Composition of compound hypoglycemic drug and preparation method thereof

Abstract

The invention relates to a composition of a compound hypoglycemic drug and a preparation method of the composition, and relates to the technical field of pharmaceutical compositions. The composition of the compound hypoglycemic drug mainly comprises metformin hydrochloride and sitagliptin phosphate, a filling agent is microcrystalline cellulose and the like, a disintegrating agent is croscarmellose sodium and the like, a binding agent is povidone K30 and the like, a lubricating agent is sodium stearyl fumarate and the like, a wetting agent is lauryl sodium sulfate and the like, and a disintegrating agent is microcrystalline cellulose and the like. The sitagliptin metformin tablet is prepared by adopting a core-coated tablet preparation technology, firstly, sitagliptin is prepared into small tablets by adopting a powder direct compression process, metformin hydrochloride is prepared into particles by adopting a wet granulation process, then the small sitagliptin tablets are pressed into tablet cores to obtain finished tablets, and then the finished tablets are coated to obtain the sitagliptin metformin tablet. The preparation process can ensure the content uniformity of the product and improve the storage stability of the product.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical composition technology, specifically to a compound hypoglycemic drug composition and its preparation method. Background Technology

[0002] Sitagliptin / metformin tablets, marketed as "Genoid," are a combination drug developed by Merck & Co., Ltd. Composed of sitagliptin phosphate and metformin hydrochloride, used in conjunction with diet and exercise to treat type 2 diabetes patients whose blood sugar is poorly controlled with metformin monotherapy or who are receiving combination therapy. It was approved by the FDA on March 30, 2007, and approved for import into my country in 2012.

[0003] The sitagliptin-metformin tablets contain 50mg sitagliptin and 850mg metformin hydrochloride, a significant difference in strength. The preparation process involves directly mixing metformin hydrochloride and sitagliptin phosphate, followed by wet granulation or fluidized bed granulation. This process results in poor material homogeneity during preparation and a risk of segregation during storage. Sitagliptin phosphate exhibits poor stability under high temperature and humidity conditions. Conventional wet granulation or fluidized bed granulation processes operate in environments with both high temperature and humidity, easily leading to changes in product quality and stability during storage. Therefore, it is necessary to optimize the formulation preparation process for sitagliptin-metformin tablet product development to ensure reproducible formulation stability and controllable quality. Summary of the Invention

[0004] The purpose of this invention is to provide a compound hypoglycemic drug composition with high content uniformity and good storage stability, and its preparation method. The compound hypoglycemic drug composition of this invention is sitagliptin-metformin tablets, mainly comprising metformin hydrochloride and sitagliptin phosphate. Fillers include microcrystalline cellulose, disintegrants include croscarmellose sodium, binders include povidone K30, lubricants include sodium stearate fumarate, and wetting agents include sodium dodecyl sulfate. The sitagliptin-metformin tablets are prepared using a chip-coating technique. First, sitagliptin is prepared into small tablets using a direct powder compression process. Metformin hydrochloride is granulated using a wet granulation process. The sitagliptin tablets are then pressed into the tablet core to obtain the finished tablets. Finally, the finished tablets are coated to obtain the final product. The preparation process of this invention ensures product content uniformity and improves product storage stability.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows:

[0006] A method for preparing a compound hypoglycemic drug composition, wherein the compound hypoglycemic drug composition comprises sitagliptin and metformin hydrochloride:

[0007] The sitagliptin components comprise the following raw materials in parts by weight:

[0008] Sitagliptin phosphate: 55-65 parts;

[0009] Filler: 45-60 parts;

[0010] Disintegrant: 3-5 parts;

[0011] Lubricant: 1-3 parts;

[0012] The metformin hydrochloride component comprises the following raw materials in parts by weight:

[0013] Metformin hydrochloride: 650-850 parts;

[0014] Filler: 80-150 parts;

[0015] Adhesive: 5-8 parts;

[0016] Wetting agent: 0.3-0.8 parts;

[0017] Lubricant: 1-5 parts;

[0018] The compound hypoglycemic drug composition is prepared using chip-coating technology, including the following steps:

[0019] (1) Raw material pretreatment:

[0020] Metformin hydrochloride was pulverized and sieved; sitagliptin phosphate was controlled to have a particle size d90≤120μm.

