RU2585378C1 - Solid dosage form for oral administration containing combination of vildagliptin and gliquidone - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents a pharmaceutical composition, made in form of a tablet, produced by direct compression. As active ingredients tablet contains a DPP-IV inhibitor vildagliptin in amount of 1.3-86 wt% and gliquidone or its pharmaceutically acceptable salt in an amount of 0.8-68.5 wt%. Active ingredients make up from 2.1 to 98 wt% of composition. Present invention also includes a multilayer tablet and a multilayer tablet with modified release, produced by direct compression method. Their core contains vildagliptin, and external layer contains gliquidone. Binding substance used is cellulose or derivatives thereof, and substance retarding vildagliptin release from core of multilayer tablet is preferably hydroxypropylcelllose in amount of 15-35 wt% of core. Invention also enables to treat a category of patients suffering type 2 diabetes mellitus accompanied by chronic renal disease.

EFFECT: invention provides stability of tablet prepared by direct compression, containing claimed composition.

19 cl, 36 ex

Description

The present invention relates to medicine and the pharmaceutical industry, and relates to a pharmaceutical composition comprising a dipeptidyl peptidase IV inhibitor (DPP-IV), preferably vildagliptin, and glycidone, tablets, multilayer tablets, modified release multilayer tablets containing these compositions, and methods for their preparation .

The terms "DPP-IV inhibitor", "glycidone", as used in this context, also means any pharmaceutically acceptable salts, crystalline forms, hydrates, solvates, diastereoisomers or enantiomers thereof.

Glycvidone is a derivative of the sulfonylurea of the second generation. It has pancreatic and extrapancreatic effects. Stimulates insulin secretion by lowering the threshold of pancreatic β-cell glucose irritation, increases insulin sensitivity and its binding to target cells, enhances the effect of insulin on muscle and liver glucose uptake (increases the number of insulin receptors in target tissues), inhibits lipolysis in adipose tissue. Acts in the second stage of insulin secretion, reduces the content of glucagon in the blood. It has a hypolipidemic effect, reduces the thrombogenic properties of blood. The hypoglycemic effect develops after 1.0-1.5 hours, the maximum effect - after 2-3 hours, and lasts 12 hours. Absorption is high, TCmax in plasma - 2-3 hours T1 / 2 - 0.5-1.5 h. Metabolized in the liver with the formation of inactive metabolites. It is excreted mainly through the gastrointestinal tract - 95%, by the kidneys - 5%. (Endocrinology. National leadership. Brief edition / edited by I.I. Dedov, G.A. Melnichenko. - M.: GEOTAR-Media, 2013. - 752 p.).

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

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

DPP-IV inhibitors are described in the state of the art. For example, DPP-IV inhibitors in general or in detail are 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 DPP-IV inhibitors are described in the following documents: WO 02053548, especially compounds 1001-1293 and examples 1-124, WO 02067918, especially compounds 1000-1278 and 2001-2159, WO 02066627, especially examples, WO 02/068420 first of all, all the compounds described in examples I-LXIII, and their corresponding analogues, more preferred are compounds 2 (28), 2 (88), 2 (119), 2 (136) listed in the table in which the values are indicated IC _50, WO 02083128 especially examples 1-13, US 2003096846 especially the described compounds, WO 2004/037181 especially examples 1 and 33 and the compounds described in paragraphs 3 -5, WO 0168603, especially the compounds described in examples 1-109, EP 1258480, especially the compounds described in examples 1-60, WO 0181337, especially examples 1-118, WO 02083109, especially examples 1A-1D WO 030003250, especially the compounds described in examples 1-166, most preferably 1-8, WO 03035067, especially the compounds described in examples, WO 03/035057, especially the compounds described in examples, US 2003216450, especially examples 1-450, WO 99/46272, especially the compounds described in paragraphs 12, 14, 15 and 17, WO 0197808, especially the compounds described in paragraph 2, WO 03002553, especially soy the dynamics described in examples 1-33, WO 01/34594, especially the compounds described in examples 1-4, WO 02051836, especially examples 1-712, EP 1245568, especially examples 1-7, EP 1258476, especially examples 1-32, US 2003087950, especially examples, WO 02/076450, especially examples 1-128, WO 03000180, especially examples 1-162, WO 03000181, especially examples 1-66, WO 03004498, especially examples 1-33, WO 0302942, especially examples 1-68, US 6482844, especially examples, WO 0155105, especially the compounds described in examples 1 and 2, WO 0202560, especially examples 1-166, WO 03004496, especially examples 1-103, WO 03/024965, especially examples 1-54, WO 0303727, especially examples 1-209, WO 0368757, especially examples 1-88, WO 03074500, especially 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, especially examples 1-53, WO 02062764, especially examples 1-293, preferably the compound described in example 95, hydrochloride (2 - {{3 - (aminomethyl) -4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl} oxy} acetamide), WO 02308090, especially 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 7-1-7-7, p. 90, with measures 8-1-8-59, pp. 91-95, examples 9-1-9-33, examples 10-1-10-20, US 2003225102, especially compounds 1-115, the compounds described in examples 1- 121, especially compounds a) -z), aa) -az), ba) -bz), ca) -cz) and da) -dk), WO 0214271, especially examples 1-320, US 2003096857, WO 2004 / 052850, especially the compounds as described in examples 1-42, and the compounds described in paragraph 1, DE 10256264 A1, especially the compounds such as described in examples 1-181, and the compounds described in paragraph 5, WO 04 / 076433, especially the compounds listed in the table. A, preferably the compounds listed in the table. B, preferably compounds I-XXXXVII, or the compounds described in paragraphs 6-49, WO 04/071454, especially the compounds described, for example, compounds 1-53, or the compounds listed in table. Ia-If, or the compounds described in paragraphs 2-55, WO 02/068420, especially the compounds described in detail, 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 analogues 1-174, or the compound described in example 3, and its analog 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 analog 1, or the compound described in example 9, or the compound described e in example 10, and its analogs 1-531, even more preferred are the compounds described in paragraph 13, WO 03/000250, especially the compounds described in detail, such as compounds 1-166, preferably the compounds described in examples 1- 9, WO 03/024942, especially the compounds described in detail, such as compounds 1-59, the compounds listed in the table. 1 (1-68), the compounds described in paragraphs 6, 7, 8, 9, WO 03024965, especially the compounds described in detail, such as the compounds 1-54, WO 03002593, the compounds described above, in particular listed in table 1 or in paragraphs 2-15, WO 03037327, in particular, the compounds described in detail, such as the compounds described in examples 1-209, WO 03/000250, especially the compounds described in detail, such as compounds 1 -166, preferably the compounds described in examples 1-9, WO 03/024942, especially the compounds described in detail, such as compounds 1-59, soy the strengths listed in table. 1 (1-68), the compounds described in paragraphs 6, 7, 8, 9, WO 03024965, especially the compounds described in detail, such as the compounds 1-54, WO 03002593, the compounds described above, in particular listed in table 1 or in paragraphs 2-15, WO 03037327, first of all, in detail described compounds, such as compounds described in examples 1-209, WO 0238541, WO 0230890, application US No. 09/788173, filed February 16 2001 (file LA50), primarily examples, WO 99/38501, primarily examples, WO 99/46272, primarily examples, and also DE 19616486 A1, primarily val-pyr, val-thiazolidide, isoleucyl-thiaz olidide, isoleucyl pyrrollylide and salts of fumaric acid and isoleucyl thiazolidide and isoleucyl pyrrolidide, WO 0238541, especially the compounds described in detail, such as the compounds described in detail in Examples 1-53, WO 03/002531, especially the compounds described such as the compounds listed on pages 9-13, more preferably the compounds described in examples 1-46, and most preferably the compound described in example 9, US No. 6395767, preferably the compounds described in examples 1-109, most preferably the compound described in the example 60.

Further preferred examples of DPP-IV inhibitors also include compounds described in US Pat. Nos. 6,124,305 and 6,107,317, WO 9819998, WO 9515309 and WO 9818763, such as 1- [2 - [(5-cyanopyridin-2-yl) aminoethylamino] acetyl-2-cyano- (S) -pyrrolidine and (2S) -1 - [(2S) -2-amino-3,3-dimethylbutanoyl] -2-pyrrolidinecarbonitrile.

WO 9819998 describes N- (N′-substituted glycyl) -2-cyanopyrrolidines, especially 1- [2- [5-cyanopyridin-2-yl] amino] ethylamino] acetyl-2-cyano- (S) -pyrrolidine . Preferred compounds are described in WO 03/002553 on pages 9-11, which is incorporated herein by reference. WO 0034241 and US Pat. No. 6,110,949 disclose N-substituted adamantylaminoacetyl-2-cyanopyrrolidines and N- (substituted glycyl) -4-cyanopyrrolidines, respectively. Preferred DPP-IV inhibitors are the compounds described in claims. 1-4. First of all, in these applications, the compound 1 - [[(3-hydroxy-1-adamantyl) amino] acetyl] -2-cyano- (S) -pyrrolidine (also known as LAF237) is described.

WO 9515309 describes 2-cyanopyrrolidinamide amino acids as DPP-IV inhibitors, and WO 9529691 describes peptidyl derivatives of α-aminoalkylphosphonic acid diesters, especially including a proline residue or similar structures. Preferred DPP-IV inhibitors are the compounds listed in table. 1-8. WO 01/72290 describes preferred DPP-IV inhibitors (Example 1 and Nos. 1, 4 and 6). WO 9310127 discloses boronic acid and proline esters useful as DPP-IV inhibitors. Preferred DPP-IV inhibitors are the compounds described in Examples 1-19. WO 9925719 describes sulfostin, which is a DPP-IV inhibitor, obtained from a Streptomyces strain. WO 9938501 discloses N-substituted 4-8 membered heterocyclic rings. Preferred DPP-IV inhibitors are the compounds described in claims. 15-20.

WO 9946272 describes phosphorus-containing compounds as DPP-IV inhibitors. Preferred DPP-IV inhibitors are the compounds described in claims. 1-23.

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

WO 9967278 and WO 9967279 describe prodrugs and DPP-IV inhibitors in the form ABC, where C is a stable or unstable DPP-IV inhibitor.

A preferred N-peptidyl-O-aroyl hydroxylamine is a compound of formula VII

Where

j is 0, 1 or 2,

R _ε1 means the side chain of a natural amino acid and

R _ε2 means (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-aroylhydroxylamine is a compound of formula VIIa

or a pharmaceutically acceptable salt thereof.

N-Peptidyl-O-aroylhydroxylamines, for example, formulas VII or VIIa, as well as their preparation are described in H.U. Demuth et al., J. Enzyme Inhibition, vol. 2, ss. 129-142, primarily ss. 130-132 (1988).

The most preferred inhibitors are N- (substituted glycyl) -2-cyanopyrrolidines of the formula (I)

Where

R is substituted adamantyl and

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

The term “substituted adamantyl” means, for example, 1- or 2-adamantyl containing one or more, for example, two substituents that are selected from the group consisting of alkyl, —OR ₁ or —NR ₂ R ₃ , where R ₁ , R ₂ and R ₃ independently means hydrogen, alkyl, C ₁ -C ₈ alkanoyl, carbamyl or —CO-NR ₄ R ₅ , where R ₄ and R ₅ independently mean alkyl, unsubstituted or substituted aryl, and where one of R ₄ and R ₅ means hydrogen or R ₄ and R ₅ together mean C ₂ -C ₇ alkylene.

