Pharmaceutical composition based on dipeptidyl peptidase-4 inhibitor

Abstract

The invention relates to medicine and the pharmaceutical industry, more particularly to compositions intended for oral administration in the prevention and treatment of type 2 diabetes. The essence of the invention consists in that the created pharmaceutical composition comprises an active ingredient having an anti-hyperglycaemic effect, i.e. a highly effective dipeptidyl peptidase-4 (DPP-4) inhibitor, namely exo-(2S)-3-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-azabicyclo[2.2.1]heptane-2-carbonitryl (substance I) in the form of pharmaceutically acceptable salt forms, auxiliary substances and carriers, which provide immediate release, extended release and modified release of the active ingredient for treating patients suffering from type 2 diabetes. Compositions also include inactive ingredients which, on one hand, maintain the efficacy of the active substance, and on the other hand - make it possible to change dosage, release and half-life thereof in a body.

Description

FIELD OF THE INVENTIONThe invention relates to medicine, particularly to the pharmaceuticalindustry, and is related to an agent for the prevention and treatment oftype 2 diabetes.BACKGROUND OF THE INVENTIONType 2 diabetes mellitus (T2DM) is a chronic endocrine diseaseassociated with insulin resistance and dysfunction of β-pancreatic cells,which causes persistent and excessive blood glucose (hyperglycaemia)levels, which, in turn, directly or indirectly trigger a cascade of all typesof metabolic disorders. T2DM is associated with endocrine systemdisorders, increased lipolysis in the adipose tissue, increased glucagonsecretion, increased renal glucose reabsorption and, finally, eatingdisorders. This disease greatly affects the patient's quality of life, andits progression leads to severe complications and consequences -disability and even death (Drucker, D.J., & Nauck, M.A. (2006). Theincretin system: glucagon-like peptide-1 receptor agonists anddipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 368(9548),1696-1705). Diabetes is a serious global medical and social problem,and the share of those suffering from this disease is constantly growing.Analysts from the International Diabetes Federation (IDF) report thatby 2045 the number of patients with T2DM will reach 700 million(Karuranga, S., Cho, N.H., Ohlrogge, A.W., Shaw, J.E., da RochaFernandes, J.D., Huang, Y., & Malanda, B. (2018). IDF Diabetes Atlas:Global estimates of diabetes prevalence for 2017 and projections for2045. Diabetes Research and Clinical Practice, 138, 271-281).In individuals predisposed to this disease and patients withT2DM, the normal glucose metabolism in the body is disrupted, and thelevel of glucose concentration as well as blood concentration of itsderivatives increases, which affects the metabolism as a whole,rendering the body unable to perform certain normal biologicalprocesses. Most patients with T2DM are significantly overweight,which is determined by carbohydrate and, consequently, lipidmetabolism disorders (Erion, D.M., Park, H.J., & Lee, H.Y. (2016). Therole of lipids in the pathogenesis and treatment of type 2 diabetes andassociated co-morbidities. BMB Reports, 49(3), 139-148).Currently, there is a number of commercially available medicinalproducts with different mechanisms of action, intended to correct thepatient's condition. Each of the products developed earlier (biguanides,thiazolidinediones, sulfonylureas, etc.) has significant limitations andside effects. One of the newest and most sought-after approaches to thetreatment of type 2 diabetes symptoms is finished dosage forms basedon dipeptidyl peptidase-4 inhibitors. The very first DPP-4 inhibitorsthat have successfully passed clinical trials and appeared on thepharmaceutical market of different countries were sitagliptin(https: / / www.lsgeotar.ru / sitagliptin.html) and vildagliptin(https: / / www.lsgeotar.ru / vildagliptin.html), which were later joined bysaxagliptin (https: / / www.lsgeotar.ru / saxagliptin.html), alogliptin(https: / / www.lsgeotar.ru / alogliptin.html), linagliptin(https: / / www.lsgeotar.ru / linagliptin.html).Clinical studies showed that DPP-4 inhibitors significantlyreduce hyperglycaemia (blood glucose levels) when administeredpostprandially and under fasting condition, reduce glycatedhaemoglobin in blood plasma, stimulate insulin synthesis, and also havea good oral bioavailability and a relatively long effect, and do not affectbody weight changes.Reference is made to a RF Patent for invention No. 2443687, "NewDPP-IV inhibitors, methods of their preparation and pharmaceuticalformulations containing them."A patent for invention, RF No. 2483716, relates to apharmaceutical formulation that contains a DPP-4 inhibitor, preferablyvildagliptin, 1.5 to 20 %, and metformin, 80 to 98.5 %. The activeingredients may constitute 60 to 98 % of the formulation. Cellulose orits derivatives are used as a binder in quantities ranging from 1 to 20 %.An application for invention, RF No. 2006121339, relates to apharmaceutical composition that contains a therapeutically effectiveamount of (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidine or its pharmaceutically acceptable salt, preferably 25-100 mg, in combination with one or more pharmaceutically acceptablecarriers, for the treatment of cardiovascular diseases or injuries, kidneydiseases or injuries, heart failure or diseases associated with heartfailure.An application for invention, RF No. 2011146335, describes apharmaceutical composition that contains a combination of thecompound 1-thio-D-glucitol, where sitagliptin or vildagliptin is used asa dipeptidyl peptidase-4 inhibitor.Reference is made to a patent, RF No. 2606840, for a composition thatcontains a long-acting insulin conjugate and a long-actinginsulinotropic peptide conjugate for the prevention or treatment ofdiabetes, as well as for a diabetes treatment method.Application for an invention, 2015122253 "Immediate-release tabletformulations", describes a pharmaceutical composition containingdapagliflozin and metformin hydrochloride.An invention, RF No. 2589258, describes pharmaceutical compositionsbased on a peptide agent that inhibits dipeptidyl peptidase-4.Reference is made to an application, WO No. 2012 / 131005 A1"Pharmaceutical composition of sitagliptin", selected by the authors asa prototype.Despite the fact that well-known products based on DPP-4inhibitors (sitagliptin or vildagliptin, etc.) are undeniably beneficial incomparison with other described anti-hyperglycaemic agents (insulin,insulinotropic peptides, metformin, glyphosines, etc.) and have beenwidely recognized since entering the pharmaceutical market, their useis limited to a fairly short time history (just over 10 years) of diseasetreatment, which is insufficient to identify the possible and undesirableside effects.In the recent years, the physiological profiles and clinicalproperties of DPP-4 inhibitor-based products, as well as the side effectsthat may be induced by them, have been intensively and widely studied.Despite the fact that commercially available products based onfive DPP-4 inhibitors (sita-, vilda-, saxa-, alo- and linagliptin) aresimilar in the manifestations of their anti-hyperglycaemic properties,their lack of effect on the body weight and the risk of hypoglycaemia,and that in general they have proven themselves well, in the recent yearscertain specific differences and side effects have been found in differentpatients taking medicinal products based on structurally differentgliptins.For example, sitagliptin doses should be carefully selected forpatients with a moderate or severe renal failure. Special caution shouldbe exercised when this product is prescribed to patients receivingdigoxin. Sitagliptin is contraindicated in type 1 diabetes and diabeticketoacidosis.In some cases, vildagliptin induced a 3-fold increase in theactivity of aminotransferases. The clinical manifestations of thiscondition are being carefully