WO2017088812A1 - Composition and eutectic of saxagliptin and metformin, and preparation method and use thereof - Google Patents

Abstract

The present invention relates to a composition and eutectic of saxagliptin and metformin, and a preparation method and use thereof. In particular, provided in the present invention are a composition and a eutectic form in which the molar ratio of saxagliptin and metformin is 1:1, wherein the X-ray powder diffraction pattern (CuK α radiation) of eutectic crystal form I thereof has characteristic peaks at 2 theta values of 17.8° ± 0.2°, 6.6° ± 0.2° and 22.4° ± 0.2° at 25ºC. The composition and eutectic provided in the present invention have good stability, low wettability, and a solubility meeting the medicinal requirements, all of which are of great value for the optimization and development of the drug in the future.

Description

Composition, eutectic of saxagliptin and metformin, preparation method and use thereof Technical field

The invention relates to the field of chemical medicine, in particular to a composition, eutectic of saxagliptin and metformin, a preparation method thereof and use thereof.

Background technique

The International Diabetes Federation (IDF) reports that people with diabetes worldwide are growing rapidly. According to the 2010 Guidelines for the Prevention and Treatment of Type 2 Diabetes in China, there are more than 92.4 million type 2 diabetes patients in China, and the prevalence rate is 9.42%. At present, China has become the world's largest diabetes country.

Even though there are many drugs for all aspects of diabetes, with the development of diabetes, it is difficult to achieve good results with monotherapy. According to the results of the UK Prospective Diabetes Study (UKPDS), monotherapy with traditional antidiabetic drugs such as sulfonylureas, insulin and metformin cannot maintain long-term compliance with glycemic control.

A lot of research evidence shows that the combination of the two drugs can bring greater benefits to diabetic patients. This is mainly reflected in the fact that the combination of drugs is better than the two drugs alone; the pathogenesis of the two drugs is different, and the synergistic effect can be used to treat the different pathogenesis and pathological aspects of type 2 diabetes; Without increasing the weight of diabetic patients, some patients can also lose weight; the risk of the two drugs combined with hypoglycemia is very low; putting the two drugs in one piece, the patient is more comfortable than eating two pills, also It is not easy to forget, increase compliance, and thus improve the efficacy.

Therefore, many international academic organizations, including the American Association of Clinical Endocrinologists (AACE), the European Diabetes Research Association (EASD), the American Diabetes Association (ADA), and the Chinese Medical Association Diabetes Association (CDS), have recommended joint DPP-4 inhibitors combined with metformin are recommended for use in medications, particularly in the guidelines for EASD and ADA.

On November 5, 2010, Bristol-Myers Squibb and AstraZeneca announced that the US Food and Drug Administration (FDA) approved its product Kombiglyze XR for the treatment of type 2 diabetes in adults. This drug is the first It is also the only combination of metformin sustained release drug and dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin which can effectively control glycated hemoglobin level (HbA1c), fasting blood glucose and postprandial blood glucose levels. Agent.

Saxagliptin is a potent dipeptidyl peptidase-4 (DPP-4) inhibitor that increases endogenous glucagon-like peptide-1 (GLP-1) by selective inhibitory DPP-4. And glucose-dependent insulinotropic polypeptide (GIP) levels, thereby regulating blood sugar. Its structure is as shown in formula (Ia):

Metformin regulates blood glucose by reducing hepatic glucose synthesis and improving insulin sensitivity. It has multiple mechanisms of action, including delaying glucose uptake by the gastrointestinal tract, increasing peripheral glucose utilization by increasing insulin sensitivity, and inhibiting liver and kidney overgrowth. The gluconeogenesis does not reduce blood sugar levels in non-diabetic patients. Its structure is as shown in formula (Ib):

Saxagliptin can be used in combination with metformin with a complementary effect. Metformin regulates blood glucose primarily by reducing hepatic glucose synthesis and improving insulin sensitivity; while saxagliptin delays incretin inactivation, promotes insulin release, reduces glucagon release, and improves glucose in the islet beta cells. The reaction regulates blood sugar. The combination of the two can enhance the efficacy of hypoglycemic and improve islet β cells Function to improve blood sugar compliance rate.

