate, silymarin, citiolone, epodemiol, ornithine oxoglurate, tidiacic arginine, myoinosite, methionine and N-acetyl methionine, choline, ornithine aspartate, cyanidanol, thiopronin, betaine, cyanocobalamin, leucine, levolose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudin, interferon. Medication preferably does not contain silidianin, and/or silicristin, and/or isosilibinin.

EFFECT: reduction of viral strain and reactivation of patients after parenteral introduction of claimed silibinin component.

21 cl, 12 dwg, 5 ex

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