Etogliflozin tablet and preparation method thereof

Abstract

The invention relates to the field of medicines, in particular to an etogliflozin tablet and a preparation method thereof. The etogliflozin tablet disclosed by the invention is prepared from the following components: L-pyroglutamic acid etogliflozin, lactose, microcrystalline cellulose, magnesium stearate and carboxymethyl starch sodium. By optimizing the preparation process, the use of auxiliaries is greatly reduced.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to an eratogliptin tablet and its preparation method. Background Technology

[0002] Etoggliflozin is an oral hypoglycemic agent belonging to the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, primarily used for glycemic control in patients with type 2 diabetes. It lowers blood glucose levels by inhibiting the reabsorption of glucose by the kidneys and promoting the excretion of excess glucose in the urine. It may also provide additional benefits such as weight loss and lower blood pressure. However, it should be noted that it may cause side effects such as urinary tract infections; medication should be taken as directed by a doctor.

[0003] Existing patent CN119523924A discloses an eltogliflozin tablet and its preparation method, but it requires the addition of a large number of excipients. We hope to provide an eltogliflozin tablet and its preparation method that can ensure product quality while reducing the addition of excipients. Summary of the Invention

[0004] This invention aims to provide an etoragliflozin tablet and its preparation method, the specific scheme of which is as follows: An eltoggliflozin tablet comprises the following components: L-pyroglutamic acid eltoggliflozin, lactose, microcrystalline cellulose, magnesium stearate, and sodium carboxymethyl starch.

[0005] The components are as follows by mass: 5-7 parts of L-pyroglutamic acid etoragliptin, 25-35 parts of lactose, 50-70 parts of microcrystalline cellulose, 0.5-2 parts of magnesium stearate, and 2-4 parts of sodium carboxymethyl starch.

[0006] A method for preparing eletogliflozin tablets, the specific steps of which are as follows: (1) Premix 1: First, add lactose, part of microcrystalline cellulose and part of magnesium stearate into the hopper and mix. Then add L-pyroglutamic acid eletoggliflozin into the hopper. (2) Granulation: The premixed material 1 is granulated and sieved using a granulator; after granulation, the granulator is rinsed with a portion of microcrystalline cellulose. (3) Premix 2: The premix 1 material after granulation, a mixture of part of microcrystalline cellulose, and sodium carboxymethyl starch are added to the hopper mixer in sequence; (4) Final mixing: Continue to add some magnesium stearate to the hopper mixer; (5) Tableting: The total mixture is compressed into tablets; (6) Coating: Add the prepared amount of gastric-soluble film coating premix to the prepared amount of purified water while stirring. After adding, continue stirring until the mixture is evenly dispersed. (7) Preheating: Turn on the exhaust, air intake, and air intake heating, and add the tablet cores to the coating pan to preheat to the tablet bed temperature of 40~50℃. (8) Coating: Turn on the peristaltic pump to spray the liquid, and maintain the temperature of the tablet bed at 30~55℃ during the spraying process; when the weight gain is about 3~5%, or when the total amount of sprayed slurry reaches the theoretical amount of slurry, stop spraying. (9) Packaging: The coated tablets are packaged using solid pharmaceutical composite hard sheets made of polyamide / aluminum / polyvinyl chloride cold stamping and pharmaceutical aluminum foil.

[0007] In step (2), the granulation screen is 1.0-2.0 mm and the granulation speed is 200-1000 rpm.

[0008] In step (5), the tableting speed is 60,000-150,000 tablets / h, the feeder speed is 35-59 rpm, the main pressure is 5KN-25KN, the theoretical tablet weight is 100mg, and the actual tableting hardness range is 20N-150N.

[0009] In step (7), the main unit speed is 2~10 rpm and the air inlet temperature is 60~90℃.

[0010] In step (8), the temperature of the tablet bed is maintained at 30~55℃ during the liquid spraying process.

[0011] In step (8), the atomization pressure is adjusted to 0.20~0.40MPa, the fan pressure is adjusted to 0.20~0.40MPa, and the main unit speed is 2~10rpm.

[0012] In step (9), the sealing pressure is 0.3~0.7MPa, the forming pressure is 0.3~0.7MPa, and the heat sealing temperature is 200~250℃.

[0013] The addition ratio of microcrystalline cellulose in steps (1) and (2) is 1:1; the addition ratio of magnesium stearate in steps (1) and (4) is 1:1.

[0014] The process of this invention is divided into premixing and final mixing. The two mixing processes ensure the uniformity of the main component content. In the premixing process, lactose, microcrystalline cellulose, etc. are first added to the hopper for mixing in order to eliminate static electricity on the hopper wall and prevent the main component from adsorbing onto the hopper wall.