Patent CN1213028C discloses that DPP-4 inhibitors can be used in combination with other types of anti-diabetic drugs, including biguanide hypoglycemic agents.

The prior art discloses that the mass ratios of saxagliptin and metformin differ greatly. In the marketed drug Kombiglyze XR, metformin hydrochloride is 500 mg, 1000 mg, while saxagliptin is only 2.5 mg, 5 mg, and metformin hydrochloride is too large. .

By studying the compositions of metformin and saxagliptin, the inventors have surprisingly found that the two active ingredients can be mixed in a fixed molar ratio of 1:1 and combined to form a eutectic in a hydrogen bond. A eutectic is a crystal containing two molecules in the same crystal structure. The interaction between the two molecules is a non-covalent bond (such as a hydrogen bond, a π-π conjugate, a halogen bond, etc.).

The formation of drug eutectic does not destroy the covalent bond of the active ingredient of the drug, and has the opportunity to improve the crystallization and physicochemical properties of the drug itself, such as bioavailability (Pharmaceut. Res. 23 (8), 2006, pp. 1888-1897). .), Stability and Process Developability (Int. J. Pham. 320, 2006, pp. 114-123.), a new choice for pharmaceutical solid formulations.

The composition and the eutectic composition of metformin and saxagliptin provided by the invention have good stability and low wettability, and the dissolution rate of each component is faster and the solubility is higher than that of the prior art, and the composition provided by the invention has a total The crystal preparation method is simple and the cost is low, which is of great value for the clinical optimization and development of the future combination drugs of metformin and saxagliptin.

Summary of the invention

The technical problem to be solved by the present invention is to provide a composition and eutectic of metformin and saxagliptin overcoming the deficiencies of the prior art.

The present invention provides a composition of metformin and saxagliptin characterized by wherein the molar ratio of metformin to saxagliptin is 1:1.

In the composition, metformin may be in free form or in the form of the hydrochloride salt, and saxagliptin may be in free form or in the form of the hydrochloride salt.

The composition of metformin and saxagliptin provided by the present invention is characterized in that the composition is a co-crystal of metformin and saxagliptin, and the molar ratio thereof is 1:1. Its structural formula is as shown in formula (I).

Where x is 0-3. More preferably, x = 2.

The eutectic provided by the present invention may be Form I, characterized in that the X-ray powder diffraction pattern (CuKα radiation) at 25 ° C is 17.8 ° ± 0.2 °, 6.6 ° ± 0.2 °, 24.4 ° ± 0.2 at 2theta. There is a characteristic peak at °.

Further, the X-ray powder diffraction pattern of Form I also has a diffraction peak at one or more of the 2theta values of 13.4 ° ± 0.2 °, 22.2 ° ± 0.2 °, and 23.1 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Form I also has diffraction peaks at one or more of the 2theta values of 10.2 ° ± 0.2 °, 20.2 ° ± 0.2 °, and 15.5 ° ± 0.2 °.

Preferably, Form I, the X-ray powder diffraction pattern (CuKα radiation) at 25 ° C has a characteristic peak at a value of 17.8 ° ± 0.2 °, 6.6 ° ± 0.2 °, 24.4 ° ± 0.2 ° at 13.4 °. There are diffraction peaks at ±0.2°, 22.2°±0.2°, 23.1°±0.2°, 10.2°±0.2°, 20.2°±0.2°, and 15.5°±0.2°.

According to a particular and preferred aspect of the invention, the X-ray powder diffraction pattern of Form I is as shown in FIG. Further, a total of 26 diffraction peaks are shown in the X-ray diffraction pattern, and the positions and peak intensities of these diffraction peaks are shown in Table 1.