The term “aryl” preferably means phenyl. The term “substituted phenyl” preferably means phenyl containing one or more, for example, two substituents, which are selected from the group consisting of, for example, alkyl, alkoxy, halogen or trifluoromethyl.

The term "alkoxy" means alkyl-O-.

The term “halogen” means fluoro, chloro, bromo and iodo.

The term “alkylene” means a straight chain bridging group 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 compounds of formula (I) wherein the adamantyl substituent is attached to the terminal atom of a bridging group or to a methylene group adjacent to the terminal atom of a bridging group. In the compounds of formula (I), where the glycyl-2-cyanopyrrolidine residue is bonded to the terminal atom of the bridging group, the R ′ substituent in the adamantyl group preferably means 3-hydroxy. In the compounds of formula (I), wherein the glycyl-2-cyanopyrrolidine residue is bonded to a methylene group adjacent to the terminal atom of the bridging group, the R ′ substituent on the adamantyl residue is preferably 5-hydroxy.

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

Where

R ′ is hydroxy, C ₁ -C ₇ alkoxy, C ₁ -C ₈ alkanoyloxy or R ₅ R ₄ N-CO-O-, where R ₄ and R ₅ independently are C ₁ -C ₇ alkyl or phenyl unsubstituted or containing substituents selected from the group consisting of C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, halogen or trifluoromethyl, and where R ₄ is hydrogen, or R ₄ and R ₅ together are C ₃ -C ₆ alkylene, and

R ″ means hydrogen, or

R ′ and R ″ independently mean C ₁ -C ₇ alkyl,

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

Such DPP-IV inhibitors of formula (I), (IA) or (IB) are described in U.S. Patent. No. 6166063, issued December 26, 2000, and in the application WO 01/52825. Examples of such inhibitors include (S) -1- {2- [5-cyanopyridin-2-yl) amino] ethylaminoacetyl) -2-cyanopyrrolidine or (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl -2-cyanopyrrolidine (product LAF237). They exist in free form or in the form of an acid addition salt. Pharmaceutically acceptable, i.e. non-toxic and physiologically acceptable salts, although other salts may be used, for example, in the isolation or purification of the compounds of the present invention. Although hydrochlorides are preferred acid addition salts, salts of methanesulfonic, sulfuric, phosphoric, citric, lactic and acetic acids may also be used.

Preferred DPP-IV inhibitors are those described in Mona Patel et al. Expert Opinion Investig Drugs., V. 12, No. 4, p. 623-633 (April 2003), paragraph 5, primarily products P32 / 98, K-364, FE-999011, BDPX, NVP-DDP-728 and others, the contents of which, primarily the description of DPP-IV inhibitors, are included in this invention by reference.

Product FE-999011 is described in WO 95/15309, p. 14, as compound 18.

Another preferred inhibitor is the compound BMS-477118 described in US patent No. 6395767 (the compound described in example 60), that is, benzoate (1S, 3S, 5S) -2 - [(28) -2-amino-2- (3 -hydroxytricyclo [3.3.1.1 ^3,7 ] dec-1-yl) -1-oxoethyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile (1: 1) of the formula M described in WO 2004/052850 , p. 2, and the corresponding free base, (1S, 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.1 ^3,7 } dec-1-yl) - 1-oxoethyl] -2-azabicyclo [3.1.0] hexane-3-carbonitrile (M ′) and its monohydrate (M ′ ′) of the formula M described in WO 2004/052850, page 3. Another name for the compound BMS- 477118 is tsya saxagliptin.

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

Other preferred DPP-IV inhibitors of the present invention are described in WO 02/076450 (primarily in Examples 1-128), as well as in Wallace T. Ashton, Bioorganic & Medicinal Chemistry Letters, v. 14, cc. 859-863 (2004), in particular Compound 1 and the compounds listed in Tables 1 and 2. A preferred compound is compound 21e (Table 1) of the formula

The product P32 / 98 or P3298 (CAS number 251572-86-8, i.e. 3 - [(2S, 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine) can be used as a mixture of 3 - [(2S , 3S) -2-amino-3-methyl-1-oxopentyl] thiazolidine and (2E) -2-butenedioate (2: 1) as shown below

and is described in WO 99/61431 and Diabetes, vol. 47, ss. 1253-1258 (1998), under the name of the company Probiodrug and compound P 93/01 of the same company.

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

The most preferred DPP-IV inhibitors are the compounds described in examples 1-13 and claims. 6-10.

Other preferred DPP-IV inhibitors are those described in WO 2004/037169, especially in Examples 1-48, and WO 02/062764, especially in Examples 1-293, more preferred are 3- (aminomethyl) -2 compounds -isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinoline carboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6 α-isoquinolyl] oxy} acetamide described on page 7, as well as in WO 2004/024184, especially in comparison examples 1-4.

Other preferred DPP-IV inhibitors are described in WO 03/004498, especially in Examples 1-33, and the most preferred compound of the formula

described in example 7 (product MK-0431 or zitaglipin).

Preferred DPP-IV inhibitors are also described in WO 2004/037181, especially in Examples 1-33, the most preferred compounds are described in claims. 3-5.

Preferred DPP-IV inhibitors are N-substituted adamantylaminoacetyl-2-cyanopyrrolidines, N- (substituted glycyl) -4-cyanopyrrolidines, N- (N′-substituted glycyl) -2-cyanopyrrolidines, N-aminoacylthiazolidines, N-amino-acyrolidines alloisoleucylthiazolidine, L-threoisolecylpyrrolidine and L-alloisolecylpyrrolidine, 1- [2 - [(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano (S) -pyrrolidine and their pharmaceutically acceptable salts.

Particularly preferred is 1- {2 - [(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2- (8) -cyanopyrrolidine dihydrochloride (product of DPP728) of the formula

first of all, its dihydrochloride,

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

as well as L-threoisolecylthiazolidine (compound code according to the Probiodrug catalog P32 / 98, as described above), MK-0431, GSK23A, BMS-477118, 3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1, 2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optional pharmaceutically acceptable salts of these compounds .

DPP728 and LAF237 are the most preferred compounds and are described in detail in WO 98/19998, Example 3, and in WO 00/34241, Example 1, respectively. The DPP-IV P32 / 98 inhibitor (see above) is described in detail in Diabetes, vol. 47, ss. 1253-1258 (1998). DPP728 and LAF237 are prepared as described on page 20 of WO 98/19998 or WO 00/34241. Preferred formulations for administration of the LAF237 product are described in provisional application US No. 60/604274.

Particularly preferred are DPP-IV inhibitors that are active when administered orally.

In all cases, especially for the compounds described in the claims and the final products described in the working examples, the subject of the final products, pharmaceutical formulations and claims is included in the present description as references to these publications or applications.

DPP-IV inhibitors, for example, compounds of formula (I), and their corresponding pharmaceutically acceptable acid addition salts, can be used in admixture with one or more pharmaceutically acceptable carriers and, optionally, with one or more standard pharmaceutical adjuvants and administered by enteral route, for example , by the oral route, in the form of tablets, capsules, mini-tablets and the like, or by the parenteral route, for example, by the intravenous route, in the form of sterile injectable solutions or suspensions. Compositions for administration by the enteral and parenteral route are prepared by standard methods.

DPP-IV inhibitors, for example, compounds of formula (I), and their corresponding pharmaceutically acceptable acid addition salts, can be formulated into pharmaceutical compositions for administration by the enteral and parenteral route, containing an amount of active agent that is effective in treating conditions mediated by inhibition of DPP- IV, and to said compositions in unit dosage form and to said compositions comprising a pharmaceutically acceptable carrier.

DPP-IV inhibitors, for example, compounds of formula (I), including those described herein and in each example, can be administered in enantiomerically pure form, for example containing more than 98%, preferably more than 99% of an individual enantiomer, or in combination with enantiomer R, for example, in the form of a racemate. The above doses are based on the compounds of formula (I) and excluding the amount of enantiomer R.

Due to the inhibitory activity against DPP-IV, DPP-IV inhibitors, for example, compounds of formula (I) and their corresponding pharmaceutically acceptable acid addition salts, can be used to treat conditions mediated by inhibition of DPP-IV. Given the above, as well as literature data, it can be expected that the compounds described in this context are suitable for the treatment of conditions such as non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantation, and calcitonin-dependent osteoporosis. In addition, given the role of glucagon-type peptides, such as GLP-1 and GLP-2, and their relationship with inhibition of DPP-IV, it can be expected that the compounds described in this context can be used, for example, to provide a calming effect or to attenuate postoperative catabolic changes or a hormonal response to stress, or to reduce mortality and morbidity of myocardial infarction, or to treat conditions associated with the above actions that are mediated by changes in GLP-1 levels and / or GLP-2 in the body.

In more detail, for example, DPP-IV inhibitors, for example, compounds of formula (I) and their corresponding pharmaceutically acceptable acid addition salts, improve the initial response to insulin by administering a provocative dose of glucose by the oral route and are therefore suitable for the treatment of non-insulin-dependent diabetes mellitus .

DPP-IV inhibitors, especially the compounds of formulas I, IA or IB of the present invention, are hygroscopic, which leads to stability problems, and, in addition, cannot be tabletted by themselves (New Composition. RF Patent 2483716), as and glycidone.

Tablets - solid dosage form obtained by pressing powders and granules containing one or more medicinal substances with or without excipients.

Among the tablets are distinguished: uncovered, effervescent, coated, gastro-resistant, with a modified release, for use in the oral cavity.

(OST 91500.05.001-00 Quality standards for medicines. General provisions. Appendix 1. Dosage forms. Terms and definitions.).

Tablets as a dosage form are widespread throughout the world. Currently, the bulk of the dosage forms are available in tablet form.

The positive qualities of the tablets provide:

- the proper level of mechanization of the main stages and operations of production, contributing to high productivity and hygiene;

- the accuracy of dosing introduced into tablets of medicinal substances;

- portability of tablets, convenient for dispensing, storage and transportation;

- long-term preservation of medicinal substances in a compressed state;

- for substances not sufficiently stable - the possibility of applying protective shells;

- the ability to mask unpleasant organoleptic properties (taste, smell, coloring ability), which is achieved by coating;

- a combination of medicinal properties that are incompatible in physicochemical properties in other dosage forms;

- localization of the action of a drug substance in a certain section of the gastrointestinal tract - by applying shells soluble in an acidic or alkaline environment;

- prolongation of the action of drugs (by coating, using special technologies and the composition of the tablet cores);

- regulation of the sequential absorption of several drugs from the tablet into the body at certain intervals (multilayer tablets);

- prevention of errors during the dispensing and taking medications - drawing on the surface of the tablets of the corresponding inscriptions.

Tablet classification

1. According to the method of obtaining, there are two classes of tablets:

1.1. Pressed, obtained by pressing medicinal powders on tablet machines with different capacities. This method is basic.

1.2. Molded or trituration tablets obtained by molding a tableted mass. Trituration tablets contain small doses of medicinal and diluting substances: their mass can be up to 0.05 g.

