Preparation method of metformin empagliflozin tablet

Abstract

The invention provides a preparation method of metformin empagliflozin tablets, and relates to the technical field of pharmaceutical preparations. The metformin empagliflozin tablet is prepared from the following auxiliary materials in percentage by mass: 8-15% of a diluent, 2-5% of an adhesive and 0.5-2% of a lubricant, and the preparation method comprises the following steps: adding empagliflozin and the adhesive into water, and heating to obtain a clear solution; the preparation method comprises the following steps: crushing metformin hydrochloride, and mixing with a diluent to obtain mixed powder; atomizing and spraying the clarified solution into the mixed powder, performing wet granulation, drying, granulating, adding a lubricant, tabletting and coating to obtain the tablet. Compared with an original product, the tablet prepared from the granules obtained by adopting a wet granulation process and optimizing auxiliary materials and a preparation process has better intra-batch and inter-batch uniformity, is shorter in disintegration time limit and smaller in friability, and has more excellent stability under an acceleration condition.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing metformin empagliflozin tablets. Background Art

[0002] Metformin hydrochloride, its molecular formula: C4H 11 N5·HCl, molecular weight: 165.63, structural formula is as follows:

[0003]

[0004] Empagliflozin, its molecular formula: C 23 H 27 ClO7, molecular weight: 450.91, structural formula is as follows:

[0005]

[0006] Metformin empagliflozin tablets were developed by Boehringer Ingelheim for the treatment of type 2 diabetes. The product name is Synjardy. It was first approved by EMA for marketing in the EU in May 2015, with specifications of 850 / 5mg, 850 / 12.5mg, 1000 / 5mg, and 1000 / 12.5mg. It was approved by the US FDA for marketing in August 2015, with specifications of 500 / 12.5mg, 500 / 5mg, 1000 / 12.5mg, and 1000 / 5mg. It was approved for import registration in my country in February 2019, with approved specifications of 850 / 5mg, 500 / 5mg, 850 / 12.5mg, 1000 / 5mg, and 1000 / 12.5mg.

[0007] The Chinese invention patent application CN104873974 A of the original preparation discloses a pharmaceutical composition, pharmaceutical dosage form, its preparation method, treatment method and use. The preparation process is fluidized bed granulation, and the intra-batch and inter-batch uniformity, friability and accelerated stability of the prepared plain tablets need to be further improved. Summary of the invention

[0008] In view of the problems existing in the prior art, the present invention provides a method for preparing metformin empagliflozin tablets. The wet granulation process is adopted. The granules obtained by optimizing the auxiliary materials and the preparation process have better intra-batch and inter-batch uniformity, less friability, and better stability under accelerated conditions than the original product.

[0009] One of the purposes of the present invention is to provide a method for preparing metformin empagliflozin tablets. Taking the mass of metformin empagliflozin tablets as 100%, the auxiliary material composition of the metformin empagliflozin tablets is: 8-15% of diluent, 2-5% of binder, and 0.5-2% of lubricant. The preparation method of metformin empagliflozin tablets is prepared by the following steps:

[0010] (1) Add empagliflozin and a binder into water and heat until dissolved to obtain a clear solution;

[0011] (2) crushing metformin hydrochloride and mixing it with a diluent to obtain a mixed powder;

[0012] (3) atomizing and spraying the clarified solution in step (1) into the mixed powder in step (2) to perform wet granulation;

[0013] (4) Drying, granulation, adding lubricant, tableting, and coating to obtain the product.

[0014] Preferably, the binder in step (1) is selected from at least one of povidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0015] Preferably, the heating in step (1) is heating to a temperature of 50-70°C.

[0016] Preferably, the diluent in step (2) is at least one selected from microcrystalline cellulose, silicified microcrystalline cellulose (a composite excipient of microcrystalline cellulose and colloidal silicon dioxide), and powdered cellulose.

[0017] Preferably, the pulverizing in step (2) is to pulverize the metformin hydrochloride to a D90 of 100-300 microns.

[0018] Preferably, the granulation time in step (3) is 5-10 min.

[0019] The second object of the present invention is to provide a metformin empagliflozin tablet prepared by the above-mentioned preparation method, wherein the mass composition of the active ingredients metformin and empagliflozin in each tablet is 850 / 5 mg, 500 / 5 mg, 850 / 12.5 mg, 1000 / 5 mg, and 1000 / 12.5 mg.

[0020] Compared with the prior art, the present invention has the following beneficial effects: the present invention adopts a wet granulation process, and the granules obtained by optimizing the auxiliary materials and the preparation process have better intra-batch and inter-batch uniformity, smaller friability, and better stability under accelerated conditions than the original product. DETAILED DESCRIPTION

[0021] It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0022] Embodiment 1:

[0023] The specifications of the metformin hydrochloride empagliflozin tablets involved are 1000 mg metformin hydrochloride / 12.5 mg empagliflozin, 850 mg metformin hydrochloride / 5 mg empagliflozin, and 500 mg metformin hydrochloride / 5 mg empagliflozin. The types and amounts of raw materials and excipients are shown in the following table.