studied currently. And it is already knownthat this product should be immediately discontinued in case of anysigns of liver dysfunction, and may not be resumed even if theparameters return to normal.Saxagliptin administration was found to increase the incidence ofupper respiratory tract infections, urinary tract infections, developmentof gastroenteritis, sinusitis, vomiting and headaches. Dizziness,identified as an adverse drug reaction, requires restrictions to the use ofvehicles or even refraining from driving.In addition to the above examples, it should be mentioned thatnot all gliptins have been studied for the treatment of children under theage of 18, as well as pregnant and lactating women; therefore, suchproducts are contraindicated in these groups of diabetic patients.The number of direct studies comparing the efficacy and sideeffects of different DPP-4 inhibitor products is still insufficient.However, it is obvious that this field of T2DM therapy has becomeincreasingly popular and sought-after in the recent years, which isevidenced by even a greater number of other potential antidiabeticagents of this type being at various stages of preclinical and clinicalstudies (e.g. teneligliptin (Kishimoto Syndrome, 2013), omarigliptin(Tatosian et al., 2014), evogliptin (Mccormack, 2015) etc.).Thus, there is still an ongoing need to expand the range of knownmedicinal products and dosage forms of dipeptidyl peptidase-4inhibitors to meet the future need for products with a similar mechanismof action, but special aspects of disease progression, burdening withother diseases, individual tolerability in different patients and groups oftype 2 diabetes patients should be taken into account.Furthermore, none of the known and above mentioned inventionsconsiders compositions and medicinal products that provide a varietyof release options and, as a consequence, the duration of action of theactive ingredient in the body, for the treatment of diabetes mellitus.The development of medicine is aimed at future personification.To ensure that treatment of any disease with products having a sametypemechanism of action is performed with consideration to thepatients' burdening with other diseases and certain aspects of individualtolerability by specific representatives, the development of newfinished dosage forms that allow for varying the doses, release andduration of action of the active ingredient, DPP-4 inhibitor, in the bodyshould be continued.SUMMARY OF THE INVENTIONThis invention is aimed to expand the range of the existingpharmaceutical compositions by developing and creating oralpharmaceutical compositions based on a new dipeptidyl peptidase-4inhibitor, an active anti-hyperglycaemic and non-toxic component forthe prevention and treatment of type 2 diabetes.The development includes pharmaceutical compositionscontaining excipients and carriers that provide different activeingredient release mechanisms, namely, immediate, prolonged andmodified release of the active ingredient. Furthermore, this invention isaimed to develop a process for preparing pharmaceutically acceptablesalt forms of the active ingredient serving as a basis for compositionsand finished dosage forms.The aim of this invention is solved by creating oral pharmaceuticalcompositions containing an active ingredient, a highly effective DPP-4inhibitor, namely, exo-(2S)-3-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-azabicyclo[2.2.1]heptane-2-carbonitryl -substance I in the form of pharmaceutically acceptable salt forms,excipients and carriers, which provide immediate release, extendedrelease and modified release of the active ingredient for treating patientssuffering from type 2 diabetes.Molecular weight 337Structure of the active ingredient - Substance I.BRIEF DESCRIPTION OF FIGURESFigure 1 shows a typical chromatogram of Substance I obtained byLC / MS with a mass detector. All LC / MS chromatograms obtainedusing a mass detector (further - examples 2-4) showed a single peakof substance I with 100 % purity. The molecular weight (M) wasdetermined using a mass detector and exactly corresponded to thecalculated mass of substance I. The molecular weight (M) wasdetermined using a mass detector and exactly corresponded to thecalculated mass of Substance I.Figure 2 shows the mass spectrum of Substance I obtained by APCILC / MS. The mass spectrum of the peak from the chromatogram shownin Fig. 1 is provided. The value m / z [M + H]+ = 338 was obtained byAPCI ionization and exactly corresponds to the molecular weight ofsubstance I (M = 337).DETAILED DESCRIPTION OF THE INVENTIONSubstance I was synthetized following the scheme below:Scheme of Substance I Synthesis.Substance I Method of Synthesis.Embodiment 1.Synthesis of Substance I in the form of trifluoroacetate salt.Ethyl-(2S,3S)-3-(1-phenylethyl)-3-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (2).50 % ethyl glyoxylate solution in toluene (19.6 mL, 0.096 mol),toluene (300 mL) and benzylamine 1 (10.3 mL, 0.08 mol) were placedin a 1 litre flask, stirred during 2 hours until water was released, thenthe water was removed using sodium sulphate, and the solvent wasevaporated. The resulting residue was dissolved in dimethylformamide(100 mL), and trifluoroacetic acid solution (6.12 mL, 0.08 mol) indimethylformamide was added while cooling on an ice bath. Thereaction mixture was stirred at room temperature for about 1 hour.Then, freshly distilled cyclopentadiene (10.6 g, 0.16 mol) was added inone portion while cooling on an ice bath. The reaction mixture wasallowed to stand at room temperature for about 24 hours. After24 hours, the reaction mixture was diluted with 400 mL of 10 % potashsolution while cooling on an ice bath, extracted with ethyl acetate3 times, 100 mL each, the organic layer was dried with sodium sulphateand evaporated at a bath temperature not exceeding 30 °C. Columnchromatography on silica gel in an ethyl acetate : petroleum ether 1 : 10system was used to isolate 8.1 g (0.0299 mol) of pure fraction ofcompound 2. The yield was 37.3 %.(2S)-3-tert-butoxycarbonyl-3-azabicyclo[2.2.1]heptene-2-carboxylicacid ethyl ester (3).Compound 2 (8.1 g, 0.0299 mol) was dissolved in 200 mL ofbenzene, and tris(triphenylphosphine)rhodium chloride (0.405 g,5 wt%) was added. Hydrogenated on a Parr apparatus at 20 psi untilhydrogen uptake ceased (about 4 hours). Completeness of thehydrogenation was monitored by LCMS data. After the reaction, thesolution was passed through a silica gel film, and the product waswashed with an ethyl acetate : petroleum ether 1 : 4 system. Theresulting solution was evaporated, 200 mL of ethanol, 5 % Pd on carbon(0.8 g), and BoC2O (6.9 g, 0.0316 mol) were added. It was thenhydrogenated at 20 psi on a Parr apparatus. Completeness of thereaction was monitored using the LCMS method. The resulting reactionmixture was used in the next step.(2S)-3-tert-butoxycarbonyl-3-azabicyclo[2.2.1]heptene-2-carboxylicacid (4)After the hydrogenation, the ethanolic solution of compound 3from the previous stage was filtered to remove the catalyst, and 50 mL(0.075 mol) of sodium hydroxide aqueous solution was added. Theresulting solution was heated for 1 hour at 60°C. After completeconversion of ether (TLC monitoring), ethanol was evaporated, theresidue was dissolved in water, the solution was acidified with 2Mhydrochloric acid to pH 3, the product was extracted with ethyl acetate,the organic extracts were washed with water, dried with sodiumsulphate and evaporated. The product was recrystallized from hexane.5.42 g (0.022 mol) of acid 4 were obtained. The yield was 90 %. Theproduct was further used without additional purification.(2S)-exo-tert-butyl-3-carbamoyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (5)3.45 mL (2.5 g) of thriethylamine was added to a solution ofacid 4 (5.42 g) in dry THF while refrigerating to -20 °C in argonatmosphere, then ethyl chloroformate (2.68 g, 0.0247 mol) was addeddropwise during 10 min. The reaction mixture was maintained cooledfor 40 min. Then ammonia was passed from a cylinder for 1 h. Thesolvent was evaporated, the residue was treated with citric acid solutionto pH 4, extracted with ethyl acetate, ethyl acetate extracts were washedwith soda solution, dried with sodium sulphate and concentrated. 