2. Classification of tablets on a constructive basis:

2.1. Composition: simple (single-component) and complex (multi-component).

2.2. According to the structure of the structure: single-layer and multi-layer (at least 2 layers), with or without coating, frame, with a modified release.

Single-layer tablets consist of a compressed mixture of medicinal and auxiliary substances and are uniform throughout the entire dosage form. In multilayer tablets, medicinal substances are arranged in layers.

Uncoated - single-layer or multilayer tablets obtained by single or multiple pressing. In multilayer tablets, each of the layers may contain different medicinal substances.

Effervescent - uncoated tablets, usually containing acidic substances and carbonates or bicarbonates, which react quickly in water with the release of carbon dioxide; they are intended to dissolve or disperse the drug in water immediately before administration.

For use in the oral cavity - usually uncoated tablets obtained by special technology with the aim of releasing a medicinal substance or substances in the oral cavity and ensuring local or general resorption (buccal, sublingual tablets, etc.).

Coated - tablets coated with one or more layers of various substances, such as natural and synthetic materials, carbohydrates, possibly with the addition of surfactants. A thin coating (less than 10% of the weight of the tablets) is usually called film. The coating of tablets is classified into: coated, film and pressed dry.

Gastro-resistant - tablets that are stable in the gastric juice and release a drug substance or substances in the intestinal juice. Obtained by coating the tablets with a gastro-resistant membrane (enteric-soluble tablets) or by compressing granules and particles previously coated with a gastro-resistant membrane or pressing drugs in a mixture with a gastro-resistant excipient (durals).

Frame, or skeletal tablets (durulas), have an insoluble frame, the voids of which are filled with a medicinal substance. A tablet is like a sponge soaked in medicine. When taken, its frame does not dissolve, maintaining its geometric shape, and the drug substance diffuses into the gastrointestinal tract.

With modified release - coated or uncoated tablets containing special excipients or obtained by special technology, which allows you to program the speed or place of release of the drug substance.

3. Depending on the purpose and method of use of the tablets, the following groups are distinguished.

Oriblettae - tablets used orally. Medicinal substances are absorbed by the mucous membrane of the stomach or intestines. These tablets are taken orally with water. The oral group of tablets is the main one.

Resoriblettae - tablets used sublingually; medicinal substances are absorbed by the oral mucosa.

Implantablettae - tablets made aseptically are used for implantation. Designed for delayed absorption of drugs in order to prolong the therapeutic effect.

Injectablettae - tablets made aseptically are used to obtain injection solutions of medicinal substances.

Solublettae - tablets used for the preparation of solutions for various pharmaceutical purposes.

Dulciblettae bacilli, boli, tirctratoria, vagitoria - pressed urethral, vaginal and rectal dosage forms.

The forms of tablets produced by the chemical and pharmaceutical industry are the most diverse: cylinders, balls, cubes, triangles, quadrangles, etc. The most common is the flat-cylindrical shape with a bevel and a biconvex shape, convenient for swallowing. In addition, punches and dies for the production of tablets are simpler to manufacture and do not cause much difficulty when they are installed on tablet machines.

Most filling and packaging machines are designed to work with flat cylindrical and biconvex tablets.

The size of the tablets varies from 4 to 26 mm in diameter, the most common - from 4 to 12 mm, tablets with a diameter of more than 25 mm are called briquettes. Tablets with a diameter of more than 9 mm have one or two risks applied perpendicularly, allowing you to divide the tablet into two or four parts and thus vary the dosage of the drug.

The weight of the tablets is mainly 0.05-0.8 g, which is determined by the dosage of the drug and the amount of excipients included in their composition. Tablets should have the correct shape, without jagged edges, smooth and uniform surface, have sufficient strength and not crumble. There are about 40 forms of tablets. The geometric shape and dimensions of the tablets are determined by the standard - OST 64-072-89 “Medicines. Pills. Types and sizes. " It provides for the release of two types of tablets: flat-cylindrical without a facet and with a facet, biconvex without a coating and with coatings: film, pressed and dragee. Flat cylindrical tablets are available in 14 sizes with diameters ranging from 4.0 to 20.0 mm; biconvex tablets without coating - 10 sizes - from 4.0 to 13.0 mm, coated tablets - from 5.0 to 10.0 mm. The diameter of the tablets is determined depending on their weight. The height of the cylindrical tablets should be within 30-40% of the diameter.

In addition to active or medicinal agents, tablets may contain a number of excipients known as excipients. They are classified according to the function that they exhibit in the final tablet. The primary composition includes a filler, a binding agent, a sizing and glidant. Other excipients that impart certain physical properties to the final tablet are colorants and flavors. In the absence of excipients, most drugs and pharmaceutical components cannot be directly compressed into tablets, mainly due to the low fluidity and cohesive properties of most drugs. Typically, excipients are added to the compositions to impart a sufficiently high flow and compression characteristics to the material to be pressed. Such properties are obtained in pretreatment stages, such as wet granulation, aggregation, spheronization or crystallization with a spray dryer. Excipients in tablet manufacturing also provide metering accuracy and tablet stability during storage.

Requirements for excipients:

- they must be chemically indifferent;

- should not have a negative impact on the patient's body, as well as on the quality of the tablets during their preparation, transportation and storage.

Fillers (diluents) are added to obtain a certain mass of tablets, they can be used to regulate certain technological parameters (strength, disintegration, etc.). Fillers determine the technological properties of the tabletting mass and the physicomechanical properties of the finished tablets.

Particles of most medicinal substances have little cohesive force between them, therefore, their tabletting requires high pressure, which often causes untimely wear of the press tool of tablet machines and the production of poor-quality tablets. To achieve the necessary cohesive strength at relatively low pressures, binders are added to the tableted substances. Filling the interparticle space, they increase the contact surface of the particles and cohesive ability. Of particular importance are binders during the pressing of complex powders, which during the operation of the tablet machine can delaminate, which leads to the production of tablets with different contents of the incoming ingredients. The use of the type of binders, their amount depends on the physico-chemical properties of the pressed substances. (OST 91500.05.001-00 Quality Standards for Medicines. Main Provisions. Appendix 1. Dosage Forms. Terms and Definitions; Industrial Technology of Medicines / Ed. By V.I. Chueshov. - X .: Basis: Publishing House of UkrFA, 1999.- T. 2.- 704 p.). The functions of binders can perform various substances. So according to the Handbook of Pharmaceutical Excipients (4th ed.), Ed. Raymond With Rowe, Science and Practice, starches, celluloses and their derivatives, for example, microcrystalline cellulose (binder / diluent 20-90 wt.% Based on the weight of the pressed composition), hydroxypropyl cellulose (binder 2-6 wt. .% based on the weight of the pressed composition), hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sucrose, etc. In addition, in an amount of from 15 to 35 wt. % hydroxypropyl cellulose can be used as a substance that slows the release of a drug from a tablet.

When pressing medicinal substances, porosity decreases sharply and thereby the penetration of liquid into the tablet is difficult. To improve disintegration or dissolution, disintegrating agents are used that provide mechanical destruction of the tablets in a liquid medium, which is necessary for the speedy release of the active substance. Baking powder is also added to the tablets if the preparation is insoluble in water or if the tablet is capable of cementing during storage.

One of the problems of tablet production is obtaining good fluidity of the pressed material in the feeding devices (funnels, bins). The obtained powders or granules have a rough surface, which makes it difficult to absorb them from the feed funnel into the matrix nests. In addition, the pressed material may adhere to the walls of the die and punches due to friction developed in the contact zones of the particles with the press tool of the tablet machine. To remove or reduce these undesirable effects, anti-friction substances are used, which are represented by a group of sliding (glidants) and lubricants (sizing).

Sliding substances, adsorbed on the surface of particles (granules), eliminate or reduce their roughness, increasing their fluidity (flowability).

Lubricants facilitate the ejection of tablets from the matrix. They are also called anti-adhesive, or anti-adhesive substances. Lubricants not only reduce friction at the contact areas, but significantly facilitate the deformation of particles due to the adsorption decrease in their strength due to penetration into microgaps. The function of lubricants is to overcome the frictional force between the pressed particles and the matrix wall, between the compressed tablet and the matrix wall at the time of expulsion by the lower punch from the matrix.

Corrective substances are added to the composition of the tablets in order to improve their taste, color and smell.

Dyes are introduced into the composition of tablets primarily to give them a presentation, as well as to indicate the therapeutic group of medicinal substances. In addition, some dyes are stabilizers of photosensitive drugs. (Industrial technology of drugs. / Ed. By V.I. Chueshov. - X .: Basis: Publishing House of UkrFA, 1999. - V. 2. - 704 p.).

There are three commercially important methods for producing compressed tablets: wet granulation, direct compression and dry granulation (aggregation or rotational pressing). The method of preparation and type of excipients is chosen to give the composition intended for tabletting, the required physical properties, providing rapid compression of the tablets. After pressing, the tablets should be characterized by a number of additional properties, such as appearance, hardness, etc. The choice of fillers and other excipients depends on the chemical and physical properties of the drug, the behavior of the mixture during processing and the properties of the finished tablets.

The properties of the drug, its dosage forms and the cost effectiveness of the preparation method determine the most suitable tabletting method. In most cases, wet granulation and direct compression are used to make tablets.

Dry granulation is used if one of the components, a drug or diluent, is characterized by cohesive properties sufficient for tabletting. The method includes mixing, aggregating the ingredients, dry sieving, adding a sizing and pressing.

Wet granulation is used to process the powder mixture into granules with flowability and cohesion properties suitable for tabletting. The method consists in mixing powders in a suitable shear mixer, followed by adding a granulating solution to the mixed powders, and granulation occurs. The wet mass is then sieved through a suitable sieve and dried in drying trays or in a fluidized bed. In another embodiment, the wet mass is first dried and then ground in a mill. The whole process includes weighing, mixing dry powders, wet granulation, drying, grinding, mixing with a sizing and pressing. However, wet granulation is not applicable for moisture sensitive drugs, such as vildagliptin.

In most cases, the powders do not have adhesive or cohesive properties sufficient to form solid, durable granules. Typically, due to the low cohesive properties of most powders, a binding agent is required to aggregate the powder particles. Medicines that are sensitive to heat and moisture cannot be processed with wet granulation. Many stages of processing and processing time lead to the problem of the high cost of processing. Wet granulation is known to reduce the compressibility of certain pharmaceutical excipients, such as microcrystalline cellulose.

Direct compression is a relatively quick process in which powdered materials are pressed directly without changing the physical and chemical properties of the drug. Prior to compression into tablets, the active component (s), excipients for direct compression and other excipients, such as glidant and sizing, are mixed in a double-housing mixer or similar low shear device. This type of mixing is important for the preparation of pharmaceutically acceptable dosage forms.

The advantage of direct pressing is the homogeneity of the mixture, in reducing the number of stages of processing, i.e. the whole process includes weighing powders, mixing and pressing, which leads to lower costs, the exclusion of heat and moisture, the primary dissociation of particles and physical stability.

