Dapagliflozin pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and particularly discloses a dapagliflozin pharmaceutical composition, the pharmaceutical composition contains dapagliflozin, a stabilizer and at least one pharmaceutically acceptable excipient, and the weight ratio of dapagliflozin to the stabilizer is not less than 20000: 1. The invention also comprises preparation and application of the pharmaceutical composition. According to the dapagliflozin pharmaceutical composition disclosed by the invention, the dapagliflozin pharmaceutical composition has excellent stability.

Description

Technical Field

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

[0002] Dapagliflozin is a new type of oral hypoglycemic drug, belonging to the sodium-glucose co-transporter 2 (SGLT2) inhibitor. It reduces glucose reabsorption and increases urinary glucose excretion by inhibiting SGLT2, thereby achieving the effect of lowering blood sugar. Dapagliflozin is mainly used to treat type 2 diabetes, and has a significant effect on improving symptoms such as polydipsia, polyphagia, polyuria and weight loss. Dapagliflozin tablets were jointly developed by Bristol-Myers Squibb and AstraZeneca. They were approved for marketing in Australia and EMA in 2012, and were approved by the US FDA in 2014. The trade name is FARXIGA.

[0003] The high temperature and high humidity stability of amorphous dapagliflozin and dapagliflozin-(s)propylene glycol-water cosolvate are both poor, which poses great challenges to formulation development. According to literature reports, the original research of dapagliflozin tablets uses dapagliflozin-(s)propylene glycol-water cosolvate as the raw material, with a melting point of about 70°C. It uses a dry granulation process, which is complex and costly. In addition, the material extrusion heats up during the dry granulation process. Above 45°C, dapagliflozin propylene glycol monohydrate will desolvate and crystallize, resulting in product instability. Amorphous dapagliflozin has strong hygroscopicity and easily becomes a semisolid after absorbing moisture, increasing viscosity, affecting the content uniformity, stability and dissolution of the product. Patent CN115869265A discloses a method for preparing dapagliflozin tablets using solid dispersion technology. Dapagliflozin and cross-linked polyvinylpyrrolidone are mixed to obtain a dapagliflozin solid dispersion, which can improve the strong hygroscopicity of the amorphous raw material of dapagliflozin under normal temperature and humidity conditions and the low glass transition temperature of dapagliflozin. However, the process for preparing the solid dispersion is complex and has high equipment requirements.

[0004] In addition, the applicant of the present invention found in actual production research that the benzylic methylene group of dapagliflozin is easily oxidized to form impurity 1, which is a genotoxic impurity. The specific route is as follows: .

[0005] Genotoxic impurities, also known as genotoxic impurities, refer to compounds that directly or indirectly damage cell DNA, produce gene mutations or in vivo mutagenesis, and have the potential or tendency to cause cancer. Genotoxic impurities are extremely toxic and can cause damage to human genetic material at very low concentrations, leading to gene mutations and possibly promoting the occurrence of tumors, posing a strong threat to the safety of medication. Since 2000, drug regulatory agencies in various countries and regions have successively issued relevant articles or guidelines, requiring API and formulation manufacturers to conduct risk control of genotoxic impurities. According to the ICH M7 guidelines, the limit of genotoxic impurities shall not exceed 150ppm.

[0006] The object of the present invention is to provide a dapagliflozin pharmaceutical composition which has excellent stability and a simple preparation process. Summary of the invention

[0007] In view of the problem of poor stability of dapagliflozin in the prior art, the first object of the present invention is to provide a pharmaceutical composition that improves the stability of dapagliflozin.

[0008] The second object of the present invention is to provide a method for preparing the dapagliflozin pharmaceutical composition, wherein the prepared pharmaceutical composition has good content uniformity.

[0009] The third object of the present invention is to provide an application of the dapagliflozin pharmaceutical composition in the preparation of a dapagliflozin oral solid preparation. The oral solid preparation prepared from the dapagliflozin pharmaceutical composition has good stability and less genotoxic impurities.

