JP2019512460A - Preparation containing oxalate salt of teneligliptin and solvate thereof - Google Patents

Abstract

The present invention relates to a pharmaceutically acceptable formulation comprising oxalate of tenelligliptin and a solvate thereof. Also provided is the combination with a biguanide and the use of a pharmaceutically acceptable formulation for the management of glucose metabolism disorders.
[Selected figure] Figure 4

Description

  The present invention relates to a pharmaceutically acceptable formulation comprising oxalate of tenelligliptin and a solvate thereof, optionally comprising an additional biguanide-based molecule. Also provided is the use of the formulation in a patient in need of treatment of a glucose metabolism disorder.

  A dipeptidyl peptidase-4 (DPP-IV) inhibitor is a class of antidiabetic that functions by inhibiting the degradation of incretin, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) It is a medicine. These compounds are generally referred to as "gliptin".

  DPP-IV inhibitors are generally used in combination therapy with other antidiabetic agents.

  There is a need in the art for the provision of new and stable formulations that are highly effective and exhibit improved stability and processability.

  In one embodiment of the present invention, an oxalate salt of a compound of formula (I) and a solvate thereof as described below and at least one of a pharmaceutically acceptable carrier, diluent, binder, lubricant, disintegrant and stabilizer. One or more pharmaceutical compositions are provided. 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 salt of stearyl fumaric acid, magnesium stearate, stearic acid, glyceryl palmitostearate, etc., 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 yet another embodiment, the stabilizer is selected from among at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof.

In one aspect of this embodiment,
(A) The oxalate salt of Compound (I) and a solvate thereof are selected from tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof,
(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 low substituted hydroxypropyl cellulose, crospovidone, or croscarmellose sodium,
(F) The pharmaceutical composition is provided, wherein the stabilizer is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA, and a combination thereof.

In another aspect of this embodiment,
(A) The oxalic acid salt of Compound (I) and a solvate thereof are tenelligliptin 3.0 oxalic acid salt n-hydrate (n is 1.0 to 4.0),
(B) the diluent is mannitol,
(C) the binder is hypromellose,
(D) The lubricant is glyceryl dibehenate,
(E) The disintegrant is low substituted hydroxypropyl cellulose,
(F) A pharmaceutical composition is provided wherein the stabilizer is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA, and combinations thereof.

In another aspect of this embodiment,
(A) The oxalic acid salt of Compound (I) and a solvate thereof are tenelligliptin 3.0 oxalic acid salt n-hydrate (n is 1.0 to 4.0),
(B) the diluent is lactose,
(C) the binder is hypromellose,
(D) The lubricant is glyceryl dibehenate,
(E) The disintegrant is low substituted hydroxypropyl cellulose,
(F) A pharmaceutical composition is provided wherein the stabilizer is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA, and combinations thereof.

  In one embodiment of the present invention, about 0.5% to about 80.0% by weight of oxalate of compound (I) and a solvate thereof, and about 10% to about 95% by weight of a diluent 0.1% to about 10.0% by weight of a binder, about 0.1% to about 20.0% by weight of a lubricant, about 0.1% to about 30% by weight of a disintegrant, and about 0 There is provided a pharmaceutical composition comprising about .05% to about 30% by weight of a stabilizer. In one aspect, the oxalate salt of Compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof. In another aspect of this embodiment, the solvate is an n-hydrate. In still another aspect of this embodiment, the oxalate salt of compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate n-hydrate or teneligliptin 3.0 oxalate n-hydrate , N is 1.0 to 4.0.

  In one embodiment of the present invention, about 5% to about 40.0% by weight of the oxalate salt of Compound (I) and a solvate thereof, about 15% to about 95% by weight of a diluent and about 0. 5%. 1% to about 10% by weight of a binder, about 0.1% to about 20.0% by weight of a lubricant, about 0.1% to about 30% by weight of a disintegrant, about 0.1% to A pharmaceutical composition is provided comprising about 20% by weight of a stabilizer. In one aspect, the oxalate salt of Compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof. In another aspect of this embodiment, the solvate is an n-hydrate. In still another aspect of this embodiment, the oxalate salt of compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate n-hydrate or teneligliptin 3.0 oxalate n-hydrate , N is 1.0 to 4.0.

  In one embodiment of the present invention, about 5% to about 40.0% by weight of the oxalate salt of Compound (I) and a solvate thereof, and about 30% to about 80% by weight of a diluent; 1% to about 10% by weight of a binder, about 0.1% to about 20.0% by weight of a lubricant, about 0.1% to about 30% by weight of a disintegrant, about 0.1% to A pharmaceutical composition is provided comprising about 20% by weight of a stabilizer. In one aspect, the oxalate salt of Compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof. In another aspect of this embodiment, the solvate is an n-hydrate. In still another aspect of this embodiment, the oxalate salt of compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate n-hydrate or teneligliptin 3.0 oxalate n-hydrate , N is 1.0 to 4.0.

  In one embodiment of the present invention, about 5% to about 15.0% by weight of tenelligliptin 3.0 oxalate n-hydrate, about 30% to about 80% by weight of a diluent, and about 0.1% To about 10% by weight of a binder, about 1.0% to about 15.0% by weight of a lubricant, about 1.0% to about 20% by weight of a disintegrant, and about 0.5% to about 15 There is provided a pharmaceutical composition comprising weight percent of a stabilizer.

  In an embodiment of the present invention, about 0.5% to about 10.0% by weight of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0); About 0.5% to about 10% by weight of a diluent, about 0.1% to about 10% by weight of a binder, about 0.5% to about 5.0% by weight of a lubricant; A pharmaceutical composition is provided that comprises, by weight, a disintegrant, about 0.1% to about 10% by weight of a stabilizer, and one or more antidiabetic agents.

  In one aspect, the one or more antidiabetic agents contained in the pharmaceutical composition of the present invention are sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, alpha glucosidase inhibitor compounds And salts thereof, SGLT2 inhibitor compounds and salts thereof, and combinations thereof.

  In one embodiment of the invention, the pharmaceutical composition comprises a stabilizer, which is oxalic acid present in an amount of about 0.5% to about 5.0% by weight.

  In one embodiment of the invention, the pharmaceutical composition comprises a stabilizer, wherein the stabilizer is β-cyclodextrin present in an amount of about 0.5% to about 5.0% by weight.

  In one embodiment of the invention, the pharmaceutical composition comprises a stabilizer, wherein the stabilizer is hydroxypropyl cellulose present in an amount of about 0.1% to about 5.0% by weight.

  In one embodiment of the invention, the pharmaceutical composition comprises a stabilizer, wherein the stabilizer is EDTA present in an amount of about 0.5% to about 5.0% by weight.

  In one embodiment of the present invention, the oxalate salt of the compound of formula (I) described below contained in the pharmaceutical composition of the present invention is 5.68 °, 6.56 °, 16.44 °, 17.72 ° , 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ, characterized by an X-ray powder diffraction pattern comprising teneri-gliptin 2.5 shu It is an acid salt n hydrate (n is 1.0 to 4.0).

  In one embodiment of the present invention, the oxalate salt of the compound of formula (I) described below contained in the pharmaceutical composition of the present invention is 5.69 °, 6.57 °, 16.43 °, 17.71 ° , Teriogramliptin 3.0 oxalate n-hydrate (where n is 1) characterized by an X-ray powder diffraction pattern including reflections of 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ 0 to 4.0).

  In one embodiment, provided is a pharmaceutical composition comprising an oxalate salt represented by a compound of Formula (I) as described below.

  In one aspect of the pharmaceutical composition of the present invention, the oxalate salt of the compound of the following formula (I) and the solvate thereof contained in the pharmaceutical composition of the present invention are substantially pure.

In one embodiment of the present invention, an oxalate salt of a compound represented by formula (I) is provided.

  Also, the oxalate salt and its solvate, sulfonylurea compound and its salt, glitazone compound and its salt, biguanide compound and its salt, α-glucosidase inhibitor compound and its salt, SGLT2 inhibitor compound and There is provided a pharmaceutical composition comprising one or more antidiabetic agents selected from the group consisting of salts thereof and combinations thereof. In one aspect of this embodiment, the pharmaceutical composition comprises a sulfonylurea-based compound, including glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide and the like. In another aspect of this embodiment, the pharmaceutical composition comprises a glitazone-based compound, including pioglitazone, rosiglitazone, and the like. In another aspect of this embodiment, the pharmaceutical composition comprises a biguanide compound comprising metformin, buformin, phenformin etc., or a pharmaceutically acceptable salt thereof. In another aspect of this embodiment, the pharmaceutical composition comprises an alpha glucoside inhibitor based compound comprising voglibose, acarbose, miglitol and the like. In another aspect of this embodiment, the pharmaceutical composition comprises SGLT2 inhibitor-based compounds, including remogliflozin, dapagliflozin, canagliflozin, empagliflozin, luceogliflozin, etc., and salts, esters or solvates thereof. Including.

  In one embodiment of the present invention, tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) and delayed release metformin, comprising tenelligliptin2. A pharmaceutical composition is provided wherein the w / w ratio of 5 oxalate n-hydrate to metformin is in the range of 1:10 to 1:50.

  In one embodiment of the present invention, it comprises teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) and delayed release metformin; Provided is a pharmaceutical composition wherein the w / w ratio of 0 oxalate n hydrate to metformin is in the range of 1:10 to 1:50.

  In one embodiment of the present invention, a mixture of teneligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) And metformin, wherein the w / w ratio of the mixture to metformin is in the range of 1:10 to 1:50.

  In one embodiment of the invention, oxalic acid of the compound of formula (I) is oxalic acid of at least 99% purity, wherein the content of the compound of formula (II) described below is less than 1.0%. Provided is a pharmaceutical composition comprising an acid salt and a solvate thereof.

In one aspect of the invention:
(I) (a) Oxalate salt of a compound of formula (I) and solvate thereof, (b) Tenelligliptin 2.5 oxalate salt wherein n is 1.0 to 4.0, preferably 1.0 at least one of n hydrate, (c) n is 1.0 to 4.0, preferably 1.0, and tenelligliptin 3.0 oxalate n hydrate;
(Ii) sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof, and combinations thereof At least one antidiabetic agent selected from the group consisting of
(Iii) Provided are pharmaceutical compositions comprising at least one or more pharmaceutically acceptable carriers, diluents and excipients.