[0021] (2) Preparation of sitagliptin tablets:

[0022] Weigh 55-65 parts of sitagliptin phosphate raw material after pretreatment in step (1), add 45-60 parts of filler and 3-5 parts of disintegrant and mix evenly, then add 1-3 parts of lubricant and mix evenly, and press to obtain sitagliptin tablets.

[0023] (3) Preparation of metformin hydrochloride granules:

[0024] Weigh 650-850 parts of metformin hydrochloride after pretreatment in step (1), add 80-150 parts of filler and mix evenly, use a mixture of 0.3-0.8 parts of wetting agent and 5-8 parts of binder for wet granulation, add 1-5 parts of lubricant after granulation and mix evenly to prepare metformin hydrochloride granules.

[0025] (4) Preparation of sitagliptin-metformin tablets:

[0026] The sitagliptin tablets prepared in step (2) and the metformin hydrochloride granules prepared in step (3) are put into a tableting machine for tableting preparation. The tableting pressure is 8-16 KN.

[0027] (5) Coating:

[0028] The film coating premix was prepared using a 30% ethanol solution and stirred for more than 2 hours to coat the sitagliptin metformin tablets prepared in step (4) to obtain the compound hypoglycemic drug composition.

[0029] In the above technical solution, in step (1), metformin hydrochloride is sieved through a 100-mesh sieve.

[0030] In the above technical solution, the diameter of the sitagliptin phosphate tablets in step (2) is 6 mm.

[0031] In the above technical solution, the drying temperature of wet granulation in step (3) is 50-60℃, and the moisture content is controlled to be ≤5%.

[0032] In the above technical solution, the temperature of the tablet bed is controlled at 40-45°C during the coating process in step (5), and the coating weight gain is 3-5%.

[0033] In the above technical solution, the filler in the sitagliptin component and the metformin hydrochloride component is mannitol, microcrystalline cellulose, pregelatinized starch or lactose; the lubricant is sodium stearate fumarate; the disintegrant is croscarmellose sodium, croscarmellose or low-substituted hydroxypropyl cellulose; the binder is povidone K30 or hydroxypropyl methylcellulose; and the wetting agent is sodium dodecyl sulfate.

[0034] A composition of a compound hypoglycemic drug prepared by the preparation method described in this invention.

[0035] The beneficial effects of this invention are:

[0036] (1) The compound hypoglycemic drug composition of the present invention is sitagliptin metformin tablets, which are prepared by a chip-packing process. First, sitagliptin is prepared into small tablets by a powder direct compression process, and metformin hydrochloride is granulated by a wet granulation process. Then, the sitagliptin tablets are pressed into the tablet core to obtain the finished tablets. The uniformity of product content is greatly improved, and A+2.2S is less than 5.0. The prescription reproducibility is good.

[0037] (2) According to the accelerated test of the bare tablets, the sitagliptin metformin tablets prepared by the present invention have better related substances, and the dissolution rate does not change significantly during the stability period.

[0038] (3) The preparation process of the present invention has good reproducibility and is suitable for industrial production. Detailed Implementation

[0039] The inventive concept of this invention is as follows: By improving the preparation process of sitagliptin-metformin tablets, this invention solves the problem of material mixing uniformity, thereby ensuring that the product content uniformity meets the requirements. The preparation process of this invention employs a chip-coating technique. Sitagliptin is prepared into small tablets using a direct powder compression process, and metformin hydrochloride is granulated using a wet granulation process. The sitagliptin tablets are then pressed into the tablet core to obtain the finished tablet, which is then coated to obtain the final product. The optimized formulation exhibits good reproducibility and stable quality; the process is highly operable. Currently, no chip-coating processes for sitagliptin-metformin tablets have been reported.

[0040] This invention provides a method for preparing a compound hypoglycemic drug composition, wherein the compound hypoglycemic drug composition comprises sitagliptin component and metformin hydrochloride component as follows;

[0041]

[0042]

[0043] Preferably, in the sitagliptin component and the metformin hydrochloride component, the filler is mannitol, microcrystalline cellulose, pregelatinized starch or lactose; the lubricant is sodium stearate fumarate; the disintegrant is croscarmellose sodium, croscarmellose or low-substituted hydroxypropyl cellulose; the binder is povidone K30 or hydroxypropyl methylcellulose; and the wetting agent is sodium dodecyl sulfate.

