Pharmaceutical composition for treating diabetes and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition for treating diabetes and a preparation method thereof.The pharmaceutical composition comprises a tablet core and a coating layer, the tablet core comprises metformin hydrochloride, linagliptin, an adhesive, a stabilizer, a diluent, a flow aid and a lubricant, the stabilizer is composed of sodium hydroxide and meglumine, and the diluent is composed of sodium hydroxide and meglumine. The pharmaceutical composition for treating diabetes mellitus has good dissolution and stability.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and in particular, relates to a pharmaceutical composition for treating diabetes and a preparation method thereof. Background Art

[0002] Linagliptin Metformin Tablets were launched in Europe (Switzerland) on July 19, 2012 under the trade name Jentadueto. They were imported into China in March 2017 under the trade name Trajenta Duo (Oushuangning). The licensee is Boehringer Ingelheim (Schweiz) GmbH. The specifications are 2.5mg:500mg and 2.5mg:850mg. Linagliptin Metformin Tablets is a combination drug used to treat type 2 diabetes. It combines two anti-diabetic drugs with different mechanisms: Linagliptin and Metformin. This combination can help control blood sugar levels and is suitable for patients who cannot effectively control blood sugar with one drug alone.

[0003] Linagliptin belongs to the class of drugs called DPP-4 inhibitors. It increases the concentration of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) in the body by blocking the action of the DPP-4 enzyme, thereby promoting pancreatic beta cells to secrete more insulin and reducing glucose production in the liver.

[0004] Metformin is a widely used oral hypoglycemic drug that helps control blood sugar primarily by reducing glucose production in the liver, reducing intestinal absorption of glucose from food, and increasing the body's sensitivity to insulin.

[0005] When linagliptin is used together with metformin hydrochloride, degradation of linagliptin may occur. To ensure the stability of the combination of linagliptin and metformin hydrochloride, the pharmaceutical company conducted extensive compatibility stress studies. These studies included the use of L-arginine and other alkaline substances as potential stabilizers, aiming to optimize the physical and chemical stability of the drug under various storage conditions.

[0006] Patent CN104840960A discloses an anti-diabetic pharmaceutical composition and a preparation method thereof, wherein meglumine is used as a stabilizer, and linagliptin and metformin hydrochloride are granulated separately to improve the stability of linagliptin in linagliptin metformin hydrochloride tablets.

[0007] Patent CN116919911A discloses a diabetes treatment drug and a preparation method thereof, which improves the dissolution of linagliptin metformin tablets by adding an alkaline excipient (methylglucamine) to the prescription, and further adds an antioxidant (such as sodium sulfobutyl beta-cyclodextrin) to the prescription to prevent the generation of impurities in linagliptin metformin tablets.

[0008] CN117618437A discloses a pharmaceutical composition containing linagliptin and metformin hydrochloride, a tablet core, a composite coated tablet and a preparation method, and solves the problem of poor stability of linagliptin by adding alkaline compounds (calcium hydroxide, magnesium hydroxide, meglumine, piperazine and sodium phosphate).

[0009] Patent CN117858703A discloses a method for preparing a pharmaceutical composition comprising linagliptin and metformin hydrochloride, by adding an acid to a granulation liquid comprising linagliptin to increase the stability of the formulation.

[0010] In the prior art, in order to enhance the compatibility and stability of the two active ingredients of linagliptin and metformin, alkaline reagents (such as meglumine and L-arginine) or acidic reagents (such as hydrochloric acid and glycine) are usually used. Nevertheless, the effects of these methods are often unsatisfactory, and some operating steps are relatively cumbersome, which limits the convenience and efficiency of their practical application. Summary of the invention

[0011] In order to solve the technical problems existing in the prior art, the present invention provides a pharmaceutical composition for treating diabetes, comprising: metformin hydrochloride, linagliptin, a binder, a stabilizer, a diluent, a glidant and a lubricant, wherein the stabilizer consists of sodium hydroxide and meglumine.

[0012] Furthermore, the mass ratio of the sodium hydroxide to the meglumine is (2-16):(20-21), preferably (2.04-15.3):20.4.

