TW201834655A - Formulations comprising oxalate salts of teneligliptin and solvates thereof - Google Patents

Abstract

The present invention relates to pharmaceutically acceptable formulations comprising oxalate salts of Teneligliptin and solvates thereof. Also provided are combinations with biguanides and use of said pharmaceutically acceptable formulations for the management of glucose metabolism disorders.

Description

   Formulation containing tricretin oxalate and its solvate   

The present invention relates to a pharmaceutically acceptable formulation comprising oxalate of teriliptin and its solvates, which optionally further comprises molecules of the biguanides class. It also provides the use of the formulation and the treatment of glucose metabolism disorders in patients in need.

Inhibitors of dipeptidyl peptidase-IV (DDP-IV) are a class of drugs that inhibit glucagon-like peptide-1 (GLP-1) by inhibiting incretins and glucagon-like peptide-1 ) And anti-diabetic drugs that act upon the degradation of glucose-dependent insulinotropic peptide (GIP). These compounds are commonly referred to as "gliptins".

DDP-IV inhibitors are usually used in combination therapy with other anti-diabetic drugs.

There is a need in the art to provide novel and stable formulations that are effective in nature and exhibit enhanced stability and processability.

In one embodiment, a pharmaceutical composition is provided, which comprises an oxalate salt of the compound of formula (I) and a solvate thereof, and at least one or more pharmaceutically acceptable (Pharmaceutically acceptable) carrier, diluent, binder, lubricant, disintegrant, and stabilizing agent. In one aspect of this embodiment, the diluent is selected from the group consisting of mannitol, sorbitol, xylitol, starch, lactose, and cellulose ( Cellulose, calcium dihydrogen phosphate and the like are preferably mannitol or lactose. In yet another aspect, the binder is selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose cellulose), hydroxypropyl methylcellulose (hypromellose), etc., preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose. In another aspect of this embodiment, the lubricant is glyceryl dibehenate, sodium stearyl fumarate or sodium or calcium strearyl fumarate, magnesium stearate, stearic acid, glyceryl palmitostearate, etc., preferably glyceryl behenate. In another aspect of this embodiment, the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium ), Sodium carboxymethyl starch (sodium starch glycolate), etc., preferably low-substituted hydroxypropyl cellulose. In yet another aspect of this embodiment, the stabilizer is selected from at least one stabilizer; at least one complexing agent; at least one polymer; at least one chelating agent; And their combinations.

In one aspect of this embodiment, the present invention provides a pharmaceutical composition, wherein: (a) is selected from teneligliptin 2.5 oxalate or teneligliptin 3.0 oxalate Oxalate and solvate of compound of formula (I); (b) diluent is selected from mannitol or lactose; (c) binder is selected from hydroxypropyl cellulose or hydroxypropyl methyl cellulose; (d) The lubricant is selected from glyceryl behenate or magnesium stearate; (e) The disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium; (f) The stabilizer is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA (ethylenediaminetetraacetic acid), and combinations thereof.

In another aspect of this embodiment, the present invention provides a pharmaceutical composition, comprising: (a) Compound (I) oxalate and its solvate, which is Teriglitin 3.0 oxalate n hydrate Of which 1.0 ~ 4.0; (b) diluent mannitol; (c) binder hydroxypropyl methylcellulose; (d) lubricant glyceryl behenate; (e) disintegrant low Substituted hydroxypropyl cellulose; (f) The stabilizer is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof.

In another aspect of this embodiment, a pharmaceutical composition is provided, comprising: (a) the oxalate salt of compound (I) and a solvate thereof, which is teriglitin 3.0 oxalate n hydrate, Among them 1.0 ~ 4.0; (b) diluent is lactose; (c) binder is hydroxypropyl methyl cellulose; (d) lubricant is glyceryl behenate; (e) dispersant is low-substituted Hydroxypropyl cellulose; (f) The stabilizer is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 0.5 wt% to about 80.0 wt% of the oxalate salt of a compound of formula (I) and a solvate thereof, about 10 wt% to about 95 wt% Diluent, about 0.1wt% to about 10.0wt% binder, about 0.1wt% to about 20.0wt% lubricant, about 0.1wt% to about 30wt% disintegrant and about 0.05wt% to about 30% wt % Stabilizer. In one aspect, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate or terilittin 3.0 oxalate and its solvate. In another aspect of this embodiment, the solvate is n-hydrate. In yet another aspect of this embodiment, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate n hydrate or terilittin 3.0 oxalate n hydrate, where n It is 1.0 ~ 4.0.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 5 wt% to about 40.0 wt% of the oxalate salt of the compound of formula (I) and its solvate, and a dilution of about 15 wt% to about 95 wt% Agent, about 0.1 wt% to about 10 wt% binder, about 0.1 wt% to about 20.0 wt% lubricant, about 0.1 wt% to about 30 wt% disintegrant and about 0.1 wt% to about 20% wt% stabilizer. In one aspect, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate or terilittin 3.0 oxalate and its solvate. In another aspect of this embodiment, the solvate is n-hydrate. In yet another aspect of this embodiment, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate n hydrate or terilittin 3.0 oxalate n hydrate, where n It is 1.0 ~ 4.0.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 5 wt% to about 40.0 wt% of the oxalate salt of a compound of formula (I) and a solvate thereof, and a dilution of about 30 wt% to about 80 wt% Agent, about 0.1 wt% to about 10 wt% binder, about 0.1 wt% to about 20.0 wt% lubricant, about 0.1 wt% to about 30 wt% disintegrant, and about 0.1 wt% to about 20 wt% stabilizer . In one aspect, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate or terilittin 3.0 oxalate and its solvate. In another aspect of this embodiment, the solvate is n-hydrate. In yet another aspect of this embodiment, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate n hydrate or terilittin 3.0 oxalate n hydrate, where n It is 1.0 ~ 4.0.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 5 wt% to about 15.0 wt% Teriglitin 3.0 oxalate n hydrate, about 30 wt% to about 80 wt% diluent, about 0.1 From wt% to about 10 wt% binder, from about 1.0 wt% to about 15.0 wt% lubricant, from about 1.0 wt% to about 20 wt% disintegrant, and from about 0.5 wt% to about 15% wt% stabilizer.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 0.5 wt% to about 10.0 wt% Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, about 5 wt% to about 40wt% diluent, about 0.1wt% to about 10wt% binder, about 0.5wt% to about 5.0wt% lubricant, about 0.5wt% to about 10wt% disintegrant, and about 0.1wt% to about 10wt% % Of stabilizers and one or more anti-diabetic agents.

In one aspect, the one or more anti-diabetic agents included in the pharmaceutical composition of the present invention are selected from the group consisting of sulfonyl urea class of compound and its salts, and glitazone class of compound) and its salts, biguanide class of compound and its salt, alpha-glucosidase inhibitor class of compound and its salt, SGLT2 inhibitor class (SGLT2 inhibitor class of compound) and its salts and their combinations.

    In one aspect    

In one embodiment of the present invention, the pharmaceutical composition includes a stabilizer, wherein the stabilizer is oxalic acid present in an amount of about 0.5 wt% to about 5.0 wt%.

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

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

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

In one embodiment, the oxalate salt of the compound of formula (I) in the pharmaceutical composition of the present invention is teriglitine 2.5 oxalate n hydrate, where n is 1.0 to 4.0, which is characterized by X-ray powder winding The X ray powder diffraction pattern contains reflections at 5.68 °, 6.56 °, 16.44 °, 17.72 °, 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ.

In one embodiment, the oxalate of the compound of formula (I) in the pharmaceutical composition of the present invention is terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, characterized by X-ray powder The radiation spectrum contains the reflections at 5.69 °, 6.57 °, 16.43 °, 17.71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ.

In one embodiment, the pharmaceutical composition comprises the oxalate salt of the compound of formula (I).

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

In one embodiment, the present invention provides a pharmaceutical composition comprising an oxalate salt of a compound of formula (I)

And solvates thereof; and at least one or more selected from the group consisting 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 their salts, and their combination of anti-diabetic agents. In one aspect of this embodiment, the pharmaceutical composition includes a sulfonylurea compound including glimepiride, glipride, tolbutamide, tolabutamide ( tolazamide), glibenclamide, gliclazide, etc. In another aspect of this embodiment, the pharmaceutical composition includes a glitazone compound, which includes pioglitazone, rosiglitazone, and the like. In another aspect, the pharmaceutical composition includes a biguanide compound including metformin, buformin, phenformin, etc. or a pharmaceutically acceptable salt thereof . In yet another aspect of this embodiment, the pharmaceutical composition includes an α-glucosidase inhibitor compound, which includes voglibose, acarbose, and miglitol )Wait. In another aspect of this embodiment, the pharmaceutical composition includes an SGLT2 inhibitor compound, which includes regligliflozin, dapagliflozin, canagliflozin, and ipagliflozin Net (empagliflozin), Lugligliflozin (luseogliflozin), etc., their salts, esters or solvates.

In one embodiment, the present invention provides a pharmaceutical composition comprising teneligliptin 2.5 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0, and extended release metformin, among which The weight ratio (w / w) of Ting 2.5 oxalate n hydrate to metformin is in the range of 1: 10 ~ 1: 50.

In one embodiment, the present invention provides a pharmaceutical composition comprising terilittin 3.0 oxalate n hydrate, wherein n is 1.0 to 4.0, preferably 1.0, and metformin, wherein terilitin 3.0 oxalate n The weight ratio of hydrate to metformin is in the range of 1: 10 ~ 1: 50.

In one embodiment, the present invention provides a pharmaceutical composition comprising a mixture of terilittin 2.5 oxalate n hydrate and terilitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0; with metformin, the weight ratio of the mixture to metformin is in the range of 1: 10 ~ 1: 50.

In one embodiment, the present invention provides a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein the purity of the oxalate salt is at least 99%, and the content of the compound of formula (II) Less than 1.0%.

In one aspect of the present invention, there is provided a pharmaceutical composition comprising: (i) at least one of the following (a) a compound of formula (I), an oxalate salt and a solvate thereof; (b) terlistatin 2.5 grass Acid salt n hydrate, where n is 1.0 ~ 4.0, preferably 1.0; (c) terilittin 3.0 oxalate, where n is 1.0 ~ 4.0, preferably 1.0; (ii) at least one or more selected from Sulfonylurea compounds and their salts, glitazone compounds and their salts, biguanide compounds and their salts, α-glucosidase inhibitors and their salts, SGLT2 inhibitor compounds and their salts, etc. Antidiabetic agents in groups; (iii) at least one or several pharmaceutically acceptable carriers, diluents and excipients.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising: (i) an oxalate salt comprising a compound of formula (I) and a solvate thereof; or (ii) terilittin 2.5 oxalate n Hydrate, where n is 1.0 to 4.0, preferably 1.0; or (iii) Terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0; or (iv) Teritritin 2.5 Oxalate n hydrate and terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0; or any one of (v) (i) to (iv) and at least one or more Selected from the group consisting of sulfonylurea compounds and their salts, glitazone compounds and their salts, biguanide compounds and their salts, α-glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and The anti-diabetic agent composed of these combinations is used for the prophylactic or curative treatment of glucose metabolism disorder in a patient.