[0010] The fourth object of the present invention is to provide an oral solid preparation containing the dapagliflozin pharmaceutical composition.

[0011] The fifth object of the present invention is to provide a method for preparing an oral solid preparation containing the dapagliflozin pharmaceutical composition, which has a simple and controllable process.

[0012] In view of the above problems, the present invention provides the following technical solutions: A dapagliflozin pharmaceutical composition comprises dapagliflozin, a stabilizer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of dapagliflozin to the stabilizer is not less than 20000:1.

[0013] The present invention shows that the combination of dapagliflozin and a stabilizer, combined with the control of the weight ratio of the two, can unexpectedly improve the stability of dapagliflozin and inhibit the generation of genotoxic impurities in dapagliflozin.

[0014] Preferably, the weight ratio of dapagliflozin to the stabilizer is not less than 2000: 1, and more preferably the weight ratio is not less than 400: 1. The present invention has found that at this preferred ratio, the stability of dapagliflozin can be further improved and the generation of genotoxic impurities of dapagliflozin can be inhibited.

[0015] The dapagliflozin pharmaceutical composition, in parts by weight, comprises 1 to 8 parts of dapagliflozin, 0.0002 to 1 parts of stabilizer, and 85 to 100 parts of excipient; preferably, the dapagliflozin is 2 to 6 parts, the stabilizer is 0.002 to 0.5 parts, and the excipient is 90 to 100 parts; further preferably, the dapagliflozin is 4 parts, the stabilizer is 0.01 to 0.1 parts, and the excipient is 92 to 94 parts.

[0016] Preferably, the dapagliflozin is amorphous dapagliflozin.

[0017] Preferably, the stabilizer is an organic stabilizer, an inorganic stabilizer or a combination thereof.

[0018] Preferably, the organic stabilizer is selected from one or more of ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, butylated p-hydroxyanisole, butylated hydroxytoluene, thiourea, cysteine, methionine, thioacetic acid, and thioglycerol.

[0019] Preferably, the inorganic stabilizer is selected from one or more of sodium sulfite, sodium bisulfite, sodium pyrosulfite and sodium thiosulfate.

[0020] Preferably, the excipients include a diluent and a disintegrant, the diluent is 75-100 parts, and the disintegrant is 2-10 parts; more preferably, the diluent is 88-90 parts, and the disintegrant is 4 parts.

[0021] Preferably, the diluent is selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate, and pregelatinized starch.

[0022] Preferably, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and sodium carboxymethyl starch.

[0023] Preferably, the diluent is a combination of anhydrous lactose and microcrystalline cellulose, with anhydrous lactose accounting for 10 to 30 parts and microcrystalline cellulose accounting for 60 to 80 parts; more preferably, anhydrous lactose accounting for 20 parts and microcrystalline cellulose accounting for 68 to 70 parts.

[0024] Based on the combination of the dapagliflozin, the stabilizer and the excipient, the hygroscopicity of the prepared dapagliflozin pharmaceutical composition is significantly improved, and the crystal form is stable when placed for a long time in a high humidity and high humidity environment.

[0025] The present invention provides a method for preparing the dapagliflozin pharmaceutical composition, which is characterized in that dapagliflozin and a stabilizer are dissolved in a solvent to prepare a wetting agent solution, and the wetting agent solution is granulated with other excipients.

[0026] Preferably, the preparation method comprises the following steps: (1) Preparing a wetting agent solution: dissolving dapagliflozin and a stabilizer in a solvent to prepare a wetting agent solution; (2) Granulation: The diluent and disintegrant are mixed evenly, and a wetting agent solution is added to granulate to obtain wet granules. The wet granules are dried and granulated to obtain the dapagliflozin pharmaceutical composition.