[0013] Furthermore, in parts by weight, it includes 800-900 parts of metformin hydrochloride, 2-3 parts of linagliptin, 55-65 parts of binder, 20-40 parts of stabilizer, 50-80 parts of diluent, 3-5 parts of glidant and 2-6 parts of lubricant.

[0014] Furthermore, the adhesive is copovidone, the diluent is pregelatinized starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.

[0015] In another aspect, the present invention provides a method for preparing the above-mentioned pharmaceutical composition for treating diabetes, comprising the following steps:

[0016] Metformin hydrochloride is crushed and then granulated together with other raw materials and auxiliary materials in a fluidized bed; the granules are dried and granulated, and then mixed, and then tableted and coated to obtain the pharmaceutical composition for treating diabetes.

[0017] Furthermore, the method further comprises the following steps: dissolving sodium hydroxide and meglumine in water as binder 1; and dissolving copovidone and linagliptin in water as binder 2.

[0018] Furthermore, the binder 1 and the binder 2 are respectively subjected to liquid spray granulation.

[0019] Furthermore, the particle size D90 of the metformin hydrochloride is less than 100 μm.

[0020] Furthermore, colloidal silicon dioxide and magnesium stearate are added during the granulation process.

[0021] Furthermore, metformin hydrochloride and pregelatinized starch are mixed, and then the binder 1 and the binder 2 are used for spray granulation respectively. After the obtained granules are dried, colloidal silicon dioxide and magnesium stearate are added to granulate them, and then the total mixing is carried out. After that, the tableting and coating steps are carried out to obtain the pharmaceutical composition for treating diabetes.

[0022] Compared with the prior art, the pharmaceutical composition for treating diabetes (hereinafter referred to as "linagliptin metformin tablets") and its preparation method of the present invention have the following advantages:

[0023] Dissolution curve consistency: The two active ingredients, linagliptin and metformin hydrochloride, can achieve dissolution curves consistent with the original drugs during the dissolution process.

[0024] Good stability: In the linagliptin metformin tablets prepared by the present invention, the related substances of the two active ingredients meet the limit requirements. In the accelerated test and long-term test, its stability performance is excellent, even surpassing the original drug.

[0025] Stable content of active ingredients: The content of active ingredients in linagliptin metformin tablets remains stable, especially the lower content of linagliptin. DETAILED DESCRIPTION

[0026] The technical solutions in the embodiments of the present application will be described clearly below. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0027] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship.

[0028] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0029] In order to solve the stability problem of Linagliptin Metformin Tablets, the original research used L-arginine, a basic amino acid. On this basis, the inventor combined the original research data with the existing technology and conducted in-depth research on various alkaline reagents, acidic reagents and their combinations. Finally, the inventor found a simple and easy-to-operate method to improve the quality of Linagliptin Metformin Tablets. The details are as follows:

[0030] The linagliptin metformin tablet comprises a tablet core and a coating layer, wherein the tablet core comprises metformin hydrochloride, linagliptin, a binder, a stabilizer, a diluent, a glidant and a lubricant, wherein the stabilizer consists of sodium hydroxide and meglumine.

[0031] In one embodiment of the present invention, the mass ratio of the sodium hydroxide to the meglumine is (2-16):(20-21), preferably (2.04-15.3):20.4, for example, 2.04:20.4, 3.06:20.4, 4.08:20.4, 5.10:20.4, 6.12:20.4, 7.14:20.4, 8.16:20.4, 9.18:20.4, 10.2:20.4, 11.22:20.4, 12.24:20.4, 13.26:20.4, 14.28:20.4 or 15.3:20.4, but is not limited to the listed values, and other unlisted values ​​within the numerical range are equally applicable.

[0032] Sodium hydroxide and meglumine are both alkaline reagents. Although their specific mechanism of action is not yet fully understood, the combined use of these two substances can effectively simulate the dissolution characteristics similar to those of the original product, while ensuring that the stability of linagliptin metformin tablets reaches a good level.