In another aspect of the present invention, there is provided a prophylactic or curative treatment method for a patient suffering from glucose metabolism disorder, which comprises administering a physiologically relevant amount of a pharmaceutical composition, which comprises : (I) an oxalate salt containing a compound of formula (I) and its solvate; or (ii) terlistatin 2.5 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0; or (iii ) Terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0; or (iv) Terilitin 2.5 oxalate n hydrate and Terilitin 3.0 oxalate n hydrate, Where n is 1.0 to 4.0, preferably 1.0; or any one of (v) (i) to (iv) and at least one or more selected from the group consisting of sulfonylurea compounds and their salts, glitazone compounds and their Salts, biguanides and their salts, α-glucosidase inhibitors and their salts, SGLT2 inhibitors and their salts, and antidiabetic agents in groups of these.

The summary of the present invention is not intended to define the essential features of the patent subject matter, nor is it intended to determine or limit the scope of the patent subject matter.

Purpose of the invention

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

An object of the present invention is to provide a pharmaceutically acceptable formulation comprising tricrate of oxalate and its solvate, which has excellent stability.

Another object of the present invention is to provide a pharmaceutically acceptable formulation, which comprises tricretin oxalate and its solvate and at least one or more selected from sulfonylurea compounds and their salts, glitazones Compounds and their salts, biguanide compounds and their salts, α-glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and combinations of these antidiabetic agents, which have excellent Characteristics such as workability and stability.

Another object of the present invention is to provide a pharmaceutically acceptable formulation, which comprises tricretin oxalate and its solvate and at least one or more selected from sulfonylurea compounds and their salts, glitazones Compounds and their salts, biguanides and their salts, α-glucosidase inhibitors and their salts, SGLT2 inhibitors and their salts, and combinations of these antidiabetic agents can be used for treatment or Controls glucose metabolism disorders in patients.

The following drawings constitute a part of the specification of the present invention and are included to further explain various aspects of the present invention. The present invention can be better understood with reference to the drawings and the detailed description of the embodiments.

Figure 1 shows the X ray powder diffraction pattern of the crystals of Terilittin 2.5 oxalate n hydrate according to an embodiment of the present invention.

Figure 2 shows the differential scanning calorimetry of terilittin 2.5 oxalate n-hydrate crystals according to an embodiment of the present invention.

FIG. 3 shows the Fourier transform infrared spectrum (FT-IR spectrum) of the crystal of Terilittin 2.5 oxalate n hydrate according to an embodiment of the present invention.

Fig. 4 shows an X-ray powder diffraction pattern of Teliliptin 3.0 oxalate n-hydrate crystals according to an embodiment of the present invention.

Figures 5a ~ 5b show the differential scanning calorimetry analysis of the crystals of terilittin 3.0 oxalate n hydrate according to an embodiment of the present invention.

Fig. 6 shows the Fourier transform infrared spectrum of the crystal of Terilittin 3.0 oxalate n hydrate according to an embodiment of the present invention.

Those skilled in the art to which the invention pertains will realize that the invention described herein can be varied and modified in addition to those specifically described. It should be understood that the invention described herein includes all such changes and modifications. The invention also includes all of these steps, features, compositions and methods referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Definition

For convenience, before describing the present invention further, specific terms used in this specification and examples are collected here. These definitions should be read in accordance with the rest of the disclosure and understood from the perspective of a person skilled in the art. Unless otherwise defined, all technical and scientific terms used in this article have the same meaning as commonly understood by those with ordinary knowledge in the technical field. Unless otherwise restricted by specific examples, the terms used throughout this specification are defined as follows.

The terms used herein are defined as follows. If the definition in this application conflicts with the definition of a non-provisional application that subsequently claims the priority of this provisional application, the definition of the non-provisional application shall prevail.

The term "solvate" ("solvate") refers to an aggregate consisting of a solute ion or molecule and one or several solvent molecules. The solvate can be, but not limited to, acetone solvate, ethanol solvate, methanol solvate, tert-butanol solvate, chloroform solvent Chloroform solvate and other organic and inorganic solvates.

The term "hydrate" ("hydrate") refers to one or several water molecules in a compound chemically bonded to other compounds or molecules or elements, the compound is usually a crystalline compound.

Unless otherwise expressly indicated in the text, the singular forms such as "a" ("a"), "one" ("an") and "the" ("the") used in the specification and patent scope include plural indicators .

The scope of the content disclosed herein is not limited by the specific embodiments herein, and these embodiments are for illustrative purposes only.

The term "salt" ("salt") or "pharmaceutically acceptable salt" ("pharmaceutically acceptable salt") used in this article is intended to denote those salts that are suitable for use with humans within a reasonable range of medical judgment Contact with the tissues of lower animals without excessive toxicity, irritation and allergic reactions, has a reasonable benefit to risk ratio, and is effective for its intended use.

As used herein, the term "crystalline" ("crystalline") refers to having a regularly repeated arrangement of molecules (arrangement of molecules) or external face plane (external face plane).

As used herein, the term "amorphous" ("amorphous") means that it does not essentially have a regularly overlapping molecular arrangement or external plane.

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

The term stabilizing agent as used herein refers to a pharmaceutically acceptable excipient, which can stabilize a pharmaceutical composition and limit or prevent the activity contained in the composition Chemical degradation of active pharmaceutical ingredients.

The term "therapeutically effective amount" is intended to mean the amount of the oxalate or solvate of the compound of formula (I), which will cause a biological response in the tissue of a patient .

In the context of treatment, the term "prophylactic" ("prophylactic") is intended to mean the amount of the compound of formula (I) oxalate or its solvate which will prevent or reduce glucose in a patient Metabolic disorders occur, or the onset of clinical symptoms of glucose metabolism disorders in a patient.

In the context of treatment, the term "curative" is intended to mean the amount of the oxalate or solvate of the compound of formula (I), which will cure or control a patient Impaired glucose metabolism.

As used herein, the term "metformin" ("metformin"), unless otherwise specified, refers to metformin, its pharmaceutically acceptable salts, or solvates thereof.

The term "excipient" ("excipient") generally refers to substances other than pharmaceutically active ingredients, which are included in the manufacturing process or in a final pharmaceutical product dosage form.

The term "carrier" generally refers to any substance or substrate used during drug delivery, which is used to enhance the selectivity of drug administration ( selectivity), effectiveness and / or safety.

The term "glucose metabolism disorder" is intended to cover various metabolic disorders involving glucose in humans, such as diabetes mellitus, hyperglycemia, hypoglycemia, and glycosuria Wait. In addition, diabetes includes type 1 (type I) and type 2 (type II) diabetes.

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

3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazole Alkanes (3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine) are also used It is called teneligliptin and can be represented by formula (I). And, throughout this specification, it is interchangeably referred to as teriliptin or a compound of formula (I).

In one embodiment, the invention provides a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) Or a solvate thereof, and at least one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, disintegrants, and stabilizers. In one embodiment, the solvate is preferably n-hydrate, where n is 1.0-4.0. 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, and cellulose ( Cellulose, calcium dihydrogen phosphate, etc. are preferably mannitol or lactose. In yet another aspect, the binder is selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose cellulose), hydroxypropyl methylcellulose (hypromellose), etc., preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose. In another aspect of this embodiment, the humectant is glyceryl dibehenate, sodium stearyl fumarate or sodium or calcium stearyl fumarate Stearyl fumarate, magnesium stearate, stearic acid, glyceryl palmitostearate, etc., preferably glyceryl behenate. In other aspects of this embodiment, the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium , Sodium carboxymethyl starch (sodium starch glycolate), etc., preferably low-substituted hydroxypropyl cellulose. In still another aspect of this embodiment, the stabilizer is selected from at least one stabilizer; at least one complexing agent; at least one polymer; at least one chelating agent; And their combinations.

In one embodiment, the pharmaceutical composition comprises teneligliptin 2.5 oxalate n.hydrate, where n is 1.0-4.0. In a preferred embodiment, the pharmaceutical composition comprises teneligliptin 2.5 oxalate 1.0 hydrate.

In another embodiment, the pharmaceutical composition comprises teneligliptin 3.0 oxalate n.hydrate, where n is 1.0-4.0. In a preferred embodiment, the pharmaceutical composition comprises teneligliptin 3.0 oxalate 1.0 hydrate.

In yet another embodiment, the pharmaceutical composition comprises terilittin 2.5 oxalate n hydrate, where n is 1.0-4.0, and terilittin 3.0 oxalate n hydrate, where n is 1.0-4.0. In a preferred embodiment, the pharmaceutical composition comprises teneligliptin 2.5 oxalate monohydrate and teneligliptin 3.0 oxalate monohydrate.

In an embodiment, the purity of the solvated oxalate salt of the teriliptin contained in the pharmaceutical composition is 10-100%. In another embodiment, the purity level 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 a preferred embodiment, the purity is greater than 99%. In a more preferred embodiment, the purity is greater than 99.5%. In one embodiment, the solvated oxalate of teriliptin contained in the pharmaceutical composition is substantially pure.

In one embodiment, the terlilitin 2.5 oxalate n hydrate contained in the pharmaceutical composition, where n is 1.0 to 4.0, preferably 1.0, and the purity is 10 to 100%. In another embodiment, the purity level 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 a preferred embodiment, the purity is greater than 99%. In a more preferred embodiment, the purity is greater than 99.5%. In one embodiment, the terlilitin 2.5 oxalate n hydrate contained in the pharmaceutical composition, where n is 1.0 to 4.0, preferably 1.0, is substantially pure.

In one embodiment, Terlistatin 3.0 oxalate n hydrate contained in the pharmaceutical composition, wherein n is 1.0 to 4.0, preferably 1.0, and the purity is 10 to 100%. In another embodiment, the purity level 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 a preferred embodiment, the purity is greater than 99%. In a more preferred embodiment, the purity is greater than 99.5%. In one embodiment, Terlistatin 3.0 oxalate n hydrate contained in the pharmaceutical composition, where n is 1.0 to 4.0, preferably 1.0, is substantially pure.

Teliliptin 2.5 oxalate n hydrate contained in the pharmaceutical composition described herein, where n is 1.0 ~ 4.0, preferably 1.0, is in crystalline form.

Teliliptin 3.0 oxalate n hydrate contained in the pharmaceutical composition described herein, where n is 1.0-4.0, preferably 1.0, is a crystalline form.

Teliliptin 2.5 oxalate n hydrate contained in the pharmaceutical composition described herein, where n is 1.0-4.0, preferably 1.0, is in an amorphous form.

Teliliptin 3.0 oxalate n hydrate contained in the pharmaceutical composition described herein, where n is 1.0-4.0, preferably 1.0, is in amorphous form.

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, wherein Teriglitin 2.5 oxalate n hydrate, wherein n is 1.0 ~ 4.0, preferably 1.0, which is characterized by X-ray powder The diffraction pattern (X-ray powder diffraction pattern) contains the reflections at 5.68 °, 6.56 °, 16.44 °, 17.72 °, 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ, and has As shown in Figure 1 X-ray powder diffraction pattern.

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, wherein terilittin 2.5 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0, is characterized by differential scanning Differential scanning calorimetry (DSC) thermograms have endotherm at 152.76 ° C and 169.68 ° C and are represented by the DSC curve in Figure 2.

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, wherein Teriglitin 2.5 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0, is characterized by infrared absorption ( Infra-red absorption) (IR) peaks are located at about 3452.22, 3011.77, 2504.88, 1721.37, 1650.04, 1207.43, 922.34, 708.96, 477.35 wave number (cm ¹ ), and are represented by the third graph.