[0027] Preferably, the solvent is 60% ethanol, and the amount of solvent used is based on the complete dissolution of dapagliflozin and the stabilizer.

[0028] Preferably, the wetting agent is added by spraying.

[0029] In the present invention, thanks to the use of the stabilizer, the dapagliflozin pharmaceutical composition can adopt a simple formulation preparation process, without the need to use preparation processes such as solid dispersions, and the solvent used is green, environmentally friendly, safe and non-toxic. The prepared dapagliflozin pharmaceutical composition has good stability and good content uniformity.

[0030] The present invention also provides an application of the pharmaceutical composition, which can be used as an intermediate to prepare a dapagliflozin oral solid preparation. The present invention has found that the use of the pharmaceutical composition to prepare an oral solid preparation can improve the stability of dapagliflozin in the preparation, control the growth of genotoxic impurities, improve the effectiveness and safety of the preparation, and the preparation has excellent solubility.

[0031] The present invention also provides a dapagliflozin oral solid preparation, which comprises the pharmaceutical composition and other auxiliary components, and the amount of the other auxiliary components is added according to actual needs.

[0032] Preferably, the auxiliary ingredients include at least one of a glidant, a lubricant, a flavor, a flavoring agent, and a coloring agent.

[0033] Preferably, the oral solid preparation is selected from granules, capsules or tablets, more preferably tablets.

[0034] The present invention also provides a method for preparing dapagliflozin tablets, comprising the following steps: (1) Tableting: Mixing the dapagliflozin pharmaceutical composition with other auxiliary ingredients and tableting to prepare plain tablets; (2) Coating: Coating the plain tablets to obtain dapagliflozin tablets.

[0035] Beneficial Effects 1. The dapagliflozin pharmaceutical composition of the present invention has good stability. The combination of dapagliflozin and a stabilizer can inhibit the generation of genotoxic impurities of dapagliflozin. The dapagliflozin crystal in the pharmaceutical composition is stable and does not undergo crystal transformation when placed at 40±2°C and 75±5% RH for 6 months.

[0036] 2. In the present invention, the stabilizer and dapagliflozin are dissolved as wetting agents, and the wetting agent is added to the excipient by spraying to prepare granules. The dapagliflozin pharmaceutical composition is prepared by the process, which is simple and controllable, and the prepared pharmaceutical composition has less genotoxic impurities and good content uniformity.

[0037] 3. The dapagliflozin pharmaceutical composition is prepared into a preparation with common auxiliary ingredients according to conventional techniques, which can improve the stability of dapagliflozin in oral solid preparations, inhibit the growth of genotoxic impurities in the preparations, and improve the safety of medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The results of the stability study of the dapagliflozin pharmaceutical composition are as follows; Figure 2 These are the results of the stability study of dapagliflozin tablets. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail through examples below. The following examples are only used to explain the present invention and do not represent the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0040] The reagents and auxiliary materials used in the present invention are all commercially available. The amorphous dapagliflozin raw material used is a homemade sample.

[0041] Examples and Comparative Examples 1. Prescription composition.

[0042] Table 1 Prescription composition

[0043]

[0044]

[0045] .

[0046] 2. Preparation method 2.1 Preparation method of pharmaceutical composition The pharmaceutical composition is prepared by the following method: (1) Preparation of wetting agent: Add the prescribed amount of stabilizer to the prescribed amount of ethanol water (60%, g / g) solution while stirring, continue stirring until completely dissolved, then add dapagliflozin API and continue stirring until completely dissolved.

[0047] (2) Preparation of soft material: Add anhydrous lactose DT, microcrystalline cellulose 101 and cross-linked polyvinylpyrrolidone XL-10 into a wet granulator for premixing and mixing for 5 minutes. Then, add the ethanol solution containing dapagliflozin and antioxidants by spray gun to prepare the soft material.

[0048] (3) Granulation: Use a portal granulator for wet granulation, with a sieve aperture of 4*4mm.