[0033] In one embodiment of the present invention, the core tablet comprises, by weight, 800-900 parts of metformin hydrochloride, 2-3 parts of linagliptin, 55-65 parts of binder, 20-40 parts of stabilizer, 50-80 parts of diluent, 3-5 parts of glidant and 2-6 parts of lubricant, preferably 800-900 parts of metformin hydrochloride, 2-3 parts of linagliptin, 60-62 parts of binder, 22-36 parts of stabilizer, 60-75 parts of diluent, 4-4.5 parts of glidant and 5-5.2 parts of lubricant, further preferably 850 parts of metformin hydrochloride, 2.5 parts of linagliptin, 61.2 parts of binder, 22.44-35.7 parts of stabilizer, 61.22-74.48 parts of diluent, 4.28 parts of glidant and 5.1 parts of lubricant.

[0034] In one embodiment of the present invention, the binder is copovidone, the diluent is pregelatinized starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.

[0035] In one embodiment of the present invention, the specific preparation method is: metformin hydrochloride and pregelatinized starch are mixed, and then the binder 1 and the binder 2 are respectively sprayed for fluidized bed granulation, and the obtained granules are dried and then added with colloidal silicon dioxide and magnesium stearate for granulation, and then the total mixing is performed, and then the tableting and coating steps are performed to obtain linagliptin metformin tablets.

[0036] In one embodiment of the present invention, sodium hydroxide and meglumine are dissolved in water as binder 1; copovidone and gliptin are dissolved in water as binder 2.

[0037] The fluidized bed granulation process used in the present invention is also called boiling granulation, which is a special wet granulation method. In this process, air enters a container through the bottom, so that the powder is suspended in the air flow to form a "boiling" state. Then, the binder solution is sprayed onto these suspended particles by spraying, so that they gradually aggregate into larger particles. Fluidized bed granulation is not limited to the use of liquid binders, but can also be used for other processing steps such as drying and coating.

[0038] The present invention does not limit the specific parameters of the mixing, granulation, drying, tableting and coating processes, as long as these processes can achieve their intended functions. This means that, under the premise of ensuring that the corresponding process effects are achieved, those skilled in the art can flexibly adjust the specific parameters of each process according to actual needs.

[0039] In one embodiment of the present invention, the coating agent is a film coating premix, and the present invention does not limit the types of raw and auxiliary materials, as long as they can play the corresponding role.

[0040] During the granulation process, binders are usually used to effectively bind powder particles together. The inventors unexpectedly found that by using a specific combination of binders to prepare the binders separately and spray granulating each binder separately, the obtained product showed excellent performance in terms of dissolution and stability.

[0041] The present invention precisely controls the mass ratio of sodium hydroxide and meglumine, and uses meglumine and sodium hydroxide as a binder 1, and copovidone and linagliptin as a binder 2. In the granulation process, the binder 1 and the binder 2 are respectively subjected to fluidized bed granulation, and the two act synergistically to ensure that the linagliptin metformin tablets have excellent dissolution performance and stability.

[0042] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0043] Table 1 Sources and functions of raw materials and auxiliary materials

[0044] Element factory effect Metformin Hydrochloride Shoukang Fuguang Pharmaceutical Co., Ltd. Active ingredients Linagliptin Ruyuan East Sunshine Pharmaceutical Co., Ltd. Active ingredients Sodium hydroxide Hunan Erkang Pharmaceutical Co., Ltd. Stabilizer Meglumine Xi'an Nippon Paint Pharmaceutical Co., Ltd. Stabilizer Copolyvidone Ashland (China) Investment Co., Ltd. Adhesives Pregelatinized starch Shanghai Colorcon Coating Technology Co., Ltd. Thinner Colloidal Silica Evonik Specialty Chemicals (Shanghai) Co., Ltd. Glidants Magnesium Stearate Huzhou Zhanwang Pharmaceutical Co., Ltd. Lubricants Film coating premix Shanghai Colorcon Coating Technology Co., Ltd. Coating agent

[0045] Table 2 Example and Comparative Example Linagliptin Metformin Tablets Prescription Composition (mg / tablet)

[0046]

[0047] (Purified water as solvent will be removed in the process)

[0048] Preparation process of linagliptin metformin tablets according to Examples 1 to 4 and Comparative Examples 1 to 3 (taking 10,000 tablets as an example):

[0049] 1. Preprocessing

[0050] Metformin hydrochloride is crushed to control the particle size D90 to be less than 100 μm.