Drug manufacturers prefer to use direct compression instead of wet or dry granulation due to reduced processing time and low cost. However, direct compression can only be used if the drug substance has the physical properties necessary to produce pharmaceutically acceptable tablets. Since most components do not possess the required properties, before direct compression, one or more excipients are mixed with the active component. Since the addition of each excipient to the composition leads to an increase in the size of the final tablet, manufacturers are often limited in the use of direct compression only for compositions with a low content of the active component in the tablet (New composition. RF Patent. 2483716; Composition and method of direct compression. RF patent. 2391097), the latter may include vildagliptin and glycvidone compositions.

An important feature of glycidon is that it is excreted mainly through the gastrointestinal tract, which allows its use in patients with kidney pathology and diabetic nephropathy at the stage of microalbuminuria, proteinuria and chronic renal failure (creatinine up to 250 μmol / L) (Endocrinology. National manual. Brief edition / edited by II Dedov, GA Melnichenko - M .: GEOTAR-Media, 2013. - 752 p .; Specialized care algorithm for patients with diabetes mellitus: clinical recommendations / edited by I . I. Dedova, MV Shestakova; Ministry of Health of the Russian Federation, Russian Association of Endocrinologists, Federal State Budgetary Institution Endocrinological Research Center - 6th edition, M., 2013)

The use of vildagliptin has been approved since 2012 in patients with moderate or severe impaired renal function by the Ministry of Health of the Russian Federation and the European Medical Agency. In patients with mild impaired renal function, dosage adjustment is not required. In patients with moderate or severe impaired renal function (including the terminal stage of chronic renal failure on hemodialysis), the drug should be used at a dose of 50 mg once a day. (Algorithm for specialized medical care for patients with diabetes mellitus: clinical recommendations / edited by II Dedov, MV Shestakova; Ministry of Health of the Russian Federation, Russian Association of Endocrinologists, FSBI Endocrinological Research Center - 6th edition, M., 2013; Information letter of LLC Novartis Pharma, 2012).

These facts are of great clinical significance, since they allow the use of this combination of drugs for renal failure, the leading cause of which, according to the WHO, is diabetes mellitus (World Report on Noncommunicable Diseases, 2010 / WHO, 2013).

An object of the present invention is to provide formulations containing a DPP-IV inhibitor, preferably vildagliptin, in the form of a cohesive powder for tabletting with a sufficiently high fluidity, and glycidone, in the form of a cohesive powder for tabletting with a sufficiently high fluidity, which can be directly compressed into tablets.

Vildagliptin is moisture sensitive and therefore unstable, i.e. active component decomposes. Vildagliptin and glycidone do not have physical properties sufficient for direct compression, however, in the composition of the present invention, vildagliptin and glycidone are present in amounts that allow the use of excipients to impart to the medicinal substances (vildagliptin and glycidon) the properties necessary for direct compression. Due to the fact that direct compression is the most rational way to obtain compressed tablets, there is a need to develop methods and pharmaceutical compositions that will allow the production on an industrial scale of tablets that meet all the regulatory requirements for this dosage form, containing a combination of vildagliptin and glycidone, direct compression.

Another object of the present invention is a tablet containing a medicinal product in the form of a dosage form comprising a DPP-IV inhibitor, preferably vildagliptin, and glycidone, characterized by suitable levels of strength, brittleness and delamination resistance.

Another object of the present invention is the use of a combination of vildagliptin and glycidone in renal failure, accompanied by type 2 diabetes.

Vildagliptin is taken orally, regardless of food intake. Glycvidone should be used at the beginning of a meal, so it seems advisable to provide patients suffering from type 2 diabetes, including type 2 diabetes, accompanied by renal failure, compressed two-layer tablets containing 25 to 100 mg of Vilagliptin tablets as the core , and as the outer layer from 15 to 60 mg of glycyvidone.

Vildagliptin does not have physical properties sufficient for direct compression, is sensitive to moisture and, therefore, is unstable, i.e. active component decomposes. To overcome this problem, the present invention has developed a composition (containing certain excipients), a direct compression method (excluding wet granulation) to provide the required tablet properties, for example, strength, brittleness, resistance to delamination, as well as the structure of the tablet.

Glycvidone does not have physical properties sufficient for direct compression. To overcome this problem, the present invention developed a composition (containing certain excipients) and a direct compression method to provide the desired tablet properties, for example, strength, brittleness, resistance to delamination, as well as the structure of the tablet.

Another object of the present invention is a method for producing a composition or tablets containing a DPP-IV inhibitor, preferably vildagliptin, and glycyvidone, or their salts.

The present invention provides compositions containing a DPP-IV inhibitor, preferably vildagliptin, and glycidone, in the form of a tablet powder, capable of direct compression into tablets with an appropriate level of strength, brittleness, delamination resistance.

In addition to the active ingredients, the tabletting powder contains a number of excipients - excipients.

A preferred composition of the present invention includes the active ingredients, namely a DPP-IV inhibitor, preferably vildagliptin, and glycidone, and a binding agent.

Examples of pharmaceutically acceptable binding agents include, but are not limited to, starches, celluloses and derivatives thereof, for example microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sucrose, dextrose and polysaccharides.

Optionally, 1, 2, 3 or more diluents are added to the compositions of the present invention. Examples of pharmaceutically acceptable excipients and pharmaceutically acceptable diluents include, but are not limited to, confectionery sugar, pressed sugar, dextrans, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. Preferred diluents include microcrystalline cellulose, which is obtained by controlled hydrolysis of α-cellulose obtained from the pulp of fibrous plant materials in the presence of dilute solutions of mineral acids. After hydrolysis, the hydroxycellulose is purified by filtration and the aqueous suspension is spray dried to give dry porous particles with a wide size distribution. The average particle size of a suitable microcrystalline cellulose is from about 20 nm to about 200 nm. Microcrystalline cellulose is produced by several manufacturing companies. Examples of suitable microcrystalline cellulose include Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105, Avicel PH 112, Avicel PH 113 from FMC Biopolymer, Celex 101 from International Specialty Products, Emcocel 50M, Vivapur 101, Vivapur 102 from JRS Pharma Most preferred of the present invention is Avicel PH 112, characterized by a porous structure, lower surface area and lower moisture content. Preferably, microcrystalline cellulose is present in the tabletting composition in an amount of from about 20 to 90 wt. % per layer, acting as a binder. As a binder, hydroxypropyl cellulose in an amount of from 2-6 wt. %, based on each layer. In addition, upon receipt of the core can be used substances that slow down the release of vildagliptin, preferably hydroxypropyl cellulose in an amount of from 15 to 35 wt. % of the core, allowing you to get a tablet with a modified release.

The composition of the present invention optionally add 1, 2, 3 or more disintegrating agents. Examples of pharmaceutically acceptable disintegrating agents include, but are not limited to, starches, clays, celluloses, alginates, gums, crosslinked polymers, for example, crosslinked polyvinylpyrrolidone, crosslinked calcium carboxymethyl cellulose calcium salt, and polysaccharide. Disintegrating agent, for example, is present in an amount of from about 2 to about 20 wt. %, for example, from about 5 to about 10 wt. %, for example, approximately 7 wt.%. based on the weight of the composition. A disintegrant is an optional but acceptable component of the tablet formulation. Disintegrating agents are included to provide an acceptable rate of disintegration. Typical disintegrants include starch derivatives and carboxymethyl cellulose salts. Preferably, the disintegrant is present in the tablet formulation in an amount of from about 0.1 to about 10 wt. %, from about 1 to about 4 wt. % and most preferably from about 1.5 to about 2.5 wt. %

The composition of the present invention optionally add 1, 2, 3 or more lubricants. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered microcellulose cellulose. The sizing, for example, is present in an amount of from about 0.1 to about 5 wt. % based on the weight of the composition, glidant, for example, is present in an amount of from about 0.1 to about 10 wt. % Sizing agents are typically added to prevent the tabletting material from sticking to the punches, to minimize friction during the pressing process, and to accelerate the removal of the compressed tablet from the die. Such lubricants are usually included in the composition of the final mixture for tabletting in an amount of less than 1 wt. % The sizing is hydrophobic or hydrophilic. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces friction between the walls of the matrix and the tabletting mixture during compression and accelerates tablet removal. It also helps prevent tablets from adhering to the punches and matrix. Magnesium stearate increases the fluidity of the powder in the hopper and in the matrix. The particle size of magnesium stearate is from 450 to 550 microns, and the density is from 1.00 to 1.80 g / ml. It is stable and does not polymerize in the composition of the tabletting mixture. A preferred sizing agent, magnesium stearate, is also added. Preferably, the sizing is present in the tabletting composition in an amount of about 0.25 to 5 wt. %, more preferably from about 0.5 to about 4 wt. % and most preferably from about 0.1 to about 2 wt. % Other possible lubricants include talc, polyethylene glycol, silicon dioxide and hardened vegetable oils. In a preferred embodiment of the present invention, a sizing agent is not added to the composition, but sprayed onto a die or punches.

Other standard excipients or carriers are also used, such as corn starch, calcium phosphate, calcium sulfate, calcium stearate, magnesium stearate, stearic acid, glycerol mono- and distearate, sorbitol, mannitol, gelatin, natural or synthetic gums, such as carboxymethyl cellulose, methyl cellulose , alginate, dextran, gum arabic, karaya gum, locust bean gum, tragacanth, etc., diluents, binders, lubricants, disintegrating agents, colorants and flavors.

Thus, in a first embodiment of the present invention, there is provided a pharmaceutical composition of drugs comprising from 8 wt. % up to 97 wt. %, from 6 wt. % up to 97 wt. %, from 4 wt. % up to 97 wt. %, from 8 to 97 wt. %, from 5 to 97 wt. %, from 3.5 to 97 wt. %, from 7 wt. % up to 97 wt. %, from 4 wt. % up to 97 wt. %, from 3 wt. % up to 97 wt. %, from 6 wt. % to 98.5 wt. %, from 3 wt. % up to 97 wt. % or from 2 wt. % up to 97 wt. % based on the weight of active ingredients, the active ingredients include a DPP-IV inhibitor, preferably vildagliptin, and glycidone or their pharmaceutically acceptable salts.

In a second embodiment of the present invention, there is provided a pharmaceutical combination of drugs comprising from 8 wt. % up to 97 wt. %, from 6 wt. % up to 97 wt. %, from 4 wt. % up to 97 wt. %, from 8 to 97 wt. %, from 5 to 97 wt. %, from 3.5 to 97 wt. %, from 7 wt. % up to 97 wt. %, from 4 wt. % up to 97 wt. %, from 3 wt. % up to 97 wt. %, from 6 wt. % to 98.5 wt. %, from 3 wt. % up to 97 wt. % or from 2 wt. % up to 97 wt. % based on the weight of active ingredients, the active ingredients include a DPP-IV inhibitor, preferably vildagliptin, and glycidone or their pharmaceutically acceptable salts.