5.29 gof colourless crystalline amide 5 were obtained. Quantitative yield.(2S)-exo-tert-butyl-3-cyano-2-azabicyclo[2.2.1]heptane-2-carboxylate(6)To a suspension of the starting amide 5 (5.29 g) in dry THF at atemperature not exceeding 4 °C two equivalents of triethylamine(6.13 mL, 4.45 g), trifluoroacetic anhydride (6.93 g, 0.033 mol) wereadded for 10 minutes, the progress of the reaction was monitored byTLC. The reaction mixture was refrigerated for 3 hours. The reactionmixture was evaporated, applied onto silica gel and separated on achromatographic column. Eluent - a mixture ofpetroleum ether : ethyl acetate 4 : 1. 4.29 g (87 %) of target nitrile 6 inthe form of a pale yellow, thick, oily substance were obtained.(2S)-exo-2-azabicyclo[2.2.1]heptane-3-carbonitryl tosylate (7).A two-fold excess of p-toluenesulfonic acid (p-TSA) (6.54 g,0.038 mol) was added to the starting BOC-nitrile 6 (4.29 g, 0.019 mol)in 30 mL of acetonitrile and was left stirred overnight. Acetonitrile wasdistilled off, the residue was triturated with diethyl ether (3-4treatments with decantation). The ether was evaporated. 4.58 g of targetCompound 7 in the form of tosylate salt were obtained.Tert-butyl-N-[(1R)-3-[(2S)-2-cyano-3-azabicyclo[2.2.1]heptane-3-yl]-3-oxo-1-[(2,4,5-trifluorophenyl)methyl]propyl]carbamate ( 9).BOP (8.27 g, 0.0187 mol) and triethylamine (4.74 mL,0.0468 mol, 3 equiv.) were added to a solution of acid 8 (5.19 g,0.0156 mol) in 60 mL of dichloromethane. After 15 minutes,amine tosylate 7 (4.57 g, 0.0156 mol) was added at room temperature.After 2 hours, LCMS showed complete conversion. Dichloromethanewas evaporated, the residue was dissolved in ethyl acetate and washedwith 10 % potash solution, then with water, dried with sodium sulphateand evaporated. A small amount of petroleum ether was added to theresidue and a crystallized product was filtered off. 5.08 g ofcompound 9 were obtained. The yield was 75 %.The N-protective group in BOC-derivative 9 is removed underany standard conditions using suitable NH acids widely used in organicchemistry. Substance I is obtained in the form of a salt of thecorresponding acid.Exo-(2S)-3-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-azabicyclo[2.2.1]heptane-2-carbonitrile (I) in the form oftrifluoroacetate salt.Compound 9 (0.21 g, 0.65 mmol) was dissolved in DCM(20 mL), and TFA (0.5 mL) was added. The mixture was stirred at roomtemperature overnight. The solvent was evaporated on a rotaryevaporator to dryness. Et2O (20 mL) was added to the residue. Theresulting precipitate was filtered off and dried in vacuum. The yield ofsubstance I in the form of a trifluoroacetate salt is 0.18 g (90 %).LC / MS: m / z [M+H]+ = 338.Embodiment 2.Synthesis of substance I in the form of tosylate salt.Compound 9 (4.37 g, 0.01 mol) was suspended in 100 mL ofacetonitrile and a two-fold excess of toluenesulfonic acid hydrate(3.8 g, 0.02 mol) was added. Stirred overnight at room temperature. Theprecipitate was filtered and washed with acetonitrile. The yield ofsubstance I in the form of a tosylate salt is 4.42 g (87 %). LC / MS: m / z[M+H]+ = 338.Embodiment 3.Synthesis of substance I in the form of hydrochloride salt.4M HCl solution in dioxane (10 mL) was added to compound 9(6 g, 0.013 mol) in 25 mL of acetonitrile and was left stirred for 2 hours.The solvent was distilled to a glassy residue. The residue was dissolvedin acetonitrile (20 mL) at 50 °C and the solution was left to cool to roomtemperature. The resulting precipitate was filtered off and dried invacuum. The yield of substance I in the form of a hydrochloride salt is3.54 g (73 %). LC / MS: m / z [M+H]+ = 338.LC / MS test conditions: column - Onix C18, 50 x 4.6 mm; eluent 1 -0.1 % TFA in water; eluent 2 - 0.1 % TFA in acetonitrile, gradient:eluent 1 - 2.9 min, eluent 2 - 0.2 min, eluent 1 - washing, flow rate3.75 mL / min, detection - UV (254 nm) and mass spectrometry.Typical chromatogram of substance I (Embodiments 2-4) obtained byLC / MS analysis with mass detection.A salt-free form (A) and a salt form (B) of substance I, which arepharmaceutically acceptable for finished dosage forms, have beendeveloped and prepared.Pharmacologically acceptable salt forms of substance I includesalts with inorganic acids - hydrochloric acid (hydrochloride),hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; andorganic acids and their derivatives from sulfo-, alkyloxy-, hydroxy-,oxo-substituted acids: formic acid, acetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonicacid and para-toluenesulfonic acid (tosylate), naphthylsulfonic acid andsulfosalicylic acid, lactic acid, racemic acid, adipic acid, gluconic acid,glucoheptonic acid, glucuronic acid, terephthalic acid, hippuric acid,1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid,pamoic acid, polygalacturonic acid, stearic acid, tannic acid, or aminoacids from among all known natural amino acids - glycine, alanine,valine, leucine, isoleucine, proline, cysteine, methionine,phenylalanine, tryptophan, serine, threonine, glutamine, tyrosine,asparagine, histidine, lysine, arginine, asparaginic acid, asparaginicacid.Salt-free form A (free base) and salt form B of substance I in general,where NH is any of the acids specified above.The salt-free form A of substance I is obtained by isolating a freebase after treating the salt forms with basic reagents using any standard,chemical and physico-chemical methods applied using a basicknowledge of organic chemistry.Embodiment 4.Preparation of substance I in the form of a free base.Potash (0.3 g, 2 mmol) and methylene chloride (10 mL) wereadded to substance I solution in the form of trifluoroacetate (0.45 g,1 mmol) in water (10 mL), and were mixed for 1 hour. The organiclayer was separated, washed with 10 % potash solution, then withwater, dried with sodium sulphate and evaporated. The residue wasdried in vacuum. Substance I in the form of a free base was obtained.The yield is 0.29 g (86 %). LC / MS: m / z [M+H]+ = 338.All pharmacologically acceptable salt forms B of substance I areobtained following a standard procedure or at the final stage ofsynthesis (removal of NH2-protective group), as shown inEmbodiments 1-3, or by any practicable and standard method(Embodiment 5), mixing equimolar amounts of any appropriate acid,its solvate or hydrate and an amino-containing substance (in this case,substance I), or by salt exchange using well-known physico-chemicalmethods, for example, ion exchange chromatography.Embodiment 5.Preparation of substance I in the form of an amino acid salt -glycinate.Glycine solution (0.076 g) in water (1 mL) was added to substance Isolution in the form of a free base (0.34 g, 1 mmol) in ethyl alcohol(5 mL). The mixture was stirred for 1 hour, the solvent was evaporated.The residue was dried in vacuum. Substance I in the form of glycinatesalt - 0.42 g was obtained. LC / MS: m / z [M+H]+ = 338.The high DPP-4 inhibitory activity of substance I in a salt formand salt-free form was experimentally confirmed in the course of invitro tests by comparing with certified (Sigma-Aldrich) samples ofcommercially available inhibitors - pharmaceutical compositionsvilda-, sita-, alo- and linagliptins. The results were obtained by aspectrophotometric method, as well as using Excel and GraphPadPrism 8 software, by comparing with the permissible values of IC50,known for commercial inhibitors from literature references.Recombinant enzyme DPP-4 D4943 (Sigma), Gly-Pro-pNA substrateand a buffer system containing 50 mM of Tris-HCl, 50 mM of NaCl,0.01 % Triton, pH = 7.6, were used in the experiments. Each substancewas analysed in a concentration range of 10-4 to 10-11 M. All theobtained IC50 values were calculated based on the optical densityparameters 30 minutes after the start of incubation at 37 °C. The resultsof IC50 assessment are shown in