[0049] (4) Drying: Use fluidized bed for drying, set the inlet air temperature to 60℃~70℃, and control the moisture content to less than 3.0%.

[0050] (5) Granulation: Dry granulation is performed using a portal granulator with a sieve aperture of Φ1.5 mm to obtain the dapagliflozin pharmaceutical composition.

[0051] 2.2 Preparation of oral solid dosage forms The dapagliflozin pharmaceutical composition can be further prepared into a dapagliflozin oral solid preparation.

[0052] Taking dapagliflozin tablets as an example, the dapagliflozin pharmaceutical composition is mixed with other pharmaceutically acceptable auxiliary ingredients such as glidants and lubricants, and prepared by the following method: (1) Mixing: Add the dapagliflozin pharmaceutical composition, silicon dioxide, and magnesium stearate into a mixer and mix for 5 minutes; (2) Tablet compression: tablet weight is designed according to the content; (3) Coating: Prepare the coating solution with Opadry coating premix and coat the plain tablets.

[0053] Experimental Example 1: Study on the stability of drug composition The present invention conducts accelerated stability study on the dapagliflozin pharmaceutical composition prepared in the embodiment and comparative example according to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Rules 9001, Guidelines for Stability Tests of APIs and Preparations and the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Rules 0512, High Performance Liquid Chromatography. Accelerated stability study is to quickly evaluate the quality changes of drugs within a certain period of time by simulating accelerated conditions, such as high temperature and high humidity, and the results can be used to predict the stability of drugs under long-term storage conditions.

[0054] The accelerated stability test conditions of the dapagliflozin pharmaceutical composition of the present invention are 40°C±2°C and RH75%±5%.

[0055] (1) Solution preparation: Weigh an appropriate amount of the dapagliflozin pharmaceutical composition and dissolve it in acetonitrile by ultrasonication to prepare a solution containing 2 mg / ml of dapagliflozin.

[0056] (2) Chromatographic conditions Test instruments: high performance liquid chromatograph, ultraviolet detector; Chromatographic column: octadecylsilane bonded silica gel as filler; Mobile phase: 0.04% trifluoroacetic acid in water as mobile phase A, 0.02% trifluoroacetic acid in acetonitrile as mobile phase B; Detection wavelength: 254nm; column temperature: 35℃; flow rate: 0.8ml / min; injection volume: 30ul; The gradient elution program is as follows: .

[0057] The results of the stability test of the pharmaceutical composition are shown in the following table. Table 2 Results of stability study of drug composition

[0058] .

[0059] The genotoxic impurity test results of the dapagliflozin drug combination at 0 day and 10 days of long-term stability study show that: (1) At 0 days, the detected genotoxic impurity contents of Examples 1 to 19 were all lower than those of Comparative Example 1. Comparative Example 1 did not contain a stabilizer, and the genotoxic impurity content was 95.8 ppm. The genotoxic impurity content of the pharmaceutical compositions prepared in Examples 1 to 15 was lower than 60 ppm.

[0060] (2) Accelerated stability test conditions: After being placed at 40°C ± 2°C and RH 75% ± 5% for 10 days, the detected genotoxic impurity contents of Examples 1 to 19 were all lower than those of the comparative examples, and the genotoxic impurity content of the dapagliflozin pharmaceutical composition of comparative example 1 was 104.3 ppm. The genotoxic impurity content of Examples 1 to 15 was less than 65 ppm, among which sodium metabisulfite had the best effect in inhibiting genotoxic impurities.

[0061] Experimental Example 2: Detection of crystal form of drug composition The blank excipients of the dapagliflozin pharmaceutical composition, the amorphous dapagliflozin API, and the pharmaceutical composition prepared in Example 4 were subjected to crystal form detection. The X-ray diffraction pattern showed that the prepared dapagliflozin pharmaceutical composition had no change in crystal form compared to the API. After being placed under the conditions of 40±2°C and 75±5%RH for 6 months, the dapagliflozin crystal form in the pharmaceutical composition was still stable without crystal transformation.