[0051] 2. Granulation

[0052] 1) Premix

[0053] About half of the metformin hydrochloride, pregelatinized starch and the remaining metformin hydrochloride were added to the wet granulator, with a stirring speed of 160 rpm and a granulating knife speed of 2000 rpm. The mixture was mixed for 10 minutes, and the discharge stirring was 10-100 rpm. The aperture of the circular screen of the granulator was 1.0 mm, and the speed was 300-900 rpm.

[0054] 2) Granulation and drying

[0055] Binder 1 (methylglucamine, sodium hydroxide solution): weigh 0.918 kg of purified water, add sodium hydroxide (if any) and meglucamine (if any) in the purified water while stirring continuously, stir until a uniform solution is obtained, and set aside as a binder.

[0056] Binder 2 (copovidone, linagliptin solution): weigh 6.12 kg of purified water, add copovidone to the purified water with continuous stirring and stir for more than 30 minutes until it is completely dissolved. After it is completely dissolved, add linagliptin and stir for 60 minutes to obtain a uniform suspension, which is used as a binder.

[0057] Preheat the boiling granulator in advance, set the air inlet temperature to 55.0±10.0℃, and the fan frequency to 10-30Hz. Pump the material obtained in step 1) into the boiling granulator by vacuum, set the air inlet temperature to 55.0±10.0℃, the fan frequency to 10-30Hz, the material temperature to 40±5℃, the atomization pressure to 2bar, and the fan pressure to 3bar. After the material temperature reaches 42.0℃, use the above-mentioned adhesives 1 and 2 in turn for spray granulation, and control the material temperature range to 30-40℃ during the spraying process.

[0058] Turn on the heating, and when the moisture content of the material is ≤2.5% (measured by a moisture meter, 105°C, 5min), the drying is finished and the material is discharged.

[0059] 3) Granulation: Add the prescribed amount of colloidal silicon dioxide and magnesium stearate into the storage tank of a fixed vacuum granulator, transfer the dried material into the storage tank of the fixed vacuum granulator, set the granulation screen aperture to 1.0 mm, and rotate at 500 rpm for granulation.

[0060] 3. Total mixing

[0061] Put the material obtained in step 2 into the hopper mixer, set the mixing speed to 8 rpm and the mixing time to 10 min.

[0062] 4. Tablet pressing

[0063] select The oval deep concave punch is used for tableting with GZPTS-45 double-discharge tablet press. The weight difference of the blank tablet is ±5%, and the hardness is between 80 and 210N.

[0064] 5. Coating

[0065] Coating solution preparation:

[0066] Prepare 15% Opadry film coating premix and coat the plain tablets obtained in step 4 using a coating machine.

[0067] The addition methods of linagliptin, copovidone, meglumine, and sodium hydroxide were investigated, and the specific conditions are shown in Table 3.

[0068] Table 3 Investigation of different adhesive addition methods

[0069]

[0070] Comparative Example 4

[0071] Step 2) The preparation method of the binder in the granulation drying is as follows, and the prescription composition and other process steps are the same as those in Example 2:

[0072] Weigh 7.038 kg of purified water, add copovidone to the purified water while stirring, stir until completely dissolved, then add meglumine, sodium hydroxide and linagliptin as a binder for later use.

[0073] Comparative Example 5

[0074] Step 2) The preparation method of the binder in the granulation drying is as follows, and the prescription composition and other process steps are the same as those in Example 2:

[0075] Binder 1 (linagliptin, meglumine, sodium hydroxide solution): weigh 0.918 kg of purified water, add sodium hydroxide, meglumine and linagliptin in sequence to the purified water under continuous stirring, stir until a uniform solution is obtained, and set aside as a binder.

[0076] Adhesive 2 (copovidone solution): weigh 6.12 kg of purified water, add copovidone into the purified water with continuous stirring, and stir for more than 30 minutes until it is completely dissolved. Use it as an adhesive for later use.