Preferably, the crystalline form I provided by the present invention begins to exhibit an endothermic peak near heating to 210 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .

Preferably, the crystalline form I provided by the present invention has a weight loss gradient of about 2.5% when heated to 120 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .

Form I is prepared by reacting metformin hydrochloride and saxagliptin hydrochloride in a nitrile solvent, or reacting metformin and saxagliptin in free form with hydrochloric acid in a nitrile solvent, stirring, and separating the solid to obtain .

Further, the nitrile solvent is preferably acetonitrile.

Further, the method of separating solids includes, but is not limited to, volatilization, filtration, centrifugation, etc., preferably centrifugation.

Another object of the invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula (I), and at least one pharmaceutically acceptable excipient.

Further, in the pharmaceutical composition of the present invention, the compound of the formula (I) can be used for the preparation of a medicament for treating diabetes.

Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

There are no patents or literatures reporting the composition of metformin and saxagliptin at a molar ratio of 1:1 and their eutectic forms. The formation of eutectic can improve the bioavailability, stability and process developability of the drug. After research, the inventors found a eutectic suitable for development.

The composition and the eutectic stability provided by the invention are good. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.

The crystal particles of the eutectic crystal form I provided by the invention are relatively small, which is beneficial to the improvement of solubility; the dispersion is relatively uniform, no agglomeration phenomenon, the residual solvent and the impurity encapsulation phenomenon are easily removed, and the quality of the process product is improved. The eutectic hygroscopicity provided by the invention is low, and meets the storage requirements of the medicine.

DRAWINGS

Figure 1 is an XRPD pattern of eutectic crystal form I

Figure 2 is a DSC diagram of eutectic crystal form I

Figure 3 is a TGA diagram of eutectic crystal form I

Figure 4 is a comparison of DVS of eutectic crystal form I with metformin hydrochloride and saxagliptin hydrochloride.

Figure 5 is a comparison of the stability of eutectic crystal form I at 25 ° C / 11.0% RH (the above figure shows the XRPD pattern before placement, the figure below shows the XRPD pattern after 3 months)

Figure 6 is a comparison of the stability of eutectic crystal form I at 25 ° C / 43.2% RH (the above figure shows the XRPD pattern before placement, the figure below shows the XRPD pattern after 3 months of placement)

Figure 7 is a PLM diagram of eutectic crystal form I

Figure 8 is a PLM diagram of saxagliptin hydrochloride

detailed description

The present invention will be further described in detail below with reference to specific embodiments, but the invention is not limited to the following examples. Conditions not specified in the examples are conventional conditions. The starting materials in the preparation method are prepared by a known method.

In the following examples, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric analysis

DVS: Dynamic moisture adsorption

PLM: polarized light microscope

X-ray powder diffraction pattern of the present invention in Panalytical Empyrean X-ray powder diffraction Collected on the instrument. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

1.540598；

1.544426

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture adsorber are as follows:

Temperature: 25 ° C

Carrier gas, flow rate: N ₂ , 200 ml / min

Unit time quality change: 0.002% / minute

Relative humidity range: 0%RH-60%RH

Example 1

Preparation method of eutectic crystal form I:

6.1 mg of metformin hydrochloride and 16.1 mg of saxagliptin hydrochloride were placed in a vial, 0.5 mL of acetonitrile was added, and the mixture was stirred at room temperature overnight, and the solid was obtained by centrifugation.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.

The molar ratio of Form I was determined by high performance liquid chromatography and ion mass spectrometry. The results showed that the molar ratio of metformin to saxagliptin and hydrochloric acid was 1:1:2.