[0024] Table 1: Amounts of raw materials and auxiliary materials described in Example 1

[0025]

[0026] Note: Since the pellets are dried after granulation, the moisture content is not included in the total amount.

[0027] Preparation process:

[0028] Add empagliflozin and hydroxypropyl cellulose to purified water, heat to 50°C in a water bath, and stir mechanically for 2 hours to fully dissolve the materials to obtain a binder solution. Grind metformin hydrochloride to a D90 of 100 microns. Place the metformin hydrochloride pulverized intermediate and silicified microcrystalline cellulose in a wet granulation pot, stir at a speed of 100 rpm and a cutter speed of 1000 rpm, mix for 5 minutes, adjust the stirring speed to 100 rpm and the cutter speed to 1500 rpm, spray the binder solution at an atomization pressure of 0.1 MPa, granulate for a total of 6 minutes, wet granulate with a 6*6 mm screen, control the material temperature at 35°C in a fluidized bed, dry, control the moisture content of the particles to 1%, and dry granulate the particles after drying with a screen of 1.0 mm. Add magnesium stearate, mix at a speed of 15 rpm for 5 minutes, press 1000 tablets on a high-speed rotary tablet press, control the hardness to 15-25 kg, and increase the coating weight by 2%.

[0029] Embodiment 2:

[0030] The specifications of the metformin hydrochloride empagliflozin tablets involved are 1000 mg metformin hydrochloride / 12.5 mg empagliflozin, 850 mg metformin hydrochloride / 5 mg empagliflozin, and 500 mg metformin hydrochloride / 5 mg empagliflozin. The types and amounts of raw materials and excipients are shown in the following table.

[0031] Table 2: Amounts of raw materials and auxiliary materials described in Example 2

[0032]

[0033] Note: Since the pellets are dried after granulation, the moisture content is not included in the total amount.

[0034] Preparation process:

[0035] Add empagliflozin and hydroxypropyl cellulose to purified water, heat to 70°C in a water bath, and stir mechanically for 2 hours to fully dissolve the materials to obtain a binder solution. Grind metformin hydrochloride to a D90 of 300 microns, place the metformin hydrochloride pulverized intermediate and silicified microcrystalline cellulose in a wet granulation pot, stir at a speed of 100 rpm and a cutter speed of 1000 rpm, mix for 5 minutes, adjust the stirring speed to 100 rpm and the cutter speed to 1500 rpm, spray the binder solution at an atomization pressure of 0.1 MPa, granulate for a total of 6 minutes, wet granulate with a 6*6 mm screen, control the material temperature at 45°C in a fluidized bed, dry, control the moisture content of the particles to 2%, and dry granulate the particles after drying with a screen of 1.0 mm. Add magnesium stearate, mix at a speed of 15 rpm for 5 minutes, press 1000 tablets on a high-speed rotary tablet press, control the hardness to 15-25 kg, and increase the coating weight by 2%.

[0036] Comparative Example 1:

[0037] According to the relevant records of patent CN104873974 A, the specifications of the metformin hydrochloride empagliflozin tablets involved are 1000 mg metformin hydrochloride / 12.5 mg empagliflozin, 850 mg metformin hydrochloride / 5 mg empagliflozin, and 500 mg metformin hydrochloride / 5 mg empagliflozin. The types and amounts of the raw materials and auxiliary materials are shown in the following table.

[0038] Table 3: Amounts of raw materials and auxiliary materials described in Comparative Example 1

[0039]

[0040] Note: Since the pellets are dried after granulation, the moisture content is not included in the total amount.

[0041] Preparation process:

[0042] Metformin hydrochloride and corn starch are sieved with a 1.0 mm sieve. At room temperature, empagliflozin and copovidone are dispersed or dissolved in purified water to obtain a granulation liquid solution. The mixture of metformin hydrochloride and corn starch is placed in a fluidized bed, the material temperature is preheated to 36° C., and fluidized bed granulation is performed. After the spraying is completed, the moisture content of the particles is dried to 1-3% at an inlet air temperature of 70° C., and the particles are sized with a 1.0 mm sieve. Colloidal silicon dioxide (passed through a 0.8 mm sieve) and magnesium stearate are added. The mixture is mixed at a speed of 15 rpm for 5 minutes, and 1000 tablets are pressed. The hardness is controlled to 15-25 kg, and the coating weight gain is 2%.

[0043] Comparative Example 2:

[0044] According to the prescription of comparative example 1, the wet granulation process was adopted for preparation, and the types and amounts of the raw materials and auxiliary materials are shown in Table 3. Preparation process:

[0045] Add empagliflozin and copovidone to purified water, heat to 50°C in a water bath, and stir mechanically for 2 hours to fully dissolve the materials to obtain a binder solution. Grind metformin hydrochloride to a D90 of 100 microns. Place the metformin hydrochloride pulverized intermediate and corn starch in a wet granulation pot, stir at a speed of 100 rpm and a cutter speed of 1000 rpm, mix for 5 minutes, adjust the stirring speed to 100 rpm and the cutter speed to 1500 rpm, spray the binder solution at an atomization pressure of 0.1 MPa, granulate for a total of 6 minutes, wet granulate with a 6*6 mm screen, control the material temperature at 35°C in a fluidized bed, dry, control the moisture content of the particles to 1%, and dry granulate the particles simultaneously with colloidal silicon dioxide after drying. The screen is 1.0 mm, magnesium stearate is added, and the mixture is mixed at a speed of 15 rpm for 5 minutes. 1000 tablets are pressed by a high-speed rotary tablet press, the hardness is controlled to 15-25 kg, and the coating weight gain is 2%.