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, wherein Terilittin 3.0 oxalate n hydrate, wherein n is 1.0 ~ 4.0, preferably 1.0, which is characterized by X-ray powder The diffraction pattern includes reflections at 5.69 °, 6.57 °, 16.43 °, 17.71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ, and has an X-ray powder diffraction pattern as shown in Figure 4 .

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, wherein Terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0, which is characterized by differential scanning The calorimetry thermogram is shown by the DSC curve in Figure 5a, which has an endotherm at 177.34 ° C, and as shown in Figure 5b, it has an endotherm at 171.6 ° C.

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, wherein Terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0, which is characterized by infrared absorption ( IR) peaks are located at about 3464.93, 3011.34, 2357.55, 1911.30, 1720.10, 1651.64, 1456.82, 1363.34, 1209.29, 922.88, 709.74, 475.21 wave number (cm ^-1 ) and are represented by FIG.

In one embodiment, a pharmaceutical composition is provided, which comprises terilittin 3.0 oxalate n hydrate, where n is 1.0-4.0, and at least one or more one or more pharmaceutically acceptable carriers, diluents And excipients. In a preferred embodiment, n is 1.0.

In a specific embodiment, there is provided a pharmaceutical composition comprising terilittin 3.0 oxalate n hydrate, wherein n is 1.0-4.0, and the salt is present in a crystalline or amorphous form.

In one embodiment, there is provided a pharmaceutical composition comprising Teliliptin 3.0 oxalate n hydrate, wherein n is 1.0 ~ 4.0, which is characterized by an X-ray powder diffraction pattern contained at 5.69 °, 6.57 °, 16.43 ° , 17.71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ reflection, and has an X-ray powder diffraction pattern as shown in Figure 4.

In one embodiment, there is provided a pharmaceutical composition comprising terilittin 3.0 oxalate n hydrate, wherein n is 1.0 to 4.0, which is substantially pure.

In one embodiment, the present invention provides a pharmaceutical composition, which includes terilittin 2.5 oxalate n hydrate and terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, and at least one or more A pharmaceutically acceptable carrier, diluent and excipient. In a preferred aspect of this embodiment, n is 1.0. In a preferred aspect of this embodiment, Teriglitine 2.5 oxalate n hydrate and Teriglitin 3.0 oxalate n hydrate are substantially pure.

In one embodiment, the present invention provides a pharmaceutical composition comprising an oxalate compound of formula (I), which comprises: a. At least one stabilizer; b. At least one complexing agent; c At least one polymer; d. At least one chelating agent; and e. A combination thereof.

In a preferred embodiment, the pharmaceutical composition further comprises at least one stabilizer, which is selected from the group consisting of oxalic acid, citric acid, and tartaric acid. Apply organic acid. In a more preferred embodiment, the stabilizer is oxalic acid.

In a preferred embodiment, the pharmaceutical composition further comprises at least one complexing agent selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin (gamma cyclodextrin), methyl β-cyclodextrin (methyl beta-cyclodextrin), hydroxypropyl-β-cyclodextrin (hydroxypropyl-beta-cyclodextrin), its derivatives and their combinations.

In a preferred embodiment, the chelating agent is hydroxypropyl-β-cyclodextrin.

In a preferred embodiment, the pharmaceutical composition further comprises at least one selected from the group consisting of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl Polymers of cellulose (ethyl cellulose), polyvinylpyrrolidone (polyvinylpyrrolidone), hydroxypropyl methyl cellulose (hydroxyl propyl methyl cellulose) and their combinations. In a more preferred embodiment, the polymer is hydroxypropyl cellulose.

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

In one embodiment, the pharmaceutical composition further includes a stabilizer and at least one polymer. The stabilizer is oxalic acid. The polymer is selected from the group consisting of gelatin, polyvinyl alcohol, co-polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose 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, co-polyvinylpyrrolidone, hydroxypropylcellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and combinations thereof The group is 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 present 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, co-polyvinylpyrrolidone, 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 (ethylenediaminetetraacetic acid), zinc sulfate, ferrous ascorbate, calcium carbonate, sodium chloride, potassium chloride, and the like. Preferably EDTA.

In one embodiment, the present invention provides a pharmaceutical composition comprising: (a) the oxalate salt of compound (I) and a solvate thereof, which is selected from teriritine 2.5 oxalate or teriritine 3.0 oxalate; (b) the diluent is selected from mannitol or lactose; (c) the binder is selected from hydroxypropyl cellulose or hydroxypropyl methyl cellulose; (d) the lubricant is selected from glycerol twenty Dialkanoate or magnesium stearate; (e) The disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium.

In one embodiment, the present invention provides a pharmaceutical composition comprising: (a) the oxalate salt of compound (I) and its solvate, which is teriglitin 3.0 oxalate n hydrate, of which 1.0 ~ 4.0; (b) Diluent mannitol; (c) Binder hydroxypropyl methylcellulose; (d) Lubricant glyceryl behenate; (e) Dispersing agent low substituted hydroxypropyl fiber (F) The stabilizing agent is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof.

In one embodiment, the present invention provides a pharmaceutical composition comprising (a) the oxalate salt of compound (I) and its solvate, which is teriglitin 3.0 oxalate n hydrate, of which 1.0 to 4.0; (b) diluent is lactose; (c) binder is hydroxypropyl methyl cellulose; (d) lubricant is glyceryl behenate; (e) dispersant is low-substituted hydroxypropyl cellulose; f) The stabilizing agent is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 0.5 wt% to about 80.0 wt% of the oxalate salt of a compound of formula (I) and a solvate thereof, about 10 wt% to about 95 wt% Diluent, about 0.1wt% to about 10.0wt% binder, about 0.1wt% to about 20.0wt% lubricant, about 0.1wt% to about 30wt% disintegrant and about 0.05wt% to about 30% wt % Of stabilizing agent.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 5 wt% to about 40.0 wt% of the oxalate salt of the compound of formula (I) and its solvate, and a dilution of about 15 wt% to about 95 wt% Agent, about 0.1 wt% to about 10 wt% binder, about 0.1 wt% to about 20.0 wt% lubricant, about 0.1 wt% to about 30 wt% disintegrant and about 0.1 wt% to about 20% wt% Stabilizing agent.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 5 wt% to about 40.0 wt% of the oxalate salt of a compound of formula (I) and a solvate thereof, and a dilution of about 30 wt% to about 80 wt% Agent, about 0.1 wt% to about 10 wt% binder, about 0.1 wt% to about 20.0 wt% lubricant, about 0.1 wt% to about 30 wt% disintegrant and about 0.1 wt% to about 20% wt% stabilizer.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 5 wt% to about 15.0 wt% Teriglitin 3.0 oxalate n hydrate, about 30 wt% to about 80 wt% diluent, about 0.1 From wt% to about 10 wt% binder, from about 1.0 wt% to about 15.0 wt% lubricant, from about 1.0 wt% to about 20 wt% disintegrant, and from about 0.5 wt% to about 15 wt% stabilizer. In one aspect of this embodiment, Teriglitin 3.0 oxalate n hydrate is crystalline terilitin 3.0 oxalate n hydrate, where n is 1.0-4.0.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising about 0.5 wt% to about 10.0 wt% Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, about 5 wt% to about 40 wt% diluent, about 0.1 wt% to about 10 wt% binder, about 0.5 wt% to about 5.0 wt% lubricant, about 0.5 wt% to about 10 wt% disintegrant, and about 0.1 wt% to about 10 % wt% stabilizer and one or more anti-diabetic agents. In one aspect of this embodiment, Teriglitin 3.0 oxalate n hydrate is crystalline terilitin 3.0 oxalate n hydrate, where n is 1.0-4.0.

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

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

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

In one embodiment, the present invention provides a pharmaceutical composition comprising a substantially pure oxalate of a compound of formula (I) and a solvate thereof, wherein the oxalate of the compound of formula (I) is terilittin 2.5 oxalic acid Salt or Teriglitin 3.0 oxalate and its solvates.

In one embodiment, the present invention also provides a pharmaceutical composition as described herein, further comprising at least one or more selected from sulfonyl urea compounds (sulfonyl urea class of compound) and its salts, glitazone compounds (glitazone class of compound) and its salt, biguanide class of compound and its salt, alpha-glucosidase inhibitor class of compound and its salt, SGLT2 inhibitor compound (SGLT2 Inhibitor class of compound) and its salts, and anti-diabetic agents composed of a combination of these.

In one embodiment, the present invention provides a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, and at least one or more compounds selected from the group consisting of sulfonylurea compounds and salts thereof, and glitazone Compounds and their salts, biguanide compounds and their salts, α-glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and combinations of these antidiabetic agents.

In one embodiment, the sulfonylurea compound used in the pharmaceutical composition of the present invention comprises glimepiride, glipride, tolbutamide, tolabutamide ( tolazamide), glibenclamide, gliclazide, etc. In a preferred embodiment, the sulfonylurea compound is glimepiride.

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

In another embodiment, the α-glucosidase inhibitor compound used in the pharmaceutical composition of the present invention comprises voglibose, acarbose, and miglitol )Wait. In a preferred embodiment, the α-glucosidase inhibitor compound is voglibose.

In one embodiment, the SGLT2 inhibitor compounds include regligliflozin, dapagliflozin, canagliflozin, empagliflozin, and rugliflozin. (luseogliflozin) etc.

In an embodiment, the biguanide compound includes metformin, buformin, phenformin, and the like. In a preferred embodiment, the member of the biguanide molecule is metformin or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the biguanide member is metformin hydrochloride. In yet another embodiment, the biguanide member is a mixture of metformin and metformin hydrochloride.

In one embodiment, the metformin portion of the pharmaceutical composition of the present invention is an immediate release layer or an extended release layer. In one embodiment, the portion of metformin contained in the pharmaceutical composition is an immediate release layer. In a preferred embodiment, the part of metformin contained in the pharmaceutical composition is a sustained release layer. In yet another embodiment, the metformin contained in the pharmaceutical composition is a mixture of immediate-release layer of metformin.

In one embodiment, the pharmaceutical composition according to the present invention further comprises at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and the like.

The pharmaceutical composition of the present invention comprises at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, or a combination thereof, to stabilize the solvated oxalate of teriliptin and inhibit the formula ( II) The compound is produced in the pharmaceutical composition.

In one embodiment, a pharmaceutical composition is provided, which includes at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, or a combination thereof to stabilize strepliptin 2.5 oxalic acid The function of salt n hydrate, where n is 1.0 ~ 4.0, preferably 1.0.

In one embodiment, a pharmaceutical composition is provided, which includes at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, or a combination thereof to stabilize strepliptin 3.0 oxalic acid The function of salt n hydrate, where n is 1.0 ~ 4.0, preferably 1.0.

In one embodiment, a pharmaceutical composition is provided, which includes at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, or a combination thereof to stabilize strepliptin 2.5 oxalic acid The function of the mixture of salt n hydrate and terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0.

In an embodiment, a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof is provided, wherein the purity of the oxalate salt is at least 99%, and the content of the compound of formula (II) is less than 1 %.

In an embodiment, a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof is provided, wherein the purity of the oxalate salt is at least 99.5%, and the content of the compound of formula (II) is less than 0.5 .0%.

In one embodiment, a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof is provided, wherein the purity of the oxalate salt is at least 99.9%, and the content of the compound of formula (II) is less than 0.1 %.

In one embodiment, there is provided a pharmaceutical composition comprising Teliliptin 2.5 oxalate and a solvate thereof, wherein the purity of the oxalate is at least 99%, and the content of the compound of formula (II) is less than 1.0%.