[0062] Experimental Example 3 Investigation of Hygroscopicity of Pharmaceutical Composition Dapagliflozin is amorphous and has strong hygroscopicity. After absorbing moisture, it easily becomes a semisolid, and the viscosity increases, which affects the content uniformity, stability and dissolution of the product. The sample investigated in the present invention is a pharmaceutical composition. The hygroscopicity of the prepared pharmaceutical composition is investigated with reference to the 2020 edition of the Chinese Pharmacopoeia, Part IV, Drug 9103 Hygroscopicity Test Guidelines. The specific test method is as follows.

[0063] (1) Take a dry glass weighing bottle with a stopper and place it in an artificial climate box one day before the test. Set the temperature to 25℃±1℃ and the relative humidity to 80%±2%. Accurately weigh the weight and calculate it as m 1 .

[0064] (2) Take 10 g of sample and spread it evenly in the above weighing bottle. Weigh it accurately and calculate the weight as m 2 .

[0065] (3) Leave the weighing bottle open and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

[0066] (4) Cover the weighing bottle and weigh it accurately, which is m. 3 .

[0067] .

[0068] Table 3 Hygroscopicity test results of pharmaceutical compositions .

[0069] The dapagliflozin pharmaceutical composition prepared in Examples 1 to 19 of the present invention was placed at 25°C ± 1°C and RH 80% ± 2% for 24 hours, and the weight gain was less than 7.0%. The dapagliflozin pharmaceutical composition prepared in Examples 1 to 19 has low hygroscopicity in a high humidity environment and can be placed for a long time, thus avoiding the problem that a single amorphous dapagliflozin absorbs moisture and becomes semi-solid or even deliquesces. Example 4 Investigation of critical relative humidity of pharmaceutical composition

[0070] Place the saturated salt solution in a desiccator and balance the desiccator in a 25°C thermostat for 24 hours. Place about 2.5 g of the dapagliflozin pharmaceutical composition at the bottom of a weighing bottle that has been weighed to a constant weight, weigh it accurately, and place it in a desiccator containing 7 supersaturated solutions of different salts listed in the table below (with the weighing bottle cap open). Place it in a 25°C thermostat for 7 days and then weigh it to calculate the moisture absorption percentage. Draw a graph with moisture absorption rate (%) as the ordinate and relative humidity (%) as the abscissa, draw tangents at both ends of the curve, and the abscissa corresponding to the intersection of the two tangents is the critical relative humidity (CRH). The critical relative humidity of the dapagliflozin pharmaceutical composition in Example 4 is 86.2%.

[0071] Table 4 Example 4 Determination of moisture absorption rate by saturated solution method .

[0072] The critical relative humidity of the dapagliflozin pharmaceutical composition prepared in the Examples and Comparative Examples is shown in the following table.

[0073] Table 5 Results of determination of critical relative humidity of pharmaceutical composition .

[0074] The critical relative humidity of the dapagliflozin pharmaceutical composition prepared in Examples 1 to 19 of the present invention is greater than 83%. The humidity of the theoretical storage condition of the dapagliflozin pharmaceutical composition of the present invention should be lower than 83%, under which the pharmaceutical composition can be stored normally.

[0075] The content uniformity of the dapagliflozin pharmaceutical composition was tested according to the General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia, and the "A+2.2S" value was calculated. If "A+2.2S" is ≤15, the content uniformity meets the standard.

[0076] The chromatographic conditions were as follows: Test instruments: high performance liquid chromatograph, ultraviolet detector; Chromatographic column: octadecylsilane bonded silica gel as filler; Mobile phase: acetonitrile-water-trifluoroacetic acid (35:65:0.05); Detection wavelength: 220nm; column temperature: 35℃; flow rate: 1.0ml / min; injection volume: 15ul; Isocratic elution.