In a third embodiment of the present invention, there is provided a multilayer tablet with a modified release, which is obtained by direct compression, containing from 8 wt. % up to 97 wt. %, from 6 wt. % up to 97 wt. %, from 4 wt. % "Up to 97 wt. %, from 8 to 97 wt. % ", From 5 to 97 wt. %, from 3.5 to 97 wt. %, from 7 wt. % up to 97 wt. %, from 4 wt. % up to 97 wt. %, from 3 wt. % up to 97 wt. %, from 6 wt. % to 98.5 wt. %, from 3 wt. % up to 97 wt. % or from 2 wt. % up to 97 wt. %, preferably from 25 wt. % up to 30 wt. % based on the weight of active ingredients, the active ingredients include a DPP-IV inhibitor, preferably vildagliptin, and glycivdone or their pharmaceutically acceptable salts.

In a fourth embodiment of the present invention, there is provided a pharmaceutical combination, a modified release multilayer tablet, which is obtained by direct compression, the core of which contains from 5.5 to 97 wt. %, from 2.5 to 97 wt. %, from 1.4 to 97 wt. %, from 5.5 to 97 wt. %, from 2.5 to 97 wt. %, from 1.4 to 97 wt. %, from 5.5 to 97 wt. %, from 2.5 to 97 wt. %, from 1.4 to 97 wt. % from 5.5 to 97 wt. %, from 2.5 to 97 wt. %, from 1.4 to 97 wt. % inhibitor of DPP-IV, preferably vildagliptin, based on the weight of the core, and the outer layer of which contains from 3 to 97 wt. %, from 3 to 97 wt. %, from 3 to 97 wt. %, from 1.5 to 97 wt. %, from 1.5 to 97 wt. %, from 1.5 to 97 wt. %, from 0.8 to 97 wt. %, from 0.8 to 97 wt. %, from 0.8 to 97 wt. % glycidone, calculated on the mass of the outer layer.

In a fifth embodiment of the present invention, there is provided a pharmaceutical combination, a modified release multilayer tablet, which is obtained by direct compression, the core of which contains from 5.5 to 61 wt. %, from 2.5 to 44 wt. %, from 1.3 to 29 wt. %, from 5.5 to 67 wt. %, from 2.5 to 51 wt. %, from 1.3 to 35 wt. %, from 5.5 to 75 wt. %, from 2.5 to 61 wt. %, from 1.3 to 44 wt. % from 5.5 to 84.5 wt. %, from 2.5 to 74.5 wt. %, from 1.3 to 61 wt. % inhibitor of DPP-IV, preferably vildagliptin, based on the weight of the core, and the outer layer of which contains from 3 to 61 wt. %, from 3 to 44 wt. %, from 3 to 29 wt. %, from 1.5 to 23 wt. %, from 1.5 to 37 wt. %, from 1.5 to 53 wt. %, from 0.8 to 13 wt. %, from 0.8 to 23 wt. %, from 0.8 to 37 wt. % glycidone, calculated on the mass of the outer layer.

The present invention also provides a combination or tablet, as described above, in which vildaglipin is present in the core of the tablet and glycidone in the outer layer.

The present invention also provides compositions, a combination or a tablet, as described above, in which vildaglipin is present in the core of the tablet, which contains at least one pharmaceutically acceptable excipient, and glycidone is contained in the outer layer, which contains at least one pharmaceutically acceptable excipient.

The present invention also provides compositions, a combination or a tablet, as described above, in which vildaglipin is present in the core of the tablet, which contains a binding agent, and glycidone is contained in the outer layer, which contains a binding agent.

The present invention also provides compositions, combination or tablet, as described above, in which vildaglipin is present in the core of the tablet, which contains from 2 to 6 wt. % and / or from 20 to 90 wt. % binding agents, preferably from 45 to 75% by weight. based on the weight of the tablet core, and glycidone is contained in the outer layer, which contains from 2 to 6 wt. % and / or from 20 to 90 wt. % binding agents, preferably from 45 to 75% by weight. based on the mass of the outer layer.

The present invention also provides compositions, combination or tablet, as described above, comprising at least one pharmaceutically acceptable excipient, which is a lubricant, in an amount of from 0.25 wt. % up to 5 wt. %, calculated on each tablet layer, preferably from 0.4 wt. % to 1 wt. %, based on each tablet layer, based on the weight of the composition. The present invention also provides a composition or tablet, as described above, in which the lubricant is magnesium stearate.

The present invention also provides compositions, a combination or a tablet, as described above, the core of which may include at least one pharmaceutically acceptable excipient, which slows the release of vildagliptin, preferably hydroxypropyl cellulose in an amount of from 15 to 35 wt. % of the core, allowing you to get a tablet with a modified release.

The present invention also provides compositions, a combination or a tablet, as described herein, in which the binding agent is selected from the group of starches, celluloses and derivatives thereof, for example, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose, , polysaccharides and gelatin.

The present invention also provides a pharmaceutical composition or tablet, as described herein, in which the binding agent is selected from the group consisting of celluloses and their derivatives, preferably microcrystalline cellulose.

The ratios of the components described in this context are determined based on the weight of the core containing the DPP-IV inhibitor, preferably vildagliptin, and excipients, for example, a binding agent, and the outer layer of the tablet containing glycvidone and excipients, for example, a binding agent.

The present invention also provides pharmaceutical compositions, as described herein, in unit dosage form. The term "unit dosage form" means any type of pharmaceutical dosage form, such as capsules, tablets (preferably, tablets obtained by direct compression), granules, chewable tablets, and the like.

In another embodiment, the present invention provides a single layer tablet or pharmaceutical composition, which as active ingredients includes:

1) from 1.3 to 86 wt. %, preferably from 8 to 36 wt. % DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof;

2) from 0.8 to 68.5 wt. %, preferably from 4 to 25 wt. % glycidone or its pharmaceutically acceptable salt.

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

1) core: from 1.3 to 97 wt. %, preferably from 30 to 40 wt. % DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof, based on core weight;

2) the outer layer: from 0.8 to 97 wt. %, preferably from 20 to 33 wt. % glycidone or its pharmaceutically acceptable salt, based on the weight of the outer layer.

In another embodiment, the present invention provides a multilayer tablet with a modified release or pharmaceutical composition, which as active ingredients includes:

1) core: from 1.3 to 97 wt. %, preferably from 25 to 35 wt. % DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof, based on core weight;

2) the outer layer: from 0.8 to 97 wt. %, preferably from 20 to 33 wt. % glycidone or its pharmaceutically acceptable salt, based on the weight of the outer layer.

The present invention also provides a tablet or pharmaceutical compositions as described herein, in which the binding agent is selected from the group of starches, celluloses and derivatives thereof, for example, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose and polis.

The present invention also provides a tablet or pharmaceutical composition as described herein, in which the binding agent is selected from the group consisting of celluloses and their derivatives, preferably microcrystalline.

The present invention also provides a pharmaceutical composition or a modified release multilayer tablet as described herein, the core of which may contain a slow release substance of a DPP-IV inhibitor, preferably vildagliptin, preferably hydroxypropyl methylcellulose, from 15 to 35 wt. % based on the weight of the core, preferably from 17 to 25 wt. % based on the mass of the core.

The compositions and tablets described in this context preferably contain at least one pharmaceutically acceptable excipient.

Other standard pharmaceutically acceptable excipients, at least one, for example, 1, 2, 3 or 4, such as standard binders, diluents, disintegrating agents, solid excipients or carriers, drug retarding agents, are optionally added to the formulations described in this context described in this context.

The present invention also provides a tablet or pharmaceutical composition, as described above, comprising at least one pharmaceutically acceptable excipient.

The present invention also provides a tablet or pharmaceutical compositions, as described above, containing at least one pharmaceutically acceptable excipient.

The present invention also provides a pharmaceutical composition as described herein, which is contained in a capsule or is prepared in the form of a tablet, preferably a compressed tablet or a tablet prepared by direct compression. The present invention also provides a multilayer tablet consisting of a core and an outer layer. The tablet may be a multi-layer, modified release. The tablet may further comprise a film coating.

Other standard pharmaceutically acceptable excipients (at least one, for example, 1, 2, 3 or 4 excipients), such as standard diluents, disintegrating agents, solid excipients, carriers, release inhibitors described herein, are optionally added to the formulations described herein context.

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

The term "pharmaceutically acceptable lubricant", as used in this context, means at least one lubricant, a mixture of, for example, 2 or 3, lubricants.

The compositions described above are primarily intended for the manufacture of pharmaceutical tablets, for example, compressed tablets or tablets obtained by direct compression, as well as microtablets (microgranules) or capsules, and are characterized by the required physical properties, as is known in the art. Thus, in yet another embodiment of the present invention, there is provided the use of any of the compositions described above for the manufacture of pharmaceutical tablets, modified release tablets, retard tablets, rapid retard tablets, microtablets or capsules by granulation, direct compression and dry granulation (aggregation or rotary compaction).

Quality control of finished tablets is carried out in accordance with the requirements of the pharmacopoeial article "Tablets", as well as private pharmacopoeial articles according to the following indicators:

- organoleptic properties (GF XI ed., issue 2, p. 154-155);

- mechanical strength (GF XI ed., issue 2, p. 157-158);

- the average weight of the tablets and the deviation in the mass of individual tablets (GF XI ed., issue 2, p. 156);

The present invention also provides a method for producing a pharmaceutical, modified release multilayer tablet containing a DPP-IV inhibitor, preferably the product LAF237, or pharmaceutically acceptable salts thereof, and glycidone or its pharmaceutically acceptable salts, which comprises the following steps:

1) mixing a drug substance of a DPP-IV inhibitor, preferably LAF237, with a binding agent / binders, for example, microcrystalline cellulose;

2) in the mixture obtained in stage 1), it is possible to add auxiliary substances that provide a controlled, slow release of the drug substance from the tablet core, for example, hydroxypropyl cellulose;

3) optional mixing of a sizing agent, for example, magnesium stearate, with the mixture obtained in stage 1) or 2), it is also possible to apply magnesium stearate on punches and / or a compression mixture;

4) obtaining the tablet core by direct compression from the mixture obtained in stage 1) or 2) or 3);

5) mixing a drug substance of glycivdone with a binding agent / binding agents, for example, microcrystalline cellulose;

6) optional mixing of a disintegrating agent, for example, corn starch with the mixture obtained in stage 5);

7) optional mixing of a sizing agent, for example, magnesium stearate with the mixture obtained in stage 5) or 6), it is also possible to apply magnesium stearate to the punches and / or pressed mixture;

8) pressing the mixture obtained in stage 5) or 6) or 7), with half of the mixture containing glycidone necessary for the manufacture of the outer layer of one tablet is placed in the matrix on the lower punch, then the previously obtained tablet core is placed on the mixture , after this, the second half of the mixture containing glycidone is placed over the core, and a standard dosage form is obtained.

Before the mixing and pressing steps, a sieving step for the main grinding composition is preferably carried out, i.e. to remove all agglomerates / large particles.