  In another aspect of the invention, (i) an oxalate salt of a compound of formula (I) and a solvate thereof, or (ii) tenelligliptin 2 wherein n is from 1.0 to 4.0, preferably 1.0 .5 oxalate n-hydrate, or (iii) tenelligliptin 3.0 oxalate n-hydrate, or (iv) n is 1 where n is 1.0 to 4.0, preferably 1.0 Tenelligliptin 2.5 oxalate n-hydrate and tenelligliptin 3.0 oxalate n-hydrate, or (v) from (i) to (iv) And any one of sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof, and a combination thereof A pharmaceutical composition is provided, comprising at least one or more anti-diabetic agents selected from the group consisting of combinations, for use in the prophylactic or therapeutic treatment of glucose metabolism disorders in a patient.

  In yet another aspect of the invention, (i) an oxalate salt of a compound of formula (I) and a solvate thereof, or (ii) n is from 1.0 to 4.0, preferably 1.0 Tenelligliptin 2.5 oxalate n-hydrate, or (iii) Tenelligliptin 3.0 oxalate n-hydrate, or (iv) n, wherein n is from 1.0 to 4.0, preferably 1.0 Tenelligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate, or (v) (i) to (iv), wherein And sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof, and For preventing or treating a patient with a glucose metabolism disorder, which comprises administering a pharmaceutical composition comprising at least one or more antidiabetic agents selected from the group consisting of combinations of physiologically relevant amounts Methods are provided.

  This summary is not intended to identify essential components of the claimed subject matter, nor is it intended to determine or limit the scope of the claimed subject matter.

  An object of the present invention is to provide a pharmaceutically acceptable formulation comprising oxalate of tenelligliptin and a solvate thereof, which has excellent processability.

  The object of the present invention is to provide a pharmaceutically acceptable formulation comprising the oxalate salt of teneligliptin and its solvate with excellent stability.

  Still another object of the present invention is oxalic acid salt of tenelligliptin and a solvate thereof, a sulfonylurea compound and a salt thereof, a glitazone compound and a salt thereof, a biguanide compound and a salt thereof, an alpha glucosidase inhibitor compound and A pharmaceutically acceptable agent having superior characteristics such as processability and stability, including one or more antidiabetic agents selected from the salts thereof, SGLT2 inhibitor compounds and salts thereof, and combinations thereof It is provision of a formulation.

  Still another object of the present invention includes tenelligliptin oxalate and a solvate thereof, and optionally, a sulfonylurea compound and a salt thereof, a glitazone compound and a salt thereof, a biguanide compound and a salt thereof, α Treatment of glucose metabolism disorder in a patient, comprising at least one or more antidiabetic agents selected from the group consisting of glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof, and combinations thereof It is a provision of a pharmaceutically acceptable formulation useful for control.

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

5 depicts the X-ray powder diffraction pattern of crystalline form of tenerigliptin 2.5 oxalate n-hydrate, according to an embodiment of the present invention.

4 depicts differential scanning calorimetry of crystalline form of tenelligliptin 2.5 oxalate n-hydrate, according to an embodiment of the present invention.

4 depicts an FT-IR spectrum of tenelligliptin 2.5 oxalate n-hydrate in crystalline form, according to an embodiment of the present invention.

5 depicts an X-ray powder diffraction pattern of tenelligliptin 3.0 oxalate n-hydrate in crystalline form according to an embodiment of the present invention.

5A-5B depict differential scanning calorimetry of crystalline form of tenelligliptin 3.0 oxalate n-hydrate, according to an embodiment of the present invention.

10 depicts FI-IR spectra of tenelligliptin 3.0 oxalate n-hydrate in crystalline form, according to an embodiment of the present invention.

  One of ordinary skill in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The present invention also includes all the steps, features, compositions and methods as mentioned or indicated herein, individually or collectively, and any combination of two or more of the steps or features. including.

[Definition]
For convenience, before describing the invention in detail, certain terms used in the specification and examples are collected here. These definitions should be interpreted as understood by a person skilled in the art in the remaining disclosure herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless limited in specific instances, the terms used throughout the specification are defined as follows.

  The terms used herein are defined as follows. If the definitions set forth in the present application do not match the definitions set forth in the non-provisional patent application subsequent to claiming priority of this provisional patent application, the non-provisional patent application definition supersedes the meaning of the term. Ru.

  The term "solvate" means an aggregate (aggregate) of solute ions or molecules with one or more solvent molecules. Solvates are, but not limited to, acetone solvates, ethanol solvates, methanol solvates, butanol solvates, TBA solvates, chloroform solvates, and other organic and inorganic solvates is there.

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

  As used in the specification and claims, the singular form includes the plural, unless specifically stated otherwise.

  The disclosure of the present invention is not limited in scope by the specific embodiments described herein, which are intended for illustration only.

  The terms "salt" or "pharmaceutically acceptable salt" as used herein are suitable or inappropriate for contact use with human and lower animal tissues within the scope of sound medical judgment. It is intended to mean those salts that are free of toxicity, irritation and allergic reactions, correspond to reasonable benefit to risk ratios, and are effective in their use.

  The term "crystalline form" as used herein means having a regular repeating arrangement of molecules or outer surface.

  The term "non-crystalline form" as used herein means essentially no regular repeating arrangement of molecules or outer surface.

  Unless stated otherwise, the percentages stated throughout this specification are weight / weight (w / w) percentages.

  The term stabilizer as used herein means a pharmaceutically acceptable pharmaceutical additive which stabilizes the pharmaceutical composition and which limits and prevents chemical degradation of the active pharmaceutical ingredient contained in the above mentioned composition. .

  The term "clinically effective amount" is intended to mean an amount of the oxalate salt of the compound of formula (I) or a solvate thereof that produces a biological response in a tissue of a patient.

  The term "prophylactic" in the context of treatment is the oxalate salt of a compound of formula (I) or a solvate thereof which prevents or reduces the occurrence of a glucose metabolism disorder in a patient or the onset of clinical symptoms of a glucose metabolism disorder in a patient. Intended to mean the quantity of things.

  The term "therapeutic" in the context of treatment is intended to mean the amount of the oxalate salt of the compound of formula (I) or a solvate thereof, which treats or manages a glucose metabolism disorder in a patient.

  Unless otherwise stated, the term "metformin" as used herein means metformin, a pharmaceutically acceptable salt thereof or a hydrate thereof.

  The term "pharmaceutical additive" generally refers to substances other than pharmaceutically active ingredients included in the manufacturing process or included in the dosage form of the finished pharmaceutical product.

  The term "carrier" generally refers to any substance or base used in the process of drug delivery that is useful for improving the selectivity, efficacy and / or safety of drug administration.

  The term "glucose metabolic disorder" is intended to encompass various metabolic disorders involving glucose in humans, such as diabetes mellitus, hyperglycemia, hypoglycemia, diabetes and the like. Additionally, diabetes mellitus includes type I and type II diabetes.

  The term "diluent" generally refers to a filler / diluent that can be used to increase bulk volume or improve flow characteristics.

3-{(2S, 4S) -4- [4- (3-Methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine is a compound of the formula (I And is interchangeably referred to as tenelligliptin or a compound of formula (I) throughout the disclosure.

またはその溶媒和物と、薬学的に許容できる担体、希釈剤、結合剤、潤滑剤、崩壊剤および安定剤の少なくとも一または複数と、を含む医薬組成物を提供する。一実施形態では、溶媒和物は、好ましくはｎ水和物（ｎは１．０〜４．０）である。好適な実施形態では、ｎは１．０である。本実施形態の一側面では、希釈剤は、マンニトール、ソルビトール、キシリトール、デンプン、ラクトース、セルロース、リン酸二水素カルシウム等からなる群から選択され、好ましくはマンニトールまたはラクトースである。他の一側面では、結合剤は、ヒドロキシプロピルセルロース、ポリビニルアルコール、ポビドン、コポビドン、エチルセルロース、ヒプロメロース等からなる群から選択され、好ましくはヒプロメロースまたはヒドロキシプロピルセルロースである。本実施形態のもう一つの側面では、潤滑剤はジベヘン酸グリセリル、ステアリルフマル酸のナトリウムまたはカルシウム塩、ステアリン酸マグネシウム、ステアリン酸、パルミトステアリン酸グリセリル等であり、好ましくはジベヘン酸グリセリルである。本実施形態の他の面では、崩壊剤は、低置換ヒドロキシプロピルセルロース、クロスポビドン、クロスカルメロースナトリウム、デンプングリコール酸ナトリウム等からなる群から選択され、好ましくは低置換ヒドロキシプロピルセルロースである。更に他の実施形態では、安定剤は、少なくとも１つの安定剤、少なくとも１つの錯化剤、少なくとも１つのポリマー、少なくとも１つのキレート剤、およびそれらの組合せのうちから選択される。 In one embodiment, the present invention relates to the oxalate salt of the compound of formula (I)

Or a pharmaceutical composition comprising a solvate thereof and at least one or more of a pharmaceutically acceptable carrier, a diluent, a binder, a lubricant, a disintegrant and a stabilizer. In one embodiment, the solvate is preferably n-hydrate (n is 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, 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 salt of stearyl fumaric acid, 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 still other embodiments, the stabilizer is selected from among at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof.

  In one embodiment, the pharmaceutical composition comprises tenelligliptin 2.5 oxalate n-hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition comprises tenelligliptin 2.5 oxalate 1.0 hydrate.

  In one embodiment, the pharmaceutical composition comprises tenelligliptin 3.0 oxalate n-hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition comprises tenelligliptin 3.0 oxalate 1.0 hydrate.

  In yet another embodiment, the pharmaceutical composition comprises tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0), tenerigliptin 3.0 oxalate n-hydrate (n is 1 And.). In a preferred embodiment, the pharmaceutical composition comprises tenelligliptin 2.5 oxalate monohydrate and tenelligliptin 3.0 oxalate monohydrate.

  In one embodiment, the solvate of oxalate of tenelligliptin included in the pharmaceutical composition is 10-100% pure. In another embodiment, the level of purity is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another embodiment, the purity is 50-100%. In another embodiment, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another embodiment, the purity is 80-100%. In another embodiment, the purity is 90-100%. In another embodiment, the purity is greater than 99%. In another embodiment, the purity is greater than 99.5%. In one embodiment, the oxalate solvate of tenelligliptin included in the pharmaceutical composition is substantially pure.