Table 1.Table 1 Comparison of the Obtained and Published Data forCommercial Pharmaceutical Compositions, DPP-4 Inhibitors, with theResults Obtained for Substance (I) in a Salt-free Form and Salt Form.Table 1There are no restrictions for the types of pharmaceuticalcompositions used for the treatment of type 2 diabetes. According tothis invention, the most preferred method of administration for thetreatment of diabetes has been selected - oral administration.This invention includes a description of pharmaceuticalcompositions in the following dosage forms - tablets, granules,granules or pellets in the form of hard gelatin capsules.As the embodiments of the invention are described in the text,this invention is not limited thereto, since, as experts assume, manymodifications or variations are possible. Such modifications orvariations, not discussed herein in detail, are considered obviousequivalents of this invention.The pharmaceutical composition for the treatment of diabetesaccording to this invention includes the active ingredient, substance I inthe form of a free base and / or in the form of a pharmacologicallyacceptable salt from among those specified above, pharmacologicallyacceptable carriers and additional components, excipients, binders,lubricants, coating substances, aqueous solvents, solubilizers thatfacilitate the preparation of an acceptable pharmaceutical compositionthat meets the requirements of the State Pharmacopoeia.The method of administration of the pharmaceutical compositionfor the treatment of diabetes according to this invention is representedby dosage forms for internal use (oral), but is not limited thereto. Thepreferred method is oral.The dosage of the composition for the treatment of diabetesaccording to thisinvention is appropriately determined based on the patient's condition,severity of symptoms, age, method of administration, and results ofmedical diagnostics. The preferred doses for oral administration are1 mg to 50 mg of substance I per day, most preferably 5 mg. The doseabove, according to this invention, should be taken once or divided intoseveral doses taken at an interval of 2-4 to 8-12 hours, depending onthe severity of the symptoms and the medical diagnosis.The product is produced in the following dosage forms - tablets,granules, granules or pellets in the form of hard gelatin capsules, withimmediate (Embodiments 6-8), modified (Embodiments 9-14) andprolonged (Embodiments 15-18) action.Embodiment 6.Preparation of a pharmaceutical composition in the form of atablet with immediate release of the active ingredient (substance I)based on substance I in a salt-free form (free base; for preparation seeEmbodiment 4).An oral pharmaceutical composition representing a film-coatedtablet containing substance I in a salt-free form (free base) at a dose of5 mg at a ratio of 5 to 94 % of the total tablet mass with the followingratio of ingredients per 100 mg, % wt, as specified in Table 2.Table 2The method of product preparation based on the pharmaceuticalcomposition containing substance I in a salt-free form (free base) as theonly active ingredient at a dose of 1 to 50 mg (expressed as base), at aratio of 5 to 94 % of the total weight of a tablet, during whichmagnesium stearate, substance I in a salt-free form (free base),microcrystalline cellulose (type 21 or equivalent), cellulose 2-hydroxypropyl ether (low-substituted, type LH-21 or equivalent), andcolloidal silica (type A 200 or equivalent) are sifted, then a mixture ofsubstance I in a salt-free form (free base), microcrystalline cellulose,cellulose 2-hydroxypropyl ether (low-substituted) (25-60 %), colloidalsilica and magnesium stearate (35-65 %) is prepared, the componentsare mixed to a homogeneous state (visual control) for 3-24 minutes ata mixing speed of 7-25 rpm, transferred to a compaction device, andthe resulting mixture is subjected to dry granulation (compaction), andthe resulting granulate is sifted through 0.71 mm and 0.25 mm sieves,while fraction over 0.71 mm and below 0.25 mm is mixed andcompacted repeatedly until the portion of fine fraction is not more than10-15 %; the mixing parameters depend on the laboratory batch size,the roller speed is not more than 2-6 rpm, the pressure is not more than37.0 bar, the mill speed is between 56 and 70.0 rpm, the sieve mesh sizeis not more than 1.0 mm; then the resulting granulate, the remainingpart of cellulose 2-hydroxypropyl ether (low-substituted, type LH-21 orequivalent), the remaining part of colloidal silica (type A 200 orequivalent) are loaded into the mixer, and the components are mixed toa homogeneous state (visual control) for 3-24 minutes at 7-25 rpm,placed in a compaction device, after which the remaining part ofmagnesium stearate is loaded into the mixer and the components aremixed to a homogeneous state (visual control), the mixing parametersare the same; then the tableting mixture is discharged into a container,a representative sample is taken for control, tableting is performed usinga compression machine with a round or oval (with or without a scoreline) press tool with 8.00-13.00 mm geometry; after setting the averagetablet weight, the compression machine is set up according to suchparameters as hardness - 80-100 N; friability - not more than 0.5 %;disintegration - not more than 1 minute; mass variation should notexceed 5.0 %; then coating is applied in a fluidized bed, where 18-22 %of the film coat suspension is used during the film coating process; thecoating has the following composition: hypromellose, titanium dioxide,polydextrose, talc, polyethylene glycol; before coating, the tablets areheated to 35-41° while periodically stirred in the coater drum; when therequired tablet temperature is reached, the film coat suspension issprayed; during the process, the tablet appearance and add-on weight ofthe coating are monitored; the coating process is performed until theaverage preset tablet weight (±5.0 %) is reached, and after the presettablet weight is reached, the process is stopped and the tablets arecooled to a temperature not higher than 33 °C; after the process end, thecontainers are sealed.The resulting pharmaceutical composition, as a dosage form,provides fo r the immediate release profile specified in Table 3.Table 3Embodiment 7.Preparation of a tablet with immediate release of the activeingredient (substance I) based on substance I in the form of ahydrochloride salt (for preparation see Embodiments 3 or 5).An oral pharmaceutical composition representing a film-coatedtablet containing substance I in the form of a hydrochloride salt wasprepared similarly to the procedure described in Embodiment 6. whilethe hydrochloride salt load was recalculated as free base in such amanner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 2.Embodiment 8.Preparation of a tablet with immediate release of the activeingredient (substance I) based on substance I in the form of a tosylatesalt (for preparation see Embodiments 2 or 5).An oral pharmaceutical composition representing a film-coatedtablet containing substance I in the form of a tosylate salt was preparedsimilarly to the procedure described in Embodiment 6, while thetosylate salt load was recalculated as free base in such a manner as toensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 2.Modified release granules are prepared according to thefollowing methods (Embodiments 9-11 and / or 12-14).Embodiment 9.Preparation of granules with modified release of the activeingredient (substance I) based on substance I in a salt-free form (freebase; for preparation see Embodiment 4).Oral pharmaceutical composition representing a capsule containinggranules of substance I in a salt-free form (free base) at a dose of 5 mgper 1 capsule (expressed as base), at a ratio of 5 to 94 % of the totalmass of the mixture, with the following ratio of ingredients per 100 mg,%wt, as provided in Table 4.Table 4Method of preparation of a pharmaceutical compositioncontaining substance I in a salt-free form (free base) as the only activeingredient at