In an embodiment, there is provided a pharmaceutical composition comprising terilittin 2.5 oxalate and a solvate thereof, wherein the purity of the oxalate is at least 99.5%, and the content of the compound of formula (II) is less than 0.5.0 %. In a preferred embodiment, the solvate is n-hydrate. In one aspect of this embodiment, there is provided a pharmaceutical composition comprising terilittin 2.5 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

In one embodiment, there is provided a pharmaceutical composition comprising Teliliptin 2.5 oxalate and its solvate, wherein the purity of the oxalate is at least 99.9%, and the content of impurity B is less than 0.1%. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising terilittin 2.5 oxalate n hydrate, where n is 1.0-4.0, preferably 1.0.

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

In one embodiment, there is provided a pharmaceutical composition comprising Teliliptin 3.0 oxalate and a solvate thereof, wherein the purity of the oxalate is at least 99.5%, and the content of impurity B is less than 0.5.0%. In a preferred embodiment, the solvate is n-hydrate. In another aspect of this embodiment, there is provided a pharmaceutical composition comprising terilittin 3.0 oxalate n hydrate, where n is 1.0-4.0, preferably 1.0.

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

In one embodiment, there is provided a pharmaceutical composition comprising terilittin 3.0 oxalate n hydrate, wherein the purity of the oxalate is at least 99%, and the content of the compound of formula (II) is less than 1.0%.

In one embodiment, there is provided a pharmaceutical composition comprising Teliliptin 3.0 oxalate n hydrate, wherein the purity of the oxalate is at least 99.5%, and the content of the compound of formula (II) is less than 0.5%.

In one embodiment, there is provided a pharmaceutical composition comprising Teliliptin 3.0 oxalate n hydrate, wherein the purity of the oxalate is at least 99.9%, and the content of the compound of formula (II) is less than 0.1%.

In one embodiment, there is provided a pharmaceutical composition comprising crystalline form of Trielitine 3.0 oxalate n hydrate with a purity of at least 99.0%, at least 99.5%, and at least 99.9%, which is a crystalline form.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising Teliliptin 3.0 oxalate n hydrate, where n is 1.0-4.0, preferably 1.0, and a sustained-release metformin, wherein Teliglitin and metformin The weight ratio is in the range of 1: 10 ~ 1: 50, preferably 1: 10 ~ 1: 40, especially about 1:15 or 1:31.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising teneligliptin 2.5 oxalate n hydrate, where n is 1.0-4.0, preferably 1.0, and a sustained-release metformin, wherein tenelitine and metformin The weight ratio is in the range of 1: 10 ~ 1: 50, preferably 1: 10 ~ 1: 40, especially about 1:15 or 1:31.

In one embodiment of the present invention, a mixture comprising a teneligliptin 2.5 oxalate n hydrate and tenelitatin 3.0 oxalate n hydrate is provided, wherein n is 1.0 to 4.0, preferably 1.0, and A pharmaceutical composition for sustained-release metformin, wherein the weight ratio of teriritin to metformin is in the range of about 1: 10 ~ 1: 50, preferably in the range of 1: 10 ~ 1: 40, especially about 1:15 Or 1:31.

In a specific embodiment of the present invention, a pharmaceutical composition is provided, which includes a terilittin 2.5 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0, and sustained release metformin and at least one or Several pharmaceutically acceptable carriers, diluents and excipients.

In a specific embodiment of the present invention, a pharmaceutical composition is provided, which comprises a terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0, and sustained release metformin, and at least one Or several pharmaceutically acceptable carriers, diluents and excipients.

In a specific embodiment of the present invention, a pharmaceutical composition is provided, which comprises a mixture of terilittin 2.5 oxalate n hydrate and terilitin 3.0 oxalate n hydrate, where n is 1.0-4.0, It is preferably 1.0, and a sustained release metformin and at least one or several pharmaceutically acceptable carriers, diluents and excipients.

The present invention provides a pharmaceutical composition as described herein for prophylactic treatment of glucose metabolism in patients.

The present invention provides a pharmaceutical composition as described herein for curative treatment of glucose metabolism in patients.

The present invention provides a prophylactic curative treatment method for patients suffering from glucose metabolism disorders, which comprises administering a physiologically relevant amount of a pharmaceutical composition as described herein.

The present invention provides a curative treatment method for patients suffering from impaired glucose metabolism, which comprises administering a physiologically relevant amount of a pharmaceutical composition as described herein.

In one embodiment of the present invention, there is provided a pharmaceutical composition as described herein, which comprises granules of n.hydrate oxalate salt of teriritide, wherein n is 1.0 ~ 4.0, preferably 1.0. In a specific embodiment, there is provided a pharmaceutical composition as described herein, which comprises granules of Teliliptin 2.5 oxalate n hydrate, where n is 1.0-4.0, preferably 1.0. In a particular embodiment, there is provided a pharmaceutical composition as described herein, which comprises particles of terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

In one embodiment, the present invention provides a method for preparing a pharmaceutical composition of a compound of formula (I) oxalate, wherein the method steps include: (a) combining the compound of formula (I) with oxalate and medicine Sifiting the acceptable excipients or one or more anti-diabetic agents or mixtures thereof; (b) granulating the sieved material of step (a) with a binder solution ; (C) drying and sieving the particles obtained in step (b); (d) lubricating the sieved particles of step (c) with a suitable lubricant to obtain a blend; (e ) Compressing the lubricated blend of step (d) to form a tablet or filling the blend of step (d) into a capsule; (f) selectively filling the step The blend of the lubricated blend of (d) and one or more anti-diabetic agents is compressed to form a tablet or the blend mixture is filled into a capsule.

Step (a) of the above method includes sieving the oxalate salt of the compound of formula (I) and its solvate with a suitable lubricant. In one embodiment, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate or terilittin 3.0 oxalate and its solvate. In a preferred embodiment, the solvate is n-hydrate. In a preferred embodiment, the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate n hydrate or teriglitin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0.

In one embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein the method steps include: (a) screening medically acceptable Accepted excipients; (b) Preparation of a binder solution containing the oxalate salt of the compound of formula (I) and its solvate; (c) Screened pharmaceutical acceptable excipient of step (a) The granules are granulated with the binder solution of step (b); (d) dried and sieved the granules obtained in step (c); (e) the sieved granules of step (c) are sieved for medicine Lubricate with an acceptable excipient to obtain the blend; (f) Compress the lubricated blend of step (d) to form a tablet or fill the blend of step (d) into a capsule; ( g) selectively compress the blend of the lubricated blend of step (d) and one or more anti-diabetic agents to form a tablet or fill the blend mixture into a capsule.

In one embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein the method steps include: (a) obtaining a compound of formula (I) A solution of oxalate and its solvate and a stabilizer or complexing agent; (b) spray drying (a) obtained in step (a); (c) obtained in step (b) of screening The spray-dried mixture; (d) lubricate the sieved particles of step (c) with sifted pharmaceutically acceptable excipients; (e) lubricate the blend of step (d) Compress to form a tablet or fill the blend of step (d) into a capsule.

In one embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein the method steps include: (a) applying terilittin 3.0 oxalic acid Salt n hydrate, where n is 1.0 ~ 4.0, sieved together with pharmaceutically acceptable excipients or one or more antidiabetic agents or mixtures thereof; (b) the sieved material of step (a) is Granulation of the binder solution; (c) drying and sieving the particles obtained in step (b); (d) lubricating the sieved particles of step (c) with a suitable lubricant to obtain a blend; (e) Compress the lubricated blend of step (d) to form a tablet or fill the blend of step (d) into a capsule; (f) selectively lubricate the blend of step (d) The blend with one or more anti-diabetic agents is compressed to form tablets or the blend mixture is filled into capsules.

In one embodiment, the present invention provides a method of preparing a pharmaceutical composition comprising terilittin 3.0 oxalate n-hydrate, wherein the method steps include: (a) screening pharmaceutically acceptable excipients ; (B) Preparation of a binder solution containing Teliliptin 3.0 oxalate n hydrate; (c) The screened pharmaceutically acceptable excipient of step (a) is bonded to step (b) Granulation of the solution; (d) drying and sieving the particles obtained in step (c); (e) lubricating the sieved particles of step (c) with sieved pharmaceutically acceptable excipients to Obtaining a blend; (f) compressing the lubricated blend of step (d) to form a tablet or filling the blend of step (d) into a capsule; and (g) selectively step ( d) The blend of the lubricated blend and one or more anti-diabetic agents is compressed to form a tablet or the blend mixture is filled into capsules.

In one embodiment, the present invention provides a method for preparing a pharmaceutical composition containing terilittin 3.0 oxalate n hydrate, wherein the method steps include: (a) obtaining terilitin 3.0 oxalate n hydrate A solution with a stabilizer or a complexing agent; (b) the solution obtained in the spray drying step (a); (c) the spray-dried mixture obtained in the screening step (b); (d) the step ( c) the sieved granules are lubricated with sieved pharmaceutically acceptable excipients; and (e) the lubricated blend of step (d) is compressed to form a tablet or step (d) The blend is filled into capsules.

In one embodiment, the particles of the oxalate salt of the compound of formula (I) and its solvate, as covered by the present invention, can be composed of the oxalate salt of the compound of (I) and its solvate and a suitable diluent , Lubricants, adhesives, fluidizing agents, disintegrating agents, solubilizing agents, etc. are made together.

In an embodiment, the particles of Teriglitine 2.5 oxalate and its solvate, as covered by the present invention, can be composed of Teritritin 2.5 oxalate and its solvate with suitable diluents, lubricants , Adhesives, fluidizing agents, disintegrating agents, co-solvents, etc.

In an embodiment, the particles of Teriglitin 3.0 oxalate and its solvate, as covered by the present invention, can be composed of Teritritin 3.0 oxalate and its solvate with suitable diluents, lubricants , Adhesives, fluidizing agents, disintegrating agents, co-solvents, etc.

In an embodiment, the particles of terilittin 2.5 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0, as covered by the present invention, can be composed of terilitin 2.5 oxalate n hydrate Made with suitable diluents, lubricants, binders, fluidizing agents, disintegrating agents, co-solvents, etc.

In an embodiment, the particles of terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, preferably 1.0, as covered by the present invention, can be composed of terilitin 3.0 oxalate n hydrate Made with suitable diluents, lubricants, binders, fluidizing agents, disintegrating agents, co-solvents, etc.

Suitable binders include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, co-polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methyl cellulose, 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 behenate, sodium stearate fumarate or calcium stearate fumarate, magnesium stearate, stearic acid, palmitic stearate Acid glycerides.

The particles of the oxalate compound of formula (I) and its solvate can be prepared by mixing the oxalate compound of formula (I) with pharmaceutically acceptable excipients; the oxalic acid of the compound of formula (I) A mixture of salt and a pharmaceutically acceptable excipient is added to a binder solution, and the wet mixture of the oxalate salt of the compound of formula (I) and a pharmaceutically acceptable excipient is dried, followed by Sieving to form granules.

