RU2742418C1 - Dosage forms containing teneligliptin oxalate salts and solvates thereof - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions refers to a pharmaceutical composition for preventive or radical treatment of diabetes mellitus containing n.hydrate 2,5 teneligliptin oxalate or n.hydrate 3,0 teneligliptin oxalate, having a concentration in range of 0.5 wt % to 80 wt %, 10 wt% to 95 wt % of at least one pharmaceutically acceptable diluent, 0.1 wt % to 10 wt % binding substances, from 0.1 wt % to 20 wt % of lubricants, from 0.1 wt % to 30 wt % disintegrating agents and optionally from 0.05 wt % to 30 wt % stabilizing agents. Group of inventions also relates to a method of producing said pharmaceutical composition comprising steps of sieving, granulating, drying and screening the granulate, lubricating the sieved granulate and pressing the mixture to obtain a tablet or filling the mixture of capsules.

EFFECT: group of inventions provides stable pharmaceutical compositions of teneligliptin.

6 cl, 7 dwg, 26 tbl, 6 ex

Description

FIELD OF TECHNOLOGY

[001] This invention relates to pharmaceutically acceptable dosage forms containing oxalate salts of teneliglyptin and their solvates, optionally further containing molecules of the biguanide class. This document also proposes the use of these dosage forms and the treatment of impaired glucose metabolism in patients in need thereof.

LEVEL OF TECHNOLOGY

[002] Dipeptidyl peptidase-4 (DPP-IV) inhibitors are a class of antidiabetic drugs that act by inhibiting the degradation of incretins, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropan peptide (GIP). These compounds are collectively referred to as "gliptins".

[003] DPP-IV inhibitors are widely used in combination therapy with other antidiabetic drugs.

[004] There is a need in the art to provide new and stable dosage forms that are inherently effective and exhibit improved stability and processability.

BRIEF DESCRIPTION OF THE INVENTION

[005] In one embodiment, the present invention provides pharmaceutical compositions comprising oxalate salts of a compound of Formula (I) and their solvates, and at least one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, disintegrants and stabilizing agents. In one aspect of this embodiment, the diluent is selected from the group consisting of mannitol, sorbitol, xylitol, starch, lactose, cellulose, calcium dihydrogen phosphate and the like, preferably mannitol or lactose. In another aspect, the binder is selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose, hypromellose, and the like, preferably hypromellose or hydroxypropyl cellulose. In another aspect of this embodiment, the lubricant is glyceryl dibehenate, sodium or calcium stearyl fumarate, magnesium stearate, stearic acid, glyceryl palmitostearate and the like, preferably glyceryl dibehenate. In another aspect of this embodiment, the disintegrant is selected from the group consisting of low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, and the like, preferably low substituted hydroxypropyl cellulose. In another aspect of this embodiment, the stabilizing agent is selected from at least one stabilizer; at least one complexing agent; at least one polymer; at least one chelating agent; and their combinations.

[006] In one aspect of this embodiment, the present invention provides a pharmaceutical composition in which

(a) the oxalate salt of compound (I) and its solvate is selected from 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and their solvates

(b) the diluent is selected from mannitol or lactose

(c) the binder is selected from hydroxypropyl cellulose or hypromellose

(d) the lubricant is selected from glyceryl dibehenate or magnesium stearate

(e) the disintegrant is selected from hydroxypropyl cellulose with a low degree of substitution, crospovidone, croscarmellose sodium

(f) the stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropylcellulose, EDTA, and combinations thereof.

[007] In one or more aspects of this embodiment, there is provided a pharmaceutical composition comprising

(a) an oxalate salt of compound (I) and its solvate, which is n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0

(b) mannitol diluent

(c) binder, which is hypromellose

(d) glyceryl dibehenate lubricant

(e) a disintegrant which is a low substituted hydroxypropyl cellulose

(f) the stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropylcellulose, EDTA, and combinations thereof.

[008] In one or more aspects of this embodiment, there is provided a pharmaceutical composition comprising

(a) the oxalate salt of compound (I) and its solvate, which is n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0

(b) a lactose diluent

(c) binder, which is hypromellose

(d) glyceryl dibehenate lubricant

(e) a disintegrant which is a low substituted hydroxypropyl cellulose

(f) the stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropylcellulose, EDTA, and combinations thereof.

[009] In one embodiment, the present invention provides pharmaceutical compositions comprising from about 0.5% to about 80.0% by weight of the oxalate salt of compound (I) and its solvate, from about 10% to about 95% by weight of a diluent, from about 0.1% to about 10.0% by weight of a binder, from about 0.1% to about 20.0% by weight of a lubricant, from about 0.1% to about 30% by weight of a disintegrant and from about 0.05% to about 30% by weight of the stabilizing agent. In one aspect, the oxalate salt of compound (I) and its solvate is 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and their solvate. In another aspect of this embodiment, the solvate is n. hydrate. In another aspect of this embodiment, the oxalate salt of compound (I) and its solvate is n. hydrate of 2.5 teneliglyptin oxalate or n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0.

[0010] In one embodiment, the present invention provides pharmaceutical compositions containing from about 5% to about 40.0% by weight of the oxalate salt of compound (I) and its solvate, from about 15% to about 95% by weight of a diluent, from about 0.1% to about 10% by weight of binder, from about 0.1% to about 20.0% by weight of lubricant, from about 0.1% to about 30% by weight of disintegrant and from about 0.1% up to about 20% by weight of the stabilizing agent. In one aspect, the oxalate salt of compound (I) and its solvate is 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and their solvate. In another aspect of this embodiment, the solvate is n. hydrate. In another aspect of this embodiment, the oxalate salt of compound (I) and its solvate is n. hydrate of 2.5 teneliglyptin oxalate or n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0.

[0011] In one embodiment, the present invention provides pharmaceutical compositions containing from about 5% to about 40.0% by weight of the oxalate salt of compound (I) and its solvate, from about 30% to about 80% by weight of a diluent, from about 0.1% to about 10% by weight of binder, from about 0.1% to about 20.0% by weight of lubricant, from about 0.1% to about 30% by weight of disintegrant and from about 0.1% up to about 20% by weight of the stabilizing agent. In one aspect, the oxalate salt of compound (I) and its solvate is 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and their solvate. In another aspect of this embodiment, the solvate is n. hydrate. In another aspect of this embodiment, the oxalate salt of compound (I) and its solvate is n. hydrate of 2.5 teneliglyptin oxalate or n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0.

[0012] In one embodiment, the invention provides pharmaceutical compositions comprising from about 5% to about 15.0% by weight n. teneliglyptin oxalate hydrate 3.0% to about 80% by weight of diluent, from about 0.1% to about 10% by weight of binder, from about 1.0% to about 15.0% by weight of lubricant , from about 1.0% to about 20% by weight of the disintegrant and from about 0.5% to about 15% by weight of the stabilizing agent.

[0013] In one embodiment, the present invention provides pharmaceutical compositions containing from about 0.5% to about 10.0% by weight n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, from about 5% to about 40% by weight of the diluent, from about 0.1% to about 10% by weight of the binder, from about 0, 5% to about 5.0% by weight of a lubricant, from about 0.5% to about 10% by weight of a disintegrant, and from about 0.1% to about 10% by weight of a stabilizing agent and one or more antidiabetic agents.

[0014] In one aspect, one or more antidiabetic agents contained in the pharmaceutical composition of this invention are selected from the group consisting of sulfonylurea class compounds and salts thereof, glitazone class compounds and their salts, biguanidine class compounds and salts thereof, inhibitor class compounds alpha-glucosidases and their salts, compounds of the SGLT2 inhibitor class and their salts, and combinations thereof. In one aspect

[0015] In one embodiment of the present invention, the pharmaceutical compositions comprise a stabilizing agent that is oxalic acid present in an amount of about 0.5% to about 5.0% by weight.

[0016] In one embodiment of the present invention, the pharmaceutical compositions comprise a stabilizing agent that is beta-cyclodextrin, contained in an amount of about 0.5% to about 5.0% by weight.

[0017] In one embodiment of the present invention, the pharmaceutical compositions comprise a stabilizing agent that is hydroxypropyl cellulose contained in an amount of from about 0.1% to about 5.0% by weight.

[0018] In one embodiment of the present invention, the pharmaceutical compositions comprise a stabilizing agent that is EDTA present in an amount of from about 0.5% to about 5.0% by weight.

[0019] In one embodiment, the oxalate salts of a compound of Formula (I) in a pharmaceutical composition of this invention are n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, characterized by an X-ray powder diffraction pattern containing reflection peaks at 5.68 °, 6.56 °, 16.44 °, 17.72 °, 18 , 34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2Θ.

[0020] In one embodiment, the oxalate salts of a compound of Formula (I) in a pharmaceutical composition of this invention are n. teneliglyptin oxalate hydrate 3.0, where n is 1.0 to 4.0, characterized by an X-ray powder diffraction pattern containing reflection peaks at 5.69 °, 6.57 °, 16.43 °, 17.71 °, 21 , 66 °, 23.15 °, 23.86 °, 24.99 ° ± 2Θ.

[0021] In one embodiment, the present invention provides pharmaceutical compositions comprising oxalate salts of a compound of Formula (I).

[0022] In one aspect of the present invention, the pharmaceutical compositions of said oxalate salts of a compound of Formula (I) and their solvates contained in the pharmaceutical composition of the present invention are substantially pure.