[0044] The compound hypoglycemic drug composition is prepared using chip-coating technology, including the following steps:

[0045] (1) Raw material pretreatment:

[0046] Crush metformin hydrochloride and pass it through a 100-mesh sieve for later use; control the particle size d90 of sitagliptin phosphate to ≤120μm for later use.

[0047] (2) Preparation of sitagliptin tablets:

[0048] Weigh 55-65 parts of sitagliptin phosphate raw material after pretreatment in step (1), add 45-60 parts of filler and 3-5 parts of disintegrant and mix evenly, then add 1-3 parts of lubricant and mix evenly, and press to obtain sitagliptin tablets with a diameter of 6 mm for later use.

[0049] The raw material sitagliptin phosphate used in this step is 55-65 parts by weight. In the process of preparing sitagliptin tablets, the content of sitagliptin phosphate is determined and converted to the final weight of sitagliptin, which is 50 parts by weight.

[0050] (3) Preparation of metformin hydrochloride granules:

[0051] Weigh 650-850 parts of metformin hydrochloride pretreated in step (1), add 80-150 parts of filler and mix evenly. Use a mixture of 0.3-0.8 parts of wetting agent and 5-8 parts of binder for wet granulation. The drying temperature is 50-60℃ and the moisture content is controlled to be ≤5%. After granulation, add 1-5 parts of lubricant and mix evenly to prepare metformin hydrochloride granules.

[0052] (4) Preparation of sitagliptin-metformin tablets:

[0053] The sitagliptin tablets prepared in step (2) and the metformin hydrochloride granules prepared in step (3) are put into a tableting machine for tableting preparation. The tableting pressure is 8-16KN.

[0054] (5) Coating:

[0055] The film coating premix was prepared using a 30% ethanol solution and stirred for more than 2 hours to coat the sitagliptin metformin tablets prepared in step (4). During the coating process, the tablet bed temperature was controlled at 40-45℃, and the coating weight gain was 3-5%, thus obtaining the composition of the compound hypoglycemic drug.

[0056] The present invention also provides a composition of a compound hypoglycemic drug prepared by the preparation method described in the present invention.

[0057] All raw materials used in the following examples are commercially available.

[0058] Example 1:

[0059] The compound hypoglycemic drug composition of the present invention comprises sitagliptin component and metformin hydrochloride component as described below;

[0060]

[0061] The preparation method of the compound hypoglycemic drug composition of the present invention includes the following steps:

[0062] (1) Preparation of sitagliptin tablets: Weigh the amount of sitagliptin phosphate raw material (control the particle size d90≤120μm), add microcrystalline cellulose 102 and cross-linked carboxymethyl cellulose sodium and mix evenly, then add sodium stearate fumarate and mix evenly, and press into tablets with a diameter of 6mm for later use; The weight of sitagliptin phosphate used in this step is 64.24 parts. In the process of preparing sitagliptin tablets, the weight of sitagliptin phosphate is converted to 50 parts after measuring the content of sitagliptin phosphate; The amount of metformin hydrochloride in step (2) below is 850 parts. Therefore, the weight ratio of sitagliptin to metformin hydrochloride in the final prepared sitagliptin-metformin tablets is 50 parts: 850 parts, that is, the mass ratio of sitagliptin to metformin hydrochloride is 50: 850.

[0063] (2) Preparation of metformin hydrochloride granules: Metformin hydrochloride was pulverized and passed through a 100-mesh sieve. The amount of metformin hydrochloride in the formulation was weighed and mixed with microcrystalline cellulose 102. The mixture was wet-granulated using a mixed solution of sodium dodecyl sulfate and povidone K30. The granules were dried at 50°C with the moisture content controlled to ≤5%. After granulation, sodium stearate fumarate was added and mixed evenly.

[0064] (3) Preparation of sitagliptin-metformin tablets:

[0065] Sitagliptin tablets and metformin hydrochloride granules were fed into a tableting machine for tableting preparation. The tableting pressure was 8 kN. The tablets were then coated. The film coating premix was prepared with a 30% ethanol solution and stirred for more than 2 hours before coating. The tablet bed temperature was controlled at 40°C during the coating process, and the coating weight gain was 3%.