Alternatively, the particles of the oxalate compound of formula (I) and its solvate can be prepared by mixing the oxalate compound of formula (I) with a pharmaceutically acceptable excipient, which can be processed in a fluidized bed In a fluidized bed-processor, a binder solution is sprayed onto the mixture, followed by drying the wet granules, which can then be selectively screened. Alternatively, flakes of the oxalate compound of formula (I) can be formed by dry mixing the oxalate compound of formula (I) with a pharmaceutically acceptable excipient. The blend is made; the blend is rolled-compacting one or more times to form a flake, which is then granulated and sieving. The oxalate particles or flakes of the compound of formula (I) can be lubricated with any lubricant mentioned above. Next, the mixture can be punched in a tableting machine or can be filled into the capsule by a capsule-filling machine. Alternatively, a coating can be applied to the tablet. The coating solution or suspension contains excipients such as hydroxypropyl methyl cellulose, polyethylene glycol, colorants such as red or yellow iron oxide, titanium dioxide ( titanium dioxide) and talc. Alternatively, these tablets can be filled into capsules of appropriate size. The volume of the capsule can be appropriately selected, ranging from 0.13 to 1.37 milliliters (mL), to accommodate the oxalate salt of the compound of formula (I) containing the lubricated blend or tablet. In one aspect of this embodiment, the oxalate used to prepare the compound of formula (I) containing teneligliptin particles is tenelitine 3.0 oxalate or a solvate thereof. In the first aspect of this example, Teriglitin 3.0 oxalate or its solvate is in crystalline form.

In an alternative, the present invention also covers a direct compression method for the production of Teriglitin tablets. The tablet is prepared by mixing teriliptin with one or more pharmaceutically acceptable excipients to produce a blend for direct compression; compressing the blend to form a tablet; as above As mentioned, a coating is selectively applied to the tablet.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof with metformin or a pharmaceutically acceptable salt thereof as described herein, wherein, The content of the metformin or its pharmaceutically acceptable salt can be appropriately selected so as to deliver metformin in a dose range of 1-2000 mg, preferably 250-1000 mg, more preferably 500-1000 mg , More preferably 500 mg or 1000 mg. Such a pharmaceutical composition contains terilittin and metformin in a separate portion. For example, a muti-layered composition containing tenelitin and metformin in different layers of a two-layer or three-layer tablet; a combination of metformin in the core layer and tenelitin in the coating And other similar variants.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising oxalate and its solvate of Teliliptin and at least one or more selected from sulfonylurea compounds and salts thereof as described herein, Glicone compounds and their salts, biguanide compounds and their salts, α-glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and antidiabetic agents composed of a combination of these, The weight concentration of oxalate and its solvate of teriliptin is in the range of 0.5-10.0%, preferably 0.5-8.0%. In a preferred embodiment, the antidiabetic agent is metformin and its salts. In a more preferred embodiment, the antidiabetic agent is a sustained release metformin. In one embodiment, the dosage of the sustained-release metformin in the pharmaceutical formulation is 500 mg. In another embodiment, the dosage of the sustained-release metformin in the pharmaceutical formulation is 1000 mg.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising tricretin oxalate and its solvate, preferably tricretin 3.0 oxalate n hydrate and metformin or its pharmaceutically acceptable The accepted salt is preferably a sustained-release metformin as described herein, wherein the weight ratio of teriglitine 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 dose of terilittin is in the range of about 5-50%, preferably 20-40%, more preferably 25-35%. In one embodiment, the dose of metformin is in the range of about 100-200 mg, preferably 500-1000 mg, more preferably 500 mg or 1000 mg.

In one embodiment of the present invention, a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and at least one other anti-diabetic agent is administered to a patient in need thereof to treat, prevent, or slow down A method of the course of a metabolic disorder, wherein the metabolic disorder is selected from the group consisting of type 1 diabetes mellitus, type II diabetes mellitus, and impaired glucose tolerance (impaired glucose tolerance (IGT)), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, insulin resistance A group of patients in need of sexual resistance and one of metabolic syndrome.

In one embodiment, the present invention provides a pharmaceutical combination by administering an oxalate comprising a compound of formula (I) and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof to a patient in need To treat type 2 diabetes.

In one embodiment, the present invention provides a method of improving glycemic control in a patient treated with an antidiabetic drug monotherapy, which is administered to a patient in need (I) A pharmaceutical composition of an oxalate salt of a compound and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, a pharmaceutical combination for administering a oxalate comprising a compound of formula (I) and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof to a patient in need is provided To improve the blood sugar control of postprandial plasma glucose and / or glycosylated hemoglobin HbA1c in a patient; A method of reducing fasting plasma glucose.

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

In one embodiment of the present invention, it is provided by administering an oxalate comprising a compound of formula (I) and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof to a patient in need A pharmaceutical composition to treat, prevent or slow down the course of degeneration of pancreatic beta cell and / or decline of the functionality of pancreatic beta cell in a patient, and / or to improve And / or a method of restoring pancreatic β-cell function and / or restoring the functionality of pancreatic insulin secretion.

Examples

The following examples are introduced to provide descriptions that are considered to be the most useful and understandable in terms of the steps and concepts of the present invention. The following examples are merely illustrative of the present invention, and are not intended to limit the present invention to the same as the disclosed embodiments. Variations and changes that are obvious to those skilled in the art are intended to be included within the scope and nature of the present invention.

Example 1

Pharmaceutical composition containing terilittin 3.0 oxalate n hydrate

The following table discloses an exemplary composition comprising Terilittin 3.0 oxalate n hydrate, preferably a monohydrate.

Table 1 provides a formula containing oxalic acid as a stabilizer to prevent the degradation of Teriritin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

Manufacturing method: 1. Sieving: co-sift (tri-lift) oxalate, low-substituted hydroxypropyl cellulose (L-HPC) and mannitol together with # 060 mesh sieve 2. Preparation of binder: Add oxalic acid and hydroxypropylcellulose in purified water under stirring and dissolve; 3. Granulation: Steps in fluidized bed (FBP) with appropriate process parameters The material of 1 is granulated with the binder solution of step 2. After the granulation is completed, the wet mass is dried until the desired loss on drying (LoD) is reached; 4. Sieve the granulated size with a # 030 mesh sieve. Grind the remainder with 1.0mm screen and screen with # 030 mesh screen; 5. Screen low substituted hydroxypropyl cellulose and glycerol 22 with # 040 mesh screen (# 040 mesh) Alkanoate; 6. Lubrication: Use a suitable blender to lubricate the particles of step 4 with the sieved excipient of step 5; 7. Compression: Compress the lubricated particles with appropriate tools and process parameters Blend; 8. coating: coating the compressed tablet with an aqueous dispersion of Opadry Yellow; and 9. packaging the film coated tablet In a blister pack.

Table 2 provides a formula containing oxalic acid, a polymer and a complexing agent to prevent the degradation of Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

Manufacturing method: 1. Screening: screen low-substituted hydroxypropyl cellulose and mannitol together with # 060 mesh screen; 2. Preparation of binder: add oxalic acid, β cyclodextrin and hydroxypropyl in purified water with stirring Cellulose and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2 in a fluidized bed (FBP) with appropriate process parameters. After the granulation is completed, dry the wet block until the desired loss on drying (LoD) is reached; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen low-substituted hydroxypropyl cellulose and glyceryl behenate together; 6. Lubrication: Use a suitable blender to lubricate the granules of step 4 with the sieved excipient of step 5; 7. Compression: Compress the lubricated blend with suitable tools and process parameters; 8. Coating: use European The aqueous dispersion of Badihuang coats the compressed tablet; and 9. Pack the coated tablet in a blister pack.

Table 3 provides a formula containing a complexing agent to prevent the degradation of Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

Manufacturing method: 1. Solution preparation: Add and dissolve mannitol, β-cyclodextrin and teriglitinate oxalate in purified water under stirring; 2. The solution of spray drying step 1; 3. Take # 030 目 网 网Sieve the spray-dried material; 4. Sieve mannitol, low-substituted hydroxypropyl cellulose and glyceryl behenate together with a # 040 mesh screen; 5. Lubricate: use a suitable blender to step 3 The granules are lubricated with the sieved excipient in step 4; 6. Compression: Compress the lubricated blend with suitable tools and process parameters; 7. Coating: Compress the lubricated dispersion using Opadry Yellow water dispersion Tablet coating; and 8. Packing the coated tablets in blister packs.

Table 4 provides a formula containing a polymer to prevent the degradation of Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

Manufacturing method: 1. Screening: Screen low-substituted hydroxypropyl cellulose and mannitol with # 060 mesh screen; 2. Preparation of binder: Add and dissolve hydroxypropyl cellulose in purified water under stirring; 3. Granulation: granulate the material of step 1 with the binder solution of step 2 in a fluidized bed (FBP) with appropriate process parameters. After the granulation is completed, dry the wet block until the desired loss on drying (LoD) is reached; 4. Sieve the granules with a # 030 mesh screen. Grind the remainder using a 1.0mm mesh screen and sieve with a # 030 mesh screen; 5. Sieve mannitol, low-substituted hydroxypropyl cellulose and glyceryl behenate together with a # 040 mesh screen; 6 .Lubrication: Use a suitable blender to lubricate the particles of step 4 with the sieved excipient of step 5; 7. Compression: Press the lubricated blend with suitable tools and process parameters; 8. Coating : Coat the compressed tablet with an aqueous dispersion of Opadry Yellow; and 9. Pack the coated tablet in a blister pack.

Table 5 provides a formula containing a polymer to prevent the degradation of Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

Manufacturing method: 1. Solution preparation: Add and dissolve mannitol, oxalic acid and teriglitinate oxalate in purified water with stirring; 2. The solution of spray drying step 1; 3. Sieve this with # 030 目 网 网Spray-dried material; 4. Screen mannitol, low-substituted hydroxypropylcellulose and glyceryl behenate together with # 040 mesh screen; 5. Lubricate: use a suitable blender Step 4: Lubricated by sieved excipients; 6. Compression: Compress the lubricated blend with suitable tools and process parameters; 7. Coating: Compress the compressed tablet using an aqueous dispersion of Opadry Yellow Coating; and 8. Packing the coated tablet in a blister pack.

Table 6 provides a formula containing a polymer and a chelating agent to prevent the degradation of Teriritin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0.

Manufacturing method: 1. Screening: Screen low-substituted hydroxypropyl cellulose and mannitol with # 060 mesh screen; 2. Preparation of binder: Add and dissolve oxalic acid, EDTA and hydroxypropyl cellulose in purified water with stirring 3. Granulation: granulate the material of step 1 with the binder solution of step 2 in a fluidized bed (FBP) with appropriate process parameters. After the granulation is completed, dry the wet block until the desired loss on drying (LoD) is reached; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen mannitol, low-substituted hydroxypropylcellulose and glyceryl behenate together; 6 .Lubrication: Use a suitable blender to lubricate the particles of step 4 with the sieved excipient of step 5; 7. Compression: Press the lubricated blend with suitable tools and process parameters; 8. Coating : Coat the compressed tablet with an aqueous dispersion of Opadry Yellow; and 9. Pack the coated tablet in a blister pack.

Those skilled in the art should understand that the exemplary formulations disclosed herein can be modified by a person skilled in the art without departing from the intended teaching of the present invention. In addition, those skilled in the relevant arts should understand that similar formulations containing Terilinetin 2.5 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0, and any modifications are included in the scope of this disclosure Within the scope of the expertise of those skilled in the art.