[0023] In one embodiment of this invention, there is provided a pharmaceutical composition comprising an oxalate salt of a compound of formula (I)

[0024] and a solvate thereof; and at least one or more antidiabetic agents selected from the group consisting of compounds of the sulfonylurea class and their salts, compounds of the class of glitazone and their salts, compounds of the class of biguanide and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of inhibitors SGLT2 and their salts, and combinations thereof. In one aspect of this embodiment, the pharmaceutical compositions comprise compounds of the sulfonylurea class, which includes glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide, and the like. In another aspect of this embodiment, the pharmaceutical compositions comprise compounds of the glitazone class, which includes pioglitazone, rosiglitazone, and the like. In another aspect of this embodiment, the pharmaceutical compositions comprise compounds of the biguanide class, which includes metformin, buformin, phenformin, and the like. or a pharmaceutically acceptable salt thereof. In another aspect of this embodiment, the pharmaceutical compositions comprise compounds of the alpha-glucosidase inhibitor class, which includes woglibose, acarbose, miglitol, and the like. In another aspect of this embodiment, the pharmaceutical compositions comprise compounds of the SGLT2 inhibitor class, which includes remogliflozin, dapagliflozin, canagliflozin, empagliflozin, luseogliflozin, and the like, salts, esters or solvates thereof.

[0025] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising teneliglyptin oxalate ptydrate 2.5, where n is 1.0 to 4.0, preferably 1.0, and sustained release metformin, with w / w. ratio n. hydrate of 2.5 teneliglyptin oxalate to metformin is in the range of 1: 10-1: 50.

[0026] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising n. hydrate of 3.0 oxalate teneliglyptin, where n is from 1.0 to 4.0, preferably 1.0, and metformin, and wt./wt. ratio n. hydrate of 3.0 teneliglyptin oxalate to metformin is in the range of 1: 10-1: 50.

[0027] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising a mixture of n. hydrate of 2.5 teneliglyptin oxalate and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; and metformin, and w / w. the ratio of this mixture to metformin is in the range of 1: 10-1: 50.

[0028] In one embodiment, the invention provides pharmaceutical compositions comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said oxalate salt having a purity of at least 99% and a compound of formula (II) of less than 1.0% ...

[0029] In one aspect, the present invention provides pharmaceutical compositions comprising: (i) at least one of (a) oxalate salts of a compound of Formula (I) and solvates thereof; (b) n. hydrate of 2.5 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; (c) 3.0 teneliglyptin oxalate, where n is 1.0 to 4.0, preferably 1.0; (ii) at least one or more antidiabetic agents selected from the group consisting of compounds of the sulfonylurea class and their salts, compounds of the class of glitazone and their salts, compounds of the class of biguanide and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds the class of SGLT2 inhibitors and their salts, and combinations thereof; and (iii) at least one or more pharmaceutically acceptable carriers, diluents and excipients.

[0030] In another aspect of this invention, there are provided pharmaceutical compositions comprising (i) oxalate salts of a compound of Formula (I) and their solvates; or (ii) n. hydrate 2.5 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; or (iii) n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; or (iv) n. hydrate of 2.5 teneliglyptin oxalate and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; or (v) any of paragraphs. (i) - (iv) and at least one or more antidiabetic agents selected from the group consisting of compounds of the sulfonylurea class and their salts, compounds of the class of glitazone and their salts, compounds of the class of biguanide and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and their combinations, for use in the prophylactic or radical treatment of impaired glucose metabolism in a patient.

[0031] In another aspect of the present invention, there is provided a method of prophylactic or radical treatment of a patient with impaired glucose metabolism, comprising administering a physiologically relevant amount of pharmaceutical compositions comprising (i) oxalate salts of a compound of Formula (I) and their solvates; or (ii) n. hydrate 2.5 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; or (iii) n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; or (iv) n. hydrate of 2.5 teneligliptin oxalate and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0; or (v) any of paragraphs. (i) - (iv) and at least one or more antidiabetic agents selected from the group consisting of compounds of the sulfonylurea class and their salts, compounds of the class of glitazone and their salts, compounds of the class of biguanide and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and combinations thereof.

[0032] the Summary of the invention is not intended to identify the essential features of the claimed subject matter, nor is it intended to be used in defining or limiting the scope of the claimed subject matter.

OBJECTIVES OF THE INVENTION

[0033] An object of this invention is to provide pharmaceutically acceptable dosage forms containing teneliglyptin oxalate salts and their solvates with excellent processability.

[0034] An object of the present invention is to provide pharmaceutically acceptable dosage forms containing teneliglyptin oxalate salts and their solvates with excellent stability.

[0035] Another object of this invention is to provide pharmaceutically acceptable dosage forms containing teneliglyptin oxalate salts and their solvates and at least one or more antidiabetic agents selected from the group consisting of sulfonylurea class compounds and their salts, glitazone class compounds and their salts, compounds of the biguanide class and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and combinations thereof, with excellent characteristics such as processability and stability.

[0036] Another object of this invention is to provide pharmaceutically acceptable dosage forms containing oxalate salts of teneligliptin and their solvates, optionally additionally containing at least one or more antidiabetic agents selected from the group consisting of compounds of the sulfonylurea class and their salts, compounds of the class glitazone and their salts, compounds of the biguanide class and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and their combinations, suitable for the treatment or control of the development of disorders of glucose metabolism in patients.

BRIEF DESCRIPTION OF ACCOMPANYING GRAPHIC MATERIALS

[0037] The following drawings form part of this specification and are included to further illustrate aspects of the invention. The invention may be better understood by reference to these drawings in combination with the detailed description of the embodiments presented herein.

[0038] FIG. 1 shows an X-ray powder diffraction diagram of crystalline n. hydrate of 2.5 oxalate teneligliptin, in accordance with one of the variants of implementation of the present invention.

[0039] FIG. 2 shows a differential scanning calorimetry thermogram of crystalline n. hydrate of 2.5 oxalate teneligliptin, in accordance with one of the variants of implementation of the present invention.

[0040] FIG. 3 shows the FTIR spectrum of crystalline n. hydrate of 2.5 oxalate teneligliptin, in accordance with one of the variants of implementation of the present invention.

[0041] FIG. 4 shows an X-ray powder diffraction diagram of crystalline n. hydrate of 3.0 oxalate teneligliptin, in accordance with one embodiment of the present invention.

[0042] FIG. 5A-B depict a differential scanning calorimetry thermogram of crystalline n. hydrate of 3.0 oxalate teneligliptin, in accordance with one embodiment of the present invention.

[0043] FIG. 6 shows the FTIR spectrum of crystalline n. hydrate of 3.0 oxalate teneligliptin, in accordance with one embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0044] Those skilled in the art will appreciate that the invention described herein is subject to changes and modifications other than those specifically described. It should be understood that the invention described herein includes all such changes and modifications. This invention also includes all steps, characteristics, compositions and methods mentioned or specified in this description, separately or in combination, and any and all combinations of any two or more of the specified steps or characteristics.

Definitions

[0045] For convenience, before further describing the present invention, some terms used in the description and examples are collected here. These definitions are to be read in light of the rest of the description and understood as understood by those skilled in the art. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as commonly understood by those of ordinary skill in the art. The terms used in this description are defined as follows, unless otherwise limited in specific cases.

[0046] The following is a definition of terms used in this document. If the definition in this application and the definition later in the claim of priority of the ordinary application based on this provisional application contradict, then in determining the meaning of the terms, the definition given in the ordinary application should be guided.

[0047] The term "solvate" means an aggregate consisting of an ion or a molecule of a solute and one or more molecules of a solvent. The solvates can be, but are not limited to, acetone solvate, ethanol solvate, methanol solvate, butanol solvate, TBA solvate, chloroform solvate, and other organic and inorganic solvates.

[0048] The term "hydrate" means a compound, usually crystalline, in which one or more water molecules are chemically bonded to another compound or molecule or element.

[0049] Throughout this specification and claims, the singular includes a reference to the plural, unless the context clearly indicates otherwise.

[0050] This description is not limited to the scope of specific implementations described herein, which are intended only for purposes of illustration.

[0051] The term "salt" or "pharmaceutically acceptable salt" in this context means salts that are medically suitable for use in contact with human and lower animal tissues without undue toxicity, irritation and allergic reaction, commensurate with a reasonable benefit / risk, and effective for the intended use.

[0052] The term "crystalline" in this context means having a repetitive arrangement of molecules or surfaces of the outer surfaces.

[0053] The term "amorphous" in this context means substantially free of repetitive arrangement of molecules or planes of the outer surfaces.

[0054] Unless otherwise indicated, the percentages given in this description are percent weight / weight (w / w).

[0055] The term "stabilizing agents" in this context means a pharmaceutically acceptable excipient that stabilizes a pharmaceutical composition and limits or prevents chemical degradation of the active pharmaceutical ingredient contained in said composition.

[0056] The term "therapeutically effective amount" means an amount of an oxalate salt of a compound of Formula (I) or a solvate thereof that induces a biological response in a patient's tissue

[0057] The term "prophylactic" in the context of treatment means an amount of an oxalate salt of a compound of Formula (I) or a solvate thereof that prevents or reduces the likelihood of a patient having a glucose metabolism disorder or clinical symptoms of a glucose metabolism disorder in a patient.

[0058] The term "radical" in the context of treatment means an amount of an oxalate salt of a compound of Formula (I) or a solvate thereof that treats or inhibits the development of a glucose metabolic disorder in a patient.

[0059] The term "metformin" in this context, unless otherwise indicated, means metformin, a pharmaceutically acceptable salt or hydrate thereof.