  In one embodiment, tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) included in the pharmaceutical composition is 10 to 100% pure. In another embodiment, the level of purity is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another embodiment, the purity is 50-100%. In another embodiment, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another embodiment, the purity is 80-100%. In another embodiment, the purity is 90-100%. In another embodiment, the purity is greater than 99%. In another embodiment, the purity is greater than 99.5%. In one embodiment, tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) included in the pharmaceutical composition is substantially pure.

  In one embodiment, tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) included in the pharmaceutical composition is 10 to 100% pure. In another embodiment, the level of purity is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another embodiment, the purity is 50-100%. In another embodiment, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another embodiment, the purity is 80-100%. In another embodiment, the purity is 90-100%. In another embodiment, the purity is greater than 99%. In another embodiment, the purity is greater than 99.5%. In one embodiment, tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) included in the pharmaceutical composition is substantially pure.

  Tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) contained in the pharmaceutical composition described herein is in a crystalline form.

  Tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) contained in the pharmaceutical composition described herein is in a crystalline form.

  Tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) contained in the pharmaceutical composition described herein is in non-crystalline form.

  Tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) contained in the pharmaceutical composition described herein is in non-crystalline form.

  In one embodiment of the present invention, teneligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably n is 1.0) is 5.68 °, 6.56 °, X-ray powder diffraction pattern including reflection at 16.44 °, 17.72 °, 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ A pharmaceutical composition is provided which is characterized by and has the X-ray powder diffraction pattern represented in FIG.

  In one embodiment of the present invention, tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably n is 1.0) is represented by the DSC curve of FIG. A pharmaceutical composition is provided, characterized by a differential scanning calorimetry (DSC) thermogram exhibiting endotherms at 76 ° C and 169.68 ° C.

In one embodiment of the present invention, tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably n is 1.0) is shown in FIG. Provided is a pharmaceutical composition characterized by an infrared absorption (IR) peak of: 77, 2540.88, 1721.37, 1650.04, 1207.43, 922.34, 708.96, 477.35 cm ¹ .

  In one embodiment of the present invention, teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably n is 1.0) is 5.69 °, 6.57 °, Characterized by an X-ray powder diffraction pattern comprising reflections at 16.43 °, 17.71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ, represented in FIG. A pharmaceutical composition is provided having an X-ray powder diffraction pattern.

  In one embodiment of the present invention, teneligliptin 3.0 oxalate n-hydrate (where n is 1.0 to 4.0, preferably n is 1.0) is represented by the DSC curves of FIGS. 5A and 5B. A pharmaceutical composition is provided, characterized by a differential scanning calorimetry (DSC) thermogram exhibiting endotherms at 177.34 ° C and 171.6 ° C.

In one embodiment of the present invention, tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably n is 1.0) is shown in FIG. .34, 2537. 55, 1911. 30, 1720. 10, 1651.64, 1456. 82, 1363.34, 1209.29, 922. 88, 709. 74, 475. 21 cm- ¹ infrared absorption (IR 2.) A pharmaceutical composition is provided, characterized by a peak.

  In one embodiment, tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0) and at least one or more of a pharmaceutically acceptable carrier, diluent and excipient Pharmaceutical compositions are provided. In a preferred embodiment, n is 1.0.

  In one particular embodiment, a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate (n is from 1.0 to 4.0) which is a salt present in crystalline or non-crystalline form Is provided.

  In one embodiment, having the X-ray powder diffraction pattern represented in FIG. 4, 5.69 °, 6.57 °, 16.43 °, 17.71 °, 21.66 °, 23.15 °, Containing teneri-gliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0) characterized by an X-ray powder diffraction pattern including a reflection of 23.86 °, 24.99 ° ± 2θ Pharmaceutical compositions are provided.

  In yet another embodiment, a pharmaceutical composition is provided comprising substantially pure tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0).

  In one embodiment, the present invention is pharmaceutically acceptable, with tenelligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0) There is provided a pharmaceutical composition comprising at least one or more of a carrier, a diluent and an excipient. In another aspect of this embodiment, n is 1.0. In a preferred aspect of this embodiment, tenelligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate are substantially pure.

In one embodiment, the present invention relates to an oxalate salt of a compound of formula (I)
a. At least one stabilizer,
b. At least one complexing agent,
c. At least one polymer,
d. At least one chelating agent,
e. And a combination thereof.

  In a preferred embodiment, the pharmaceutical composition further comprises 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.

  In a preferred embodiment, the pharmaceutical composition further comprises α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, their derivatives and combinations thereof And at least one complexing agent selected from the group consisting of

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

  In a preferred embodiment, the pharmaceutical composition further comprises 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, the polymer is hydroxypropyl cellulose.

  In one embodiment, the pharmaceutical composition further comprises at least one chelating agent selected from the group consisting of EDTA, zinc sulfate, iron ascorbate, calcium carbonate, sodium chloride, potassium chloride and combinations thereof. In a more preferred embodiment, the chelating agent is EDTA.

  In one embodiment, the pharmaceutical composition further comprises a stabilizer and at least one polymer. The stabilizer is oxalic acid. The polymer is selected from the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose and combinations thereof, preferably hydroxypropyl cellulose.

  In a preferred embodiment, the pharmaceutical composition further comprises at least one stabilizer, at least one polymer and at least one complexing agent. In one embodiment, the stabilizer is oxalic acid. In another embodiment, the polymer is selected from 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, the complexing agent is selected from the group consisting of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and combinations thereof, preferably hydroxypropyl-β-cyclodextrin.

  In a preferred embodiment, the pharmaceutical composition of the invention further comprises at least one polymer and at least one chelating agent. In one embodiment, the polymer is selected from 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, the chelating agent is selected from the group consisting of EDTA, zinc sulfate, iron ascorbate, calcium carbonate, sodium chloride, potassium chloride and combinations thereof, preferably EDTA.

In one embodiment, the present invention
(A) The oxalate salt of Compound (I) and a solvate thereof are selected from tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof,
(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 pharmaceutical composition comprising a disintegrant selected from low substituted hydroxypropyl cellulose, crospovidone, or croscarmellose sodium.

In one embodiment, the present invention
(A) An oxalic acid salt of Compound (I) and a solvate thereof, which are teneligliptin 3.0 oxalate n hydrate (n is 1.0 to 4.0)
(B) a diluent which is mannitol;
(C) a binder which is hypromellose,
(D) a lubricant which is glyceryl dibehenate,
(E) a disintegrant which is low substituted hydroxypropyl cellulose,
(F) A pharmaceutical composition is provided comprising a stabilizer selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA, and combinations thereof.

In one embodiment, the present invention
(A) Tenelliliptin 3.0 oxalate n hydrate (n is 1.0 to 4.0) The oxalate of compound (I) and its solvate,
(B) a diluent which is lactose;
(C) a binder which is hypromellose,
(D) a lubricant which is glyceryl dibehenate,
(E) a disintegrant which is low substituted hydroxypropyl cellulose,
(F) A pharmaceutical composition is provided comprising a stabilizer selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA, and combinations thereof.

  In one embodiment of the present invention, about 0.5% to about 80.0% by weight of oxalate of compound (I) and a solvate thereof, and about 10% to about 95% by weight of a diluent 0.1% to about 10.0% by weight of a binder, about 0.1% to about 20.0% by weight of a lubricant, about 0.1% to about 30% by weight of a disintegrant, and about 0 There is provided a pharmaceutical composition comprising about .05% to about 30% by weight of a stabilizer.

  In one embodiment of the present invention, about 5% to about 40.0% by weight of the oxalate salt of Compound (I) and a solvate thereof, about 15% to about 95% by weight of a diluent and about 0. 5%. 1% to about 10% by weight of a binder, about 0.1% to about 20.0% by weight of a lubricant, about 0.1% to about 30% by weight of a disintegrant, about 0.1% to A pharmaceutical composition is provided comprising about 20% by weight of a stabilizer.

  In one embodiment of the present invention, about 5% to about 40.0% by weight of the oxalate salt of Compound (I) and a solvate thereof, and about 30% to about 80% by weight of a diluent; 1% to about 10% by weight of a binder, about 0.1% to about 20.0% by weight of a lubricant, about 0.1% to about 30% by weight of a disintegrant, about 0.1% to A pharmaceutical composition is provided comprising about 20% by weight of a stabilizer.

  In one embodiment of the present invention, about 5% to about 15.0% by weight of tenelligliptin 3.0 oxalate n-hydrate, about 30% to about 80% by weight of a diluent, and about 0.1% To about 10% by weight of a binder, about 1.0% to about 15.0% by weight of a lubricant, about 1.0% to about 20% by weight of a disintegrant, and about 0.5% to about 15 There is provided a pharmaceutical composition comprising weight percent of a stabilizer. In one aspect of this embodiment, tenelligliptin 3.0 oxalate n-hydrate is the crystalline form of tenelligliptin 3.0 oxalate n-hydrate, and n is 1.0 to 4.0.

  In an embodiment of the present invention, about 0.5% to about 10.0% by weight of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0); About 0.5% to about 10% by weight of a diluent, about 0.1% to about 10% by weight of a binder, about 0.5% to about 5.0% by weight of a lubricant; A pharmaceutical composition is provided that comprises, by weight, a disintegrant, about 0.1% to about 10% by weight of a stabilizer, and one or more antidiabetic agents. In one aspect of this embodiment, tenelligliptin 3.0 oxalate n-hydrate is the crystalline form of tenelligliptin 3.0 oxalate n-hydrate, and n is 1.0 to 4.0.

  In one embodiment, the present invention provides a pharmaceutical composition comprising substantially pure oxalate of a compound of formula (I) and a solvate thereof.

  In another embodiment, the present invention provides a pharmaceutical composition, wherein the purity of oxalate of the compound of formula (I) is more than 98.0%.

  In another embodiment, the present invention provides a pharmaceutical composition, wherein the oxalate purity of the compound of formula (I) is greater than 99.0%.

  In another embodiment, the present invention provides a pharmaceutical composition, wherein the purity of oxalate of the compound of formula (I) is more than 99.5%.