[0077] Comparative Example 6

[0078] Step 2) The preparation method of the binder in the granulation drying is as follows, and the prescription composition and other process steps are the same as those in Example 2:

[0079] Binder 1 (linagliptin, meglumine solution): weigh 0.918 kg of purified water, add meglumine and linagliptin in sequence to the purified water under continuous stirring, and stir until a uniform solution is obtained. The solution is used as a binder for later use.

[0080] Binder 2 (copovidone, sodium hydroxide solution): weigh 6.12 kg of purified water, add copovidone to the purified water with continuous stirring and stir for more than 30 minutes until it is completely dissolved, then add sodium hydroxide and stir for 60 minutes to obtain a uniform suspension, which is used as a binder.

[0081] Comparative Example 7

[0082] Step 2) The preparation method of the binder in the granulation drying is as follows, and the prescription composition and other process steps are the same as those in Example 2:

[0083] Binder 1 (linagliptin, sodium hydroxide solution): weigh 0.918 kg of purified water, add sodium hydroxide and linagliptin in sequence to the purified water while stirring continuously, and stir until a uniform solution is obtained. The solution is used as a binder for later use.

[0084] Binder 2 (copovidone, meglumine solution): weigh 6.12 kg of purified water, add copovidone to the purified water with continuous stirring and stir for more than 30 minutes until it is completely dissolved, then add meglumine and stir for 60 minutes to obtain a uniform suspension, which is used as a binder.

[0085] Comparative Example 8

[0086] Step 2) The preparation method of the binder in the granulation drying is as follows, and the prescription composition and other process steps are the same as those in Example 2:

[0087] Binder 1 (methylglucamine solution): weigh 0.918 kg of purified water, add meglucamine to the purified water while stirring continuously, and stir until a uniform solution is obtained. The solution is used as a binder.

[0088] Binder 2 (copovidone, linagliptin, sodium hydroxide solution): weigh 6.12 kg of purified water, add copovidone to the purified water with continuous stirring, stir for more than 30 minutes until it is completely dissolved, then add linagliptin and sodium hydroxide, stir for 60 minutes to obtain a uniform suspension, which is used as a binder.

[0089] Comparative Example 9

[0090] Step 2) The preparation method of the binder in the granulation drying is as follows, and the prescription composition and other process steps are the same as those in Example 2:

[0091] Binder 1 (sodium hydroxide solution): weigh 0.918 kg of purified water, add sodium hydroxide to the purified water while stirring continuously, and stir until a uniform solution is obtained. The solution is used as a binder.

[0092] Binder 2 (copovidone, linagliptin, meglumine solution): weigh 6.12 kg of purified water, add copovidone to the purified water with continuous stirring and stir for more than 30 minutes until it is completely dissolved, then add linagliptin and meglumine and stir for 60 minutes to obtain a uniform suspension, which is used as a binder.

[0093] Comparative Example 10

[0094] The granulation operation mode of step 2 is as follows, and the formulation composition and other process steps are the same as those of Example 2:

[0095] 2. Granulation

[0096] 1) Premix

[0097] About half of the metformin hydrochloride, pregelatinized starch, copovidone, sodium hydroxide, linagliptin, meglumine and the remaining metformin hydrochloride were added to the wet granulator, the stirring speed was 160 rpm, the granulator speed was 2000 rpm, the mixing was carried out for 10 minutes, the discharge stirring was 10-100 rpm, the granulator circular screen aperture was 1.0 mm, and the speed was 300-900 rpm.

[0098] 2) Granulation and drying

[0099] Preheat the boiling granulator in advance, set the air inlet temperature to 55.0±10.0℃, and the fan frequency to 10-30Hz. The material obtained in step 1) is vacuum pumped into the boiling granulator, and the air inlet temperature is set to 55.0±10.0℃, the fan frequency is set to 10-30Hz, the material temperature is 40±5℃, the atomization pressure is 2bar, and the fan pressure is 3bar. After the material temperature reaches 42.0℃, spray 7.038kg of purified water for granulation, and control the material temperature range to 30-40℃ during the spraying process.

[0100] Turn on the heating, and when the moisture content of the material is ≤2.5% (measured by a moisture meter, 105°C, 5min), the drying is finished and the material is discharged.