[0077] The content uniformity test results of the dapagliflozin pharmaceutical compositions prepared in Examples 1 to 19 are shown in the following table.

[0078] Table 6 Content uniformity test results .

[0079] According to the experimental results, according to the method for preparing the pharmaceutical composition, the content uniformity "A+2.2S" of the dapagliflozin pharmaceutical composition prepared in Examples 1 to 19 is less than 3, and the content uniformity meets the standard.

[0080] Example 6 Stability Study of Preparation

[0081] With reference to the genotoxic impurity detection method of the dapagliflozin pharmaceutical composition, the stability test of the dapagliflozin tablets prepared in the examples and comparative examples was carried out. Among them, the long-term stability study refers to the storage and quality evaluation of the drug under normal temperature and humidity conditions. The accelerated stability study is to quickly evaluate the quality changes of the drug within a certain period of time by simulating accelerated conditions, such as high temperature and high humidity. The results can be used to predict the stability of the drug under long-term storage conditions.

[0082] The dapagliflozin tablets used in the experiment were all packaged in aluminum plastic. The conditions for the accelerated stability study were 40℃±2℃, RH75%±5%; the conditions for the long-term stability study were 30℃±2℃, RH65%±5%.

[0083] (1) Solution preparation: Place 5 dapagliflozin tablets in a 25 ml volumetric flask, dissolve them in acetonitrile by ultrasonication and dilute to the mark. The concentration of dapagliflozin is about 2 mg / ml.

[0084] (2) The chromatographic conditions were the same as those for the stability study of the dapagliflozin drug composition.

[0085] The results of the preparation stability study are shown in the following table.

[0086] Table 7 Preparation stability test results .

[0087] The stability of dapagliflozin tablets was investigated, and the experimental results showed that: (1) At 0 days, the detected genotoxic impurity contents of Examples 1 to 19 were all lower than those of Comparative Example 1. Comparative Example 1 did not contain a stabilizer, and the genotoxic impurity content was 100.6 ppm. The genotoxic impurity content of the dapagliflozin tablets prepared in Examples 1 to 15 was lower than 60 ppm.

[0088] (2) Long-term stability study Simulating normal storage conditions, 30°C ± 2°C, RH 65% ± 5% After 30 days, the genotoxic impurity content of Examples 1 to 19 was less than that of Comparative Example 1, and the genotoxic impurity content of Comparative Example 1 was 105.7 ppm. The genotoxic impurity content of Examples 1 to 15 was less than 70 ppm.

[0089] (3) The accelerated stability test simulated a high temperature and high humidity environment. After being placed at 40°C ± 2°C and RH 75% ± 5% for 30 days, the genotoxic impurity content of Examples 1 to 19 was still less than that of Comparative Example 1. Comparative Example 1 did not contain a stabilizer and had a genotoxic impurity content of 113.7 ppm. The genotoxic impurity content of the pharmaceutical compositions prepared in Examples 1 to 15 was less than 75 ppm.

[0090] Overall, the genotoxic impurity content and growth trend of the dapagliflozin tablets and dapagliflozin pharmaceutical compositions of the embodiments and comparative examples are basically the same. From the perspective of the amount of stabilizer used and the genotoxic impurity content, sodium pyrosulfite has the best effect in inhibiting genotoxic impurities, followed by ascorbic acid, ascorbyl palmitate, tert-butyl 4-hydroxyanisole, thiourea, cysteine, and methionine.

[0091] Example 7 Preparation Dissolution Test

[0092] The dissolution test of the dapagliflozin tablets prepared in Examples 1 to 19 was carried out using the first method of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia.

[0093] (1) Dissolution test conditions: Dissolution test was performed according to the first method of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia. 900 ml of hydrochloric acid solution (9→1000) was used as the dissolution medium, the rotation speed was 100 revolutions per minute, and the operation was carried out according to the law. Samples were taken at 5, 10, 15, 30, and 45 minutes respectively.