  In one embodiment, the present invention provides a substantially pure formula (wherein the oxalate salt of the compound of formula (I) is tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof There is provided a pharmaceutical composition comprising the oxalate salt of the compound of I) and a solvate thereof.

  In one embodiment, the present invention also provides sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof And at least one antidiabetic agent selected from the group consisting of and combinations thereof.

  In one embodiment, the present invention relates to oxalic acid salt of a compound of formula (I) and solvates thereof, sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, alpha glucosidase There is provided a pharmaceutical composition comprising at least one or more antidiabetic agents selected from the group consisting of inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof, and combinations thereof.

  In one embodiment, the sulfonylurea-based compound used in the pharmaceutical composition of the present invention comprises glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide and the like. In a preferred embodiment, the sulfonylurea compound is glimepiride.

  In one embodiment, the glitazone-based compound used in the pharmaceutical composition of the present invention includes pioglitazone, rosiglitazone and the like. In a preferred embodiment, the glitazone-based compound is pioglitazone.

  In another embodiment, the alpha glucosidase inhibitor based compounds used in the pharmaceutical composition of the present invention include voglibose, acarbose, miglitol and the like. In a preferred embodiment, the alpha-glucosidase inhibitor is voglibose.

  In one embodiment, SGLT2 inhibitor-based compounds include remogliflozin, dapagliflozin, canagliflozin, empagliflozin, ruseogliflozin, and the like.

  In one embodiment, biguanide-based compounds include metformin, buformin, phenformin and the like. In a preferred embodiment, the member of the biguanide-based molecule is metformin or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the member of the biguanide-based molecule is metformin hydrochloride. In yet another embodiment, the members of the biguanide-based molecule are a mixture of metformin and metformin hydrochloride.

  In one embodiment, the metformin moiety of the pharmaceutical composition of the present invention is an immediate release layer or a delayed release layer. In one embodiment, the metformin moiety included in the pharmaceutical composition is an immediate release layer. In a preferred embodiment, the metformin moiety included in the pharmaceutical composition is a delayed release layer. In yet another embodiment, the metformin included in the pharmaceutical composition is a mixture of immediate and delayed release layers of metformin.

  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.

The pharmaceutical composition of the present invention comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent or a combination thereof stabilizes a solvate of tenelligliptin oxalate To prevent the formation of the compound of formula (II) in the pharmaceutical composition.

  In one embodiment, at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof, and tenerigliptin 2.5 oxalate n-hydrate (n is 1 A pharmaceutical composition is provided which has the function of stabilizing .0 to 4.0, preferably 1.0).

  In one embodiment, comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof, and tenerigliptin 3.0 oxalate n-hydrate (n is 1 A pharmaceutical composition is provided which has the function of stabilizing .0 to 4.0, preferably 1.0).

  In one embodiment, at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof, tenerigliptin 2.5 oxalate n-hydrate and teneligliptin 3. A pharmaceutical composition is provided which has the function of stabilizing a mixture of n-oxalate n hydrate (n is 1.0 to 4.0, preferably 1.0).

  In one embodiment, the oxalate salt of a compound of formula (I) and solvates thereof, wherein the oxalate salt is at least 99% pure and the content of compound of formula (II) is less than 1.0%. A pharmaceutical composition comprising the substance is provided.

  In one embodiment, the oxalate salt of a compound of formula (I) and its oxalate salt, wherein the oxalate salt is at least 99.5% pure and the content of compound of formula (II) is less than 0.5% Pharmaceutical compositions comprising a solvate are provided.

  In one embodiment, the oxalate salt of a compound of formula (I) and its oxalate salt, wherein the oxalate salt is at least 99.9% pure and the content of compound of formula (II) is less than 0.1%. Pharmaceutical compositions comprising a solvate are provided.

  In one embodiment, a medicament comprising tenelligliptin 2.5 oxalate and a solvate thereof, wherein the oxalate is at least 99% pure and the content of the compound of formula (II) is less than 1.0%. A composition is provided.

  In one embodiment, tenerigliptin 2.5 oxalate and a solvate thereof, wherein the oxalate is at least 99.5% pure and the content of the compound of formula (II) is less than 0.5%. Pharmaceutical compositions are provided. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

  In one embodiment, a pharmaceutical composition comprising tenelligliptin 2.5 oxalate and a solvate thereof, wherein the oxalate is at least 99.9% pure and the content of impurity B is less than 0.1%. Is provided. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

  In one embodiment, a medicament comprising tenelligliptin 3.0 oxalate and a solvate thereof, wherein the oxalate is at least 99% pure and the content of the compound of formula (II) is less than 1.0%. A composition is provided. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

  In one embodiment, the oxalate is at least 99.5% pure, and the content of impurity B is 0. 01. Provided is a pharmaceutical composition comprising less than 5% of tenelligliptin 3.0 oxalate and a solvate thereof. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

  In one embodiment, a pharmaceutical composition comprising tenelligliptin 3.0 oxalate and a solvate thereof, wherein the oxalate is at least 99.9% pure and the content of impurity B is less than 0.1%. Is provided. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

  In one embodiment, the invention provides tenelligliptin 3.0 oxalate n-hydrate, wherein the oxalate is at least 99% pure and the content of compound of formula (II) is less than 1.0%. Providing a pharmaceutical composition comprising

  In one embodiment, the present invention is tenelligliptin 3.0 oxalate n water, wherein the oxalate is at least 99.5% pure and the content of the compound of formula (II) is less than 0.5%. Provided is a pharmaceutical composition comprising a solvate.

  In one embodiment, the present invention is tenelligliptin 3.0 oxalate n water, wherein the oxalate is at least 99.9% pure and the content of the compound of formula (II) is less than 0.1%. Provided is a pharmaceutical composition comprising a solvate.

  In one embodiment, the present invention is in the crystalline form, at least 99.0% purity, at least 99.5% purity, or at least 99.9% purity, and in crystalline form, Tenelligliptin 3.0 oxalate n water Provided is a pharmaceutical composition comprising a solvate.

  In one embodiment of the present invention, tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) and delayed release metformin, wherein tenerigliptin versus metformin A pharmaceutical composition is provided wherein the ratio of (w / w) is in the range of 1:10 to 1:50, preferably in the range of 1:10 to 1:40, especially about 1:15 to 1:31.

  In one embodiment of the present invention, the compound comprises teneligliptin 2.5 oxalate n-hydrate (n is from 1.0 to 4.0, preferably 1.0) and delayed release metformin, wherein the teneligliptin versus metformin A pharmaceutical composition is provided wherein the ratio of (w / w) is in the range of 1:10 to 1:50, preferably in the range of 1:10 to 1:40, especially about 1:15 to 1:31.

  In one embodiment of the present invention, a mixture of teneligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) And delayed release metformin, and the ratio of mixture to metformin (w / w) is in the range of 1:10 to 1:50, preferably 1:10 to 1:40, and more preferably about 1:15 to 1). Provides a pharmaceutical composition that is in the range of

  In a specific embodiment of the present invention, tenelligliptin 2.5 oxalate n-hydrate (n is from 1.0 to 4.0, preferably 1.0) and pharmaceutically acceptable delayed release metformin There is provided a pharmaceutical composition comprising at least one or more of a carrier, a diluent and an excipient.

  In a specific embodiment of the present invention, tenelligliptin 3.0 oxalate n-hydrate (n is from 1.0 to 4.0, preferably 1.0) and pharmaceutically acceptable delayed release metformin There is provided a pharmaceutical composition comprising at least one or more of a carrier, a diluent and an excipient.

  In a specific embodiment of the present invention, a mixture of teneligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) And a delayed release metformin, and at least one or more of a pharmaceutically acceptable carrier, a diluent and an excipient.

  The present invention provides a pharmaceutical composition for use in the prophylactic treatment of glucose metabolism in a patient.

  The present invention provides a pharmaceutical composition for use in the therapeutic treatment of glucose metabolism in a patient.

  The present invention provides a method for the prophylactic or therapeutic treatment of a patient having a glucose metabolism disorder, comprising administering the pharmaceutical composition described herein in a physiologically relevant amount.

  The present invention provides a method for the therapeutic treatment of a patient having a glucose metabolism disorder, which comprises administering the pharmaceutical composition described herein in a physiologically relevant amount.

  In one embodiment of the present invention, a pharmaceutical composition is provided which comprises granules of n-hydrate (n is 1.0 to 4.0, preferably 1.0) of tenelligliptin oxalate. In a specific embodiment, a pharmaceutical composition is provided comprising granules of tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0). In a specific embodiment, a pharmaceutical composition is provided comprising granules of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

In one embodiment, the present invention provides a process for preparing a pharmaceutical composition of an oxalate salt of a compound of formula (I), said process comprising the steps of
(A) screening the oxalate salt of a compound of formula (I) with a pharmaceutically acceptable excipient, or one or more antidiabetic agents, or a mixture thereof;
(B) granulating the sieved material in step (a) with a binder solution;
(C) drying and sieving the granules obtained in step (b);
(D) Lubricating the screened granules in step (c) with a suitable lubricant to obtain a blend;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(F) optionally compacting the lubricated blend of step (d) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture .
Step (a) of the above process involves screening of the oxalate salt of the compound of formula (I) and its solvates with suitable excipients. In one embodiment, the oxalate salt of the compound of formula (I) and a solvate thereof are teneligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt, and a solvate thereof. In a preferred embodiment, the solvate is n-hydrate. In a preferred embodiment, the oxalate salt of the compound of formula (I) and a solvate thereof are: tenelligliptin 2.5 oxalate n-hydrate or teneligliptin 3.0 oxalate n-hydrate (where n is 1.0 to 4.0, preferably 1.0).

In one embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said process comprising the steps of
(A) sieving a pharmaceutically acceptable excipient;
(B) preparing a binder solution comprising an oxalate salt of a compound of formula (I) and a solvate thereof;
(C) granulating the sieved pharmaceutically acceptable excipient of step (a) with the binder solution of step (b);
(D) drying and sieving the granules obtained in step (c);
(E) Lubricating the sieved granules in step (c) with sieved pharmaceutically acceptable excipients to obtain a blend;
(F) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(G) optionally compacting the lubricated blend of step (e) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture .

In one embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said process comprising the steps of
(A) obtaining a solution comprising an oxalate salt of a compound of formula (I) and a solvate thereof together 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 screened granules in step (c) with a pharmaceutically acceptable excipient;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule.