[0066] Example 2:

[0067] The compound hypoglycemic drug composition of the present invention comprises sitagliptin component and metformin hydrochloride component as described below;

[0068]

[0069] The preparation method of the compound hypoglycemic drug composition of the present invention includes the following steps:

[0070] (1) Preparation of sitagliptin tablets: Weigh the amount of sitagliptin phosphate raw material (control the particle size d90≤120μm), add mannitol and cross-linked polyvinylpyrrolidone and mix evenly, then add magnesium stearate and mix evenly, and press into tablets with a diameter of 6mm for later use; The weight of sitagliptin phosphate used in this step is 64.24 parts. In the process of preparing sitagliptin tablets, the weight of sitagliptin phosphate is converted to 50 parts after measuring the content of sitagliptin phosphate; The amount of metformin hydrochloride in step (2) below is 850 parts. Therefore, the weight ratio of sitagliptin to metformin hydrochloride in the final prepared sitagliptin-metformin tablets is 50 parts: 850 parts, that is, the mass ratio of sitagliptin to metformin hydrochloride is 50: 850.

[0071] (2) Preparation of metformin hydrochloride granules: Metformin hydrochloride was crushed and passed through a 100-mesh sieve. The amount of metformin hydrochloride in the formula was weighed, and mannitol was added and mixed evenly. The granules were wet-processed using a mixed solution of sodium dodecyl sulfate and povidone K30. The granules were dried at 60°C, and the moisture content was controlled to be ≤5%. After granulation, magnesium stearate was added and mixed evenly.

[0072] (3) Preparation of sitagliptin-metformin tablets:

[0073] Sitagliptin tablets and metformin hydrochloride granules were fed into a tableting machine for tableting preparation. The tableting pressure was 16 kN. Then, the tablets were coated. The film coating premix was prepared with a 30% ethanol solution and stirred for more than 2 hours before coating. The tablet bed temperature was controlled at 45°C during the coating process, and the coating weight gain was 5%.

[0074] Example 3:

[0075] The compound hypoglycemic drug composition of the present invention comprises sitagliptin component and metformin hydrochloride component as described below;

[0076]

[0077]

[0078] The preparation method of the compound hypoglycemic drug composition of the present invention includes the following steps:

[0079] (1) Preparation of sitagliptin tablets: Weigh the amount of sitagliptin phosphate raw material (control the particle size d90≤120μm), add pregelatinized starch and low-substituted hydroxypropyl cellulose and mix evenly, then add magnesium stearate and mix evenly, and press into tablets with a diameter of 6mm for later use; The weight of sitagliptin phosphate used in this step is 64.24 parts. In the process of preparing sitagliptin tablets, the weight of sitagliptin phosphate is converted to 50 parts after measuring the content of sitagliptin phosphate; The amount of metformin hydrochloride in step (2) below is 850 parts. Therefore, the weight ratio of sitagliptin to metformin hydrochloride in the final prepared sitagliptin-metformin tablets is 50 parts: 850 parts, that is, the mass ratio of sitagliptin to metformin hydrochloride is 50: 850.

[0080] (2) Preparation of metformin hydrochloride granules: Metformin hydrochloride was pulverized and passed through a 100-mesh sieve. The amount of metformin hydrochloride in the formulation was weighed, and pregelatinized starch was added and mixed evenly. The granules were wet-processed using a mixed solution of sodium dodecyl sulfate and hydroxypropyl methylcellulose. The granules were dried at 55°C with the moisture content controlled to ≤5%. After granulation, magnesium stearate was added and mixed evenly.

[0081] (3) Preparation of sitagliptin-metformin tablets:

[0082] Sitagliptin tablets and metformin hydrochloride granules were fed into a tableting machine for tableting preparation. The tableting pressure was 10 kN. Then, the tablets were coated. The film coating premix was prepared with a 30% ethanol solution and stirred for more than 2 hours before coating. The tablet bed temperature was controlled at 40°C during the coating process, and the coating weight gain was 3%.