[0094] (2) Solution preparation: Test solution: Take an appropriate amount of the dissolution solution, filter it, and take the filtrate.

[0095] Preparation of reference solution: Take an appropriate amount of dapagliflozin reference substance, weigh accurately, add 1% glacial acetic acid-acetonitrile (45:55) to dissolve it and dilute it with dissolution medium to make a solution containing approximately 11 μg of dapagliflozin per 1 ml.

[0096] (3) Chromatographic conditions Test instruments: high performance liquid chromatograph, ultraviolet detector; Chromatographic column: octadecylsilane bonded silica gel as filler; Mobile phase: 1% glacial acetic acid-acetonitrile (45:55); Detection wavelength: 223nm; column temperature: 30℃; flow rate: 1.0ml / min; injection volume: 20ul; Isocratic elution.

[0097] Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the dissolution amount of each tablet by the peak area according to the external standard method. The cumulative dissolution in 30 minutes should reach 85% of the labeled amount.

[0098] The dissolution test results are shown in the following table.

[0099] Table 8 Dissolution test results of the examples .

[0100] From the dissolution test results, it can be seen that according to the preparation process of the present invention, the cumulative dissolution of the dapagliflozin tablets prepared in Examples 1 to 19 is greater than 95% in 30 minutes, the dissolution meets the standard requirements, and the batch-to-batch difference is very small.

Claims

1. A dapagliflozin pharmaceutical composition, It is characterized in that The pharmaceutical composition contains dapagliflozin, a stabilizer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of dapagliflozin to the stabilizer is not less than 20000:

1.

2. The pharmaceutical composition according to claim 1, It is characterized in that The weight ratio of dapagliflozin to stabilizer is not less than 2000:

1.

3. The pharmaceutical composition according to claim 1 or 2, It is characterized in that The dapagliflozin is amorphous dapagliflozin.

4. The pharmaceutical composition according to any one of claims 1 to 3, It is characterized in that The stabilizer is an organic stabilizer, an inorganic stabilizer or a combination thereof; The organic stabilizer is selected from one or more of ascorbic acid, ascorbyl palmitate, tocopherol, tocopherol acetate, propyl gallate, butylated p-hydroxyanisole, butylated hydroxytoluene, thiourea, cysteine, methionine, thioacetic acid, and thioglycerol; The inorganic stabilizer is selected from one or more of sodium sulfite, sodium bisulfite, sodium pyrosulfite and sodium thiosulfate.

5. The pharmaceutical composition according to any one of claims 1 to 4, It is characterized in that The excipients include diluents and disintegrants; The diluent is selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate, and pregelatinized starch; The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and sodium carboxymethyl starch.

6. A method for preparing the pharmaceutical composition according to any one of claims 1 to 5, It is characterized in that Dapagliflozin and a stabilizer are dissolved in a solvent to prepare a wetting agent solution, which is then granulated with other excipients. The wetting agent solution is added in a spraying manner.

7. Use of the pharmaceutical composition according to any one of claims 1 to 5, It is characterized in that It is used as an intermediate for the preparation of dapagliflozin oral solid preparations.

8. A dapagliflozin oral solid preparation, It is characterized in that The pharmaceutical composition according to claim 1 and other auxiliary ingredients are included, the oral solid preparation is selected from granules, capsules or tablets, and the auxiliary ingredients include at least one of a glidant, a lubricant, a flavoring agent, and a colorant.

9. The oral solid preparation according to claim 8, It is characterized in that The oral solid preparation is dapagliflozin tablets.

10. A method for preparing the dapagliflozin tablets according to claim 9, comprising the following steps: (1) mixing the dapagliflozin pharmaceutical composition with other auxiliary ingredients and tableting to prepare plain tablets; (2) Coating the plain tablets to obtain dapagliflozin tablets.

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