Table 1

2theta d interval strength% 6.63 13.33 83.01 10.19 8.68 7.82 11.55 7.66 3.73 13.43 6.59 15.13 14.00 6.33 4.52 15.49 5.72 7.52 17.80 4.98 100.00 20.22 4.39 5.94 22.17 4.01 9.68 22.59 3.94 2.57 23.06 3.86 7.07 24.39 3.65 15.89 25.69 3.47 2.17 26.25 3.40 1.32 27.07 3.29 3.73 28.10 3.18 6.18 29.32 3.05 5.91 31.10 2.88 7.69 32.36 2.77 3.19 33.97 2.64 2.07 35.38 2.54 2.78

35.61 2.52 3.24 36.20 2.48 8.64 36.92 2.43 1.50 37.83 2.38 4.42 39.20 2.30 2.35

Example 2

Study on the wettability of eutectic crystal form I:

About 10 mg of Form I, metformin hydrochloride, and saxagliptin hydrochloride of the present invention were each subjected to dynamic moisture adsorption (DVS) test. The result is shown in Figure 4.

The results show that the eutectic wettability of the present invention is much smaller than that of saxagliptin hydrochloride, which effectively reduces the risk of moisture absorption of the saxagliptin hydrochloride sample.

Example 3

Study on the stability of eutectic crystal form I:

Two samples of the crystal form of the present invention were placed under the conditions of 25 ° C / 11.0% RH, 25 ° C / 43.2% RH, and XRPD was sampled after 3 months. The experimental results are shown in Table 2 below.

Table 2

The results showed that the crystalline form I of the present invention was allowed to stand under conditions of 25 ° C / 11.0% RH and 25 C / 43.2 % RH for 3 months, and the crystal form did not change.

Example 4

Crystal morphology of eutectic crystal form I:

Taking the eutectic crystal form I of the present invention and saxagliptin hydrochloride for PLM comparison, the results are shown in Figures 7 and 8, respectively, as can be seen from the figure, the eutectic crystal form I particles are relatively small, which is favorable for solubility. Improve; more uniform dispersion, no agglomeration, easy to remove residual solvent and impurity encapsulation, improve the quality of process products.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (10)

A composition of metformin or a hydrochloride thereof and saxagliptin or a hydrochloride thereof, wherein the molar ratio of metformin to saxagliptin is 1:1. The composition according to claim 1, wherein the composition is a eutectic of metformin and saxagliptin having a molar ratio of 1:1, and the structural formula is as shown in formula (I).

Where x is 0-3. The eutectic according to claim 2, wherein the eutectic is Form I, characterized in that the X-ray powder diffraction pattern (CuKα radiation) at 25 ° C is 17.8 ° ± 0.2 °, 6.6 ° ± 0.2 at 2 theta. Characteristic peak at °, 24.4 ° ± 0.2 °. The crystal form I according to claim 3, wherein the X-ray powder diffraction pattern is further one or more of 2theta values of 13.4 ° ± 0.2 °, 22.2 ° ± 0.2 °, and 23.1 ° ± 0.2 °. There is a diffraction peak at the place. The crystal form I according to claim 4, wherein the X-ray powder diffraction pattern is further one or more of 2theta values of 10.2 ° ± 0.2 °, 20.2 ° ± 0.2 °, and 15.5 ° ± 0.2 °. There is a diffraction peak at the place. Form I according to any one of claims 2 to 5, characterized in that its X-ray powder diffraction pattern is substantially identical to that of Figure 1. The method for preparing Form I according to any one of claims 2 to 6, wherein the Form I is prepared by treating metformin hydrochloride and saxagliptin hydrochloride in a nitrile solvent. Medium reaction, or metformin and saxagliptin free form in hydrochloric acid, nitrile solvent, stirring, analysis Crystal is obtained. The method according to claim 7, wherein the nitrile solvent is acetonitrile. A pharmaceutical composition comprising an effective amount of the composition of claim 1 or the eutectic according to any one of claims 2 to 6 and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 9, characterized in that the composition of claim 1 or the eutectic according to any one of claims 2 to 6 is used for the preparation of a medicament for treating diabetes.

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