Example 2: Method of combining terilittin 3.0 oxalate and metformin hydrochloride

Metformin fraction (for a 500 mg dose): Use a multimill to grind metformin hydrochloride. Screen the ground metformin hydrochloride and carboxymethyl cellulose sodium with a # 40 mesh stainless steel screen (# 40 mesh s.s. sieve). Sieve the guar gum with a # 100 mesh stainless steel screen (# 100 mesh s.s.sieve). The sieved metformin hydrochloride, carboxymethyl cellulose and Guanhua bean gum were granulated in a rapid mixer granulator for 20 minutes. Methylparaben and propylparaben were added to the purified water with stirring to prepare a binder solution. In a fluidized bed dryer, the mixture of metformin hydrochloride, carboxymethyl cellulose and Guanhua bean gum is granulated with a binder solution. The obtained wet granulated mass is dried to obtain granules. Vibratory sifter was used to sieve the obtained particles with a # 16 mesh screen. Collect oversized particles and grind them using multiple grinders. The ground particles were collected and sieved with a # 16 mesh screen using a vibrating screen. Use a vibrating screen to screen hydroxypropyl methylcellulose, pregelatinized starch, polyethylene oxide and hydrogenated castor oil together with a # 40 mesh screen. Sieve magnesium stearate through a mesh screen. A pre-mix is prepared by mixing fine granules and co-sifted hydroxypropyl methylcellulose, pregelatinized starch, polyethylene oxide, and hydrogenated castor oil. The ground particles are lubricated with a lubrication pre-mix in a blender to obtain a metformin hydrochloride blend.

Metformin portion (for 1000 mg dose): Use a multiple mill to grind metformin hydrochloride and sieve with a # 40 mesh stainless steel screen. Sieve sodium carboxymethyl cellulose with a # 40 mesh stainless steel screen. Screen the Guanhua bean gum with # 100 mesh stainless steel screen. The sieved metformin hydrochloride, carboxymethyl cellulose and Guanhua bean gum are granulated in a rapid mixing granulator for 20 minutes. Methyl paraben and propyl paraben were added to the purified water with stirring to prepare a binder solution. Using suitable process parameters, granulate a mixture of metformin hydrochloride, carboxymethyl cellulose and purified water. The wet particulate material obtained was semi-dried and sieved with a # 16 mesh screen. The semi-dried particles are dried in a fluidized bed dryer. Use a vibrating screen to sieve the dried particles with a # 16 mesh screen. Collect oversized particles and grind them using multiple grinders. The ground particles were collected and sieved with a # 16 mesh screen using a vibrating screen. Using a vibrating screen, hydroxypropyl methylcellulose and maize starch were screened together with a # 40 mesh screen, and magnesium stearate was screened with a # 60 mesh screen. In a suitable blender, lubricate the ground granules with co-screened hydroxypropyl methylcellulose, corn starch and screened magnesium stearate.

Example 3

Stability of Teliliptin 3.0 oxalate n hydrate in the formulation: Table 7 below describes the stability profile of the formulation of Table 1 at 1 month and 2 months.

As can be seen from Table 7 above, even after 2 months of storage at 40 ± 20 ° C and 75 ± 5% relative humidity (RH), the level of impurity B (one of the undesirable by-products of this formulation, which can cause Loss of oxalate) is 1 wt% below the allowable level. Similar results were observed for the formulations described in Tables 2-6. It should be understood that the enhanced stability of each formulation in Tables 1 to 6 is due to the specific presence of oxalic acid, a polymer, a complexing agent, a chelating agent, or a combination thereof. In view of the following lack of any formula of oxalic acid, a polymer, a complexing agent, a chelating agent, or a combination thereof, the level of impurity B content increases beyond the allowable limit, it can be further understood that any oxalic acid, a Formulas in which polymers, a complexing agent, a chelating agent, or combinations thereof exist, have many advantages and unexpected stability.

Table 8 describes a formula whose impurity B content is at an unacceptable level.

Table 9 describes the stability profile of the formulation in Table 8.

Table 10 describes a formulation whose impurity B content is at an unacceptable level.

Table 11 describes the stability profile of the formulation in Table 10.

Table 12 describes a formula whose impurity B content is at an unacceptable level.

Table 13a describes the stability profile of the formulation in Table 12.

Table 13b describes the stability profile of the formulation in Table 12.

Example 4

Formulations containing Teliliptin 3.0 oxalate n hydrate and glimepiride: Table 14a describes a formulation containing Teliliptin 3.0 oxalate n hydrate and glimepiride.

Table 14b describes a formulation (monolayer strategy 2) comprising Teliliptin 3.0 oxalate n hydrate and glimepiride.

A brief strategy for the manufacturing method of the formulas in Tables 14a to 14b: 1. Screening: Screening Teliglitin oxalate, glimepiride, low-substituted hydroxypropyl cellulose and mannitol together with # 060 mesh screen; 2 . Preparation of binder: Add oxalic acid and hydroxypropyl cellulose to purified water under stirring and dissolve; 3. Granulate: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen the low-substituted hydroxypropyl cellulose and glyceryl behenate together; 6. Lubrication: Use a suitable blender to lubricate the granules of step 4 with the sieved excipient of step 5; 7. Compression: Compress the lubricated blend with suitable tools and process parameters; 8. Coating: use European The aqueous dispersion of Badihuang coats the compressed tablet; and 9. Pack the coated tablet in a blister pack.

Table 14c describes a formulation containing Teliliptin 3.0 oxalate n hydrate and glimepiride.

Table 14d describes a formulation (bilayer strategy 2) containing Teliliptin 3.0 oxalate n hydrate and glimepiride.

A brief strategy for the manufacturing method of the formulas in Tables 14c to 14d: Teliglitin Part: 1. Screening: Screening Teliglitin oxalate with low-substituted hydroxypropylcellulose and mannitol together with # 060 mesh screen; 2 . Preparation of binder: Add oxalic acid and hydroxypropyl cellulose to purified water under stirring and dissolve; 3. Granulate: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen the low-substituted hydroxypropyl cellulose and glyceryl behenate together; and 6. Lubricate : Use a suitable blender to lubricate the particles from step 4 with the sieved excipient from step 5.

Glimepiride part: 1. Screening: Screening Glimepiride with low-substituted hydroxypropyl cellulose and mannitol together with # 060 mesh screen; Screening iron oxide yellow with # 0100 mesh screen; 2. Bonding Preparation of the agent: Add polysorbate 80 and hydroxypropyl cellulose to the purified water under stirring and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Grind the remainder using a 1.0mm mesh screen and sieve with a # 030 mesh screen; 5. Sift together low-substituted hydroxypropyl cellulose and magnesium stearate with a # 040 mesh screen; and 6. Lubricate: use appropriate The blender lubricates the particles from step 4 with the sieved excipient from step 5.

Compression, coating, packaging: A bilayer compression machine is used to compress the lubricated blend of the Teliglitin portion and the Glimepiride portion with suitable tools. The compressed tablets were coated with Opadry yellow water dispersion. The coated tablets are packaged in blister packs.

Example 5

Formulations containing teriglitin 3.0 oxalate n hydrate and pioglitazone: Table 15a describes a formulation containing terilitin 3.0 oxalate n hydrate and pioglitazone (single layer strategy 1).

Table 15b describes a formulation containing Teriglitin 3.0 oxalate n-hydrate and pioglitazone.

The brief strategy of the manufacturing method of the formulas in Tables 15a ~ 15b: 1. Screening: Screening Teliglitin oxalate, pioglitazone, low-substituted hydroxypropylcellulose and mannitol together with # 060 mesh screen; 2. Adhesive Preparation of: Add oxalic acid and hydroxypropyl cellulose in purified water under stirring and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Grind the remainder using a 1.0mm mesh screen and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen the low-substituted hydroxypropyl cellulose and glyceryl behenate together; and 6. Lubricate : Use a suitable blender to lubricate the particles of step 4 with the sieved excipient of step 5; 7. Compression: Press the lubricated blend with suitable tools and process parameters; 8. Coating: Use The aqueous dispersion of Opadry Yellow coats the compressed tablet; and 9. Pack the coated tablet in a blister pack.

Table 15c describes a formulation containing Teriglitin 3.0 oxalate n hydrate and pioglitazone (bilayer strategy 1).

Table 15d describes a formulation containing Teriglitin 3.0 oxalate n-hydrate and pioglitazone.

A brief strategy for the manufacturing method of the formulas in Tables 15c to 15d: Teriglitin: Part 1. Screening: Screening Teritridin oxalate with low-substituted hydroxypropylcellulose and mannitol together with # 060 mesh screen; 2 . Preparation of binder: Add oxalic acid and hydroxypropyl cellulose in purified water under stirring and dissolve; 3. Granulate: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen low-substituted hydroxypropyl cellulose and glyceryl behenate together; and 6. Lubricate : Use a suitable blender to lubricate the particles from step 4 with the sieved excipient from step 5.

Pioglitazone part: 1. Screening: Screening of pioglitazone with low-substituted hydroxypropylcellulose and mannitol with # 060 mesh screen; screening of iron oxide yellow with # 0100 mesh screen; 2. Preparation of binder: stirring Next, add hydroxypropyl cellulose in purified water and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen the low-substituted hydroxypropyl cellulose and magnesium stearate together; and 6. Lubrication: use appropriate The blender of step 4 lubricates the granules of step 4 with the sieved excipients of step 5; compression, coating, packaging: using a double-layer tablet press to press the parts of teriglitin and pioglitazone with suitable tools Blend. The compressed tablets were coated with Opadry yellow water dispersion. The coated tablets are packaged in blister packs.

Example 6

Formulations containing Triglitin 3.0 oxalate n hydrate and voglibose: Table 16a describes a formulation containing Triglitin 3.0 oxalate n hydrate and voglibose.

Table 16b describes a formulation containing Teriglitin 3.0 oxalate n hydrate and voglibose.

A brief strategy for the manufacturing method of the formulas in Tables 16a to 16b: 1. Screening: Screening Teliglitin oxalate, voglibose, low-substituted hydroxypropylcellulose and mannitol together with # 060 mesh 2. Preparation of binder: Add oxalic acid and hydroxypropyl cellulose in purified water under stirring and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen the low-substituted hydroxypropyl cellulose and glyceryl behenate together; and 6. Lubricate : Use a suitable blender to lubricate the particles of step 4 with the sieved excipient of step 5; 7. Compression: Press the lubricated blend with suitable tools and process parameters; 8. Coating: Use The aqueous dispersion of Opadry Yellow coats the compressed tablet; and 9. Pack the coated tablet in a blister pack.

Table 16c describes a formulation containing Teriglitin 3.0 oxalate n hydrate and voglibose.

Table 16d describes a formulation containing Terilittin 3.0 oxalate n hydrate and voglibose.

A brief strategy for the manufacturing method of the formulas in Tables 16c to 16d: Teliglitin: 1. Screening: Screening Teliglitin oxalate with low-substituted hydroxypropylcellulose and mannitol together with # 060 mesh screen; 2 . Preparation of binder: Add oxalic acid and hydroxypropyl cellulose in purified water under stirring and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen low-substituted hydroxypropyl cellulose and glyceryl behenate together; and 6. Lubricate : Use a suitable blender to lubricate the particles from step 4 with the sieved excipient from step 5.

Voglibose section

1. Screening: Screening voglibose, low-substituted hydroxypropyl cellulose and mannitol together with # 060 mesh screen; screening iron oxide yellow with # 0100 mesh screen; 2. Preparation of adhesive: Add hydroxypropyl cellulose to the purified water with stirring and dissolve; 3. Granulation: granulate the material of step 1 with the binder solution of step 2. After granulation is completed, the wet block is dried; 4. Sieve the granules with a # 030 mesh screen. Use a 1.0mm mesh screen to grind the remainder and sieve with a # 030 mesh screen; 5. Use a # 040 mesh screen to screen the low-substituted hydroxypropyl cellulose and magnesium stearate together; and 6. Lubrication: use appropriate The blender lubricates the particles from step 4 with the sieved excipient from step 5.

Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments and examples are merely illustrative of the principles and applications of the present invention. Therefore, it should be understood that many modifications can be made to these illustrative embodiments, and other arrangements can be devised without departing from the spirit and scope of the invention disclosed herein.

Claims (91)

Several pharmaceutical compositions, including several oxalates and solvates of compounds of formula (I); and At least one or several pharmaceutically acceptable carriers, diluents, binders, lubricants, disintegrating agents and stabilizers.     The pharmaceutical composition according to item 1 of the patent application scope, 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 as described in item 2 of the patent application, wherein the diluent is mannitol.         The pharmaceutical composition as described in item 2 of the patent application, wherein the diluent is lactose.         The pharmaceutical composition according to item 1 of the patent application scope, wherein the binder is selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, copolyvinylpyrrolidone, ethyl cellulose, and hydroxypropylmethyl Cellulose, etc.         The pharmaceutical composition as described in item 5 of the patent application, wherein the binder is hydroxypropyl methylcellulose.         The pharmaceutical composition as described in item 5 of the patent application, wherein the binder is hydroxypropyl cellulose.         The pharmaceutical composition according to item 1 of the patent application scope, wherein the lubricant is glyceryl behenate, sodium stearyl fumarate, calcium stearate fumarate, or stearin Magnesium acid, stearic acid, glyceryl palmitate stearate, etc.         The pharmaceutical composition according to item 8 of the patent application scope, wherein the lubricant is glyceryl behenate.         The pharmaceutical composition according to item 1 of the patent application scope, wherein the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch group.         The pharmaceutical composition as described in item 10 of the patent application range, wherein the disintegrant is a low-substituted hydroxypropyl cellulose.         The pharmaceutical composition according to item 1 of the patent application scope, wherein the stabilizer is selected from at least one stabilizer; at least one complexing agent; at least one polymer; at least one chelating agent; and combinations thereof.         The pharmaceutical composition as described in item 12 of the patent application range, wherein the stabilizer is a stabilizer selected from the group of pharmaceutically acceptable organic acids oxalic acid, citric acid, tartaric acid and their hydrates.         The pharmaceutical composition as described in item 13 of the patent application scope, wherein the stabilizer is oxalic acid and its hydrate.         The pharmaceutical composition according to item 12 of the patent application scope, wherein the stabilizer is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl β-cyclodextrin, and hydroxypropyl Based on the complex group of β-cyclodextrin, its derivatives and their combinations.         The pharmaceutical composition as described in item 15 of the patent application, wherein the complexing agent is β-cyclodextrin.         The pharmaceutical composition according to item 12 of the patent application scope, wherein the stabilizer is selected from the group consisting of gelatin, polyvinyl alcohol, co-polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl Group of polymers based on cellulose and their combinations.         The pharmaceutical composition according to item 17 of the patent application scope, wherein the polymer is hydroxypropyl cellulose.         The pharmaceutical composition according to item 12 of the patent application scope, wherein the stabilizer is a chelating agent selected from the group consisting of EDTA, zinc sulfate, ferrous ascorbate, calcium carbonate, sodium chloride, potassium chloride, and combinations thereof .         The pharmaceutical composition according to item 19 of the patent application scope, wherein the chelating agent is EDTA.         The pharmaceutical composition as described in item 1 of the patent application scope, wherein (a) the oxalate salt of the compound of formula (I) and its solvate are teriglitin 2.5 oxalate or terilitin 3.0 oxalate and Its solvate; (b) Diluent is mannitol or lactose; (c) Binder is hydroxypropyl cellulose or hydroxypropyl methyl cellulose; (d) Lubricant is glyceryl behenate or hard Magnesium fatty acid; (e) Dispersing agent series low-substituted hydroxypropyl cellulose, crospovidone or croscarmellose sodium; and (f) Stabilizer system oxalic acid, β-cyclodextrin, hydroxypropyl cellulose , EDTA, or a combination thereof.         The pharmaceutical composition as described in item 21 of the patent application scope, wherein (a) the oxalate salt of the compound of formula (I) and its solvate are terlistatin 3.0 oxalate n hydrate, of which 1.0 to 4.0; (b) Diluent mannitol; (c) Binder hydroxypropyl methyl cellulose; (d) Lubricant glyceryl behenate; (e) Dispersing agent low-substituted hydroxypropyl cellulose; And (f) the stabilizer is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA, or a combination thereof.         The pharmaceutical composition as described in item 21 of the patent application scope, wherein (a) the oxalate salt of the compound of formula (I) and its solvate are terlistatin 3.0 oxalate n hydrate, of which 1.0 to 4.0; ( b) diluent-based lactose; (c) binder-based hydroxypropyl methyl cellulose; (d) lubricant-based glyceryl behenate; (e) dispersant-based low-substituted hydroxypropyl cellulose; and ( f) The stabilizer is selected from oxalic acid, β-cyclodextrin, hydroxypropyl cellulose, EDTA, or a combination thereof.         The pharmaceutical composition according to item 1 of the patent application scope, wherein the pharmaceutical composition comprises about 0.5 wt% to about 80.0 wt% of the oxalate salt of the compound of formula (I) and its solvate, about 10 wt% to About 95 wt% diluent, about 0.1 wt% to about 10.0 wt% binder, about 0.1 wt% to about 20.0 wt% lubricant, about 0.1 wt% to about 30 wt% disintegrant, and about 0.05 wt% to About 30% wt% stabilizer.         The pharmaceutical composition according to item 24 of the patent application scope, wherein the pharmaceutical composition comprises about 5 wt% to about 40.0 wt% of the oxalate salt of the compound of formula (I) and its solvate, about 15 wt% to about 95wt% diluent, about 0.1wt% to about 10wt% binder, about 0.1wt% to about 20.0wt% lubricant, about 0.1wt% to about 30wt% disintegrant, and about 0.1wt% to about 20 % wt% stabilizer.         The pharmaceutical composition according to item 25 of the patent application scope, wherein the pharmaceutical composition comprises about 5 wt% to about 40.0 wt% of the oxalate salt of the compound of formula (I) and its solvate, about 30 wt% to about 80wt% diluent, about 0.1wt% to about 10wt% binder, about 0.1wt% to about 20.0wt% lubricant, about 0.1wt% to about 30wt% disintegrant, and about 0.1wt% to about 20 % wt% stabilizer.         The pharmaceutical composition as described in item 21 of the patent application range, wherein the pharmaceutical composition comprises about 5 wt% to about 15.0 wt% Teriglitin 3.0 oxalate n hydrate, a dilution of about 30 wt% to about 80 wt% Agent, about 0.1 wt% to about 10 wt% binder, about 1.0 wt% to about 15.0 wt% lubricant, about 1.0 wt% to about 20 wt% disintegrant, and about 0.5 wt% to about 15% wt% stabilizer.         The pharmaceutical composition as described in item 21 of the patent application range, wherein the pharmaceutical composition comprises about 0.5 wt% to about 10.0 wt% Teriglitin 3.0 oxalate n hydrate, about 5 wt% to about 40 wt% Diluent, about 0.1 wt% to about 10 wt% binder, about 0.5 wt% to about 5.0 wt% lubricant, about 0.5 wt% to about 10 wt% disintegrant and about 0.1 wt% to about 10% wt% Stabilizers and one or more anti-diabetic agents.         The pharmaceutical composition according to item 28 of the patent application scope, wherein one or more antidiabetic agents are selected from the group consisting of sulfonylurea compounds and their salts, glitazone compounds and their salts, biguanide compounds and their salts , Α-glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and other groups in combination.         The pharmaceutical composition according to item 29 of the patent application scope, wherein the antidiabetic agent is metformin or a pharmaceutically acceptable salt thereof.         The pharmaceutical composition according to item 29 of the patent application scope, wherein the antidiabetic agent is voglibose.         The pharmaceutical composition according to item 29 of the patent application scope, wherein the antidiabetic agent is glimepiride.         The pharmaceutical composition according to item 29 of the patent application scope, wherein the antidiabetic agent is pioglitazone.         The pharmaceutical composition according to item 29 of the patent application scope, wherein the antidiabetic agent is repagliptin, its salt, ester, or solvate.         The pharmaceutical composition comprises from about 5 wt% to about 15.0 wt% of Trielitine 3.0 oxalate n hydrate, from about 30 wt% to about 80 wt% of diluent, from about 0.1 wt% to about 10 wt% of binder, about 1.0 wt % To about 15.0% by weight of lubricant, about 1.0% to about 20% by weight of disintegrant and about 0.5% to about 15% by weight of stabilizer.         The pharmaceutical composition according to item 35 of the patent application scope, wherein the composition comprises about 5 wt% to about 15.0 wt% Teriglitin 3.0 oxalate n hydrate, about 30 wt% to about 80 wt% mannitol , About 0.1wt% to about 10wt% hydroxypropyl methyl cellulose, about 1.0wt% to about 15.0wt% glyceryl behenate, about 1.0wt% to about 20wt% low-substituted hydroxypropyl fiber And about 0.5wt% to about 15% wt% stabilizer.         The pharmaceutical composition of claim 36, wherein the stabilizer is oxalic acid present in an amount of about 0.5 wt% to about 15.0 wt%.         The pharmaceutical composition according to item 36 of the patent application scope, wherein the stabilizer is β-cyclodextrin present in an amount of about 0.5 wt% to about 10.0 wt%.         The pharmaceutical composition according to item 36 of the patent application scope, wherein the stabilizer is hydroxypropyl cellulose present in an amount of about 0.5 wt% to about 10.0 wt%.         The pharmaceutical composition as described in item 36 of the patent application range, wherein the stabilizer is EDTA present in an amount of about 0.5 wt% to about 10.0 wt%.         Several pharmaceutical compositions, including about 0.5wt% to about 10.0wt% Teriglitin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, about 5wt% to about 40wt% binder, about 0.1wt% Up to about 10 wt% binder, about 0.5 wt% to about 5.0 wt% lubricant, about 0.5 wt% to about 10 wt% disintegrant, and about 0.1 wt% to about 10% wt% stabilizer and one or more An anti-diabetic agent.         The pharmaceutical composition as described in item 41 of the patent application range, wherein the composition comprises about 0.5 wt% to about 10.0 wt% Teriglitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, about 5 wt % To about 40% by weight of mannitol, about 0.1% to about 10% by weight of hydroxypropyl methylcellulose, about 0.5% to about 5.0% by weight of glyceryl behenate, about 0.5% to about 10 wt% of low-substituted hydroxypropylcellulose and about 0.1 wt% to about 10 wt% of stabilizer and one or more antidiabetic agents.         The pharmaceutical composition according to item 41 of the patent application scope, wherein the stabilizer is oxalic acid present in an amount of about 0.5 wt% to about 5.0 wt%.         The pharmaceutical composition according to item 41 of the patent application scope, wherein the stabilizer is β-cyclodextrin present in an amount of about 0.5 wt% to about 5.0 wt%.         The pharmaceutical composition according to item 41 of the patent application scope, wherein the stabilizer is hydroxypropyl cellulose present in an amount of about 0.1 wt% to about 5.0 wt%.         The pharmaceutical composition as described in item 41 of the patent application scope, wherein the stabilizer is EDTA present in an amount of about 0.5 wt% to about 5.0 wt%.         The pharmaceutical composition as described in item 1 of the patent application scope includes terilittin 2.5 oxalate n hydrate, where n is 1.0 to 4.0, and is characterized by the X-ray powder diffraction pattern contained at 5.68 °, 6.56 °, Reflections at 16.44 °, 17.72 °, 18.34 °, 21.12 °, 21.67 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ.         