[0060] The term "excipients" refers generally to substances other than pharmaceutically active ingredients that are involved in the manufacturing process or are contained in the finished dosage form of a pharmaceutical product.

[0061] The term "carriers" refers generally to any substance or substrate used in a drug delivery process that serves to improve the selectivity, efficacy, and / or safety of drug administration.

[0062] The term "impaired glucose metabolism" includes various metabolic disorders involving glucose in humans, such as diabetes mellitus, hyperglycemia, hypoglycemia, glycosuria, and the like. In addition, diabetes mellitus includes type I and type II diabetes.

[0063] The term "diluents" refers generally to fillers / diluents that can be used to increase bulk volume or improve flow characteristics.

[0064] 3 - {(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine, also known as teneligliptin, is represented by Formula (I), and is interchangeably referred to herein as teneligliptin or a compound of Formula (I).

[0065] In one embodiment, the present invention provides pharmaceutical compositions containing oxalate salts of a compound of Formula (I).

or a solvate thereof and at least one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, disintegrants and stabilizing agents. In one embodiment, said solvate is preferably n. hydrate, where n is from 1.0 to 4.0. In a preferred embodiment, n is 1.0. In one aspect of this embodiment, the diluent is selected from the group consisting of mannitol, sorbitol, xylitol, starch, lactose, cellulose, calcium dihydrogen phosphate and the like, preferably mannitol or lactose In another aspect, the binder is selected from the group consisting of hydroxypropyl cellulose , polyvinyl alcohol, povidone, copovidone, ethylcellulose, hypromellose and the like, preferably hypromellose or hydroxypropylcellulose. In another aspect of this embodiment, the lubricant is glyceryl dibehenate, sodium or calcium stearyl fumarate, magnesium stearate, stearic acid, glyceryl palmitostearate and the like, preferably glyceryl dibehenate. In another aspect of this embodiment, the disintegrant is selected from the group consisting of low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, and the like, preferably low substituted hydroxypropyl cellulose. In another aspect of this embodiment, the stabilizing agent is selected from at least one stabilizer; at least one complexing agent; at least one polymer; at least one chelating agent; and their combinations.

[0066] In one embodiment, the pharmaceutical composition comprises n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition comprises 1.0 hydrate of 2.5 teneliglyptin oxalate.

[0067] In another embodiment, the pharmaceutical composition comprises n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition comprises 1.0 hydrate of 3.0 teneliglyptin oxalate.

[0068] In another embodiment, the pharmaceutical composition comprises n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition is teniliglyptin oxalate monohydrate 2.5 and teniligliptin oxalate monohydrate 3.0.

[0069] In one embodiment, the solvated teneliglyptin oxalate salt contained in the pharmaceutical composition is 10-100% pure. In another embodiment, the purity is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another implementation, the purity is 50-100%. In another embodiment, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another implementation, the purity is 80-100%. In another implementation, the purity is 90-100%. In a preferred embodiment, the purity is greater than 99%. In a more preferred embodiment, the purity is greater than 99.5%. In one embodiment, the solvated teneliglyptin oxalate salt contained in the pharmaceutical composition is substantially pure.

[0070] In one embodiment, n. teneliglyptin oxalate hydrate 2.5, where n is from 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical composition has a purity of 10-100%. In another embodiment, the purity is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another implementation, the purity is 50-100%. In another implementation, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another implementation, the purity is 80-100%. In another implementation, the purity is 90-100%. In a preferred embodiment, the purity is greater than 99%. In a more preferred embodiment, the purity is greater than 99.5%. In one embodiment, n. teneligliptin oxalate hydrate 2.5, where n is 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical composition is substantially pure.

[0071] In one embodiment, n. hydrate 3.0 of teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical composition has a purity of 10-100%. In another embodiment, the purity is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another implementation, the purity is 50-100%. In another embodiment, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another implementation, the purity is 80-100%. In another implementation, the purity is 90-100%. In a preferred embodiment, the purity is greater than 99%. In a more preferred embodiment, the purity is greater than 99.5%. In one embodiment, the teneliglyptin oxalate agidrate 3.0, wherein n is 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical composition is substantially pure.

[0072] n. Teneliglyptin oxalate hydrate 2.5, where n is from 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical compositions described herein exists in crystalline form.

[0073] n. A hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical compositions described herein exists in crystalline form.

[0074] n. Teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical compositions described herein exists in amorphous form.

[0075] n. A hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0, contained in the pharmaceutical compositions described herein exists in amorphous form.

[0076] In one embodiment, the present invention provides pharmaceutical compositions described herein, in which n. teneliglyptin oxalate hydrate 2.5, where n is from 1.0 to 4.0, preferably 1.0, characterized by an X-ray powder diffraction pattern containing reflection peaks at 5.68 °, 6.56 °, 16.44 °, 17 , 72 °, 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2 °, and has the X-ray powder diffraction pattern shown in FIG. one.

[0077] In one embodiment, the invention provides pharmaceutical compositions described herein, wherein n. teneliglyptin oxalate hydrate 2.5, where n is from 1.0 to 4.0, preferably 1.0, is characterized by a differential scanning calorimetry (DSC) thermogram with endotherm at 152.76 ° C and 169.68 ° C, and the curve shown The DSC in FIG. 2.

[0078] In one embodiment, the present invention provides pharmaceutical compositions described herein, in which n. teneliglyptin oxalate hydrate 2.5, where n is from 1.0 to 4.0, preferably 1.0, characterized by infrared absorption (IR) peaks at 3452.22, 3011.77, 2540.88, 1721.37, 1650, 04, 1207.43, 922.34, 708.96, 477.35 cm ^-1 and shown in FIG. 3.

[0079] In one embodiment, the present invention provides pharmaceutical compositions described herein, in which n. teneliglyptin oxalate hydrate 3.0, where n is 1.0 to 4.0, preferably 1.0, characterized by an X-ray powder diffraction pattern containing reflection peaks at 5.69 °, 6.57 °, 16.43 °, 17 , 71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2 °, and has the X-ray powder diffraction pattern shown in FIG. 4.

[0080] In one embodiment, the present invention provides pharmaceutical compositions described herein, in which n. teneligliptin oxalate hydrate 3.0, where n is 1.0 to 4.0, preferably 1.0, is characterized by a differential scanning calorimetry (DSC) thermogram with endotherm at 177.34 ° C. and represented by the DSC curve in FIG. 5A and at 171.6 ° C as shown in FIG. 5B.

[0081] In one embodiment, the present invention provides pharmaceutical compositions described herein, in which n. hydrate of teneliglyptin oxalate 3.0, where n is from 1.0 to 4.0, preferably 1.0, characterized by infrared absorption (IR) peaks at 3464.93, 3011.34, 2537.55, 1911.30, 1720, 10, 1651.64, 1456.82, 1363.34, 1209.29, 922.88, 709.74, 475.21 cm ^-1 , and presented in FIG. 6.

[0082] In one embodiment, pharmaceutical compositions are provided comprising n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, and at least one or more pharmaceutically acceptable carriers, diluents and excipients. In one preferred embodiment, n is 1.0.

[0083] In one specific embodiment, pharmaceutical compositions are provided comprising n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, and the specified salt exists in crystalline or amorphous form.

[0084] In one embodiment, pharmaceutical compositions are provided comprising n. teneliglyptin oxalate hydrate 3.0, where n is 1.0 to 4.0, characterized by an X-ray powder diffraction pattern containing reflection peaks at 5.69 °, 6.57 °, 16.43 °, 17.71 °, 21 , 66 °, 23.15 °, 23.86 °, 24.99 ° ± 2 °, and having the X-ray powder diffraction pattern shown in FIG. 4.

[0085] In another embodiment, pharmaceutical compositions are provided comprising n. a hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, which is substantially pure.

[0086] In one embodiment, the present invention provides pharmaceutical compositions comprising n. hydrate of 2.5 teneligliptin oxalate and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, and at least one or more pharmaceutically acceptable carriers, diluents and excipients. In a preferred aspect of this embodiment, n is 1.0. In a preferred aspect of this embodiment, n. hydrate of 2.5 teneligliptin oxalate and n. teneligliptin oxalate hydrate 3.0 are substantially pure.

[0087] In one embodiment, the present invention provides pharmaceutical compositions comprising oxalate salts of a compound of Formula (I) that comprise

a. at least one stabilizer;

b. at least one complexing agent;

c. at least one polymer;

d. at least one chelating agent; and

e. their combinations.

[0088] In a preferred embodiment, said pharmaceutical compositions further comprise at least one stabilizer, which is a pharmaceutically acceptable organic acid selected from the group consisting of oxalic acid, citric acid, tartaric acid. In a more preferred embodiment, the stabilizer is oxalic acid.

[0089] In a preferred embodiment, said pharmaceutical compositions further comprise at least one complexing agent selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, their derivatives and their combinations.

[0090] In a more preferred embodiment, the complexing agent is hydroxypropyl beta-cyclodextrin.

[0091] In a preferred embodiment, said pharmaceutical compositions further comprise at least one polymer selected from the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, and combinations thereof. In a more preferred embodiment, said polymer is hydroxypropyl cellulose.

[0092] In one embodiment, said pharmaceutical compositions further comprise at least one chelating agent selected from the group consisting of ETDC, zinc sulfate, iron (II) ascorbate, calcium carbonate, sodium chloride, potassium chloride, and combinations thereof. In a more preferred embodiment, the chelating agent is EDTA.

[0093] In one embodiment, said pharmaceutical compositions further comprise a stabilizer and at least one polymer. The specified stabilizer is oxalic acid. Said polymer is selected from the bottom of the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose and combinations thereof, preferably hydroxypropyl cellulose.