[0083] Comparative Example 1:

[0084] The comparative example of a compound hypoglycemic drug composition comprises the following components in parts by weight:

[0085]

[0086]

[0087] The preparation method of the compound hypoglycemic drug composition of this comparative example includes the following steps:

[0088] (1) Pretreatment of raw and auxiliary materials: Metformin hydrochloride is pulverized and passed through a 100-mesh sieve for later use;

[0089] (2) Metformin hydrochloride, sitagliptin phosphate (controlling particle size d90≤120μm), microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose were added to wet granulation and mixed evenly. Wet granulation was carried out using a mixed solution of sodium dodecyl sulfate and povidone K30. The granules were dried at 55°C, and the moisture content was controlled to be ≤5%. After drying, the granules were sized and mixed with sodium stearate fumarate. The mixture was then tableted (the tableting pressure was 13KN, and the punch and the chip coating punch were kept consistent) and coated (see Example 1 for the coating process).

[0090] Comparative Example 2:

[0091] The comparative example of a compound hypoglycemic drug composition comprises the following components in parts by weight:

[0092] composition Dosage Metformin Hydrochloride 820 copies Sitagliptin phosphate 61.9 copies Mannitol 130 copies Low-substituted hydroxypropyl cellulose 4 copies Hydroxypropyl methylcellulose 7 copies Sodium dodecyl sulfate 0.5 copies magnesium stearate 5 copies

[0093] The preparation method of the compound hypoglycemic drug composition of this comparative example includes the following steps:

[0094] (1) Pretreatment of raw and auxiliary materials: Metformin hydrochloride is pulverized and passed through a 100-mesh sieve for later use;

[0095] (2) Sitagliptin phosphate and metformin hydrochloride raw materials were mixed in equal increments. After mixing evenly, mannitol and low-substituted hydroxypropyl cellulose were added and mixed evenly. The mixture was wet-granulated using a mixed solution of sodium dodecyl sulfate and hydroxypropyl methylcellulose. The granules were dried at 55°C with the moisture content controlled to ≤5%. After drying, the granules were sized and magnesium stearate was added for total mixing, tableting (the tableting pressure was 13KN, and the punch and the chip coating punch were kept consistent), and coating (see Example 1 for the coating process).

[0096] The dissolution rate, content uniformity, and contents of sitagliptin phosphate and metformin hydrochloride of the compositions prepared in Examples 1-3 and Comparative Examples 1-2 of this invention were determined below. The experimental procedures are as follows:

[0097] Dissolution test:

[0098] Dissolution conditions: Use 900 mL of 0.025 mol / L sodium chloride solution as the dissolution medium, rotate at 75 rpm, operate according to the procedure, and take samples after 20 minutes.

[0099] Test solution: Take an appropriate amount of the dissolution solution, filter it, and collect the filtrate.

[0100] Reference solution: Weigh appropriate amounts of sitagliptin phosphate and metformin hydrochloride reference standards accurately, dissolve and quantitatively dilute with the mobile phase to prepare a mixed solution containing approximately 0.058 mg sitagliptin and 0.8 mg metformin hydrochloride per 1 mL.

[0101] Chromatographic conditions: Sulfonic acid-based cation exchange bonded silica gel was used as the stationary phase (e.g., Phenomenex Luna-SCX, 50×4.6mm, 5μm or other equivalent columns); phosphate buffer (0.05mol / L potassium dihydrogen phosphate, pH adjusted to 3.5 with phosphoric acid)-acetonitrile (3:1) was used as the mobile phase; the flow rate was 2.0 mL / min; the column temperature was 30℃; and the detection wavelength was 255 nm.

[0102] System suitability: Accurately measure 10 μL of the reference solution and inject it into the liquid chromatograph. Sitagliptin and metformin will elute sequentially. The resolution between the metformin peak and the sitagliptin peak should not be less than 1.2. Repeat the injection 5 times. The relative standard deviation of the peak area of ​​the sitagliptin peak and the metformin peak should not exceed 2.0%.

[0103] Content uniformity test:

[0104] Solvent: 0.1% phosphoric acid-acetonitrile (20:1)

[0105] Test solution: Take 1 tablet of this product (i.e., take the tablets of Examples 1-3 and Comparative Examples 1-2 respectively), place them in a 250 mL volumetric flask, add solvent [0.1% phosphate-acetonitrile (20:1)], shake vigorously until the tablet is completely broken down, sonicate, dilute to the mark with solvent, shake well, filter, accurately measure an appropriate amount of the filtrate, and quantitatively dilute with solvent to prepare a solution containing approximately 0.012 mg sitagliptin and 0.2 mg metformin hydrochloride per 1 mL, which is used as the test solution.