The pharmaceutical composition as described in item 1 of the patent application scope includes terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, and is characterized by the X-ray powder diffraction pattern contained at 5.69 °, 6.57 °, Reflections at 16.43 °, 17.71 °, 21.66 °, 23.15 °, 23.86 °, 24.99 ° ± 2θ.         The pharmaceutical composition according to item 1 of the patent application scope, wherein the oxalate and solvate of the compound of formula (I) are substantially pure.         Several pharmaceutical compositions contain a substantially pure oxalate salt of the compound of formula (I) and its solvate.         The pharmaceutical composition according to item 50 of the patent application scope, wherein the purity of the oxalate of the compound of formula (I) is greater than 98.0%.         The pharmaceutical composition as described in item 50 of the patent application scope, wherein the purity of the oxalate of the compound of formula (I) is greater than 99.0%.         The pharmaceutical composition according to item 50 of the patent application scope, wherein the purity of the oxalate of the compound of formula (I) is greater than 99.5%.         The pharmaceutical composition as described in items 50-53 of the patent application range, wherein the oxalate of the compound of formula (I) is teriglitin 2.5 oxalate or terilitin 3.0 oxalate and a solvate thereof.     Several pharmaceutical compositions, including: (a) the oxalate salt of the compound of formula (I) and its solvate; and (b) at least one or more antidiabetic agents selected from the group consisting of sulfonylurea compounds and their salts, glitazone compounds and their salts, biguanide compounds and their salts, α-glucosidase inhibitor compounds and Its salts, SGLT2 inhibitor compounds and their salts, and other groups in combination.     The pharmaceutical composition as described in item 55 of the patent application scope, wherein the oxalate of the compound of formula (I) is teriglitin 2.5 oxalate or terilitin 3.0 oxalate and a solvate thereof.         The pharmaceutical composition as described in item 55 of the patent application range, wherein the sulfonylurea compound comprises glimepiride, glipazone, tolbutamide, tolazamide, glibenclamide, gliclazone Zit et al.         The pharmaceutical composition according to item 55 of the patent application range, wherein the glitazone compound includes pioglitazone, rosiglitazone, and the like.         The pharmaceutical composition according to item 58 of the patent application scope, wherein the glitazone is pioglitazone.         The pharmaceutical composition according to item 55 of the patent application range, wherein the biguanide compound includes metformin, buformin, phenformin, or a pharmaceutically acceptable salt thereof.         The pharmaceutical composition according to item 60 of the patent application scope, wherein the biguanide is metformin or a pharmaceutically acceptable salt thereof.         The pharmaceutical composition as described in item 55 of the patent application scope includes terilittin 2.5 oxalate n hydrate, where n is 1.0-4.0, preferably 1.0, and sustained-release metformin, wherein terilitin 2.5 oxalic acid The weight ratio of salt n hydrate to metformin is in the range of 1: 10 ~ 1: 50.         The pharmaceutical composition as described in item 55 of the patent application scope includes terilittin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0, and metformin, wherein terilitin 3.0 oxalate n The weight ratio of hydrate to metformin is in the range of 1: 10 ~ 1: 50.         The pharmaceutical composition as described in item 55 of the patent application scope includes a mixture of terilittin 2.5 oxalate n hydrate and terilitin 3.0 oxalate n hydrate, where n is 1.0 to 4.0, preferably 1.0; with metformin, wherein the weight ratio of the mixture to metformin is in the range of 1: 10 ~ 1: 50.         The pharmaceutical composition according to item 55 of the patent application range, wherein the α-glucosidase inhibitor compound includes voglibose, acarbose, miglitol, and the like.         The pharmaceutical composition according to item 65 of the patent application range, wherein the α-glucosidase inhibitor is voglibose.         The pharmaceutical composition as described in item 55 of the patent application scope, wherein the SGLT2 inhibitor compounds include repaglin, dapagliflozin, cangregliflozin, ipagliflozin, rugligliflozin, etc., Its salts, esters or solvates.         The pharmaceutical composition according to item 67 of the patent application scope, wherein the SGLT2 inhibitor is repagliptin, and its salt, ester or solvate.         Several pharmaceutical compositions include the oxalate salt of the compound of formula (I) and its solvate, wherein the purity of the oxalate salt is at least 99%, and the content of the compound of formula (II) is less than 1.0%.         Several pharmaceutical compositions include the oxalate salt of the compound of formula (I) and its solvate, wherein the purity of the oxalate salt is at least 99.5%, and the content of the compound of formula (II) is less than 0.5%.         Several pharmaceutical compositions include the oxalate salt of the compound of formula (I) and its solvate, wherein the purity of the oxalate salt is at least 99.9%, and the content of the compound of formula (II) is less than 0.1%.         The pharmaceutical composition as described in any one of the patent application items 69 to 71, wherein the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate or terilitin 3.0 grass Acid salts and solvates.         The pharmaceutical composition according to any one of patent application items 69 to 71, wherein the solvate is n-hydrate.         The pharmaceutical composition as described in any one of the patent application items 69 to 71, wherein the oxalate salt of the compound of formula (I) and its solvate are Teliliptin 2.5 oxalate n-hydrate or Teligli Ting 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0.         A method for preparing a pharmaceutical composition of the oxalate salt of the compound of formula (I) and its solvate, wherein the method steps include: (a) the oxalate salt of the compound of formula (I) is pharmaceutically acceptable The excipients or one or more anti-diabetic agents or mixtures thereof are sieved together; (b) the sieved material of step (a) is granulated with a binder solution; (c) dried and sieved step (b) Granules obtained in step (d) lubricate the screened granules of step (c) with a suitable lubricant to obtain a blend; (e) compress the lubricated blend of step (d) to form a tablet , Or fill the blend of step (d) into a capsule; and (f) selectively compress the blend of the lubricated blend of step (d) and one or more antidiabetic agents to form Tablets or fill the blend mixture into capsules.         The method as described in item 75 of the patent application scope, wherein the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate or terilittin 3.0 oxalate and its solvate.         The method according to item 75 of the patent application scope, wherein the solvate is n-hydrate.         The method as described in item 75 of the patent application scope, wherein the oxalate salt of the compound of formula (I) and its solvate are teriglitine 2.5 oxalate n hydrate or terilittin 3.0 oxalate n hydrate , Where n is 1.0 ~ 4.0.         The method of claim 75, wherein one or more antidiabetic agents are selected from the group consisting of sulfonylurea compounds and their salts, glitazone compounds and their salts, biguanide compounds and their salts, α -Groups of glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and combinations thereof.         The method of claim 75, wherein one or more ek7 antidiabetic agents are selected from the group consisting of voglibose, glimepiride, pioglitazone, and metformin or pharmaceutically acceptable salts thereof.         The method of claim 75, wherein the pharmaceutical composition obtained by the method is a single-layer or double-layer tablet.         A method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein the method steps include: (a) screening pharmaceutically acceptable excipients; (b) Preparing a binder solution containing the oxalate salt of the compound of formula (I) and its solvate; (c) combining the screened pharmaceutically acceptable excipient of step (a) with the binder of step (b) Granulation of the solution; (d) drying and sieving the particles obtained in step (c); (e) lubricating the sieved particles of step (c) with sieved pharmaceutically acceptable excipients to Obtaining a blend; (f) compressing the lubricated blend of step (d) to form a tablet or filling the blend of step (d) into a capsule; and (g) selectively step ( d) The blend of the lubricated blend and one or more antidiabetic agents is compressed to form a tablet or the blend mixture is filled into capsules.         A method for preparing a pharmaceutical composition comprising an oxalate salt of a compound of formula (I) and a solvate thereof, wherein the method steps include: (a) obtaining an oxalate salt of a compound of formula (I) and a solvate thereof A solution with a stabilizer or a complexing agent; (b) the solution obtained in the spray drying step (a); (c) sieving the spray dried mixture obtained in the step (b); (d) the process of step (c) The sieved granules are lubricated with sieved pharmaceutically acceptable excipients; and (e) the lubricated blend of step (d) is compressed to form a tablet or the blend of step (d) Fill into capsules.         A method for preparing a pharmaceutical composition containing terilittin 3.0 oxalate n hydrate, where n is 1.0 ~ 4.0, wherein the method steps include: (a) terilitin 3.0 oxalate n hydrate, Where n is 1.0 ~ 4.0, sieved together with pharmaceutically acceptable excipients or one or more anti-diabetic agents or mixtures thereof; (b) the screened material of step (a) is prepared with a binder solution Granules; (c) drying and sieving the particles obtained in step (b); (d) lubricating the sieved particles of step (c) with a suitable lubricant to obtain a blend; (e) step (d) ) The lubricated blend is compressed to form a tablet or the blend of step (d) is filled into a capsule; and (f) the lubricated blend of step (d) is selectively combined with one or Blends of various anti-diabetic agents are compressed to form tablets or the blend mixture is filled into capsules.         The method of claim 84, wherein at least one or more anti-diabetic agents are selected from the group consisting of sulfonylurea compounds and their salts, glitazone compounds and their salts, biguanide compounds and their salts, Groups of α-glucosidase inhibitor compounds and their salts, SGLT2 inhibitor compounds and their salts, and combinations thereof.         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 pharmaceutically acceptable salts thereof.         A method for preparing a pharmaceutical composition containing teriglitin 3.0 oxalate n hydrate, wherein the method steps include: (a) screening pharmaceutically acceptable excipients; (b) preparing teriary Binder solution of Ting 3.0 oxalate n hydrate; (c) Granulate the sieve pharmaceutically acceptable excipient of step (a) with the binder solution of step (b); (d) Drying and sieving the particles obtained in step (c); (e) lubricating the sieved particles of step (c) with sieved pharmaceutically acceptable excipients to obtain a blend; (f) Pressing the lubricated blend of step (d) to form a tablet or filling the blend of step (d) into a capsule; and (g) selectively blending the lubricated blend of step (d) The blend of the substance and one or more antidiabetic agents is compressed to form a tablet or the blend mixture is filled into capsules.         A method for preparing a pharmaceutical composition containing teriritin 3.0 oxalate n hydrate, wherein the method steps include: (a) obtaining a solution of terilitin 3.0 oxalate n hydrate and a stabilizer or complexing agent (B) the solution obtained in the spray drying step (a); (c) the spray-dried mixture obtained in the screening step (b); (d) the screened particles of the step (c) to be screened A pharmaceutically acceptable excipient for lubrication; and (e) compressing the lubricated blend of step (d) to form a tablet or filling the blend of step (d) into a capsule.         The pharmaceutical composition as described in items 1 to 74 of the patent application scope is used for the preventive or curative treatment of a glucose metabolism disorder in a patient.         The pharmaceutical composition as described in items 1 to 74 of the patent application scope is used for the preventive or curative treatment of diabetes in a patient.         A preventive or curative treatment method for a patient suffering from glucose metabolism disorder, comprising administering a physiologically relevant amount of the pharmaceutical composition as described in items 1 to 74 of the patent application.