a dose of 5 mg per 1 capsule (expressed as base), at a ratioof 5 to 94 % of the total mass of the mixture, during which substance Iin a salt-free form (free base), lactose monohydrate 200, hypromellose(e.g. type 2208), Povidone-K30 are sifted through a 0.25-0.5 mm sieve.Herewith, a capsule contains granules covered with an enteric coatingand a coating providing for delayed release. The ratio of pellets rangesbetween 5 : 90 and 90 : 5.Next, a humidifier solution based on Povidone-K30 is prepared.The product is mixed until completely dissolved (visual control). Acalculated amount of the substance is added to the resulting solution.Substance I in a salt-free form (free base), hypromellose (e.g.type 2208), lactose monohydrate, and corn starch are loaded into themixer. The powder mixture is stirred.Next, the powder mixture is transferred to a fluidized bedgranulation unit. Granules are obtained by spraying a humidifiermixture where substance I in a salt-free form (free base) was previouslydissolved in the fluidized bed.The resulting granulate is calibrated through a 0.25-0.5 mmsieve. Granule fractions over 0.5 mm and below 0.25 mm areconsidered substandard.At the next stage, the resulting granules are covered with anenteric coating. Hypromellose (for example, type 2208) is added topurified water and mixed, then Polysorbate-80 is added. All activitiesare performed at a temperature between 40 and 55 degrees. Then acalculated amount of talc is added, and the product is thoroughly mixedagain for 5-15 minutes. After that, neutral copolymer film coatingbased on ethyl acrylate and methyl methacrylate (e.g. EUDRAGITNM 30 D / NE 30 D) is added, mixed for 5 minutes and filtered through0.5 mm sieves.Next, a coating is applied in the fluidized bed unit. Beforecoating application, the granules are heated to 35-37 °C whileperiodically stirred in the fluidized bed.After the set temperature of the granules is reached, spraying ofthe film coat suspension begins. During this process, the granuleappearance is monitored.Process parameters: product temperature 27-37 °C.After the entire suspension has been consumed, the process isstopped, and the granules are cooled to a temperature not exceeding33 °C. After the process is finished, the containers are sealed.Representative granule samples are taken for intermediate control inline with the specification.Next, technological operations for applying the second type ofcoating onto the granules are performed.An aqueous solution of methacrylic acid and ethyl acrylate, talc,titanium dioxide, iron oxide (yellow), silica, sodium bicarbonate, andsodium lauryl sulphate (e.g. Acryl-EZE) is used. The suspension ismixed to a homogeneous state (visual control).Next, a coating is applied in the fluidized bed unit. Beforecoating application, the granules are heated to 35-37 °C whileperiodically stirred in the fluidized bed.After the set temperature of the granules is reached, spraying ofthe film coat suspension begins. During this process, the pelletappearance is monitored.Process parameters: product temperature 27-37 °C.After the entire suspension has been consumed, the process isstopped, and the granules are cooled to a temperature not exceeding33 °C. After the process is finished, the containers are sealed.Representative granule samples are taken for intermediate control inline with the specification.Then the resulting granules are encapsulated, based on a pelletratio of 5 : 90 to 90 : 5. Herewith, the dose of active ingredient I in1 capsule should be 5 mg.The resulting pharmaceutical composition provides for therelease profile specified in Table 5.Table 5Embodiment 10.Preparation of granules based on substance I in the form of ahydrochloride salt (for preparation see Embodiment 3) with modifiedrelease of the active ingredient (substance I).An oral pharmaceutical composition representing granules forinternal use containing substance I in the form of a hydrochloride saltwas prepared similarly to the procedure described in Embodiment 9,while the hydrochloride salt load was recalculated as free base in sucha manner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 3.Embodiment 11.Preparation of granules based on substance I in the form of atosylate salt (for preparation see Embodiment 2) with modified releaseof the active ingredient (substance I).An oral pharmaceutical composition representing granules forinternal use containing substance I in the form of a tosylate salt wasprepared similarly to the procedure described in Embodiment 9, whilethe hydrochloride salt load was recalculated as free base in such amanner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 5.Granules in the form of modified-release hard gelatin capsulesare prepared in the following manner.Embodiment 12.Preparation of granules in the form of hard gelatin capsules withmodified release of the active ingredient (substance I) based onsubstance I in a salt-free form (free base; for preparation seeEmbodiment 4).Oral pharmaceutical composition consisting of granules in the form ofhard gelatin capsules for internal use containing substance I in a saltfreeform at a dose of 5 mg per 1 dose, at a ratio of 5 to 94 % of the totalmass of the mixture, with the ratio of ingredients per 100 mg, %wt,specified in Table 6.Table 6Description Amount in %Substance I in a salt-free form (free base) 5.0-94.0Lactose monohydrate 200 20.0-65.0Corn starch 10.0-45.0Hypromellose (e.g. type 2208) 1.0-8.5Aqueous solution of methacrylic acid copolymerand ethyl acrylate (1 : 1) (e.g. Vivacoat E) 1.2-10.5Film coating of grafted macrogol copolymer andpolyvinyl alcohol (e.g. Kollicoat IR) 1.5-9.8The method of preparation of a pharmaceutical compositioncontaining substance I in a salt-free form (free base) as the only activeingredient at a dose of 5 mg per 1 dose (expressed as base), at a ratio of5 to 94 % of the total mass of the mixture, during which substance I ina salt-free form (free base), lactose monohydrate 200, hypromellose(e.g. type 2208) are sifted through a 0.25-0.5 mm sieve. The ratio ofgranules in 1 dose per single administration varies between 5 : 90 and90 : 5.Next, a hypromellose-based humidifier solution is prepared.Polymer is swollen in a portion of water (1 / 3), after that the remainingportion (2 / 3) is added with further homogenization using a mechanicalstirrer. A calculated amount of the substance is added to the resultingsolution. The polymer dissolution and swelling quality is evaluatedafter solution preparation (visual control). Lactose monohydrate andcorn starch are loaded into the mixer. The powder mixture is stirred.Next, the powder mixture is transferred to a fluidized bedgranulation unit. Granules are obtained by spraying a humidifiermixture where substance I in a salt-free form (free base) was previouslydissolved in the fluidized bed.The resulting wet granulate is calibrated through a 0.25-0.5 mmsieve. Granule fractions over 0.5 mm and below 0.25 mm areconsidered substandard.At the next stage, the resulting granules are coated with a filmcoating of grafted macrogol copolymer and polyvinyl alcohol (e.g.Kollicoat IR). A calculated amount (1.5-9.8 %) of Kollicoat IR isadded to purified water and mixed for 5 minutes, then filtered through0.5 mm sieves.Next, a coating is applied in the fluidized bed unit. Beforecoating application, the granules are heated to 35-37 °C whileperiodically stirred in the fluidized bed.After the set temperature of the granules is reached, spraying ofthe film coat suspension begins. During this process, the granuleappearance is monitored.Process parameters: product temperature 27-37 °C.After the entire suspension has been consumed, the process isstopped, and the granules are cooled to a temperature not exceeding33 °C. After the process is finished, the containers are sealed.Representative granule samples are taken for intermediate control inline with the specification.Next, technological operations for applying the second type ofcoating onto the granules are performed.An aqueous solution of methacrylic acid copolymer