[0094] In a preferred embodiment, said pharmaceutical compositions further comprise at least one stabilizer, at least one polymer, and at least one complexing agent. In one embodiment, said stabilizer is oxalic acid. In another embodiment, said polymer is selected from the bottom of the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, and combinations thereof, preferably hydroxypropyl cellulose. In one embodiment, said complexing agent is selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and combinations thereof, preferably hydroxypropyl-beta-cyclodextrin.

[0095] In a preferred embodiment, the pharmaceutical compositions of this invention further comprise at least one polymer and at least one chelating agent. In one embodiment, said polymer is selected from the bottom of the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, and combinations thereof, preferably hydroxypropyl cellulose. In another embodiment, said chelating agent is selected from the group consisting of ETDA, zinc sulfate, iron (II) ascorbate, calcium carbonate, sodium chloride, potassium chloride, and combinations thereof, preferably EDTA.

[0096] In one embodiment, the present invention provides pharmaceutical compositions comprising

(a) oxalate salt of compound (I) and its solvate selected from 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and their solvates

(b) a diluent selected from mannitol or lactose

(c) a binder selected from hydroxypropyl cellulose or hypromellose

(d) a lubricant selected from glyceryl dibehenate or magnesium stearate

(e) a disintegrant selected from low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium

[0097] In one embodiment, the invention provides pharmaceutical compositions comprising

(a) an oxalate salt of compound (I) and its solvate, which is n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0

(b) mannitol diluent

(c) binder, which is hypromellose

(d) glyceryl dibehenate lubricant

(e) a disintegrant which is a low substituted hydroxypropyl cellulose

(f) a stabilizing agent selected from oxalic acid, beta-cyclodextrin, hydroxypropylcellulose, EDTA, and combinations thereof.

[0098] In one embodiment, the invention provides pharmaceutical compositions comprising

(a) an oxalate salt of compound (I) and its solvate, which is n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0

(b) a lactose diluent

(c) binder, which is hypromellose

(d) glyceryl dibehenate lubricant

(e) a disintegrant which is a low substituted hydroxypropyl cellulose

(f) a stabilizing agent selected from oxalic acid, beta-cyclodextrin, hydroxypropylcellulose, EDTA, and combinations thereof.

[0099] In one embodiment, the present invention provides pharmaceutical compositions comprising from about 0.5% to about 80.0% by weight of the oxalate salt of compound (I) and its solvate, from about 10% to about 95% by weight of a diluent, from about 0.1% to about 10.0% by weight of a binder, from about 0.1% to about 20.0% by weight of a lubricant, from about 0.1% to about 30% by weight of a disintegrant and from about 0.05% to about 30% by weight of the stabilizing agent.

[00100] In one embodiment, the present invention provides pharmaceutical compositions comprising from about 5% to about 40.0% by weight of the oxalate salt of compound (I) and its solvate, from about 15% to about 95% by weight of a diluent, from about 0.1% to about 10% by weight of binder, from about 0.1% to about 20.0% by weight of lubricant, from about 0.1% to about 30% by weight of disintegrant and from about 0.1% up to about 20% by weight of the stabilizing agent.

[00101] In one embodiment, the present invention provides pharmaceutical compositions comprising from about 5% to about 40.0% by weight of the oxalate salt of compound (I) and its solvate, from about 30% to about 80% by weight of a diluent, from about 0.1% to about 10% by weight of binder, from about 0.1% to about 20.0% by weight of lubricant, from about 0.1% to about 30% by weight of disintegrant and from about 0.1% up to about 20% by weight of the stabilizing agent.

[00102] In one embodiment, the present invention provides pharmaceutical compositions containing from about 5% to about 15.0% by weight of n. teneliglyptin oxalate hydrate 3.0% to about 80% by weight of diluent, from about 0.1% to about 10% by weight of binder, from about 1.0% to about 15.0% by weight of lubricant , from about 1.0% to about 20% by weight of the disintegrant and from about 0.5% to about 15% by weight of the stabilizing agent. In one aspect of this embodiment, n. teneliglyptin oxalate hydrate 3.0 is crystalline n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0.

[00103] In one embodiment, the present invention provides pharmaceutical compositions containing from about 0.5% to about 10.0% by weight of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, from about 5% to about 40% by weight of the diluent, from about 0.1% to about 10% by weight of the binder, from about 0, 5% to about 5.0% by weight of a lubricant, from about 0.5% to about 10% by weight of a disintegrant, and from about 0.1% to about 10% by weight of a stabilizing agent and one or more antidiabetic agents. In one aspect of this embodiment, n. teneliglyptin oxalate hydrate 3.0 is crystalline n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0.

[00104] In one embodiment, the invention provides pharmaceutical compositions comprising a substantially pure oxalate salt of a compound of formula (I) and its solvates.

[00105] In one embodiment, the present invention provides pharmaceutical compositions in which the purity of the oxalate salt of the compound of formula (I) is greater than 98.0%.

[00106] In another embodiment of the present invention, pharmaceutical compositions are provided in which the purity of the oxalate salt of the compound of formula (I) is greater than 99.0%.

[00107] In one embodiment, the present invention provides pharmaceutical compositions in which the purity of the oxalate salt of the compound of formula (I) is greater than 99.5%.

[00108] In one embodiment, the invention provides pharmaceutical compositions comprising a substantially pure oxalate salt of a compound of formula (I) and solvates thereof, said oxalate salt of a compound of formula (I) being 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and their solvates.

[00109] In one embodiment, the present invention also provides pharmaceutical compositions described herein further comprising at least one or more antidiabetic agents selected from the group consisting of sulfonylurea class compounds and salts thereof, glitazone class compounds and their salts, compounds of the biguanidine class and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and their combinations.

[00110] In one embodiment, the present invention provides pharmaceutical compositions comprising an oxalate salt of a compound of formula (I) and its solvates and at least one or more antidiabetic agents selected from the group consisting of compounds of the sulfonylurea class and their salts, compounds of the glitazone class and their salts, compounds of the biguanide class and their salts, compounds of the class of alpha-glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and combinations thereof.

[00111] In one embodiment, said sulfonylurea class compounds used in the pharmaceutical compositions of this invention include glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide and the like. In a preferred embodiment, the sulfonylurea compound is glimepiride.

[00112] In one embodiment, said glitazone class compounds used in the pharmaceutical compositions of this invention include pioglitazone, rosiglitazone, and the like. In a preferred embodiment, the glitazone compound is pioglitazone.

[00113] In another embodiment, said compounds of the class of alpha-glucosidase inhibitors used in the pharmaceutical compositions of this invention include voglibose, acarbose, miglitol, and the like. In a preferred embodiment, the alpha-glucosidase inhibitor is voglibose.

[00114] In one embodiment, said compounds of the SGLT2 inhibitor class include remogliflozin, dapagliflozin, canatliflozin, empagliflozin, luseogliflozin, and the like.

[00115] In one embodiment, said biguanide class compounds include metformin, buformin, phenformin, and the like. In a preferred embodiment, said member of the biguanide class molecules is metformin or a pharmaceutically acceptable salt thereof. In a preferred embodiment, said biguanide class member is metformin hydrochloride. In another embodiment, said class of biguanide is a mixture of metformin and metformin hydrochloride.

[00116] In one embodiment, the metformin portion of the pharmaceutical composition of this invention is an instant release layer or a sustained release layer. In one embodiment, the metformin moiety contained in said pharmaceutical compositions is an instant release layer. In a preferred embodiment, the metformin moiety contained in said pharmaceutical compositions is a sustained release layer. In another embodiment, the metformin contained in said pharmaceutical compositions is a mixture of instant and sustained release metformin layers.

[00117] In one embodiment, the pharmaceutical compositions described herein further comprise at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof.

[00118] The pharmaceutical compositions of this invention containing at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, or combinations thereof, stabilize the solvated oxalate salts of teneligliptin and inhibit the formation of a compound of Formula ( II) in the specified pharmaceutical compositions.

[00119] In one embodiment, pharmaceutical compositions are provided comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof, act to stabilize n. hydrate of 2.5 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00120] In one embodiment, pharmaceutical compositions are provided comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof, act to stabilize n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00121] In one embodiment, pharmaceutical compositions are provided comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof, act to stabilize mixture n. hydrate of 2.5 teneliglyptin oxalate and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00122] In one embodiment, pharmaceutical compositions are provided comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said oxalate salt having a purity of at least 99% and a compound of formula (II) less than 1.0%.

[00123] In one embodiment, pharmaceutical compositions are provided comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said oxalate salt having a purity of at least 99.5% and a compound of formula (II) being less than 0.5% ...

[00124] In one embodiment, pharmaceutical compositions are provided comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said oxalate salt having a purity of at least 99.9% and a compound of formula (II) of less than 0.1% ...

[00125] In one embodiment, pharmaceutical compositions are provided comprising teneliglyptin 2.5 oxalate and a solvate thereof, said oxalate salt having a purity of at least 99% and a compound of formula (II) being less than 1.0%.

[00126] In one embodiment, pharmaceutical compositions are provided comprising 2.5 teneliglyptin oxalate and a solvate thereof, said oxalate salt having a purity of at least 99.5% and a compound of formula (II) less than 0.5%. In a preferred embodiment, the solvate is n. hydrate. In another aspect of this embodiment, pharmaceutical compositions are provided comprising n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, preferably 1.0.