In another embodiment, the present invention also provides a method for producing a pharmaceutical, modified release multi-layer tablet containing a DPP-IV inhibitor, preferably the product LAF237, or pharmaceutically acceptable salts thereof, and glycidone or pharmaceutically acceptable salts thereof, which comprises the steps of :

1) mixing the drug substance glycidone with a binding agent / binding agents, for example, microcrystalline cellulose;

2) optional mixing of a sizing agent, for example, magnesium stearate with the mixture obtained in stage 1), it is also possible to apply magnesium stearate on the punches and / or pressed mixture;

3) optional mixing of a disintegrating agent, for example, corn starch with the mixture obtained in stage 1) or 2);

4) mixing the drug substance of the DPP-IV inhibitor, preferably LAF237, with a binding agent / binders, for example, microcrystalline cellulose;

5) in the mixture obtained in stage 4), it is possible to add auxiliary substances, for example, hydroxypropyl cellulose, which provide a controlled, slow release of the drug substance from the tablet core;

6) pressing the resulting mixture, while half of the resulting mixture containing glycidone, to obtain one tablet, is placed in the matrix on the lower punch, then the mixture containing the DPP-IV inhibitor, preferably the product LAF237, is placed in the amount necessary to obtain one tablet, then placed the second half of the mixture containing glycidone to obtain one tablet, while receiving a standard dosage form.

Before the mixing and pressing steps, a sieving step for the main grinding composition is preferably carried out, i.e. to remove all agglomerates / large particles.

In another embodiment, the present invention also provides a method for producing a pharmaceutical, modified release multilayer tablet containing a DPP-IV inhibitor, preferably LAF237, or pharmaceutically acceptable salts thereof, and glycvidone or pharmaceutically acceptable salts thereof, which comprises the following stages:

1) mixing a drug substance of a DPP-IV inhibitor, preferably product LAF237, with a binder and providing a controlled, slow release of the drug from the tablet core with an agent, for example, hydroxypropyl cellulose;

2) optional mixing of a sizing agent, for example, magnesium stearate with the mixture obtained in stage 1) or 2), it is also possible to apply magnesium stearate to punches and / or a compression mixture;

3) obtaining the tablet core by direct compression from the mixture obtained in stage 1) or 2);

4) mixing the drug substance of glycivdone with a binding agent / binding agents, for example, microcrystalline cellulose;

5) optional mixing a disintegrating agent, for example, corn starch with the mixture obtained in stage 4);

6) optional mixing of a sizing agent, for example, magnesium stearate with the mixture obtained in stage 4) or 5), it is also possible to apply magnesium stearate to the punches and / or pressed mixture;

7) pressing the mixture obtained in stage 4) or 5) or 6), in this case, half of the mixture obtained containing glycidone, necessary for the manufacture of the outer layer of one tablet, is placed in the matrix on the lower punch, then the previously obtained mixture is placed the core of the tablet, after which, on top of the core is placed the second half of the mixture containing glycidone, and a standard dosage form is obtained.

Before the mixing and pressing steps, a sieving step for the main grinding composition is preferably carried out, i.e. to remove all agglomerates / large particles.

In another embodiment, the present invention also provides a method for producing a pharmaceutical, modified release multi-layer tablet containing a DPP-IV inhibitor, preferably the product LAF237, or pharmaceutically acceptable salts thereof, and glycidone or pharmaceutically acceptable salts thereof, which comprises the steps of :

1) mixing the drug substance glycidone with a binding agent / binding agents, for example, microcrystalline cellulose;

2) optional mixing of a sizing agent, for example, magnesium stearate, with the mixture obtained in stage 1), it is also possible to apply magnesium stearate on punches and / or a compression mixture;

3) optional mixing of a disintegrating agent, for example, corn starch with the mixture obtained in stage 1) or 2);

4) mixing the drug substance of the DPP-IV inhibitor, preferably the LAF237 product, with a binder and providing a controlled, slow release of the drug from the tablet core with an agent, for example, hydroxypropyl cellulose;

5) pressing the resulting mixture, with half of the mixture containing glycidone to produce one tablet, placed in the matrix on the lower punch, then the mixture containing the DPP-IV inhibitor, preferably the product LAF237, is placed in the amount necessary to obtain one tablet, then placed the second half of the mixture containing glycidone to produce one tablet, while receiving a standard dosage form.

Before the mixing and pressing steps, a sieving step for the main grinding composition is preferably carried out, i.e. to remove all agglomerates / large particles.

In another embodiment, the present invention also provides a method for producing a pharmaceutical tablet containing a DPP-IV inhibitor, preferably the product LAF237, or their pharmaceutically acceptable salts, and glycidone or its pharmaceutically acceptable salts, which comprises the following steps:

1) mixing drug substances of a DPP-IV inhibitor, preferably LAF237, and glycvidone with a binding agent / binding agents, for example, microcrystalline cellulose;

2) optional mixing of a disintegrating agent, for example, corn starch with the mixture obtained in stage 1);

3) optional mixing of a sizing agent, for example, magnesium stearate with the mixture obtained in stage 1) or 2), it is also possible to apply magnesium stearate to the punches and / or pressed mixture;

4) pressing the mixture obtained in stage 1) or 2) or 3), while receiving a standard dosage form.

Before the mixing and pressing steps, a sieving step for the main grinding composition is preferably carried out, i.e. to remove all agglomerates / large particles.

In another embodiment of the present invention, there is provided a capsule containing the pharmaceutical compositions described above.

The final product is obtained in the form of tablets, microtablets, capsules and the like using standard tabletting methods or similar machines.

The most preferred DPP-IV inhibitor for the compositions, compressed tablets or methods described herein is selected from 1- {2 - [(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2- (S) -cyanopyrrolidine dihydrochloride, ( S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine, L-threoisolecylthiazolidine, products MK-0431, GSK23A, BMS-477118, 3- (aminomethyl) -2-isobutyl-1- oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide and 2 - {[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and optionally their pharmaceutically acceptable salts.

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

The dose of (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyanopyrrolidine (vildagliptin) is preferably from 10 to 150 mg per day, most preferably from 25 to 150 mg, or from 50 to 100 mg, or 25 to 100 mg per day. Preferred examples of daily doses for oral administration are 25, 30, 35, 45, 50, 55, 60, 70, 80, 90 or 100 mg. The active ingredient can be administered up to 3 times per day, preferably 1 or 2 times per day.

The most preferred sulfonylurea derivative is N - [(Cyclohexylamino) carbonyl] -4- [2- (3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolinyl ) ethyl] benzenesulfonamide (glycidone) or its pharmaceutically acceptable salts.

Dose N - [(Cyclohexylamino) carbonyl] -4- [2- (3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolinyl) ethyl] benzenesulfonamide (glycvidone ) is preferably from 15 mg to 120 mg per day, most preferably from 15 to 60 mg, which can be prescribed in one go.

Thus, in another embodiment of the present invention, there is provided a tablet or composition containing the following active ingredients:

1) from 15 to 120 mg, preferably from 15 to 60 mg of glycivdone,

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

The present invention also provides a pharmaceutical unit dosage form, preferably a tablet or capsule, comprising a composition of the present invention containing the following active ingredients:

1) from 15 to 120 mg, preferably from 15 to 60 mg of glycidone,

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

The present invention also provides a pharmaceutical unit dosage form, preferably a tablet or capsule, comprising the composition of the present invention, comprising the following active ingredients:

1) 25 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,

2) 25 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,

3) 25 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,

4) 25 mg vildagliptin and 60 mg glycidone or in each case their pharmaceutically acceptable salts,

5) 50 mg vildagliptin and 15 mg glycidone or, in each case, their pharmaceutically acceptable salts,

6) 50 mg vildagliptin and 30 mg glycidone or in each case their pharmaceutically acceptable salts,

7) 50 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,

8) 50 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts,

9) 100 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,

10) 100 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,

11) 100 mg vildagliptin and 45 mg glycidone or in each case their pharmaceutically acceptable salts or

12) 100 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts.

The present invention also provides a composition or tablet of the present invention, comprising:

a) active ingredients, including:

1) 25 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,

2) 25 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,

3) 25 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,

4) 25 mg vildagliptin and 60 mg glycidone or in each case their pharmaceutically acceptable salts,

5) 50 mg vildagliptin and 15 mg glycidone or, in each case, their pharmaceutically acceptable salts,

6) 50 mg vildagliptin and 30 mg glycidone or in each case their pharmaceutically acceptable salts,

7) 50 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,

8) 50 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts

9) 100 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,

10) 100 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,

11) 100 mg vildagliptin and 45 mg glycidone or in each case their pharmaceutically acceptable salts or

12) 100 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts, and

b) a tablet or pharmaceutical composition, which as active ingredients includes:

from 1.3 to 86 wt. %, preferably from 8 to 36 wt. % DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof;

from 0.8 to 68.5 wt. %, preferably from 4 to 25 wt. % glycidone or its pharmaceutically acceptable salt.

C) a composition, optionally comprising at least one additional excipient, for example, from 0.25 to 5 wt. % magnesium stearate.

The present invention also provides a multilayer tablet, or pharmaceutical composition, which as active ingredients includes:

core: from 1.3 to 97 wt. %, preferably from 30 to 40 wt. % DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof, based on core weight;

outer layer: from 0.8 to 97 wt. %, preferably from 20 to 33 wt. % glycidone or its pharmaceutically acceptable salt, based on the weight of the outer layer.

The present invention also provides a modified release multilayer tablet or pharmaceutical composition, which comprises:

core: from 1.3 to 97 wt. %, preferably from 25 to 35 wt. % DPP-IV inhibitor, preferably vildagliptin, or a pharmaceutically acceptable salt thereof, based on core weight;

core: may include at least one pharmaceutically acceptable excipient that slows the release of vildagliptin, preferably hydroxypropyl cellulose in an amount of from 15 to 35 wt. % of the core, preferably from 17 to 25 wt. %, based on the weight of the core, allowing you to get a prolonged tablet;

outer layer: from 0.8 to 97 wt. %, preferably from 20 to 33 wt. % glycidone or its pharmaceutically acceptable salt, based on the weight of the outer layer.

The implementation of the invention.

Example 1

The composition of the pill:

(1) vildagliptin - 25 mg

(2) glycidone - 15 mg

(3) microcrystalline cellulose - 80 mg

(4) magnesium stearate - 1 mg

The total weight of the tablet is 121 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3) and (4) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 2

The composition of the pill:

(1) vildagliptin - 25 mg

(2) glycidone - 30 mg

(3) microcrystalline cellulose - 110 mg

(4) magnesium stearate - 1.5 mg

The total weight of the tablets is 166.5 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3) and (4) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 3

The composition of the pill:

(1) vildagliptin - 25 mg

(2) glycidone - 45 mg

(3) microcrystalline cellulose - 140 mg

(4) magnesium stearate - 1.7 mg

The total mass of the tablets is 211.7 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3) and (4) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 4

The composition of the pill:

(1) vildagliptin - 25 mg

(2) glycidone - 60 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 5 mg

(5) magnesium stearate - 2 mg

Total tablet weight - 242 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3) and (4) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 5

The composition of the pill:

(1) vildagliptin - 50 mg

(2) glycidone - 15 mg

(3) microcrystalline cellulose - 130 mg

(4) magnesium stearate - 2 mg

Total tablet weight - 197 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3) and (4) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 6

The composition of the pill:

(1) vildagliptin - 50 mg

(2) glycidone - 30 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 5 mg

(5) magnesium stearate - 2 mg; total tablet weight - 234 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 7

The composition of the pill:

(1) vildagliptin - 50 mg

(2) glycidone - 45 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 10 mg

(5) magnesium stearate - 2.5 mg

The total weight of the tablet is 257.5 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 8

The composition of the pill:

(1) vildagliptin - 50 mg

(2) glycidone - 60 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 10 mg

(5) magnesium stearate - 2.5 mg

The total weight of the tablets is 272.5 mg

A vildagliptin / glycidone tablet was prepared as follows: To produce one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 9

The composition of the pill:

(1) vildagliptin - 100 mg

(2) glycidone - 15 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 10 mg

(5) magnesium stearate - 3 mg

Total tablet weight - 278 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 10

The composition of the pill:

(5) vildagliptin - 100 mg

(6) glycidone - 30 mg

(7) microcrystalline cellulose - 150 mg

(8) hydroxyproryl cellulose - 10 mg

(5) magnesium stearate - 3 mg

Total tablet weight - 293 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 11

The composition of the pill:

(1) vildagliptin - 100 mg

(2) glycidone - 45 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 15 mg

(5) magnesium stearate - 3 mg

The total weight of the tablet is 313 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 12

The composition of the pill:

(1) vildagliptin - 100 mg

(2) glycidone - 60 mg

(3) microcrystalline cellulose - 150 mg

(4) hydroxyproryl cellulose - 15 mg

(5) magnesium stearate - 3 mg

Total tablet weight - 328 mg

A vildagliptin / glycidone tablet was prepared as follows:

To get one tablet:

(1), (2), (3), (4) and (5) are mixed, the resulting composition is pressed.