[0106] Reference solution: Weigh appropriate amounts of sitagliptin phosphate and metformin hydrochloride reference standards accurately, dissolve them in solvent and dilute quantitatively to prepare a solution containing approximately 0.02 mg sitagliptin and 0.2 mg metformin hydrochloride per 1 mL, which is used as the reference solution.

[0107] Chromatographic conditions: Sulfonic acid-based cation exchange bonded silica gel was used as the stationary phase (e.g., Phenomenex Luna-SCX, 50 × 4.6 mm, 5 μm or other equivalent columns); the mobile phase was phosphate buffer (0.05 mol / L potassium dihydrogen phosphate, pH adjusted to 3.5 with phosphoric acid) - acetonitrile (4:1); the flow rate was 1.5 mL / min; the column temperature was 30 °C; the detection wavelength was 255 nm. The injection volume was 40 μL.

[0108] Related substances determination test of sitagliptin phosphate:

[0109] Solvent: 0.1% phosphoric acid-acetonitrile (20:1)

[0110] Chromatographic conditions:

[0111] Chromatographic columns: Octadecylsilane-bonded silica gel as the packing material (e.g., Waters YMC-pack ODS-AM, 150×4.6mm, 3μm or other equivalent columns), and impurity trapping columns (e.g., Welch Ghost-Buster Column II, 3.0×50mm or other equivalent columns).

[0112] Control solution: Accurately measure an appropriate amount of the test solution and dilute it quantitatively with solvent to prepare a solution containing approximately 0.1 μg of sitagliptin per 1 mL.

[0113] System suitability solution: Take 1 tablet of this product, place it in a 50mL volumetric flask, add 10mg of sodium stearate fumarate, add 10mL of water, sonicate until the tablet is completely broken down, seal, place in a water bath and heat for 2 hours to generate degradation impurities (RRT is about 1.11), remove, cool, dilute to the mark with diluent, shake well, centrifuge, and collect the filtrate.

[0114] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (e.g., Waters YMC-pack ODS-AM, 150×4.6mm, 3μm or other equivalent columns), with the addition of impurity-collecting columns (e.g., Welch Ghost-Buster Column II, 3.0×50mm or other equivalent columns); phosphate buffer (0.025mol / L sodium dihydrogen phosphate solution, pH adjusted to 2.5 with phosphoric acid)-acetonitrile (20:1) was used as mobile phase A, and acetonitrile was used as mobile phase B, with linear gradient elution performed according to the table below:

[0115]

[0116] The detection wavelength was 205 nm; the flow rate was 1.0 mL per minute; and the column temperature was 45 °C.

[0117] Determination of related substances of metformin hydrochloride:

[0118] Test solution: Take 10 tablets of this product (i.e., take the tablets of Examples 1-3 and Comparative Examples 1-2 respectively), weigh them accurately, grind them into a fine powder, take an appropriate amount of the fine powder (approximately equivalent to 500 mg of metformin hydrochloride), weigh it accurately, add it to the mobile phase to dissolve and quantitatively dilute it to prepare a solution containing approximately 5 mg of metformin hydrochloride per 1 mL.

[0119] Reference solution: Weigh an appropriate amount of dicyandiamide reference standard accurately, dissolve it in water and dilute quantitatively to prepare a solution containing approximately 0.1 mg per mL. Accurately measure an appropriate amount and dilute quantitatively with the mobile phase to prepare a solution containing approximately 1 μg per mL.

[0120] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to prepare a solution containing approximately 5 μg of metformin hydrochloride per 1 mL.

[0121] System suitability solution: Weigh appropriate amounts of metformin hydrochloride and melamine reference standards, dissolve and dilute them in water to prepare a solution containing approximately 0.25 mg of metformin hydrochloride and 0.1 mg of melamine per 1 mL. Accurately measure an appropriate amount of the above solution and quantitatively dilute it with the mobile phase to prepare a solution containing approximately 5 μg of metformin hydrochloride and 2 μg of melamine per 1 mL.