[00127] In one embodiment, pharmaceutical compositions are provided comprising 2.5 teneliglyptin oxalate and a solvate thereof, said oxalate salt having a purity of at least 99.9% and an impurity B content of less than 0.1%. In a preferred embodiment, the solvate is n. hydrate. In another aspect of this embodiment, pharmaceutical compositions are provided comprising n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, preferably 1.0.

[00128] In one embodiment, pharmaceutical compositions are provided comprising 3.0 teneliglyptin oxalate and a solvate thereof, said oxalate salt having a purity of at least 99%, and containing a compound of formula (II) less than 1.0%. In a preferred embodiment, the solvate is n. hydrate. In another aspect of this embodiment, pharmaceutical compositions are provided comprising n. hydrate of 3.0 teneliglyptin oxalate, where n is 1.0 to 4.0, preferably 1.0.

[00129] In one embodiment, pharmaceutical compositions are provided comprising 3.0 teneliglyptin oxalate and a solvate thereof, said oxalate salt having a purity of at least 99.5% and an impurity B content of less than 0.5%. In a preferred embodiment, the solvate is n. hydrate. In another aspect of this embodiment, pharmaceutical compositions are provided comprising n. hydrate of 3.0 teneliglyptin oxalate, where n is 1.0 to 4.0, preferably 1.0.

[00130] In one embodiment, pharmaceutical compositions are provided comprising 3.0 teneliglyptin oxalate and a solvate thereof, said oxalate salt having a purity of at least 99.9% and an impurity B content of less than 0.1%. In a preferred embodiment, the solvate is n. hydrate. In another aspect of this embodiment, pharmaceutical compositions are provided comprising n. hydrate of 3.0 teneliglyptin oxalate, where n is 1.0 to 4.0, preferably 1.0.

[00131] In one embodiment, the invention provides pharmaceutical compositions comprising n. teneliglyptin oxalate hydrate 3.0 and its solvate, said oxalate salt having a purity of at least 99% and the content of the compound of formula (II) being less than 1.0%.

[00132] In one embodiment, the invention provides pharmaceutical compositions comprising n. teneliglyptin oxalate hydrate 3.0 and its solvate, said oxalate salt having a purity of at least 99.5% and the content of the compound of formula (II) being less than 0.5%.

[00133] In one embodiment, the invention provides pharmaceutical compositions comprising n. teneliglyptin oxalate hydrate 3.0 and its solvate, said oxalate salt having a purity of at least 99.9% and the content of the compound of formula (II) being less than 0.1%.

[00134] In one embodiment, the invention provides pharmaceutical compositions comprising n. a hydrate of 3.0 oxalate of teneligliptin having a purity of at least 99.0%, at least 99.5%, at least 99.9%, in crystalline form.

[00135] In one embodiment, the present invention provides pharmaceutical compositions comprising n. hydrate of 3.0 oxalate teneliglyptin, where n is from 1.0 to 4.0, preferably 1.0, and metformin with prolonged release, in which wt./wt. the ratio of teneligliptin to metformin is in the range 1: 10-1: 50, preferably in the range 1: 10-1: 40, in particular about 1:15 or 1:31.

[00136] In one embodiment, the present invention provides pharmaceutical compositions comprising n. hydrate of 2.5 oxalate teneliglyptin, where n is from 1.0 to 4.0, preferably 1.0, and metformin with prolonged release, in which w / w. the ratio of teneligliptin to metformin is in the range 1: 10-1: 50, preferably in the range 1: 10-1: 40, in particular about 1:15 or 1:31.

[00137] In one embodiment, the present invention provides pharmaceutical compositions comprising a mixture of n. hydrate of 2.5 teneliglyptin oxalate and n. hydrate of 3.0 oxalate teneliglyptin, where n is from 1.0 to 4.0, preferably 1.0, and metformin with prolonged release, in which w / w. the ratio of teneligliptin to metformin is in the range of about 1: 10-1: 50, preferably in the range of about 1: 10-1: 40, in particular about 1:15 or 1:31.

[00138] In a specific embodiment, the present invention provides pharmaceutical compositions containing n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, preferably 1.0, and sustained release metformin, and at least one or more pharmaceutically acceptable carriers, diluents and excipients.

[00139] In a specific embodiment, the present invention provides pharmaceutical compositions containing n. teneliglyptin oxalate hydrate 3.0, where n is 1.0 to 4.0, preferably 1.0, and sustained release metformin; and at least one or more pharmaceutically acceptable carriers, diluents and excipients.

[00140] In a specific embodiment of the present invention, pharmaceutical compositions are provided comprising mixture n. hydrate of 2.5 teneliglyptin oxalate and n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0, and sustained release metformin, and at least one or more pharmaceutically acceptable carriers, diluents and excipients.

[00141] The present invention provides pharmaceutical compositions described herein for use in the prophylactic treatment of a glucose metabolic disorder in a patient.

[00142] This invention provides the pharmaceutical compositions described herein for use in the radical treatment of a glucose metabolic disorder in a patient.

[00143] This invention provides a method for prophylactic and radical treatment of a patient with impaired glucose metabolism, comprising administering a physiologically relevant amount of the pharmaceutical compositions described herein.

[00144] The present invention provides a method for the radical treatment of a patient with impaired glucose metabolism, comprising administering a physiologically relevant amount of the pharmaceutical compositions described herein.

[00145] In one embodiment of the present invention, there are provided pharmaceutical compositions as described herein containing n granules. hydrate of teneliglyptin oxalate salts, where n is 1.0 to 4.0, preferably 1.0. In a specific embodiment, the pharmaceutical compositions described herein are provided containing granules n. hydrate of 2.5 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0. In a specific embodiment, the pharmaceutical compositions described herein are provided containing granules n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00146] In one embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition of an oxalate salt of a compound of formula (I), comprising the steps of:

(a) sieving the oxalate salt of a compound of formula (I) with pharmaceutically acceptable adjuvants or one or more antidiabetic agents or a mixture thereof;

(b) granulating the screened material obtained in step (a) with a binder solution;

(c) drying and sieving the granulate obtained in step (b);

(d) lubricating the sieved granulate obtained in step (c) with a suitable lubricating agent to form a mixture;

(e) compressing the lubricated mixture obtained in step (d) into a tablet, or filling capsules with the mixture obtained in step (d);

(f) optionally compressing the lubricated mixture obtained in step (d) with the mixture of one or more anti-diabetic agents to form a tablet, or filling capsules with said mixture.

Step (a) of the above process comprises sieving the oxalate salt of the compound of formula (I) and its solvate with suitable auxiliaries. In one embodiment, the oxalate salt of a compound of formula (I) and its solvate is 2.5 teneliglyptin oxalate or 3.0 teneliglyptin oxalate and a solvate thereof. In one preferred embodiment, said solvate is n. hydrate. In one preferred embodiment, the oxalate salt of the compound of formula (I) and its solvate is n. hydrate of 2.5 teneliglyptin oxalate or n. hydrate of 3.0 teneliglyptin oxalate, where n is 1.0 to 4.0, preferably 1.0.

[00147] In one embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, comprising the steps of:

(a) sieving pharmaceutically acceptable excipients;

(b) preparing a binder solution containing an oxalate salt of a compound of formula (I) and a solvate thereof;

(c) granulating the sieved pharmaceutically acceptable excipients obtained in step (a) with the binder solution obtained in step (b);

(d) drying and sieving the granulate obtained in step (c);

(e) lubricating the sieved granulate obtained in step (c) with sieved pharmaceutically acceptable auxiliaries to form a mixture;

(f) compressing the lubricated mixture obtained in step (d) into a tablet, or filling capsules with the mixture obtained in step (d);

(g) optionally compressing the lubricated mixture obtained in step (d) with the mixture of one or more antidiabetic agents to form a tablet, or filling capsules with said mixture.

[00148] In one embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, comprising the steps of:

(a) preparing a solution of an oxalate salt of a compound of formula (I) and a solvate thereof with a stabilizer or complexing agent

(b) spray drying the solution obtained in step (a)

(c) sieving the spray-dried mixture obtained in step (b)

(d) lubricating the sieved granulate obtained in step (c) with sieved pharmaceutically acceptable excipients;

(e) compressing the lubricated mixture obtained in step (d) into a tablet, or filling capsules with the mixture obtained in step (d).

[00149] In one embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, comprising the steps of:

(a) sieving n. hydrate of 3.0 oxalate teneligliptin, where n is from 1.0 to 4.0, with pharmaceutically acceptable excipients or one or more antidiabetic agents or a mixture thereof;

(b) granulating the screened material obtained in step (a) with a binder solution;

(c) drying and sieving the granulate obtained in step (b);

(d) lubricating the sieved granulate obtained in step (c) with a suitable lubricating agent to form a mixture;

(e) compressing the lubricated mixture obtained in step (d) into a tablet, or filling capsules with the mixture obtained in step (d);

(f) optionally compressing the lubricated mixture obtained in step (d) with the mixture of one or more anti-diabetic agents to form a tablet, or filling capsules with said mixture.

[00150] In one embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising n. hydrate of 3.0 oxalate teneligliptin, including the stages:

(a) sieving pharmaceutically acceptable excipients;

(b) obtaining a binder solution containing n. hydrate 3.0 of teneliglyptin oxalate;

(c) granulating the sieved pharmaceutically acceptable excipients obtained in step (a) with the binder solution obtained in step (b);

(d) drying and sieving the granulate obtained in step (c);

(e) lubricating the sieved granulate obtained in step (c) with sieved pharmaceutically acceptable auxiliaries to form a mixture;

(f) compressing the lubricated mixture obtained in step (d) into a tablet, or filling capsules with the mixture obtained in step (d); and

(g) optionally compressing the lubricated mixture obtained in step (d) with the mixture of one or more antidiabetic agents to form a tablet, or filling capsules with said mixture.