In one embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, said process comprising the steps of
(A) Tenelliliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0), a pharmaceutically acceptable excipient, or one or more antidiabetic agents, or Sifting with the mixture,
(B) granulating the sieved material in step (a) with a binder solution;
(C) drying and sieving the granules obtained in step (b);
(D) Lubricating the screened granules in step (c) with a suitable lubricant to obtain a blend;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(F) optionally compressing the lubricated blend of step (e) with the blend of one or more antidiabetic agents to form a tablet, or to form a capsule filler of the blended mixture .

In one embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate, said process comprising the steps of:
(A) sieving a pharmaceutically acceptable excipient;
(B) preparing a binder solution comprising tenelligliptin 3.0 oxalate n-hydrate;
(C) granulating the sieved pharmaceutically acceptable excipient of step (a) with the binder solution of step (b);
(D) drying and sieving the granules obtained in step (c);
(E) lubricating the sieved granules of step (c) with a pharmaceutically acceptable excipient to obtain a blend;
(F) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(G) optionally compacting the lubricated blend of step (d) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture .

In one embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate, said process comprising the steps of:
(A) obtaining a solution comprising tenelligliptin 3.0 oxalate n-hydrate together 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 screened granules in step (c) with a pharmaceutically acceptable excipient;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule.

  In one embodiment, granules of the oxalate salt of Compound (I) and a solvate thereof are prepared by combining the oxalate salt of Compound (I) and a solvate thereof with a suitable diluent, lubricant, binder, fluidization It can be produced from the combination with agents, disintegrants, solubilizers and the like.

  In one embodiment, the granules of tenelligliptin 2.5 oxalate and a solvate thereof, comprising tenerigliptin 2.5 oxalate and a solvate thereof, and a suitable diluent, lubricant, binder, fluidizing agent, It can be produced from a combination with a disintegrant, a solubilizer and the like.

  In one embodiment, the granules of teneligliptin 3.0 oxalate and a solvate thereof are teneligliptin 3.0 oxalate and a solvate thereof and a suitable diluent, lubricant, binder, fluidizer, It can be produced from a combination with a disintegrant, a solubilizer and the like.

  In one embodiment, the granules (n is 1.0 to 4.0, preferably 1.0) of tenelligliptin 2.5 oxalate n-hydrate is tenerigliptin 2.5 oxalate n-hydrate, It can be produced from a combination with suitable diluents, lubricants, binders, fluidizers, disintegrants, solubilizers and the like.

  In one embodiment, the granules of tenelligliptin 3.0 oxalate n-hydrate are a mixture of teneligliptin 3.0 oxalate n-hydrate and a suitable diluent, lubricant, binder, fluidizer, disintegrant And solubilizers and the like.

  Suitable binders include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose, hypromellose and the like.

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

  Suitable lubricants include, but are not limited to, glyceryl dibehenate, sodium or calcium salt of stearyl fumaric acid, magnesium stearate, stearic acid, glyceryl palmitostearate.

  The oxalate salt of the compound of formula (I) and the granules of a solvate thereof are prepared by mixing the oxalate salt of the compound of formula (I) with a pharmaceutically acceptable excipient and combining the compound of formula (I) The binder solution is added to a mixture of pharmaceutically acceptable excipients and a pharmaceutically acceptable excipient, and the wet mixture of the oxalate salt of the compound of formula (I) and the pharmaceutically acceptable excipient is dried and sieved. , Can be prepared by forming granules.

  Alternatively, the granules of the oxalate salt of the compound of formula (I) and the solvates thereof are treated in a fluid bed process after mixing the oxalate salt of the compound of formula (I) with a pharmaceutically acceptable excipient. The mixture can be prepared by spraying the binder solution in an apparatus followed by drying of the wet granules and then optionally sieving. Alternatively, the oxalate flakes of the compound of formula (I) are dry mixed with the oxalate of the compound of formula (I) and a pharmaceutically acceptable excipient to form a blend The blend can be prepared by roll compacting one or more times to form flakes, followed by granulation and sieving of the flakes. The oxalate granules or debris of the compounds of formula (I) can be lubricated using any of the above mentioned lubricants. This mixture can then be compressed with a tableting device or can be filled into capsules with a capsule filling device. Optionally, a coating can be applied to the tablet. The coating solution or suspension comprises excipients such as hypromellose, polyethylene glycol, colorants (eg red or yellow iron oxide), titanium dioxide and talcum powder. Alternatively, these tablets can be filled into capsules of appropriate size. The volume of the capsule can be suitably selected in the range of 0.13 to 1.37 ml corresponding to a lubricated blend or tablet comprising the oxalate salt of the compound of formula (I). In one aspect of the embodiments of the present invention, the oxalate salt of the compound of formula (I) used for the preparation of granules comprising tenelligliptin is tenelligliptin 3.0 oxalate salt or a solvate thereof. In one example of the embodiment, tenelligliptin 3.0 oxalate or a solvate is in crystalline form.

  Alternatively, a direct compression step to produce a tablet of tenelligliptin is also contemplated in the present invention. Tablets are prepared by mixing tenelligliptin with one or more pharmaceutically acceptable excipients to prepare a blend for direct compression, pressing the blend to form a tablet, and optionally, coating the above coating into a tablet It is prepared by applying.

  In one embodiment of the present invention there is provided a pharmaceutical composition comprising an oxalic acid salt of a compound of formula (I) and a solvate thereof, metformin or a pharmaceutically acceptable salt thereof, wherein metformin or The pharmaceutically acceptable salt content thereof is suitably in the range capable of transporting metformin in the range of 1-2000 mg, preferably 250-1000 mg, more preferably 500-1000 mg, more preferably 500 mg or 1000 mg. It can be selected. Such pharmaceutical composition comprises, in separate parts, teneligliptin and metformin. For example, a multi-layered composition in which teneligliptin and metformin are separated as a bilayer or three-layered tablet, a composition containing metformin in the core and a composition containing teneligliptin in a coating, and other similar variations are included. .

  In one embodiment of the present invention, oxalic acid salt of tenelligliptin and a solvate thereof, a sulfonylurea compound and a salt thereof, a glitazone compound and a salt thereof, a biguanide compound and a salt thereof, an alpha glucosidase inhibitor compound and a compound thereof There is provided a pharmaceutical composition comprising at least one or more antidiabetic agents selected from the group consisting of salts, SGLT2 inhibitor compounds and salts thereof, and combinations thereof, wherein the oxalate salt of teneligliptin and The weight concentration of the solvate is in the range of 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 delayed release metformin. In one embodiment, the dosage of delayed release metformin in the pharmaceutical formulation is 500 mg. In one embodiment, the dosage of delayed release metformin in the pharmaceutical formulation is 1000 mg.

  In one embodiment of the present invention, oxalic acid salt of teneligliptin and a solvate thereof (preferably teneligliptin 3.0 oxalate n-hydrate), metformin or a pharmaceutically acceptable salt thereof (preferably herein) And a delayed release type of metformin), wherein the weight ratio (w / w) of tenelligliptin to metformin in the composition is in the range of 1:10 to 1:50. In one embodiment, the weight ratio is about 1:15. In another embodiment, the weight ratio is about 1:31. In one embodiment, the dosage of teneligliptin is in the range of about 5 to 50%, preferably 20 to 40%, more preferably 25 to 35%. In one embodiment, the dosage of metformin is in the range of 100 to 2000 mg, preferably 500 to 1000 mg, more preferably 500 mg or 1000 mg.

  In one embodiment, the present invention relates to a patient in need thereof by administering to the patient a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent. A method for treating, preventing or delaying the progress of metabolic disorders, wherein the metabolic disorders are type 1 diabetes, type 2 diabetes, glucose intolerance (IGT), abnormal fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia The method is provided selected from the group consisting of: disease, weight gain, obesity, insulin resistance and metabolic syndrome.

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

  In one embodiment, the invention is a method of improving glycemic control in a patient treated with a monotherapy of antidiabetic agents, in a patient in need thereof an oxalate salt of a compound of formula (I) There is provided a method by administering a pharmaceutical composition comprising: and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof.

  In one embodiment, the present invention is a method of improving glycemic control and / or reducing fasting blood glucose, postprandial blood glucose and / or glycosylated hemoglobin HbA1c in a patient, wherein the patient is in need thereof. A method is provided by administering a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof.

  In one embodiment, the present invention is a method of treating, preventing or delaying the progression of a condition or disorder selected from the group consisting of the following complications of diabetes mellitus in a patient, comprising administering to the patient a compound of formula (I) The present invention provides a method by administering a pharmaceutical composition comprising an oxalate salt of and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof. Complications of diabetes mellitus according to the present invention include cataract, and nephropathy, retinopathy, neuropathy, learning and memory impairment, neurodegeneration or cognitive impairment, cardiovascular or cerebrovascular disorder, tissue ischemic state, diabetes Foot lesions, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart attack, cardiac rhythm disorder And capillary and macrovascular diseases such as vascular restenosis

  In one embodiment, the present invention treats, prevents or slows down the treatment, prevention or progression of pancreatic beta cell degeneration and / or pancreatic beta cell dysfunction in a patient, and / or improves pancreatic beta cell function and / or Method for recovery and / or functional recovery of pancreatic insulin secretion, in a patient in need thereof, an oxalate salt of a compound of formula (I) and at least one other antidiabetic agent or pharmaceutical thereof The method is provided by administering a pharmaceutical composition comprising a pharmaceutically acceptable salt.

  The following examples are presented to provide the most useful and understandable description of the procedural and conceptual aspects of the invention. The examples provided are merely illustrative of the invention and are not intended to limit the invention to the scope of the disclosed embodiments. Variations and changes which are obvious to one skilled in the art are considered to be within the scope and nature of the invention.

Example 1
Pharmaceutical Composition Comprising Tenelligliptin 3.0 Oxalate n-Hydrate:
The table below discloses a typical composition comprising tenelligliptin 3.0 oxalate n-hydrate (preferably monohydrate).