[0122] Chromatographic conditions: Sulfonic acid-based cation exchange bonded silica gel was used as the packing material (e.g., Welch Ultimate XB-SCX, 250×4.6mm, 5μm or other equivalent columns); 1.7% ammonium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid) was used as the mobile phase; the flow rate was 1.5 mL per minute; the detection wavelength was 218 nm; and the injection volume was 20 μL.

[0123] The test results are as follows:

[0124] Results of the 0-day trial:

[0125]

[0126] Accelerated die testing:

[0127] Accelerated die testing (40℃ / 75%RH) was conducted on Examples 1-3 and Comparative Examples 1-2. The results are shown in the table below.

[0128]

[0129] The experimental results show that the compound hypoglycemic drug composition prepared by the present invention, namely sitagliptin metformin tablets, has better content uniformity and meets the dissolution requirements. The stability test also shows that the impurity growth rate is lower than that of the comparative example, indicating that the compound hypoglycemic drug composition prepared by the present invention has a significant improvement on its content uniformity and stability.

[0130] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing a compound hypoglycemic drug composition, characterized in that, The compound hypoglycemic drug composition includes sitagliptin and metformin hydrochloride: The sitagliptin components comprise the following raw materials in parts by weight: Sitagliptin phosphate: 55-65 parts; Filler: 45-60 parts; Disintegrant: 3-5 parts; Lubricant: 1-3 parts; The metformin hydrochloride component comprises the following raw materials in parts by weight: Metformin hydrochloride: 650-850 parts; Filler: 80-150 parts; Adhesive: 5-8 parts; Wetting agent: 0.3-0.8 parts; Lubricant: 1-5 parts; The compound hypoglycemic drug composition is prepared using chip-coating technology, including the following steps: (1) Raw material pretreatment: Metformin hydrochloride was pulverized and sieved; sitagliptin phosphate was controlled to have a particle size d90≤120μm. (2) Preparation of sitagliptin tablets: Weigh 55-65 parts of sitagliptin phosphate raw material after pretreatment in step (1), add 45-60 parts of filler and 3-5 parts of disintegrant and mix evenly, then add 1-3 parts of lubricant and mix evenly, and press to obtain sitagliptin tablets. (3) Preparation of metformin hydrochloride granules: Weigh 650-850 parts of metformin hydrochloride after pretreatment in step (1), add 80-150 parts of filler and mix evenly, use a mixture of 0.3-0.8 parts of wetting agent and 5-8 parts of binder for wet granulation, add 1-5 parts of lubricant after granulation and mix evenly to prepare metformin hydrochloride granules. (4) Preparation of sitagliptin-metformin tablets: The sitagliptin tablets prepared in step (2) and the metformin hydrochloride granules prepared in step (3) are put into a tableting machine for tableting preparation. The tableting pressure is 8-16 KN. (5) Coating: The film coating premix was prepared using a 30% ethanol solution and stirred for more than 2 hours to coat the sitagliptin metformin tablets prepared in step (4) to obtain the compound hypoglycemic drug composition.

2. The method for preparing the compound hypoglycemic drug composition according to claim 1, characterized in that, In step (1), metformin hydrochloride is sieved through a 100-mesh sieve.

3. The method for preparing the compound hypoglycemic drug composition according to claim 1, characterized in that, In step (2), the diameter of the sitagliptin phosphate tablets is 6 mm.

4. The method for preparing the compound hypoglycemic drug composition according to claim 1, characterized in that, In step (3), the drying temperature of wet granulation is 50-60℃, and the moisture content is controlled to be ≤5%.

5. The method for preparing the compound hypoglycemic drug composition according to claim 1, characterized in that, In step (5), the temperature of the coating bed is controlled at 40-45℃, and the coating weight gain is 3-5%.

6. The method for preparing the compound hypoglycemic drug composition according to claim 1, characterized in that, In the sitagliptin component and the metformin hydrochloride component, the filler is mannitol, microcrystalline cellulose, pregelatinized starch or lactose; the lubricant is sodium stearate fumarate; the disintegrant is croscarmellose sodium, croscarmellose or low-substituted hydroxypropyl cellulose; the binder is povidone K30 or hydroxypropyl methylcellulose; and the wetting agent is sodium dodecyl sulfate.

7. A composition of a compound hypoglycemic drug prepared by the preparation method according to any one of claims 1-6.

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