[00151] In one embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising n. hydrate of 3.0 oxalate teneligliptin, including the stages:

(a) obtaining solution n. hydrate of 3.0 oxalate teneligliptin with a stabilizer or complexing agent;

(b) spray drying the solution obtained in step (a);

(c) sieving the spray-dried mixture obtained in step (b);

(d) lubricating the sieved granulate obtained in step (c) with sieved pharmaceutically acceptable excipients; and

(e) compressing the lubricated mixture obtained in step (d) into a tablet, or filling capsules with the mixture obtained in step (d).

[00152] In one embodiment, the granules of the oxalate salt of compound (I) and its solvate provided by this invention may be prepared from the oxalate salt of compound (I) and its solvate in combination with suitable diluents, lubricants, binders, thinning agents, disintegrants , solubilizers, etc.

[00153] In one embodiment, the beads of teneligliptin oxalate 2.5 and its solvate provided by this invention can be prepared from teneliglyptin 2.5 oxalate and its solvate in combination with suitable diluents, lubricants, binders, thinning agents, disintegrants, solubilizers etc.

[00154] In one embodiment, beads of teneligliptin oxalate and its solvate 3.0 of the present invention can be prepared from teneliglyptin oxalate 3.0 and its solvate in combination with suitable diluents, lubricants, binders, thinning agents, disintegrants, solubilizers etc.

[00155] In one embodiment, beads n. hydrate of 2.5 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0, provided by this invention, can be obtained from n. teneligliptin oxalate hydrate 2.5 in combination with suitable diluents, lubricants, binders, thinning agents, disintegrants, solubilizers and the like.

[00156] In one embodiment, the granule n. hydrate of 3.0 oxalate teneliglyptin provided by this invention can be obtained from n. teneliglyptin oxalate hydrate 3.0 in combination with suitable diluents, lubricants, binders, thinning agents, disintegrants, solubilizers and the like.

[00157] A suitable binder includes, but is not limited to, hydroxypropyl cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose, hypromellose, and the like.

[00158] Suitable diluents include, but are not limited to, mannitol, sorbitol, xylitol, starch, lactose, cellulose, calcium dihydrogen phosphate, and the like.

[00159] Suitable lubricants include, but are not limited to, glyceryl dibehenate, sodium or calcium stearyl fumarate, magnesium stearate, stearic acid, glyceryl palmitostearate.

[00160] Granules of the oxalate salt of the compound of formula (I) and its solvate can be prepared by mixing the oxalate salt of the compound of formula (I) and pharmaceutically acceptable excipients; adding a binder solution to a mixture of a compound of formula (I) and pharmaceutically acceptable excipients; and drying a wet mixture of an oxalate salt of a compound of formula (I) and pharmaceutically acceptable excipients, followed by sieving to obtain granules.

[00161] Alternatively, granules of the oxalate salt of the compound of formula (I) and its solvate can be obtained after mixing the oxalate salt of the compound of formula (I) and pharmaceutically acceptable auxiliaries, the binder solution can be sprayed onto the mixture in a fluidized bed reactor, followed by drying wet granules and further optional sieving. Alternatively, flakes of the oxalate salt of a compound of formula (I) can be prepared by dry mixing the oxalate salt of a compound of formula (I) and pharmaceutically acceptable auxiliaries to form a mixture; compaction of the mixture by rolling one or more times to obtain flakes, followed by granulating and sieving the flakes. Granules or flakes of the oxalate salt of the compound of formula (I) can be lubricated with any of the lubricants mentioned above. The mixture can then be fed into a tabletting machine, or it can be filled into capsules using a capsule filling machine. Optionally, the tablet can be coated. The coating agent solution or suspension contains adjuvants such as hypromellose, polyethylene glycol, coloring agent such as red or yellow iron oxide, titanium dioxide and talc. Alternatively, said tablets can be filled into capsules of a suitable size. The volume of the capsule can be suitably selected in the range of 0.13 to 1.37 ml to accommodate a lubricated mixture or tablets containing the oxalate salt of a compound of formula (I). In one aspect of this embodiment, the oxalate salt of the compound of formula (I) used to prepare the granules containing teneliglyptin is 3.0 teneliglyptin oxalate or a solvate thereof. In a first aspect of this embodiment, 3.0 teneliglyptin oxalate or a solvate thereof exists in crystalline form.

[00162] Alternatively, a direct compression method for preparing teneligliptin tablets is also provided by this invention. Tablets are prepared by mixing teneligliptin with one or more pharmaceutically acceptable excipients to form a direct compression mixture; compressing the specified mixture to obtain a tablet; optionally, the tablet can be coated as described above.

[00163] In one embodiment, the invention provides pharmaceutical compositions comprising an oxalate salt of a compound of formula (I) and a solvate thereof and metformin or a pharmaceutically acceptable salt thereof as described herein, wherein the content of metformin or a pharmaceutically acceptable salt thereof may be suitably is selected to deliver a dose of metformin in the range of 1-2000 mg, preferably 250-1000 mg, more preferably 500-1000 mg, even more preferably 500 mg or 1000 mg. Such a pharmaceutical composition contains teneliglyptin and metformin in separate parts. For example, a multilayer composition containing teneliglyptin and metformin in separate layers of a two- or three-layer tablet; a composition containing metformin in the core and teneligliptin in the coating, and the like.

[00164] In one embodiment, the present invention provides pharmaceutical compositions comprising teneliglyptin oxalate salts and their solvates and at least one or more antidiabetic agents selected from the group consisting of sulfonylurea class compounds and salts thereof, glitazone class compounds and their salts, compounds of the biguanide class and their salts, compounds of the class of glucosidase inhibitors and their salts, compounds of the class of SGLT2 inhibitors and their salts, and combinations thereof, as described herein, the weight concentration of teneliglyptin oxalate salts and their solvates being from 0.5 to 10, 0%, preferably 0.5 to 8.0%. In a preferred embodiment, the antidiabetic agent is metformin and salts thereof. In a more preferred embodiment, the antidiabetic agent is sustained release metformin. In one embodiment, the dosage size of sustained release metformin in said pharmaceutical composition is 500 mg. In another embodiment, the dosage size of sustained release metformin in said pharmaceutical composition is 1000 mg.

[00165] In one embodiment, the invention provides pharmaceutical compositions comprising the oxalate salts of teneliglyptin and a solvate thereof, preferably n. hydrate of 3.0 oxalate teneligliptin, and metformin or a pharmaceutically acceptable salt thereof, preferably metformin with prolonged release, as described herein, and w / w. the ratio of teneligliptin to metformin in said composition is in the range of 1: 10-1: 50. In one embodiment, the specified w / w. the ratio is about 1:15. In another embodiment, the specified w / w. The ratio is around 1:31. In one embodiment, the dose size of teneligliptin is in the range of about 5-50%, preferably 20-40%, more preferably 25-35%. In one embodiment, the dose size of metformin is in the range of 100-2000 mg, preferably 500-1000 mg. more preferably 500 mg or 1000 mg.

[00166] In one embodiment of the present invention, there is provided a method of treating, preventing or slowing the progression of a metabolic disorder by administering to a patient in need thereof a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent, said metabolic a disorder selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, insulin resistance, and metabolic syndrome, in a patient in need of it.

[00167] In one embodiment, the present invention provides a method of treating type 2 diabetes mellitus by administering to a patient in need thereof a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent, or pharmaceutically acceptable salts thereof.

[00168] In one embodiment of the present invention, there is provided a method of improving glycemic control in a patient undergoing antidiabetic drug monotherapy by administering to a patient in need thereof a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent, or their pharmaceutically acceptable salts.

[00169] In one embodiment of the present invention, there is provided a method of improving glycemic control and / or decreasing fasting plasma glucose, postrandial plasma glucose and / or glycosylated hemoglobin HbA1c in a patient by administering to a patient in need thereof a pharmaceutical composition containing an oxalate salt compounds of formula (I) and at least one other antidiabetic agent or pharmaceutically acceptable salts thereof.

[00170] In one embodiment of the present invention, there is provided a method of treating, preventing or slowing the progression of a pathological condition or disorder selected from the group consisting of complications of diabetes mellitus in a patient by administering to a patient in need thereof a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent, or pharmaceutically acceptable salts thereof. Complications of diabetes mellitus according to this invention include cataracts and micro- or macrovascular diseases such as nephropathy, retinopathy, neuropathy, learning and memory impairment, neurodegenerative or cognitive disorders, cardio or cerebrovascular disease, tissue ischemia, diabetic foot syndrome or ulcers, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, occlusive peripheral arterial disease, cardiomyopathy, heart failure, cardiac arrhythmias and vascular restenosis, etc.

[00171] In one embodiment, the present invention provides a method for treating, preventing or slowing the progression of pancreatic beta cell degeneration and / or reducing the functionality of pancreatic beta cells; and / or improving and / or restoring the functionality of pancreatic beta cells and / or restoring the functionality of pancreatic insulin secretion in a patient by administering to a patient in need thereof a pharmaceutical composition containing an oxalate salt of a compound of formula (I) and at least one other an antidiabetic agent; or a pharmaceutically acceptable salt thereof.

EXAMPLES

[00172] The following examples are presented to provide what is believed to be the most applicable and understandable description of the methods and conceptual aspects of the present invention. The examples below are purely illustrative of the present invention and are not intended to limit it to the described embodiments. Variants and variations understood by those skilled in the art are within the scope and spirit of the present invention.