[0101] 3) Granulation: Add the prescribed amount of colloidal silicon dioxide and magnesium stearate into the storage tank of a fixed vacuum granulator, transfer the dried material into the storage tank of the fixed vacuum granulator, set the granulation screen aperture to 1.0 mm, and rotate at 500 rpm for granulation.

[0102] The dissolution, related substances and Linagliptin content (Reference preparation: Trade name Trajenta Duo (Oushuangning), licensee is Boehringer Ingelheim (Schweiz) GmbH, batch number is 205650)

[0103] Dissolution determination method: Determine according to the dissolution and release determination method (Method 2, 0931, General Rules of Part 4 of the 2020 Edition of Chinese Medicines).

[0104] Dissolution medium volume: 900ml

[0105] Speed: 50 rpm

[0106] Sampling time: 5, 10, 15, 20, 30 minutes

[0107] Sampling volume: 10ml

[0108] Rehydration volume: 10ml

[0109] Preparation of dissolution medium (0.1mol / L hydrochloric acid medium): 0.1mol / L hydrochloric acid medium: measure 9ml of hydrochloric acid, dilute it to 1000ml with water, shake well, and obtain.

[0110] Table 4 Dissolution test results of the embodiments and comparative examples (0.1 mol / L hydrochloric acid)

[0111]

[0112]

[0113] The 15 min dissolution rates of the two active substances in the linagliptin metformin tablets obtained in the reference preparation, the examples and the comparative examples all satisfy>85%, and it can be determined that the dissolution curves are similar.

[0114] Because the content of linagliptin is small and there is a risk of degradation, we further investigated the content of linagliptin after being placed at 60°C for 1 month, 3 months, and 6 months. 25 H 28 N8O2) should be 94.0% to 105.0% of the labeled amount. Content determination method: Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512).

[0115] Table 5 Content of linagliptin (%)

[0116]

[0117]

[0118] According to the data in Table 5, it can be seen that the degradation amount of linagliptin in the linagliptin metformin tablets of Comparative Examples 1 to 10 within 6 months is significantly higher than that of Examples 1 to 4 and the reference preparation. At the same time, the degradation amount of linagliptin in the preparations obtained in Examples 1 to 4 is also significantly better than that of the reference preparation. This shows that in the composition and preparation process of linagliptin metformin tablets, the type and amount of stabilizer, as well as the method and timing of adding linagliptin, copovidone, meglumine and sodium hydroxide are crucial to ensure the stability of linagliptin.

[0119] The results of the accelerated and long-term tests were further investigated after 3 and 6 months. .

[0120] Accelerated test conditions: 40±2℃&RH75%±5%

[0121] Long-term test conditions: 25±2℃&RH60%±5%

[0122] Related substance detection method: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512)

[0123] Table 6 Impurity information

[0124]

[0125]

[0126] Table 7 Related substances of linagliptin

[0127]

[0128]

[0129]

[0130] Table 8 Related substances of metformin hydrochloride

[0131]

[0132]

[0133]

[0134]

[0135] From the related substance detection results of linagliptin and metformin hydrochloride in Tables 7 and 8, it can be seen that the related substances of the linagliptin metformin tablets obtained in Examples 1 to 4 are all within the limit range, and the number and content of impurities are lower than those of the reference preparation. In addition, in the accelerated test and the long-term test, after 3 months and 6 months, the corresponding impurity content in the example samples is also significantly lower than that of the reference preparation, showing excellent stability.

[0136] By comparing the impurity contents of linagliptin and metformin hydrochloride in Examples 1 to 4 and Comparative Examples 1 to 3, it can be seen that, under the same other conditions, the impurities of linagliptin in the preparations of Examples 1 to 4 (the mass ratio of sodium hydroxide and meglumine is (2.04 to 15.3): 20.4) are significantly lower than those in Comparative Example 1 (the mass ratio of sodium hydroxide and meglumine is 0:20.4), Comparative Example 2 (the mass ratio of sodium hydroxide and meglumine is 20.4:20.4) and Comparative Example 3 (the mass ratio of sodium hydroxide and meglumine is 20.4:0), and the "total impurities" of linagliptin in the preparations of Comparative Examples 1 to 3 increase most significantly after 6 months of acceleration, which is very close to the limit value of 1.0%; the impurities of metformin hydrochloride in the preparations of Examples 1 to 4 are significantly lower than those in Comparative Examples 1 to 3, and the "other single impurities" in Comparative Examples 1 to 3 obviously exceed the limit value of 0.1%. It can be seen that the mass ratio of sodium hydroxide to meglumine is (2.04-15.3):20.4, which is more conducive to controlling impurities in the preparation.