and ethylacrylate (1 : 1) (e.g. Vivacoat E) is used. To prepare polymersuspension, an overhead stirrer is used. A measured amount of water istransferred to a beaker and the stirrer is turned on so that a cone isformed. Then the coating is gradually poured into the formed cone.Stirring is further continued for another 45 minutes. After that, the finalsolution is filtered through a 0.5 mm sieve.Next, a coating is applied in the fluidized bed unit. Beforecoating application, the granules are heated to 35-37 °C whileperiodically stirred in the fluidized bed.After the set temperature of the granules is reached, spraying ofthe film coat suspension begins. During this process, the pelletappearance is monitored.Process parameters: product temperature 27-37 °C.After the entire suspension has been consumed, the process isstopped, and the granules are cooled to a temperature not exceeding33 °C. After the process is finished, the containers are sealed.Representative granule samples are taken for intermediate control inline with the specification.Then the resulting granules are dosed, based on a granule ratio of5 : 90 to 90 : 5. Herewith, the dose of active ingredient I per1 administration should be 5 mg.The resulting pharmaceutical composition provides for therelease profile specified in Table 7.Table 7Embodiment 13.Preparation of granules in the form of hard gelatin capsules basedon substance I in the form of a hydrochloride salt (for preparation seeEmbodiment 3) with modified release of the active ingredient(substance I).An oral pharmaceutical composition representing granules forinternal use containing substance I in the form of a hydrochloride saltwas prepared similarly to the procedure described in Embodiment 12,while the hydrochloride salt load was recalculated as free base in sucha manner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 4.Embodiment 14.Preparation of granules based on substance I in the form of atosylate salt (for preparation see Embodiment 2) with modified releaseof the active ingredient (substance I).An oral pharmaceutical composition representing granules forinternal use containing substance I in the form of a tosylate salt wasprepared similarly to the procedure described in Embodiment 12, whilethe hydrochloride salt load was recalculated as free base in such amanner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 4.Prolonged release pellets are prepared according to the followingmethod.Embodiment 15.Preparation of pellets with prolonged release of the active ingredient(substance I) based on substance I in a salt-free form (free base; forpreparation see Embodiment 4).An oral pharmaceutical composition representing a capsule with pelletscontaining substance I in a salt-free form at a dose of 5 mg per1 capsule, at a ratio of 5 to 94 % of the total mass of the mixture. Theratios are provided in Table 8.Table 8Description Amount in %Substance I in a salt-free form (free base) 5.0-94.0Pellets with a fraction size of 0.25-0.5 mm madeof microcrystalline cellulose / sugar 20.0-90.0Hypromellose (e.g. type 2208) 1.0-8.5Polyvinyl acetate (e.g. Kollicoat SR 30D) 1.8-12.5Method of preparation of a pharmaceutical compositioncontaining substance I in a salt-free form (free base) as the only activeingredient at a dose of 5 mg per 1 capsule, at a ratio of 5 to 94 % of thetotal mass of the mixture, during which substance I in a salt-free form(free base), hypromellose (e.g. type 2208) are sifted through a 0.25-0.5 mm sieve. Herewith, a capsule contains pellets covered with a pH765independent coating.Next, a hypromellose-based humidifier solution is prepared. Thepolymer is swollen in a portion of water (1 / 3), after that the remainingportion (2 / 3) is added with further homogenization using a mechanicalstirrer. A calculated amount of the substance is added to the resultingsolution. The polymer dissolution and swelling quality is evaluatedafter solution preparation (visual control).Next, a calculated amount of pellets with a fraction size of 0.25-0.5 mm (20-90 %) is transferred to the fluidized bed unit for pelletpreparation, and the pellets are heated to 40-45 degrees. Then, amixture of hypromellose with substance I in a salt-free form (free base)is sprayed. The spraying rate is 12-20 g / min. The temperature of theinlet air stream is 60-65 degrees. The spraying process is continueduntil the film-forming solution is depleted. After that, the pellets arefurther dried in a warm air stream for 10-15 minutes. After that, theresulting pellets are discharged.The resulting pellets are calibrated through a 0.25-0.5 mm sieve.Granule fractions over 0.5 mm and below 0.25 mm are consideredsubstandard.Representative pellet samples are taken for intermediate controlin line with the specification.Next, the resulting pellets are encapsulated in such a manner that1 capsule contains 5 mg of the active ingredients.The resulting pharmaceutical composition provides for theprolonged release profile specified in Table 9.Table 9Embodiment 16.Preparation of granules with prolonged release of the activeingredient (substance I) based on substance I in a hydrochloride saltform (for preparation see Embodiment 3).An oral pharmaceutical composition representing granules forinternal use containing substance I in the form of a hydrochloride saltwas prepared similarly to the procedure described in Embodiment 15,while the hydrochloride salt load was recalculated as free base in sucha manner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 5.Embodiment 17.Preparation of pellets with prolonged release of the activeingredient (substance I) based on substance I in a tosylate salt form (forpreparation see Embodiment 2).An oral pharmaceutical composition representing pellets forinternal use containing substance I in the form of a tosylate salt wasprepared similarly to the procedure described in Embodiment 15, whilethe hydrochloride salt load was recalculated as free base in such amanner as to ensure that the dose of substance I (5 mg) was the same.The resulting pharmaceutical composition provides for a releaseprofile similar to that shown in Table 9.Another objective of the invention, consisting in the use of thedeveloped compositions and finished dosage forms as an antihyperglycaemicagent for the prevention and treatment of type 2diabetes, was achieved by studying the effects and indicators during invivo experiments in rats. The ethical rules of humane treatment ofanimals set out in the directives of the Council of the EuropeanCommunity 86 / 609 / EEC were observed.The tests aimed to identify the effects of substance I in a finisheddosage form were performed during in vivo experiments involving thedetermination of the main parameters:- glycosylated haemoglobin (HbA1c) level- glucose level- body weight variationThe glycosylated haemoglobin (HbA1c) and glucose levels, as wellas body weight variations of the animals were evaluated in experimentsusing the composition described in Embodiment 7.The acute toxicity index was evaluated in experiments usingsubstance I in the form of a hydrochloride salt.The technical result of the invention is an anti-hyperglycaemiceffect and positive body weight variation in animals of the selected ratmodels - streptozotocin-induced (STZ) diabetes and glucosechallenge models. Another result consists in low toxicity upon oraladministration (toxicity class 4), obtained in acute toxicity tests in rats.The results obtained are illustrated by the following examples.Embodiment 18.Effect of substance I in the composition described inEmbodiment 7 on a model ofSTZ-induced diabetes in rats.In the experiment on a STZ-induced diabetes model, one type ofanimals was used: white outbred male CD rats.In the course of experiment planning and designing, it was takeninto account that the probability of inducing diabetes in rats using STZis not always equal to 100 %. For this reason, of the 60 male ratsincluded into the experiment, 50 animals received STZ injections, and10 animals constituted a control group (healthy control).Diabetes was