Example 1

Pharmaceutical compositions containing n. hydrate 3.0 teneliglyptin oxalate

[00173] The tables below describe exemplary compositions comprising n. hydrate of 3.0 teneliglyptin oxalate, preferably monohydrate.

[00174] Table 1 shows a dosage form containing oxalic acid as a stabilizer to prevent degradation of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00175] Manufacturing process:

1. Screening: co-screened teneliglyptin oxalate, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting a binder: added and dissolved with stirring, oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: Granulated the materials obtained in step 1 with the binder solution obtained in step 2 at suitable process parameters in a fluidized bed reactor (FBP). After the completion of the granulation, the wet mass was dried until the desired LoD value was reached;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00176] Table 2 shows a dosage form containing oxalic acid, a polymer and a complexing agent to prevent degradation of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00177] Manufacturing process:

1. Screening: co-screened L-HPC and mannitol through a # 060 mesh sieve;

2. Getting a binder: added and dissolved with stirring, oxalic acid, β-cyclodextrin and hydroxypropyl cellulose in purified water;

3. Granulation: Granulated the materials obtained in step 1 with the binder solution obtained in step 2 at suitable process parameters in a fluidized bed reactor (FBP). After the completion of the granulation, the wet mass was dried until the desired LoD value was reached;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00178] Table 3 shows a dosage form containing a complexing agent to prevent degradation of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00179] Manufacturing process:

1. Preparation of solution: added and dissolved mannitol, B-cyclodextrin and teneliglyptin oxalate in purified water with stirring;

2. Spray dried the solution obtained in step 1;

3. Sieve the spray dried material through a # 30 mesh sieve;

4. Co-sieved mannitol, L-hydroxypropyl cellulose and glyceryl dibehenate through a # 040 mesh sieve;

5. Lubrication: Lubricate the granules obtained in step 3 with the sieved auxiliaries obtained in step 4 in a suitable mixer;

6. Compression: the lubricated mixture was compressed using suitable equipment and process parameters;

7. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

8. Pack the film-coated tablets in blister packs.

[00180] Table 4 shows a dosage form containing a polymer to prevent degradation of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00181] Manufacturing process:

1. Screening: screened L-HPC and mannitol through a # 060 mesh sieve;

2. Getting a binder: added and dissolved with stirring hydroxypropyl cellulose in purified water;

3. Granulation: Granulated the materials obtained in step 1 with the binder solution obtained in step 2 at suitable process parameters in a fluidized bed reactor (FBP). After the completion of the granulation, the wet mass was dried until the desired LoD value was reached;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Co-sieved mannitol, L-hydroxypropyl cellulose and glyceryl dibehenate through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00182] Table 5 shows a dosage form containing a polymer to prevent degradation of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00183] Manufacturing process:

1. Obtaining a solution: added and dissolved mannitol, oxalic acid and teneliglyptin oxalate in purified water with stirring;

2. Spray dried the solution obtained in step 1;

3. Sieve the spray dried material through a # 30 mesh sieve;

4. Co-sieved mannitol, L-hydroxypropyl cellulose and glyceryl dibehenate through a # 040 mesh sieve;

5. Lubrication: Lubricate the granules obtained in step 3 with the sieved auxiliaries obtained in step 4 in a suitable mixer;

6. Compression: the lubricated mixture was compressed using suitable equipment and process parameters;

7. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

8. Pack the film-coated tablets in blister packs.

[00184] Table 6 shows a dosage form containing a polymer and a chelating agent to prevent degradation of n. hydrate of 3.0 teneliglyptin oxalate, where n is from 1.0 to 4.0, preferably 1.0.

[00185] Manufacturing process:

1. Screening: co-screened L-HPC and mannitol through a # 060 mesh sieve;

2. Getting the binder: added and dissolved with stirring oxalic acid, EDTA and hydroxypropyl cellulose in purified water;

3. Granulation: Granulated the materials obtained in step 1 with the binder solution obtained in step 2 at suitable process parameters in a fluidized bed reactor (FBP). After the completion of the granulation, the wet mass was dried until the desired LoD value was reached;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00186] Those skilled in the art will understand that the illustrative dosage forms described herein may be modified by those skilled in the art without departing from the intended spirit of the invention. In addition, it is clear to those skilled in the art that such dosage forms containing n. teneliglyptin oxalate hydrate 2.5, where n is 1.0 to 4.0, preferably 1.0, are contemplated herein and are within the skill of the art to which they relate, including any modifications.

Example 2: Method for Combining Teneligliptin Oxalate 3.0 and Metformin HCl

[00187] Metformin portion (for a dose of 500 mg): Metformin hydrochloride was ground using a universal grinder. Crushed metformin hydrochloride and sodium carboxymethyl cellulose were co-sieved through a No. 40 mesh stainless steel sieve. Guar gum was screened through a # 100 mesh stainless steel sieve. The sifted metformin hydrochloride, carboxymethyl cellulose and guar gum were granulated in a high speed mixer granulator for 20 minutes. A binder solution was prepared by adding methylparaben and propylparaben to purified water with stirring. A granular mixture of metformin hydrochloride, carboxymethyl cellulose and guar gum was granulated with a binder solution in a fluid bed dryer. The resulting wet granular mass was dried to obtain granules. The resulting granules were sieved through a No. 16 sieve on a vibrating sieve. The oversized granules were collected and crushed in a universal grinder. The crushed granules were collected and sieved through a No. 16 sieve on a vibrating sieve. Hydroxypropyl methylcellulose, pregelatinized starch, polyethylene oxide, and hydrogenated castor oil were sieved together through a No. 40 sieve, and magnesium stearate was sieved through a No. 40 sieve on a vibrating sieve. The resulting premix was lubricated by mixing fine granules and co-sieved hydroxypropyl methylcellulose, pregelatinized starch, polyethylene oxide, and hydrogenated castor oil. The crushed granules were lubricated with a lubricating premix in a blender to form a metformin HCl mixture.

[00188] Metformin portion (for a dose of 1000 mg): Metformin hydrochloride was ground on a universal grinder and sieved through a # 40 stainless steel sieve. Sieve sodium carboxymethyl cellulose through a No. 40 mesh stainless steel sieve. Guar gum was screened through a # 100 mesh stainless steel sieve. The screened metfluorine hydrochloride and carboxymethyl cellulose were granulated in a high-speed mixer granulator for 20 minutes. A binder solution was prepared by adding methylparaben and propylparaben to purified water with stirring. A mixture of metformin hydrochloride, carboxymethyl cellulose and purified water was granulated using suitable processing parameters. The resulting wet granular mass was partially dried and sieved through a No. 16 sieve. The partially dried granules were dried in a fluidized bed dryer. Sifted the dried granules through a No. 16 sieve on a vibrating sieve. The oversized granules were collected and crushed in a universal grinder. The crushed granules were collected and sieved through a No. 16 sieve on a vibrating sieve. Hydroxypropyl methylcellulose and maize starch were sieved together through a No. 40 sieve on a vibrating sieve, and magnesium stearate was sieved through a No. 60 sieve. The crushed granules were lubricated with co-sieved hydroxypropyl methylcellulose and maize starch and sieved magnesium stearate in a suitable mixer.

Example 3

Stability n. hydrate of 3.0 oxalate teneligliptin in dosage forms

[00189] The stability profile of the dosage form described in Table 1 after 1 month and 2 months is presented in Table 7 below.

[00190] As shown in Table 7 above, it can be concluded that even after 2 months of storage at 40 ° C ± 2 ° C and 75% OB ± 5% RH, the content of impurity B (an undesirable by-product of the dosage form leading to the loss of oxalate) below the allowable value of 1% w / w. The same results were observed for the dosage forms presented in Tables 2-6. It should be understood that the improved stability of each of the dosage forms shown in Tables 1-6 is due, in part, to the presence of oxalic acid, polymer, complexing agent, chelating agent, or combinations thereof. The advantageous and unexpected stability of the dosage form obtained with the addition of any of the compounds: oxalic acid, polymer, complexing agent, chelating agent, or combinations thereof can be even more understandable when considering dosage forms presented below that do not contain oxalic acid, polymer, complexing agent. agent, chelating agent, or combinations thereof and, therefore, exhibit an increased content of impurity B outside the acceptable range.

[00191] Table 8 provides a dosage form showing an unacceptable level of impurity B.

[00192] Table 9 shows the stability profile of the dosage form described in Table 8.

[00193] Table 10 shows a dosage form showing an unacceptable level of impurity B.

[00194] Table 11 shows the stability profile of the dosage form described in Table 10.

[00195] Table 12 presents a dosage form showing an unacceptable level of impurity B.

[00196] Table 13a presents the stability profile of the dosage form described in Table 12.

[00197] Table 13b shows the stability profile of the dosage form described in Table 12.

Example 4

Dosage forms containing n. hydrate of 3.0 teneliglyptin and glimepiride

[00198] Table 14a presents a dosage form containing n. hydrate of 3.0 teneliglyptin oxalate and glimepiride.

[00199] Table 14b shows a dosage form containing n. teneliglyptin oxalate hydrate 3.0 and glimepiride (monolayer strategy 2).

[00200] A brief manufacturing process strategy for preparing the dosage form described in Table 14a-b.

1. Screening: co-screened teneliglyptin oxalate, glimepiride, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting a binder: added and dissolved with stirring, oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of the granulation, the wet mass was dried;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00201] Table 14 c shows the dosage form containing n. hydrate of 3.0 teneliglyptin oxalate and glimepiride.