[0137] Comparing the impurity content of linagliptin and metformin hydrochloride in Example 2 and Comparative Examples 4 to 10, it can be seen that under the same other conditions, the impurities of linagliptin and metformin hydrochloride in the linagliptin metformin tablets obtained by using meglumine and sodium hydroxide as binder 1, copolyvidone and linagliptin as binder 2, and fluidized bed granulation of binder 1 and binder 2 are significantly lower than those of the preparations of Comparative Examples 4 to 10 in both accelerated and long-term tests. The "other single impurities" in Comparative Examples 4 to 10 obviously exceed the limit value of 0.1%, and the total impurities of individual batches also exceed the limit value of 0.6% after 6 months of acceleration, such as Comparative Example 6 (0.782%), Comparative Example 9 (0.668%) and Comparative Example 10 (0.738%). It can be seen that meglumine and sodium hydroxide are used as binder 1, copolyvidone and linagliptin are used as binder 2, and the way of fluidized bed granulation of binder 1 and binder 2 is more conducive to controlling impurities in the preparation.

[0138] The embodiments of the present application are described above, but the present application is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A pharmaceutical composition for treating diabetes, characterized in that: The invention comprises a tablet core and a coating layer, wherein the tablet core comprises metformin hydrochloride, linagliptin, an adhesive, a stabilizer, a diluent, a glidant and a lubricant, wherein the stabilizer consists of sodium hydroxide and meglumine.

2. The pharmaceutical composition for treating diabetes according to claim 1, characterized in that: The mass ratio of the sodium hydroxide to the meglumine is (2-16):(20-21), preferably (2.04-15.3):20.

4.

3. The pharmaceutical composition for treating diabetes according to claim 2, characterized in that: The tablet core comprises, by weight, 800-900 parts of metformin hydrochloride, 2-3 parts of linagliptin, 55-65 parts of binder, 20-40 parts of stabilizer, 50-80 parts of diluent, 3-5 parts of glidant and 2-6 parts of lubricant.

4. The pharmaceutical composition for treating diabetes according to claim 3, characterized in that: The binder is copolyvidone, the diluent is pregelatinized starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.

5. A method for preparing the pharmaceutical composition for treating diabetes according to any one of claims 1 to 4, comprising the following steps: Metformin hydrochloride is crushed and then granulated together with other raw materials and auxiliary materials in a fluidized bed; the granules are dried and granulated, and then mixed, and then tableted and coated to obtain the pharmaceutical composition for treating diabetes.

6. The method for preparing the pharmaceutical composition for treating diabetes according to claim 5, characterized in that: The method further comprises the following steps: dissolving sodium hydroxide and meglumine in water as binder 1; and dissolving copovidone and linagliptin in water as binder 2.

7. The method for preparing the pharmaceutical composition for treating diabetes according to claim 6, characterized in that: The binder 1 and the binder 2 are respectively subjected to liquid spray granulation.

8. The method for preparing the pharmaceutical composition for treating diabetes according to claim 7, characterized in that: The particle size D90 of the metformin hydrochloride is less than 100 μm.

9. The method for preparing the pharmaceutical composition for treating diabetes according to claim 8, characterized in that: Colloidal silicon dioxide and magnesium stearate are added during the granulation process.

10. The method for preparing the pharmaceutical composition for treating diabetes according to claim 9, characterized in that: Metformin hydrochloride and pregelatinized starch are mixed, and then the binder 1 and the binder 2 are used for spray granulation respectively. After the obtained granules are dried, colloidal silicon dioxide and magnesium stearate are added to granulate, and then the granules are mixed, and then tableting and coating processes are performed to obtain the pharmaceutical composition for treating diabetes.

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