induced by a single intraperitoneal streptozotocininjection (60 mg / kg, dissolved in 0.1M sodium citrate buffer). Thecontrol group (healthy control) received injections of equal amounts ofsodium citrate buffer.After streptozotocin injections, the animals were monitored for96 hours. Induced diabetes was confirmed by measuring the bloodglucose levels with an Accu-Check Active glucose meter. Rats with ablood glucose level of more than 15 mM / L were included into the study.Animals with confirmed diabetes were randomized to three groupsby the body weight as a criterion.The test product, being the composition described inEmbodiment 7, was prepared for daily oral administration at thebeginning of the study with 1 % starch solution, in concentrationsproviding for a dose of substance I (expressed as free base) of 5 and20 mg / kg and was administered before noon every day after oral STZinduction, since this the route of administration corresponds to theclinical one. Animals from the diabetic and healthy control groupsreceived 1 % starch solution as placebo.The specific pharmacological activity of substance I in thecomposition was assessed by the glycosylated haemoglobin (HbA1c)level. On the day sixty, scheduled sacrifice was performed with bloodsampling for HbA1c analysis. The glycosylated haemoglobin level inthe groups upon the administration of the composition described inEmbodiment 7 at doses of 5 mg / kg and 20 mg / kg statisticallysignificantly decreased as compared to the control group (diabeticgroup) (Table 10).Table 10 - Glycosylated Haemoglobin Levels in the STZ DiabetesThe blood glucose level of the animals was measured weekly.Starting from day forty-nine, the blood glucose level in theexperimental groups statistically differs from that in the diabetic group(p < 0.05). (Table 11)Table 11 - Blood Glucose Level Variations over Time in Rats withSTZ Diabetes (M ± SD).Body weight variations of the animals were simultaneouslymonitored. Starting from day seven after induction of STZ diabetes, adecrease in the animals' body weight was observed in the experimentalgroups and in the diabetic control group as compared to the healthycontrol group. On day seven of STZ diabetes induction, the animals inall groups fell behind by the weight gain variation over time. On daythirty-five, the animals in the experimental groups gained weight fasteras compared to the diabetic control group (p < 0.05). The positiveweight gain dynamics kept on throughout the study. (Table 12).Table 12 - Body Weight Variations over Time in Rats in the STZDiabetes Model (M ± SD).Embodiment 19.Effect of the product, the composition described inEmbodiment 7, in a glucose challenge model.In the experiment with a glucose challenge model, one type ofanimals was used: white outbred male CD rats.The glucose challenge was induced by oral administration of 5 g ofglucose per rat. Glucose was prepared in 10 % starch solution. Thecontrol group (healthy control) received equal amounts of 10 % starch.After glucose administration, the animals were monitored for4 hours. The glucose level was measured with an Accu-Check Activeglucose meter 0.5, 1, 1.5, 2, 3 and 4 hours after the glucose challenge.The test composition described in Embodiment 7 and the referenceproduct, oral vildagliptin, were prepared at the beginning of the studyin 10 % starch solution, in concentrations providing for a test productdose of 20 mg / kg. The products were administered half an hour beforethe glucose challenge in a volume of 1 mL / animal. Animals in thediabetic and healthy control groups received saline as placebo.The specific pharmacological activity was assessed by the bloodglucose level. Glucose was measured with an Accu-Check Activeglucose meter.Beginning at 30 minutes after the study start, the product, thecomposition described in Embodiment 7, with active substance I at adose of 20 mg / kg, showed a statistically significant reduction of theblood glucose levels as compared to the control. (Table 13).Table 13 - Blood Glucose Levels during Glucose Challenge(M ± SD).In the STZ diabetes model, a dose of 20 mg / kg was more effectivethan 5 mg / kg in terms of blood glucose, body weight and glycosylatedhaemoglobin levels. The glucose levels in the groups upon theadministration of the composition described in Embodiment 7 at dosesof 5 mg / kg and 20 mg / kg statistically significantly decreased ascompared to the control group (diabetic group).In the glucose challenge model, the composition described inEmbodiment 7 showed a higher activity than vildagliptin.In the experiments described in Embodiments 18 and 19 using thecomposition described in Embodiment 7 with active substance I atdoses of 5 and 20 mg / kg, no toxic effect was identified - no deathcases were registered.The toxic effect was additionally investigated in acute toxicitytests with a single administration of large doses of substance I in theform of a hydrochloride salt to rats.Embodiment 20.Single-dose (acute) toxicity study of substance I in the form of ahydrochloride salt.Single-dose toxicity studies are conducted for the purpose ofqualitative and quantitative assessment of toxic reactions occurringafter a single administration (usually oral or intravenous) of a large doseof a substance. Such studies are usually conducted on rodents. Rats arethe preferred species for the study.Single-dose toxicity studies of the product, substance I in the formof a hydrochloride salt, were conducted upon oral administration tooutbred rats of both sexes. The product was administered once orally tooutbred CD rats at doses of 500, 1000 and 2000 mg / kg. In the first hoursafter administration, there were obvious signs of intoxication:decreased muscle tone, decreased spontaneous motor activity,general depression. No deaths were registered (Table 10), it wasimpossible to calculate half-lethal doses, LD50 > 2000 mg / kg.According to the Hodge and Sterner toxicity classification (1943), thedeveloped pharmaceutical composition containing substance I, whenadministered orally to rats, refers to toxicity class 4 (low toxicity).Table 14 - Results of an Acute Toxicity Test on CD Rats (Males andFemales) after a Single Oral Administration of the Test PharmaceuticalComposition as a Medicinal Product, Substance I in the Form of aThe measured biochemical and haematological parameters didnot differ significantly between the experimental and control groupsand varied within the physiological norm (Tables 15 and 16).Table 15 - Mean Haematological Parameters of CD Rats.Control 500 mg / kg 1000 mg / kg 2000 mg / kgMales Females Males Females Males Females Males FemalesTable 16 - Mean Biochemical Parameters of CD Rats.Control 500 mg / kg 1000 mg / kg 2000 mg / kgMales Females Males Females Males Females Males FemalesThus, the objectives of the present invention are solved bydeveloping pharmaceutical compositions and oral finished dosageforms containing inactive excipients and carriers that provide forimmediate and / or prolonged, and / or modified release of the activeingredient, substance I, being a highly efficient dipeptidyl peptidase-4inhibitor, low-toxic (toxicity class 4) and exhibiting active antihyperglycaemiceffects, for the prevention and treatment of type 2diabetes mellitus. Confirmed by embodiments.Industrial ApplicabilityAll the embodiments provided also confirm the industrialapplicability of the invention.List of Abbreviations.DM — diabetes mellitusDPP-4 — dipeptidyl peptidase-4DCM — dichloromethane (methylene chloride)MeOH — methanol EtOH — ethanol 990 CHCl3 — chloroformp-TSA — para-toluenesulfonic acid HCl — hydrogen chloride Et2O — diethyl ether B0C2O — di-tert-butyl bicarbonate TFA — trifluoroacetic acidNaHCO3 — sodium hydrogen carbonate TEA — triethylamine DIPEA — diisopropylethylamine Na2SO4 — sodium sulphateBOP — benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateLC / MS — high performance liquid chromatograph with mass-detection DMSO — dimethyl sulfloxide TFAA — trifluoroacetic anhydride THF — tetrahydrofuranHbA1c — glycosylated haemoglobin