Table 1 provides a formulation comprising oxalic acid as a stabilizer that prevents degradation of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

[Manufacturing process]
1. Sift: Sift together tenerigliptin oxalate, L-HPC and mannitol through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: Set the process parameters of FBP appropriately and granulate the material of step 1 with the binder solution of step 2. After granulation is complete, the wet material is dried until the desired LoD is obtained.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 2 shows formulations containing oxalic acid and a polymer and a complexing agent that prevent the degradation of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) Indicates

[Manufacturing process]
1. Sieve: Pass L-HPC and mannitol together through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid, beta cyclodextrin and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: Set the process parameters of FBP appropriately and granulate the material of step 1 with the binder solution of step 2. After granulation is complete, the wet material is dried until the desired LoD is obtained.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 3 provides a formulation comprising a complexing agent to prevent degradation of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

[Manufacturing process]
1. Solution preparation: Mannitol, β-cyclodextrin and tenelligliptin oxalate are added in purified water and dissolved with stirring.
2. Spray dry the solution obtained in step 1.
3. Sift the spray dried granules through a # 030 mesh screen.
4. Sift through a # 040 mesh screen with mannitol, L-hydroxypropyl cellulose and glyceryl dibehenate.
5. Lubrication: Lubricate the granules of step 3 with the sieved in step 4 using a suitable mixing device.
6. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
7. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
8. The membrane coated tablets are packaged in blister packs.

Table 4 provides a formulation comprising a polymer to prevent degradation of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

[Manufacturing process]
1. Sieve: Pass L-HPC and mannitol together through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: Set the process parameters of FBP appropriately and granulate the material of step 1 with the binder solution of step 2. After granulation is complete, the wet material is dried until the desired LoD is obtained.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sift through a # 040 mesh screen with mannitol, L-hydroxypropyl cellulose and glyceryl dibehenate.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 5 provides a formulation comprising a polymer to prevent degradation of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

[Manufacturing process]
1. Solution preparation: Mannitol, oxalic acid and tenelligliptin oxalate are added to purified water and dissolved with stirring.
2. Spray dry the solution obtained in step 1.
3. Sift the spray dried granules through a # 030 mesh screen.
4. Sift through a # 040 mesh screen with mannitol, L-hydroxypropyl cellulose and glyceryl dibehenate.
6. Lubrication: Lubricate the granules of step 3 with the sieved in step 4 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 6 shows a formulation comprising a polymer and a chelating agent that prevents degradation of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0).

[Manufacturing process]
1. Sieve: Pass L-HPC and mannitol together through a # 060 mesh screen.
2. Preparation of binder: In purified water, add oxalic acid, EDTA and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: Set the process parameters of FBP appropriately and granulate the material of step 1 with the binder solution of step 2. After granulation is complete, the wet material is dried until the desired LoD is obtained.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

  It is obvious to one skilled in the art that the exemplary formulations disclosed in the present examples can be improved by one skilled in the art without departing from the intended teaching of the invention. Furthermore, those skilled in the art will appreciate that similar formulations optionally modified, including tenelligliptin 2.5 oxalate n-hydrate (n is from 1.0 to 4.0, preferably 1.0) It is self-evident that it is included within the scope of the disclosure herein and within the expertise of one of ordinary skill in the art.

Example 2
How to Combine Teneri Gliptin 3.0 Oxalate with Metformin HCl:
Metformin Moiety (500 mg dose): Mill metformin hydrochloride using a multimill. # 40 mesh s. s. The metformin hydrochloride and sodium carboxymethylcellulose were sieved together through a sieve. Guar Gum # 100 mesh s. s. Sift through a sieve. The sieved metformin hydrochloride, carboxymethylcellulose and guar gum were granulated for 20 minutes in a rapid mixing granulator. While stirring, methyl paraben and propyl paraben were added to purified water to prepare a binder solution. A granular mixture of metformin hydrochloride, carboxymethylcellulose and guar gum was granulated with a binder solution in a fluid bed dryer. The obtained wet granular mass was dried to obtain granular. The resulting granules were sieved on a 16 # sieve using a vibrating sieve. The oversized granules were collected and milled using a multimill. The milled granules were collected and sieved through a # 16 sieve using a vibrating sieve. The hydroxypropyl methylcellulose, pregelatinized starch, oxidized polyethylene and hydrogenated castor oil were sieved together with a # 40 sieve, and the magnesium stearate was sieved using a sieve # 40 and a vibrating sieve. The micronized granules were mixed with co-screened hydroxypropyl methylcellulose, pregelatinized starch, oxidized polyethylene and hydrogenated castor oil to prepare a lubricated premix. The milled granules were lubricated with a lubricated premix in a blender to obtain a metformin HCl blend.

  Metformin Moiety (for 1000 mg dosage form): Metformin hydrochloride was ground using a multimill to s. s. Sift through a sieve. Carboxymethylcellulose sodium was used as a # 40 mesh s. s. Sift through a sieve. Guar Gum # 100 mesh s. s. Sift through a sieve. The sieved metformin hydrochloride, carboxymethyl cellulose was granulated for 20 minutes in a rapid mixing granulator. While stirring, methyl paraben and propyl paraben were added to purified water to prepare a binder solution. Metformin hydrochloride, carboxymethylcellulose was mixed with purified water and granulated with appropriate process parameters. The resulting wet granular mass was semi-dried and sieved with 16 # sieve. The semi-dried granules were dried in a fluid bed dryer. The dried granules were sieved with sieve # 16 using a vibrating screen. The oversized granules were collected and milled using a multimill. The milled granules were collected and sieved through a # 16 sieve using a vibrating sieve. The hydroxypropyl methylcellulose and corn starch were sieved with sieve # 40 using a vibrating sieve and magnesium stearate was sieved with sieve # 60. The ground granules were lubricated with a suitable blender using co-screened hydroxypropyl methylcellulose and corn starch and sieved magnesium stearate.

Example 3
Stability of tenelligliptin 3.0 oxalate n-hydrate in formulations:
Table 7 below shows the stability profile of the formulations of Table 1 after 1 and 2 months.

  Impurity B (undesired by-product in formulation leading to loss of oxalate) even after storage at 40 ° C. ± 2 ° C. and 75% RH ± 5% RH, 2 months as shown in Table 7 above Level of less than 1% w / w tolerance level. Similar results were observed for the formulations shown in Tables 2-6. The enhanced stability of each of the formulations of Tables 1-6 is observed, inter alia, due to the presence of oxalic acid, polymers, complexing agents, chelating agents or combinations thereof. The advantageous unexpected stability of the formulations obtained by the presence of either oxalic acid, polymers, complexing agents, chelating agents or combinations thereof, is that of oxalic acid, polymers, complexing agents, chelating agents or combinations thereof It is further observed from the formulations shown below, where the level of Impurity B exceeds the acceptable level due to the lack of either.

Table 8 shows formulations that exhibit unacceptable levels of Impurity B content.

Table 9 shows the stability profile of the formulations of Table 8.

Table 10 shows formulations that exhibit unacceptable levels of Impurity B content.

Table 11 shows the stability profile of the formulations of Table 10.

Table 12 shows formulations that exhibit unacceptable levels of Impurity B content.

Table 13a shows the stability profile of the formulations of Table 12.

Table 13b shows the stability profile of the formulations of Table 12.

Example 4
Formulations containing teneligliptin 3.0 oxalate n-hydrate and glimepiride:
Table 14a represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and glimepiride.

Table 14b represents a formulation containing tenelligliptin 3.0 oxalate n-hydrate and glimepiride (monolayer strategy 2).

Summary of manufacturing process strategies for the formulations of Tables 14a-b:
1. Sift: Sift together tenericliptin oxalate, glimepiride and L-HPC and mannitol through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 14c represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and glimepiride.

Table 14d represents a formulation containing tenelligliptin 3.0 oxalate n-hydrate and glimepiride (monolayer strategy 2).

Summary of manufacturing process strategies for the formulations of Tables 14c-d:
Tenegligliptin moiety 1. Sift: Sift together tenerigliptin oxalate, L-HPC and mannitol through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
Glimepiride part 1. Sieve: Glimepiride, L-HPC and mannitol are sieved together through a # 060 mesh screen. Sift the yellow iron oxide through a # 0100 mesh screen.
2. Preparation of binder: In purified water, add Tween 80 and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. The L-hydroxypropyl cellulose and magnesium stearate are sieved together through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
Compression, Coating, Packaging: Appropriate equipment configuration using a two-layer compression apparatus to compress the mixture of lubricated tenelligliptin and glimepiride moieties. The compressed tablets are coated with an aqueous dispersion of opadry yellow. The membrane coated tablets are packaged in blister packs.

Example 5
Formulations containing teneligliptin 3.0 oxalate n-hydrate and pioglitazone:
Table 15a represents a formulation containing tenelligliptin 3.0 oxalate n-hydrate and pioglitazone (monolayer strategy 1).

Table 15b represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and pioglitazone.

Summary of manufacturing process strategies for the formulations of Tables 15a-b:
1. Sift: Sift together tenericliptin oxalate, pioglitazone and L-HPC and mannitol through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 15c represents a formulation containing tenelligliptin 3.0 oxalate n-hydrate and pioglitazone (monolayer strategy 1).

Table 15d represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and pioglitazone.

Summary of manufacturing process strategies for the formulations of Tables 15c-d:
Tenegligliptin moiety 1. Sift: Sift together tenerigliptin oxalate, L-HPC and mannitol through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
Pioglitazone part 1. Sieve: Sift together pioglitazone, L-HPC and mannitol through a # 060 mesh screen. Sift the yellow iron oxide through a # 0100 mesh screen.
2. Preparation of Binder: In purified water, add hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. The L-hydroxypropyl cellulose and magnesium stearate are sieved together through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
Compression, coating, packaging: Compress the mixture of lubricated tenelligliptin portion and pioglitazone portion with proper equipment configuration using a two-layer compression device. The compressed tablets are coated with an aqueous dispersion of opadry yellow.

Example 6
Formulations containing teneligliptin 3.0 oxalate n-hydrate and voglibose:
Table 16a represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and voglibose.

Table 16b represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and voglibose.

Summary of manufacturing process strategies for the formulations of Tables 16a-b:
1. Sift: Sieve tenelligliptin oxalate, voglibose and L-HPC and mannitol together through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
7. Compression: Compress the lubricated blend with appropriate equipment and process parameters.
8. Coating: The compressed tablet is coated with an aqueous dispersion of opadry yellow. next,
9. The membrane coated tablets are packaged in blister packs.