[00202] Table 14d shows a dosage form containing pltshrate 3.0 of teneliglyptin oxalate and glimepiride (two-layer strategy 2).

[00203] A brief manufacturing process strategy for preparing the dosage form described in Table 14c-d.

Teneliglyptin part:

1. Screening: co-screened teneliglyptin oxalate, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting a binder: added and dissolved with stirring, oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of the granulation, the wet mass was dried;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve; and

6. Lubrication: Lubricate the granules from step 4 with the sieved auxiliaries from step 5 in a suitable mixer.

Glimepiride part:

1. Screening: Glimepiride, L-HPC and mannitol were screened together through a # 060 mesh sieve; Sieve yellow iron (III) oxide through a # 0100 mesh sieve;

2. Getting a binder: added and dissolved with stirring Tween 80 and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of the granulation, the wet mass was dried;

4. Sieve the graded granules through a # 30 mesh sieve. Crushed the residue using a 1.0 mm sieve and sieved through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and magnesium stearate together through a # 040 mesh sieve; and

6. Lubrication: Lubricate the granules from step 4 with the sieved auxiliaries from step 5 in a suitable mixer.

Compression, Coating, Packing: Compressed both lubricated mixtures of the teneliglyptin portion and the glimepiride portion with a suitable device using a double layer compression machine. The compressed tablets were coated with an aqueous dispersion of yellow opadine. The film-coated tablets were packaged in a blister pack.

Example 5

Dosage forms containing n. hydrate 3.0 teneligliptin and pioglitazone

[00204] Table 15a shows a dosage form containing n. teneligliptin oxalate hydrate 3.0 and pioglitazone (monolayer strategy 1).

[00205] Table 15b shows a dosage form containing n. hydrate 3.0 of teneligliptin oxalate and pioglitazone.

[00206] A brief manufacturing process strategy for preparing the dosage form described in Table 15a-b.

1. Screening: together screened teneliglyptin oxalate, pioglitazone, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting the binder: added and dissolved with stirring oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of granulation, the wet mass was dried;

4. Sieve the sorted granules through a # 30 mesh sieve. The residue was crushed with a 1.0 mm sieve and passed through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with the sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00207] Table 15 c shows the dosage form containing n. teneligliptin oxalate hydrate 3.0 and pioglitazone (two-layer strategy 1).

[00208] Table 15d shows a dosage form containing n. hydrate 3.0 of teneligliptin oxalate and pioglitazone.

[00209] A brief manufacturing strategy for the preparation of the dosage form described in Table 15c-d.

Teneliglyptin part:

1. Screening: co-screened teneliglyptin oxalate, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting the binder: added and dissolved with stirring oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of granulation, the wet mass was dried;

4. Sieve the sorted granules through a # 30 mesh sieve. The residue was crushed with a 1.0 mm sieve and passed through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve; and

6. Lubrication: Lubricate the granules from step 4 with the sieved auxiliaries from step 5 in a suitable mixer.

Pioglitazone part

1. Screening: co-screened pioglitazone, L-HPC and mannitol through a # 060 mesh sieve; Sieve yellow iron (III) oxide through a # 0100 mesh sieve;

2. Getting a binder: added and dissolved with stirring hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of granulation, the wet mass was dried;

4. Sieve the sorted granules through a # 30 mesh sieve. The residue was crushed with a 1.0 mm sieve and passed through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and magnesium stearate together through a # 040 mesh sieve; and

6. Lubrication: Lubricate the granules from step 4 with the sieved auxiliaries from step 5 in a suitable mixer.

Compression, coating, packaging: Compressed both lubricated mixtures of the teneligliptin portion and the pioglitazone portion with a suitable device using a double-layer compression machine. The compressed tablets were coated with an aqueous dispersion of yellow opadine.

Example 6

Dosage forms containing n. hydrate 3.0 teneligliptin and voglibose

[00210] Table 16a shows a dosage form containing n. hydrate of 3.0 oxalate teneligliptin and voglibose.

[00211] Table 16b shows a dosage form containing n. hydrate of 3.0 oxalate teneligliptin and voglibose.

[00212] A brief manufacturing process strategy for preparing the dosage form described in Table 16a-b.

1. Screening: co-screened teneliglyptin oxalate, voglibose, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting the binder: added and dissolved with stirring oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of granulation, the wet mass was dried;

4. Sieve the sorted granules through a # 30 mesh sieve. The residue was crushed with a 1.0 mm sieve and passed through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve;

6. Lubrication: Lubricate the granules obtained in step 4 with sieved auxiliaries obtained in step 5 in a suitable mixer;

7. Pressing: the lubricated mixture was pressed using suitable equipment and process parameters;

8. Coating: Coated the compressed tablets using an aqueous dispersion of opadry yellow; and

9. Pack the film-coated tablets in blister packs.

[00213] Table 16 c shows the dosage form containing n. hydrate of 3.0 oxalate teneligliptin and voglibose.

[00214] Table 16d shows a dosage form containing n. hydrate of 3.0 oxalate teneligliptin and voglibose.

[00215] A brief manufacturing process strategy for preparing the dosage form described in Table 16c-d:

Teneliglyptin part:

1. Screening: co-screened teneliglyptin oxalate, L-HPC and mannitol through a # 060 mesh sieve;

2. Getting the binder: added and dissolved with stirring oxalic acid and hydroxypropyl cellulose in purified water;

3. Granulation: the materials obtained in step 1 were granulated with the binder solution obtained in step 2. After the completion of granulation, the wet mass was dried;

4. Sieve the sorted granules through a # 30 mesh sieve. The residue was crushed with a 1.0 mm sieve and passed through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and glyceryl dibehenate together through a # 040 mesh sieve; and

6. Lubrication: Lubricate the granules from step 4 with the sieved auxiliaries from step 5 in a suitable mixer.

Voglibose part

1. Screening: co-screened voglibose, L-HPC and mannitol through a # 060 mesh sieve; Sieve yellow iron (III) oxide through a # 0100 mesh sieve;

2. added and dissolved with stirring hydroxypropyl cellulose in purified water;

3. granulate the materials obtained in step 1 with the binder solution obtained in step 2. After the completion of the granulation, dry the wet mass;

4. Sieve the sorted granules through a # 30 mesh sieve. The residue was crushed with a 1.0 mm sieve and passed through a # 30 mesh sieve;

5. Sieve L-hydroxypropyl cellulose and magnesium stearate together through a # 040 mesh sieve; and

6. Lubrication: Lubricate the granules from step 4 with the sieved auxiliaries from step 5 in a suitable mixer.

[00216] While this invention has been described with reference to specific embodiments, it should be understood that these embodiments and examples are merely illustrative of the principles and applications of the invention. Therefore, it should be understood that numerous modifications can be made to the illustrative embodiments, and that other schemes can be devised without departing from the spirit and scope of the invention as described herein.

Claims (11)

1. A pharmaceutical composition for the prophylactic or radical treatment of diabetes mellitus containing n. Hydrate 2.5 oxalate teneliglyptin or n. Hydrate 3.0 oxalate teneliglyptin, having a concentration in the range from 0.5 wt.% To 80 wt.%, And at least one or more pharmaceutically acceptable diluents having a concentration in the range from 10 wt.% to 95 wt.% and selected from the group consisting of mannitol, lactose and starch; binders having a concentration in the range from 0.1 wt.% to 10 wt.% and selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, povidone, ethyl cellulose and hypromellose; lubricants having a concentration in the range from 0.1 wt.% to 20 wt.% and selected from the group consisting of glyceryl dibehenate and magnesium stearate; disintegrants having a concentration in the range from 0.1 wt.% to 30 wt.% and selected from the group consisting of hydroxypropyl cellulose with a low degree of substitution and sodium starch glycolate; and optionally stabilizing agents having a concentration ranging from 0.05 wt% to 30 wt% selected from the group consisting of oxalic acid, beta cyclodextrin, hydroxypropyl beta cyclodextrin, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose and EDTA. 2. A pharmaceutical composition according to claim 1, characterized in that said n in the hydrate is from 1.0 to 4.0. 3. Pharmaceutical composition for prophylactic or radical treatment of diabetes mellitus, containing: from 5 wt.% To 15.0 wt.% N. Hydrate 3.0 oxalate teneligliptin; 30 wt% to 80 wt% of a diluent selected from mannitol and starch; from 0.1 wt.% to 10 wt.% of a binder selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose; from 1.0 wt.% to 15.0 wt.% a lubricant selected from magnesium stearate and glyceryl dibehenate; 1.0 wt% to 20 wt% a disintegrant selected from low substituted hydroxypropyl cellulose and sodium starch glycolate; and optionally from 0.5 wt% to 15 wt% oxalic acid. 4. A pharmaceutical composition according to claim 3, wherein said n in the hydrate is from 1.0 to 4.0. 5. A method of obtaining a pharmaceutical composition according to PP. 1-3, including stages: (a) sieving teneliglyptin n.hydrate 2.5 oxalate or teneligliptin n.hydrate 3.0 oxalate with pharmaceutically acceptable excipients; (b) granulating the screened material obtained in step (a) with a binder solution; (c) drying and sieving the granulate obtained in step (b); (d) lubricating the sieved granulate obtained in step (c) with a suitable lubricating agent to form a mixture; and (e) compressing the lubricated mixture obtained in step (d) into a tablet or filling capsules with the mixture obtained in step (d). 6. The method according to claim 5, characterized in that n is from 1.0 to 4.0.

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