Claims

1. A pharmaceutical composition for the treatment of type 2 diabetes and concomitant conditions, in the pathogenesis wherein the DPP- 4 enzyme is involved, for the prevention or treatment of different disorders, including those associated with body weight disorders in diabetes mellitus, as well as wound healing, cicatrization and diabetic foot, based on the active ingredient, a highly efficient dipeptidyl peptidase-4 inhibitor (substance I), exo-(2S)-3-[(3R)-3- amino-4-(2,4,5-trifluorophenyl)butanoyl]-3- azabicyclo[2.2.1]heptane-2-carbonitrile, containing pharmaceutically acceptable carriers and excipients, while the active ingredient has the following structure:

2. The pharmaceutical composition according to claim 1 is different in that active ingredient I is in the form of a free base or a pharmaceutically acceptable salt form.

3. The pharmaceutical composition according to claims 1, 2 is different in that the salt forms of active ingredient I represent salts with inorganic acids - hydrochloric acid - hydrochloride, or hydrobromic acid, or nitric acid, or sulfuric acid, or phosphoric acid; or organic acids and their derivatives from sulfo-, or alkyloxy- , or hydroxy-, or oxo-substituted acids - formic acid, or acetic acid, or fumaric acid, or oxalic acid, or tartaric acid, or maleic acid, or citric acid, or succinic acid, or malic acid, or methanesulfonic acid, or trifluoromethanesulfonic acid, or benzenesulfonic acid, or paratoluenesulfonic acid (tosylate), or naphthylsulfonic acid, or sulfosalicylic acid, or lactic acid, or racemic acid, or adipic acid, or gluconic acid, or glucogeptonic acid, or glucuronic acid, or terephthalic acid, or hippuric acid, or 1,2-ethanedisulfonic acid, or isethionic acid, or lactobionic acid, or oleic acid, or pamoic acid, or polygalacturonic acid, or stearic acid, or tannic acid; or amino acids from among all known natural amino acids - glycine, or alanine, or valine, or leucine, or isoleucine, or proline, or cysteine, or methionine, or phenylalanine, or tryptophan, or serine, or threonine, or glutamine, or tyrosine, or asparagine, or histidine, or lysine, or arginine, or asparaginic acid, or asparaginic acid.

4. The pharmaceutical composition according to claim 1 is different in that the quantity of the active ingredient per unit dose of the drug is from 1mg to 50mg, preferably 5mg.

5. The pharmaceutical composition according to claim 1 is different in that for oral administration it represents one of the following dosage forms: tablets, capsules containing granules and / or pellets.

6. The pharmaceutical composition according to claim 1 is different in that it additionally contains pharmaceutically acceptable excipients that provide for immediate and / or prolonged, and / or modified release of the active ingredient.

7. The pharmaceutical composition according to claims 1, 6 is different in that it pharmacologically acceptable carriers, binders, lubricants, coating substances, aqueous solvent, solubilising substances are used as excipient substances.

8. The pharmaceutical composition according to claims 1, 6, 7 is different in that microcrystalline cellulose, low-substituted cellulose 2-hydroxypropyl ether, type LH-21, lactose, monohydrate 200, corn starch, hypromellose, pellets with a fraction size of 0.25- 0.5mm made of microcrystalline cellulose / sugar are used as carriers.

9. The pharmaceutical composition according to claims 1, 6, 7 is different in that microcrystalline cellulose, low-substituted cellulose 2-hydroxypropyl ether, type LH-21, povidone K30 are used as binders.

10. The pharmaceutical composition according to claims 1, 6, 7 is different in that magnesium stearate, talc are used as lubricants.

11. The pharmaceutical composition according to claims 1, 6, 7 is different in that a mixture of coating components with the following composition: hypromellose, titanium dioxide, polydextrose, talc, polyethylene glycol; aqueous solution of methacrylic acid and ethyl acrylate, talc, titanium dioxide, iron oxide (yellow), silicon dioxide, sodium bicarbonate and sodium lauryl sulphate, film coating of neutral copolymer based on ethyl acrylate and methyl methacrylate, aqueous solution of methacrylic acid copolymer and ethyl acrylate (1:1), film coating of macrogol polyvinyl alcohol grafted copolymer, polyvinyl acetate are used as coating substances.

12. The pharmaceutical composition according to claims 1, 6, 7 is different in that purified water is used as a solvent.

13. The pharmaceutical composition according to claims 1, 6, 7 is different in that Tween 80 is used as a solubilising substance.