Table 16c represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and voglibose.

Table 16d represents a formulation comprising tenelligliptin 3.0 oxalate n-hydrate and voglibose.

Summary of manufacturing process strategies for the formulations of Tables 16c-d:
Tenegligliptin moiety 1. Sift: Sift together tenerigliptin oxalate, L-HPC and mannitol through a # 060 mesh screen.
2. Preparation of Binder: In purified water, add oxalic acid and hydroxypropyl cellulose and dissolve with stirring.
3. Granulation: The material of step 1 is granulated with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. Sieve with L-hydroxypropylcellulose and glyceryl dibehenate through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.
Boglibose part 1. Sieving: Sift together with voglibose, L-HPC and mannitol through a # 060 mesh screen. Sift the yellow iron oxide through a # 0100 mesh screen.
2. In purified water, add hydroxypropyl cellulose and dissolve with stirring.
3. Granulate the material of step 1 with the binder solution of step 2. After granulation is complete, the wet material is dried.
4. Sift the granules of a predetermined size through a # 030 mesh sieve. The residue is crushed using a 1.0 mm screen and sieved through a # 030 mesh screen.
5. The L-hydroxypropyl cellulose and magnesium stearate are sieved together through a # 040 mesh screen.
6. Lubrication: Lubricate the granules of step 4 with the sieved in step 5 using a suitable mixing device.

  Although the invention has been described with reference to particular embodiments, it is to be understood that these embodiments and examples merely illustrate the principles and applications of the invention. It is contemplated that various modifications may be made to the illustrated embodiments, and that other configurations may be devised without departing from the spirit and scope of the invention disclosed herein.

Claims (91)

Oxalate salt of the compound represented by formula (I)

And a solvate thereof and at least one or more of a pharmaceutically acceptable carrier, a diluent, a binder, a lubricant, a disintegrant, and a stabilizer.   The pharmaceutical composition according to claim 1, wherein the diluent is selected from the group consisting of mannitol, sorbitol, xylitol, starch, lactose, cellulose, calcium dihydrogen phosphate and the like.   The pharmaceutical composition according to claim 2, wherein the diluent is mannitol.   The pharmaceutical composition according to claim 2, wherein the diluent is lactose.   The pharmaceutical composition according to claim 1, wherein the binder is selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose, hypromellose and the like.   The pharmaceutical composition according to claim 5, wherein the binding agent is hypromellose.   6. The pharmaceutical composition of claim 5, wherein the binder is hydroxypropyl cellulose.   The pharmaceutical composition according to claim 1, wherein the lubricant is glyceryl dibehenate, sodium or calcium salt of stearyl fumaric acid, magnesium stearate, stearic acid, glyceryl palmitostearate and the like.   The pharmaceutical composition according to claim 8, wherein the lubricant is glyceryl dibehenate.   The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from the group consisting of low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate and the like.   The pharmaceutical composition according to claim 10, wherein the disintegrant is low substituted hydroxypropyl cellulose.   The pharmaceutical composition according to claim 1, wherein the stabilizer is selected from among at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof.   The pharmaceutical composition according to claim 12, wherein the stabilizer is a stabilizer selected from the group of pharmaceutically acceptable organic acids oxalic acid, tartaric acid, citric acid and their hydrates.   The pharmaceutical composition according to claim 13, wherein the stabilizer is oxalic acid and hydrates thereof.   The stabilizer is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, their derivatives, and combinations thereof The pharmaceutical composition according to claim 12, which is a complexing agent.   The pharmaceutical composition according to claim 15, wherein the complexing agent is β-cyclodextrin.   The pharmaceutical composition according to claim 12, wherein the stabilizer is a polymer selected from the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, and combinations thereof.   18. The pharmaceutical composition of claim 17, wherein the polymer is hydroxypropyl cellulose.   13. The pharmaceutical composition of claim 12, wherein the stabilizer is a chelating agent selected from the group consisting of EDTA, zinc sulfate, iron ascorbate, calcium carbonate, sodium chloride, potassium chloride, and combinations thereof.   20. The pharmaceutical composition of claim 19, wherein the chelating agent is EDTA. (A) The oxalate salt of Compound (I) and a solvate thereof are tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof,
(B) the diluent is mannitol or lactose,
(C) the binder is hydroxypropyl cellulose or hypromellose,
(D) The lubricant is glyceryl dibehenate or magnesium stearate,
(E) The disintegrant is low substituted hydroxypropyl cellulose, crospovidone, or croscarmellose sodium, and
(F) The pharmaceutical composition according to claim 1, wherein the stabilizer is oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA or a combination thereof. (A) The oxalic acid salt of Compound (I) and a solvate thereof are tenelligliptin 3.0 oxalic acid salt n-hydrate (n is 1.0 to 4.0),
(B) the diluent is mannitol,
(C) the binder is hypromellose,
(D) The lubricant is glyceryl dibehenate,
(E) the disintegrant is low substituted hydroxypropyl cellulose, and
22. The pharmaceutical composition according to claim 21, wherein (f) the stabilizer is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA, or a combination thereof. (A) The oxalic acid salt of Compound (I) and a solvate thereof are tenelligliptin 3.0 oxalic acid salt n-hydrate (n is 1.0 to 4.0),
(B) the diluent is lactose,
(C) the binder is hypromellose,
(D) The lubricant is glyceryl dibehenate,
(E) the disintegrant is low substituted hydroxypropyl cellulose, and
22. The pharmaceutical composition according to claim 21, wherein the stabilizer is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA, and combinations thereof.   About 0.5% to about 80.0% by weight of the oxalate salt of Compound (I) and a solvate thereof; about 10% to about 95% by weight of a diluent; and about 0.1% to about 10. 0 wt% binder, about 0.1% to about 20.0 wt% lubricant, about 0.1% to about 30 wt% disintegrant, about 0.05% to about 30 wt% The pharmaceutical composition according to claim 1, comprising a stabilizer of   About 5% to about 40.0% by weight of the oxalate salt of Compound (I) and a solvate thereof; about 15% to about 95% by weight of a diluent; and about 0.1% to about 10% by weight Binder, about 0.1% to about 20.0% by weight of lubricant, about 0.1% to about 30% by weight of disintegrant, and about 0.1% to about 20% by weight of stabilizer The pharmaceutical composition according to claim 24, comprising   About 5% to about 40.0% by weight of the oxalate salt of the compound (I) and a solvate thereof; about 30% to about 80% by weight of a diluent; and about 0.1% to about 10% by weight Binder, about 0.1% to about 20.0% by weight of lubricant, about 0.1% to about 30% by weight of disintegrant, and about 0.1% to about 20% by weight of stabilizer The pharmaceutical composition according to claim 25, comprising   About 5% to about 15.0% by weight tenelligliptin 3.0 oxalate n-hydrate, about 30% to about 80% by weight diluent, and about 0.1% to about 10% by weight binder And about 1.0% to about 15.0% by weight of a lubricant, about 1.0% to about 20% by weight of a disintegrant, and about 0.5% to about 15% by weight of a stabilizer 22. A pharmaceutical composition according to claim 21 comprising.   About 0.5% to about 10.0% by weight of tenelligliptin 3.0 oxalate n-hydrate, about 5% to about 40% by weight of a diluent, and about 0.1% to about 10% by weight Binder, about 0.5% to about 5.0% by weight of lubricant, about 0.5% to about 10% by weight of disintegrant, and about 0.1% to about 10% by weight of stabilizer 22. A pharmaceutical composition according to claim 21, comprising one or more antidiabetic agents.   The one or more antidiabetic agents include sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof The pharmaceutical composition according to claim 28, selected from the group consisting of: and combinations thereof.   The pharmaceutical composition according to claim 29, wherein the antidiabetic agent is metformin or a pharmaceutically acceptable salt thereof.   30. The pharmaceutical composition according to claim 29, wherein the antidiabetic agent is voglibose.   30. The pharmaceutical composition of claim 29, wherein the antidiabetic agent is glimepiride.   The pharmaceutical composition according to claim 29, wherein the antidiabetic agent is pioglitazone.   The pharmaceutical composition according to claim 29, wherein the antidiabetic agent is remogliflozin, a salt or ester thereof, or a solvate thereof.   About 5% to about 15.0% by weight tenelligliptin 3.0 oxalate n-hydrate, about 30% to about 80% by weight diluent, and about 0.1% to about 10% by weight binder And about 1.0% to about 15.0% by weight of a lubricant, about 1.0% to about 20% by weight of a disintegrant, and about 0.5% to about 15% by weight of a stabilizer Pharmaceutical composition containing.   About 5% to about 15.0% by weight tenelligliptin 3.0 oxalate n-hydrate, about 30% to about 80% by weight mannitol and about 0.1% to about 10% by weight hypromellose About 1.0% to about 15.0% by weight glyceryl dibehenate; about 1.0% to about 20% by weight low substituted hydroxypropyl cellulose; about 0.5% to about 15% by weight stabilizer 36. The pharmaceutical composition according to claim 35, comprising   37. The pharmaceutical composition of claim 36, wherein the stabilizer is oxalic acid in an amount of about 0.5% to about 15.0% by weight.   37. The pharmaceutical composition of claim 36, wherein the stabilizer is beta-cyclodextrin present in an amount of about 0.5% to about 10.0% by weight.   37. The pharmaceutical composition of claim 36, wherein the stabilizer is hydroxypropyl cellulose present in an amount of about 0.5% to about 10.0% by weight.   37. The pharmaceutical composition of claim 36, wherein the stabilizer is EDTA present in an amount of about 0.5% to about 10.0% by weight.   About 0.5% to about 10.0% by weight of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0) and about 5% to about 40% by weight of binder About 0.1% to about 10% by weight of a binder, about 0.5% to about 5.0% by weight of a lubricant, about 0.5% to about 10% by weight of a disintegrant; Pharmaceutical composition comprising from 0.1% to about 10% by weight of a stabilizer and one or more antidiabetic agents.   About 0.5% to about 10.0% by weight of tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0) and about 5% to about 40% by weight of mannitol About 0.1% to about 10% by weight hypromellose, about 0.5% to about 5.0% by weight glyceryl dibehenate, and about 0.5% to about 10% by weight low substituted hydroxypropyl cellulose 42. The pharmaceutical composition of claim 41, comprising about 0.1% to about 10% by weight of a stabilizer and one or more antidiabetic agents.   42. The pharmaceutical composition of claim 41, wherein the stabilizer is oxalic acid present in an amount of about 0.5% to about 5.0% by weight.   42. The pharmaceutical composition of claim 41, wherein the stabilizer is beta-cyclodextrin present in an amount of about 0.5% to about 5.0% by weight.   42. The pharmaceutical composition of claim 41, wherein the stabilizer is hydroxypropyl cellulose present in an amount of about 0.1% to about 5.0% by weight.   42. The pharmaceutical composition of claim 41, wherein the stabilizer is EDTA present in an amount of about 0.5% to about 5.0% by weight.   5.68 °, 6.56 °, 16.44 °, 17.72 °, 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± The pharmaceutical composition according to claim 1, comprising tenelligliptin 2.5 oxalate n-hydrate (n is from 1.0 to 4.0) characterized by an X-ray powder diffraction pattern comprising a reflection of 2θ. .   5.69 °, 6.57 °, 16.43 °, 17.71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ reflections including X-ray powder diffraction pattern The pharmaceutical composition according to claim 1, comprising tenelligliptin 3.0 oxalate n-hydrate (n is from 1.0 to 4.0) characterized by   The pharmaceutical composition according to claim 1, wherein the oxalate salt of the compound of formula (I) and a solvate thereof are substantially pure.   Pharmaceutical compositions comprising the substantially pure oxalate salt of a compound of formula (I) and a solvate thereof.   51. The pharmaceutical composition according to claim 50, wherein the oxalate purity of the compound of formula (I) is greater than 98.0%.   51. The pharmaceutical composition according to claim 50, wherein the oxalate purity of the compound of formula (I) is greater than 99.0%.   51. The pharmaceutical composition according to claim 50, wherein the oxalate purity of the compound of formula (I) is greater than 99.5%.   54. A pharmaceutical composition according to any one of claims 50 to 53, wherein the oxalate salt of the compound of formula (I) is tenelligliptin 2.5 oxalate salt or tenelligliptin 3.0 oxalate salt and solvates thereof object. (A) Oxalate salt of the compound represented by formula (I)