The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 13

core - 82.5 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 37.5 mg

(3) hydroxyproryl cellulose - 20 mg

outer layer - 46.5 mg

(4) glycidone - 15 mg

(5) microcrystalline cellulose - 30 mg

(6) hydroxyproryl cellulose - 1 mg

(7) magnesium stearate - 0.5 mg

Total tablet weight - 129 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 0.25 mg (7) are placed in the matrix, then 23 mg of the mixture containing (4) are placed, ( 5) and (6), then 82.5 mg of mixture (1), (2) and (3) are placed, on top of which 23 mg of mixture (4), (5) and (6) are added, and then 0.25 mg (7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 14

core - 82.5 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 37.5 mg

(3) hydroxyproryl cellulose - 20 mg

outer layer - 93 mg

(4) glycidone - 30 mg

(5) microcrystalline cellulose - 60 mg

(6) hydroxyproryl cellulose - 2 mg

(7) magnesium stearate - 1 mg

The total weight of the tablet is 175.5 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 0.5 mg (7) is placed in the matrix, then 46 mg of the mixture containing (4), ( 5) and (6), then 82.5 mg of mixture (1), (2) and (3) are placed, on top of which 46 mg of mixture (4), (5) and (6) are added, and then 0.5 mg (7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 15

core - 82.5 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 37.5 mg

(3) hydroxyproryl cellulose - 20 mg

outer layer - 139.5 mg

(4) glycidone - 45 mg

(5) microcrystalline cellulose - 90 mg

(6) hydroxyproryl cellulose - 3 mg

(7) magnesium stearate - 1.5 mg

Total tablet weight - 222 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, (4), (5) and (6) are mixed separately, 0.75 mg (7) is placed in the matrix, then 69 mg of the mixture containing (4), is placed 5) and (6), then 82.5 mg of mixture (1), (2) and (3) are placed, over which 69 mg of mixture (4), (5) and (6) are added, and then 0.75 mg (7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 16

core - 82.5 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 37.5 mg

(3) hydroxyproryl cellulose - 20 mg

outer layer - 186 mg

(1) glycidone - 60 mg

(2) microcrystalline cellulose - 120 mg

(3) hydroxyproryl cellulose - 4 mg

(4) magnesium stearate - 2 mg

Total tablet weight - 268.5 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 1 mg (7) is placed in the matrix, then 92 mg of the mixture containing (4), (5) is placed and (6) then 82.5 mg of mixture (1), (2) and (3) are placed, on top of which 92 mg of mixture (4), (5) and (6) are added, and then 1 mg (7) is added . Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 17

core - 165 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 75 mg

(3) hydroxyproryl cellulose - 40 mg

outer layer - 46.5 mg

(4) glycidone - 15 mg

(5) microcrystalline cellulose - 30 mg

(6) hydroxyproryl cellulose - 1 mg

(7) magnesium stearate - 0.5 mg

The total weight of the tablets is 211.5 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 0.25 mg (7) are placed in the matrix, then 23 mg of the mixture containing (4) are placed, ( 5) and (6), then 165 mg of mixture (1), (2) and (3) are placed, on top of which 23 mg of mixture (4), (5) and (6) are added, and then 0.25 mg ( 7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 18

core - 165 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 75 mg

(3) hydroxyproryl cellulose - 40 mg

outer layer - 93 mg

(4) glycidone - 30 mg

(5) microcrystalline cellulose - 60 mg

(6) hydroxyproryl cellulose - 2 mg

(7) magnesium stearate - 1 mg

The total weight of the tablet is 258 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 0.5 mg (7) is placed in the matrix, then 46 mg of the mixture containing (4), ( 5) and (6), then 165 mg of mixture (1), (2) and (3) are placed, over which 46 mg of mixture (4), (5) and (6) are added, and then 0.5 mg ( 7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 19

core - 165 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 75 mg

(3) hydroxyproryl cellulose - 40 mg

outer layer - 139.5 mg

(4) glycidone - 45 mg

(5) microcrystalline cellulose - 90 mg

(6) hydroxyproryl cellulose - 3 mg

(7) magnesium stearate - 1.5 mg

Total tablet weight - 304.5 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, (4), (5) and (6) are mixed separately, 0.75 mg (7) is placed in the matrix, then 69 mg of the mixture containing (4), is placed 5) and (6), then 165 mg of mixture (1), (2) and (3) are placed, on top of which 69 mg of mixture (4), (5) and (6) are added, and then 0.75 mg ( 7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 20

core - 165 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 75 mg

(3) hydroxyproryl cellulose - 40 mg

outer layer - 186 mg

(4) glycidone - 60 mg

(5) microcrystalline cellulose - 120 mg

(6) hydroxyproryl cellulose - 4 mg

(7) magnesium stearate - 2 mg

The total weight of the tablets is 351 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 1 mg (7) is placed in the matrix, then 92 mg of the mixture containing (4), (5) is placed and (6), then 165 mg of mixture (1), (2) and (3) are placed, over which 92 mg of mixture (4), (5) and (6) are added, and then 1 mg (7) is added. Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 21

core - 330 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 150 mg

(3) hydroxyproryl cellulose - 80 mg

outer layer - 46.5 mg

(4) glycidone - 15 mg

(5) microcrystalline cellulose - 30 mg

(6) hydroxyproryl cellulose - 1 mg

(7) magnesium stearate - 0.5 mg

The total weight of the tablet is 376.5 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 0.25 mg (7) are placed in the matrix, then 23 mg of the mixture containing (4) are placed, ( 5) and (6), then 330 mg of mixture (1), (2) and (3) are placed, on top of which 23 mg of mixture (4), (5) and (6) are added, and then 0.25 mg ( 7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 22

core - 330 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 150 mg

(3) hydroxyproryl cellulose - 80 mg

outer layer - 93 mg

(4) glycidone - 30 mg

(5) microcrystalline cellulose - 60 mg

(6) hydroxyproryl cellulose - 2 mg

(7) magnesium stearate - 1 mg

Total tablet weight - 423 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 0.5 mg (7) is placed in the matrix, then 46 mg of the mixture containing (4), ( 5) and (6), then 330 mg of mixture (1), (2) and (3) are placed, on top of which 46 mg of mixture (4), (5) and (6) are added, and then 0.5 mg ( 7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 23

core - 330 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 150 mg

(3) hydroxyproryl cellulose - 80 mg

outer layer - 139.5 mg

(4) glycidone - 45 mg

(5) microcrystalline cellulose - 90 mg

(6) hydroxyproryl cellulose - 3 mg

(7) magnesium stearate - 1.5 mg

The total weight of the tablets is 469.5 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, (4), (5) and (6) are mixed separately, 0.75 mg (7) is placed in the matrix, then 69 mg of the mixture containing (4), is placed 5) and (6), then 330 mg of mixture (1), (2) and (3) are placed, on top of which 69 mg of mixture (4), (5) and (6) are added, and then 0.75 mg ( 7). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 24

core - 330 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 150 mg

(3) hydroxyproryl cellulose - 80 mg

outer layer - 186 mg

(4) glycidone - 60 mg

(5) microcrystalline cellulose - 120 mg

(6) hydroxyproryl cellulose - 4 mg

(7) magnesium stearate - 2 mg

Total tablet weight - 516 mg

A multilayer tablet of vildagliptin / glycidone with a modified release of vildagliptin was prepared as follows:

(1), (2) and (3) are mixed, separately mixed (4), (5) and (6), 1 mg (7) is placed in the matrix, then 92 mg of the mixture containing (4), (5) is placed and (6), then 330 mg of mixture (1), (2) and (3) are placed on top of which 92 mg of mixture (4), (5) and (6) are added, and then 1 mg (7) is added. Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 25

core - 75 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 50 mg

outer layer - 46.5 mg

(3) glycidone - 15 mg

(4) microcrystalline cellulose - 30 mg

(5) hydroxyproryl cellulose - 1 mg

(6) magnesium stearate - 0.5 mg

The total weight of the tablet is 121.5 mg

The multilayer tablet vildagliptin / glycidone was prepared as follows:

(1) and (2) are mixed, (3), (4) and (5) are mixed separately, 0.25 mg (6) is placed in the matrix, then 23 mg of the mixture containing (3), (4) and ( 5), then 75 mg of mixture (1) and (2) are placed, over which 23 mg of mixture (3), (4) and (5) are added, and then 0.25 mg (6) is added. Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 26

core - 75 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 50 mg

outer layer - 93 mg

(3) glycidone - 30 mg

(4) microcrystalline cellulose - 60 mg

(5) hydroxyproryl cellulose - 2 mg

(6) magnesium stearate - 1 mg

Total tablet weight - 168 mg

The multilayer tablet vildagliptin / glycidone was prepared as follows:

(1) and (2) are mixed, (3), (4) and (5) are mixed separately, 0.5 mg (6) is placed in the matrix, then 46 mg of the mixture containing (3), (4) and ( 5), then 75 mg of mixture (1) and (2) are placed, over which 46 mg of mixture (3), (4) and (5) are added, and then 0.5 mg (6) is added. Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 27

core - 75 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 50 mg

outer layer - 139.5 mg

(3) glycidone - 45 mg

(4) microcrystalline cellulose - 90 mg

(5) hydroxyproryl cellulose - 3 mg

(6) magnesium stearate - 1.5 mg

The total weight of the tablets is 214.5 mg

The multilayer tablet vildagliptin / glycidone was prepared as follows:

(1) and (2) are mixed, (3), (4) and (5) are separately mixed, 0.75 mg (6) is placed in the matrix, then 69 mg of the mixture containing (3), (4) and ( 5), then 75 mg of mixture (1) and (2) are placed, over which 69 mg of mixture (3), (4) and (5) are added, and then 0.75 mg (6) is added. Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 28

core - 75 mg

(1) vildagliptin - 25 mg

(2) microcrystalline cellulose - 50 mg

outer layer - 186 mg

(3) glycidone - 60 mg

(4) microcrystalline cellulose - 120 mg

(5) hydroxyproryl cellulose - 4 mg

(6) magnesium stearate - 2 mg

The total weight of the tablet is 261 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.75 mg (6) was placed in a matrix, then 92 mg of a mixture containing (3), (4) and (5), then 75 mg of the mixture (1) and (2) are placed, over which 92 mg of the mixture (3), (4) and (5) are added, and then 0.75 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 29

core - 150 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 100 mg

outer layer - 46.5 mg

(3) glycidone - 15 mg

(4) microcrystalline cellulose - 30 mg

(5) hydroxyproryl cellulose - 1 mg

(6) magnesium stearate - 0.5 mg

The total weight of the tablet is 196.5 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.25 mg (6) was placed in a matrix, then 23 mg of a mixture containing (3), (4) and (5), then 150 mg of mixture (1) and (2) are placed, on top of which 23 mg of mixture (3), (4) and (5) are added, and then 0.25 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 30

core - 150 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 100 mg

outer layer - 93 mg

(3) glycidone - 30 mg

(4) microcrystalline cellulose - 60 mg

(5) hydroxyproryl cellulose - 2 mg

(6) magnesium stearate - 1 mg

The total weight of the tablet is 243 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.5 mg (6) was placed in a matrix, then 46 mg of a mixture containing (3), (4) and (5), then 150 mg of mixture (1) and (2) are placed, on top of which 46 mg of mixture (3), (4) and (5) are added, and then 0.5 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 31

core - 150 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 100 mg

outer layer - 139.5 mg

(3) glycidone - 45 mg

(4) microcrystalline cellulose - 90 mg

(5) hydroxyproryl cellulose - 3 mg

(6) magnesium stearate - 1.5 mg

The total weight of the tablet is 289.5 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.75 mg (6) was placed in a matrix, then 69 mg of a mixture containing (3), (4) and (5), then 150 mg of mixture (1) and (2) are placed, on top of which 69 mg of mixture (3), (4) and (5) are added, and then 0.75 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 32

core - 150 mg

(1) vildagliptin - 50 mg

(2) microcrystalline cellulose - 100 mg

outer layer - 186 mg

(3) glycidone - 60 mg

(4) microcrystalline cellulose - 120 mg

(5) hydroxyproryl cellulose - 4 mg

(6) magnesium stearate - 2 mg

The total weight of the tablet is 336 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.75 mg (6) was placed in a matrix, then 92 mg of a mixture containing (3), (4) and (5), then 150 mg of mixture (1) and (2) are placed, on top of which 92 mg of mixture (3), (4) and (5) are added, and then 0.75 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 33

core - 300 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 200 mg

outer layer - 46.5 mg

(3) glycidone - 15 mg

(4) microcrystalline cellulose - 30 mg

(5) hydroxyproryl cellulose - 1 mg

(6) magnesium stearate - 0.5 mg

The total weight of the tablet is 346.5 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.25 mg (6) was placed in a matrix, then 23 mg of a mixture containing (3), (4) and (5), then 300 mg of mixture (1) and (2) are placed, on top of which 23 mg of mixture (3), (4) and (5) are added, and then 0.25 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 34

core - 300 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 200 mg

outer layer - 93 mg

(3) glycidone - 30 mg

(4) microcrystalline cellulose - 60 mg

(5) hydroxyproryl cellulose - 2 mg

(6) magnesium stearate - 1 mg

The total weight of the tablet is 393 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.5 mg (6) was placed in a matrix, then 46 mg of a mixture containing (3), (4) and (5), then 300 mg of mixture (1) and (2) are placed, over which 46 mg of mixture (3), (4) and (5) are added, and then 0.5 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 35

core - 300 mg

(1) vildagliptin -100 mg

(2) microcrystalline cellulose - 200 mg

outer layer - 139.5 mg

(3) glycidone - 45 mg

(4) microcrystalline cellulose - 90 mg

(5) hydroxyproryl cellulose - 3 mg

(6) magnesium stearate - 1.5 mg

The total weight of the tablet is 439.5 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.75 mg (6) was placed in a matrix, then 69 mg of a mixture containing (3), (4) and (5), then 300 mg of mixture (1) and (2) are placed, over which 69 mg of mixture (3), (4) and (5) are added, and then 0.75 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Example 36

core - 300 mg

(1) vildagliptin - 100 mg

(2) microcrystalline cellulose - 200 mg

outer layer - 186 mg

(3) glycidone - 60 mg

(4) microcrystalline cellulose - 120 mg

(5) hydroxyproryl cellulose - 4 mg

(6) magnesium stearate - 2 mg

Total tablet weight - 486 mg

A multilayer tablet of vildagliptin / glycidone was prepared as follows: (1) and (2) were mixed, (3), (4) and (5) were separately mixed, 0.75 mg (6) was placed in a matrix, then 92 mg of a mixture containing (3), (4) and (5), then 300 mg of mixture (1) and (2) are placed, on top of which 92 mg of mixture (3), (4) and (5) are added, and then 0.75 mg (6). Pressed. The solid dosage form obtained according to the invention, according to the studied parameters, meets the requirements of the State Pharmacopoeia XI ed.

Claims (19)

1. A pharmaceutical composition that is a tablet prepared by direct compression, which as active ingredients comprises from 1.3 to 86 wt.%, Preferably from 8 to 36 wt.%, A DPP-IV inhibitor vildagliptin or a pharmaceutically acceptable salt thereof, and from 0.8 to 68.5 wt.%, preferably from 4 to 25 wt.%, glycidone or a pharmaceutically acceptable salt thereof, the active ingredients being from 2.1 to 98 wt.%, preferably from 32 to 65.5 wt.%, composition. 2. The pharmaceutical composition of claim 1, wherein at least one standard pharmaceutical acceptable excipient is added. 3. The pharmaceutical composition according to claim 1, in which the pharmaceutical acceptable excipient is selected from the group consisting of binding agents, diluents, disintegrating agents, lubricants, solid excipients, carriers and substances that provide a controlled, delayed, gradual release of drugs from the tablet. 4. The pharmaceutical composition of claim 1, wherein the binding agent is selected from the group of starches, celluloses and derivatives thereof, for example microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose and polysaccharides. 5. The pharmaceutical composition of claim 4, wherein at least one standard pharmaceutical acceptable excipient is added. 6. The pharmaceutical composition according to claim 1, including:
1) 25 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,
2) 25 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,
3) 25 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,
4) 25 mg vildagliptin and 60 mg glycidone or in each case their pharmaceutically acceptable salts,
5) 50 mg vildagliptin and 15 mg glycidone or, in each case, their pharmaceutically acceptable salts,
6) 50 mg vildagliptin and 30 mg glycidone or in each case their pharmaceutically acceptable salts,
7) 50 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,
9) 100 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,
10) 100 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,
11) 100 mg vildagliptin and 45 mg glycidone or in each case their pharmaceutically acceptable salts or
12) 100 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts. 7. The pharmaceutical composition according to claim 1, where the composition is included in one of the layers of a two-layer or three-layer tablets. 8. The pharmaceutical composition, which is a multilayer tablet obtained by direct compression, containing as active ingredients in the core from 1.3 to 97 wt.%, Preferably from 30 to 40 wt.%, A DPP-IV inhibitor vildagliptin or its pharmaceutically acceptable salt, based on the weight of the core, in the outer layer from 0.8 to 97 wt.%, preferably from 20 to 33 wt.%, glycvidone or its pharmaceutically acceptable salt, based on the weight of the outer layer. 9. The pharmaceutical composition of claim 8, wherein at least one standard pharmaceutical acceptable excipient is added. 10. The pharmaceutical composition according to claim 8, in which the pharmaceutical acceptable excipient is selected from the group comprising binding agents, diluents, disintegrating agents, lubricants, solid excipients, carriers and substances that provide a controlled, delayed, gradual release of drugs from the tablet. 11. The pharmaceutical composition of claim 8, wherein the binding agent is selected from the group of starches, celluloses and derivatives thereof, for example microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose and polysaccharides. 12. The pharmaceutical composition of claim 11, wherein at least one standard pharmaceutical acceptable excipient is added. 13. The pharmaceutical composition according to claim 8, including:
1) 25 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,
2) 25 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,
3) 25 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,
4) 25 mg vildagliptin and 60 mg glycidone or in each case their pharmaceutically acceptable salts,
5) 50 mg vildagliptin and 15 mg glycidone or, in each case, their pharmaceutically acceptable salts,
6) 50 mg vildagliptin and 30 mg glycidone or in each case their pharmaceutically acceptable salts,
7) 50 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,
9) 100 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,
10) 100 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,
11) 100 mg vildagliptin and 45 mg glycidone or in each case their pharmaceutically acceptable salts or
12) 100 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts. 14. The pharmaceutical composition, which is a multilayer tablet with a modified release, obtained by direct compression, containing in the core from 1.3 to 97 wt.%, Preferably from 25 to 35 wt.%, A DPP-IV inhibitor vildagliptin or its pharmaceutically acceptable salt, based on the weight of the core, which includes at least one pharmaceutically acceptable excipient that slows the release of vildagliptin, preferably hydroxypropyl cellulose in an amount of from 15 to 35 wt.%, preferably from 17 to 25 ma .%, based on the weight of the core, allowing you to get a prolonged tablet, with a modified release, in the outer layer from 0.8 to 97 wt.%, preferably from 20 to 33 wt.% glycvidone, or its pharmaceutically acceptable salt, based on mass of the outer layer. 15. The pharmaceutical composition according to claim 14, to which at least one standard pharmaceutical acceptable excipient is added. 16. The pharmaceutical composition according to p. 14, in which the pharmaceutical acceptable excipient is selected from the group comprising binding agents, diluents, disintegrating agents, lubricants, solid excipients, carriers and substances that provide controlled, delayed, gradual release of drugs from the tablet. 17. The pharmaceutical composition of claim 14, wherein the binding agent is selected from the group of starches, celluloses and derivatives thereof, for example microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose and polysaccharides. 18. The pharmaceutical composition of claim 17, wherein at least one standard pharmaceutical acceptable excipient is added. 19. The pharmaceutical composition according to p. 14, including:
1) 25 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,
2) 25 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,
3) 25 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,
4) 25 mg vildagliptin and 60 mg glycidone or in each case their pharmaceutically acceptable salts,
5) 50 mg vildagliptin and 15 mg glycidone or, in each case, their pharmaceutically acceptable salts,
6) 50 mg vildagliptin and 30 mg glycidone or in each case their pharmaceutically acceptable salts,
7) 50 mg vildagliptin and 45 mg glycidone or, in each case, their pharmaceutically acceptable salts,
9) 100 mg vildagliptin and 15 mg glycidone or in each case their pharmaceutically acceptable salts,
10) 100 mg vildagliptin and 30 mg glycidone or, in each case, their pharmaceutically acceptable salts,
11) 100 mg vildagliptin and 45 mg glycidone or in each case their pharmaceutically acceptable salts or
12) 100 mg vildagliptin and 60 mg glycidone or, in each case, their pharmaceutically acceptable salts.