[0046] Test Example 1: Basic properties of tablets

[0047] The hardness, disintegration time (Chinese Pharmacopoeia 2020 Edition Part 4 0921) and friability (Chinese Pharmacopoeia 2020 Edition Part 4 0923) of the tablets (uncoated) obtained in the above embodiments and comparative examples were measured. The specific results are shown in the table below.

[0048] Table 4: Basic properties of tablets (plain tablets)

[0049]

[0050] According to the above results, it can be seen that the disintegration time of the tablets obtained in the examples of the present invention is shorter than that in the comparative example, and the friability is lower.

[0051] Test Example 2: Dissolution Test

[0052] Take samples of Example 1, Example 2, Comparative Example 1, and Comparative Example 2, and follow the dissolution and release determination method (General Rules of the Four Parts of the 2020 Edition of the Chinese Pharmacopoeia), adopt the second method paddle method, the rotation speed is 50 revolutions per minute, and 900mL of 0.1mol / L hydrochloric acid solution is used as the dissolution medium. Samples are taken at different time points, and high performance liquid chromatography is used to detect the content of empagliflozin and metformin hydrochloride in different preparations, and the intra-batch differences are calculated. At the same time, Example 1 (specification 850 / 5) and commercially available tablet samples (specification 850 / 5, manufacturer Boehringer Ingelheim) are taken to determine the content of related substances according to the aforementioned method, and the batch differences are calculated. Specific results are shown in Tables 5 and 6.

[0053] Table 5: Intra-batch variation of dissolution profiles

[0054]

[0055]

[0056] Table 6: Inter-batch dissolution variability results

[0057]

[0058] According to the dissolution test results, the RSD of the dissolution rate of the tablets prepared according to the preparation method of the present invention is within 10% both within the batch and between batches, which is better than the dissolution results of the comparative example and the commercially available samples.

[0059] Test Example 3: Accelerated Experiment

[0060] The tablet samples of Example 1, Example 2, Comparative Example 1, and Comparative Example 2 were placed at 40°C and 75% RH at the same time, and a 6-month accelerated experiment was performed. The content of the relevant substances in the samples at the beginning of the test and the 6-month accelerated experiment was detected. The samples to be tested were taken, and the second method paddle method was adopted according to the dissolution and release determination method (General Rules of the Four Parts of the 2020 Edition of the Chinese Pharmacopoeia), with a rotation speed of 50 revolutions per minute, and 900mL of 0.1mol / L hydrochloric acid solution was used as the dissolution medium. Samples were taken at 30 minutes of dissolution, and high performance liquid chromatography was used for detection. The results are shown in the table below.

[0061] Table 7: Acceleration test results

[0062]

[0063] It can be seen from the above data that the metformin empagliflozin tablets prepared by the method of the embodiment of the present invention are superior to the comparative example in terms of the stability of related substances in the accelerated test.

[0064] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing metformin empagliflozin tablets, wherein the mass of metformin empagliflozin tablets is 100%, and the auxiliary materials of the metformin empagliflozin tablets are composed of: 8-15% diluent, 2-5% binder, and 0.5-2% lubricant. The metformin empagliflozin tablets are prepared by the following steps: (1) Add empagliflozin and a binder into water and heat until dissolved to obtain a clear solution; (2) crushing metformin hydrochloride and mixing it with a diluent to obtain a mixed powder; (3) atomizing and spraying the clarified solution in step (1) into the mixed powder in step (2) to perform wet granulation; (4) Drying, granulation, adding lubricant, tableting, and coating to obtain the product.

2. The method according to claim 1, characterized in that The binder in step (1) is selected from at least one of povidone, hydroxypropyl cellulose and hypromellose.

3. The method according to claim 1, characterized in that The heating in step (1) is heating to a temperature of 50-70°C.

4. The method according to claim 1, characterized in that: The diluent in step (2) is at least one selected from microcrystalline cellulose, silicified microcrystalline cellulose, and powdered cellulose.

5. The method according to claim 1, characterized in that The pulverization in step (2) is to pulverize the metformin hydrochloride to a D90 of 100-300 microns.

6. The method according to claim 1, characterized in that The granulation time in step (3) is 5-10 minutes.

7. A metformin empagliflozin tablet prepared according to the preparation method according to any one of claims 1 to 6, characterized in that: The mass composition of the active ingredients metformin and empagliflozin in each metformin empagliflozin tablet is 850 / 5mg, 500 / 5mg, 850 / 12.5mg, 1000 / 5mg, and 1000 / 12.5mg.

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