And a solvate thereof,
(B) Sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof, and combinations thereof A pharmaceutical composition comprising at least one or more anti-diabetic agents selected from the group.   56. The pharmaceutical composition according to claim 55, wherein the oxalate salt of the compound of formula (I) is tenelligliptin 2.5 oxalate salt or tenelligliptin 3.0 oxalate salt and a solvate thereof.   56. The pharmaceutical composition according to claim 55, wherein the sulfonylurea compound includes glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide and the like.   56. The pharmaceutical composition according to claim 55, wherein the glitazone compound comprises pioglitazone, rosiglitazone and the like.   59. The pharmaceutical composition of claim 58, wherein the glitazone is pioglitazone.   56. The pharmaceutical composition according to claim 55, wherein the biguanide compound comprises metformin, buformin, phenformin etc., or a pharmaceutically acceptable salt thereof.   61. The pharmaceutical composition of claim 60, wherein the biguanide is metformin or a pharmaceutically acceptable salt thereof.   Tenelligliptin 2.5 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) and delayed release metformin, comprising teneligliptin 2.5 oxalate n-hydrate 56. The pharmaceutical composition of claim 55, wherein the w / w ratio of to metformin is in the range of 1:10 to 1:50.   Tenelligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0) and metformin, comprising teneligliptin 3.0 oxalate n-hydrate vs metformin 56. The pharmaceutical composition according to claim 55, wherein the w / w ratio is in the range of 1:10 to 1:50.   A mixture of teneligliptin 2.5 oxalate n-hydrate and teneligliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0, preferably 1.0), and metformin 56. The pharmaceutical composition of claim 55, wherein the w / w ratio of mixture to metformin is in the range of 1:10 to 1:50.   56. The pharmaceutical composition of claim 55, wherein the alpha glucoside inhibitor based compound comprises voglibose, acarbose, miglitol and the like.   66. The pharmaceutical composition of claim 65, wherein the alpha-glucosidase is voglibose.   56. The pharmaceutical composition according to claim 55, wherein said SGLT2 inhibitor-based compound comprises remogliflozin, dapagliflozin, canagliflozin, empagliflozin, luceogliflozin, etc., and salts, esters or solvates thereof.   68. The pharmaceutical composition of claim 67, wherein the SGLT2 inhibitor is remogliflozin, a salt, an ester or a solvate thereof.   A medicament comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein said oxalate salt is at least 99% pure and the content of compound of formula (II) is less than 1.0%. Composition.   An oxalate salt of a compound of formula (I) and a solvate thereof, wherein said oxalate salt is at least 99.5% pure and the content of compound of formula (II) is less than 0.5%; Pharmaceutical composition containing.   An oxalate salt of a compound of formula (I) and a solvate thereof, wherein said oxalate salt is at least 99.9% pure and the content of compound of formula (II) is less than 0.1%. Pharmaceutical composition containing.   72. Any one of claims 69 to 71, wherein the oxalate salt of the compound of formula (I) and a solvate thereof are teneligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof. Pharmaceutical composition as described in-.   72. The pharmaceutical composition of any one of claims 69-71, wherein the solvate is an n-hydrate.   The oxalate salt of the compound of formula (I) is tenelligliptin 2.5 oxalate n-hydrate or teneligliptin 3.0 oxalate n-hydrate, and n is 1.0 to 4.0. 72. The pharmaceutical composition according to any one of claims 69-71. A process for the preparation of a pharmaceutical composition of the oxalate salt of a compound of formula (I) and a solvate thereof,
(A) screening the oxalate salt of a compound of formula (I) with a pharmaceutically acceptable excipient, or one or more antidiabetic agents, or a mixture thereof;
(B) granulating the sieved material in step (a) with a binder solution;
(C) drying and sieving the granules obtained in step (b);
(D) Lubricating the screened granules in step (c) with a suitable lubricant to obtain a blend;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(F) optionally compacting the lubricated blend of step (d) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture Method.   76. The method of claim 75, wherein the oxalate salt of the compound of formula (I) and a solvate thereof are tenelligliptin 2.5 oxalate salt or teneligliptin 3.0 oxalate salt and a solvate thereof.   76. The method of claim 75, wherein the solvate is n-hydrate.   The oxalate salt of the compound of the formula (I) and a solvate thereof are tenelligliptin 2.5 oxalate n-hydrate or teneligliptin 3.0 oxalate n-hydrate, and n is 1.0 to 4 76. The method of claim 75, wherein.   The one or more antidiabetic agents include sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof 76. The method of claim 75, wherein the method is selected from the group consisting of: and combinations thereof.   76. The method of claim 75, wherein the one or more anti-diabetic agents are selected from the group consisting of voglibose, glimepiride, pioglitazone and metformin, or a pharmaceutically acceptable salt thereof.   76. The method of claim 75, wherein the pharmaceutical composition obtained by the method is a one or two layer tablet. A process for the preparation of a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof,
(A) sieving a pharmaceutically acceptable excipient;
(B) preparing a binder solution comprising an oxalate salt of a compound of formula (I) and a solvate thereof;
(C) granulating the sieved pharmaceutically acceptable excipient of step (a) with the binder solution of step (b);
(D) drying and sieving the granules obtained in step (c);
(E) lubricating the sieved granules of step (c) with a pharmaceutically acceptable excipient to obtain a blend;
(F) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(G) optionally compacting the lubricated blend of step (d) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture Method. A process for the preparation of a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof,
(A) obtaining a solution comprising an oxalate salt of a compound of formula (I) and a solvate thereof together 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 screened granules in step (c) with a pharmaceutically acceptable excipient;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule. A process for the preparation of a pharmaceutical composition of tenelligliptin 3.0 oxalate n-hydrate, wherein n is from 1.0 to 4.0,
(A) Tenelliliptin 3.0 oxalate n-hydrate (n is 1.0 to 4.0), a pharmaceutically acceptable excipient, or one or more antidiabetic agents, or Sifting with the mixture,
(B) granulating the sieved material in step (a) with a binder solution;
(C) drying and sieving the granules obtained in step (b);
(D) Lubricating the screened granules in step (c) with a suitable lubricant to obtain a blend;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(F) optionally compacting the lubricated blend of step (d) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture Method.   The one or more antidiabetic agents include sulfonylurea compounds and salts thereof, glitazone compounds and salts thereof, biguanide compounds and salts thereof, α-glucosidase inhibitor compounds and salts thereof, SGLT2 inhibitor compounds and salts thereof 85. The method of claim 84, wherein the method is selected from the group consisting of: and combinations thereof.   86. The method of claim 85, wherein the one or more anti-diabetic agents are selected from the group consisting of voglibose, glimepiride, pioglitazone and metformin, or a pharmaceutically acceptable salt thereof. A method of preparing a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate comprising:
(A) sieving a pharmaceutically acceptable excipient;
(B) preparing a binder solution comprising tenelligliptin 3.0 oxalate n-hydrate;
(C) granulating the sieved pharmaceutically acceptable excipient of step (a) with the binder solution of step (b);
(D) drying and sieving the granules obtained in step (c);
(E) lubricating the screened granules in step (c) with a pharmaceutically acceptable excipient to obtain a blend;
(F) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule;
(G) optionally compacting the lubricated blend of step (d) with the blend of one or more antidiabetic agents to form a tablet, or forming a capsule filler of the blended mixture Method. A method of preparing a pharmaceutical composition comprising tenelligliptin 3.0 oxalate n-hydrate comprising:
(A) obtaining a solution comprising tenelligliptin 3.0 oxalate n-hydrate together 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 screened granules in step (c) with appropriate excipients;
(E) compressing the lubricated blend in step (d) to form a tablet, or filling the blend of step (d) into a capsule.   75. The pharmaceutical composition according to any one of claims 1 to 74 for use in the prophylactic or therapeutic treatment of glucose metabolism disorders in a patient.   75. The pharmaceutical composition according to any one of claims 1 to 74 for use in the prophylactic or therapeutic treatment of a true glucose metabolism disorder.   75. A method of prophylactic or therapeutic treatment of a patient having a glucose metabolism disorder, comprising administering the pharmaceutical composition according to any one of claims 1 to 74 in a physiologically appropriate amount.

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