[0015] This invention has the following advantages: First, the process parameters are scientifically and precisely designed. Key parameters for each step (such as tableting speed of 60,000-150,000 tablets / h, main pressure of 5KN-25KN, and tablet bed temperature of 30-55℃) have all been systematically optimized and verified. This ensures that the weight variation of eletogliflozin tablets is controlled within a minimal range, the hardness is stable within the ideal range of 20N-150N, and the coating layer is uniform and dense, with the drug dissolution rate meeting pharmacopoeia standards. Second, the excipient ratio is rationally controlled. The addition ratio of microcrystalline cellulose at 1:1 (added in two stages) improves the material's... The addition ratio of magnesium stearate (1:1, added in two batches) effectively reduces production defects such as sticking and cracking, significantly improving the product qualification rate, thus improving flowability and compressibility. Secondly, the production process offers both controllability and efficiency, with a wide and stable range of parameters for each process, suitable for large-scale industrial continuous production and reducing unit production costs. Thirdly, the product exhibits excellent stability, with reasonable settings for sealing pressure, heat sealing temperature, and other parameters in the packaging process, effectively isolating the drug from external environmental influences, extending shelf life, and ensuring the safety and effectiveness of clinical use. Detailed Implementation Example 1

[0016] 1. Etoggliflozin tablets formula

[0017]

[0018] 2. Process The main processing steps for this product include weighing, premixing 1, granulation, premixing 2, total mixing, tableting, coating, and packaging. The production process steps are shown below.

[0019] 2.1 Weighing of raw and auxiliary materials Weigh the following ingredients according to the batch prescription: microcrystalline cellulose 1, lactose, magnesium stearate 1, microcrystalline cellulose 2, sodium carboxymethyl starch, magnesium stearate 2, and L-pyroglutamic acid etanerceptin.

[0020] 2.2 Premixed 1 First, add lactose, microcrystalline cellulose 1, and magnesium stearate 1 to the hopper, set the mixing speed to 10-30 rpm, and mix for 5-10 minutes to rinse the inner wall of the hopper. Then, add L-pyroglutamic acid eletogliflozin to the hopper, set the mixing speed to 10-30 rpm, and mix for 5-10 minutes.

[0021] 2.3 Granulation The premixed material 1 is granulated and sieved using a granulator with a screen size of 1.0-2.0 mm and a granulation speed of 200-1000 rpm. After granulation, the granulator is rinsed with microcrystalline cellulose 2 (microcrystalline cellulose 2 is introduced into the raw material bag for rinsing before rinsing), with a screen size of 1.0-2.0 mm and a granulation speed of 200-1000 rpm. Granulation results in more uniform particles, which is beneficial for the subsequent direct compression process of powder. It also makes the weight difference more stable.

[0022] 2.4 Premixed 2 Add the granulated premix 1 material, the mixture of microcrystalline cellulose 2 and sodium carboxymethyl starch to the hopper mixer in sequence, set the mixing speed to 10-30 rpm, and mix for 10-20 minutes.

[0023] 2.5 Total Mixture Add magnesium stearate 2 to the hopper mixer, set the mixing speed to 10-20 rpm, and mix for 5-10 minutes.

[0024] 2.6 Tableting The mixed material is compressed into tablets using a Ф6mm shallow concave circular die. The tableting speed is 60,000-150,000 tablets / hour, the feeder speed is 35-59 rpm, the main pressure is 5KN-25KN, the theoretical tablet weight is 100mg, and the actual tableting hardness range is 20N-150N. The friability is ≤1.0%, and there should be no cracking or fragmentation.

[0025] 2.7 Coating Preparation of coating solution: Add the prepared amount of gastric-soluble film coating premix to the prepared amount of purified water while stirring. After the addition is complete, continue stirring for 30-60 minutes until the mixture is evenly dispersed, and then pass it through an 80-mesh sieve.

[0026] Preheating: Turn on the exhaust, air intake, and air intake heating. Set the main unit speed to 2-10 rpm, air intake temperature to 60-90℃, and air intake volume. Add the wafer cores to the coating pan and preheat to a wafer bed temperature of 40-50℃. Coating: Adjust the atomization pressure to 0.20~0.40MPa, adjust the fan-shaped pressure to 0.20~0.40MPa, and the main unit speed to 2~10rpm. Turn on the peristaltic pump to spray the liquid. During the spraying process, maintain the bed temperature at 30~55℃. When the weight gain is about 3~5%, or when the total amount of sprayed slurry reaches the theoretical slurry usage, the spraying can be stopped. 2.8 Packaging The coated tablets are packaged using solid pharmaceutical composite rigid sheets formed by cold stamping of polyamide / aluminum / polyvinyl chloride and pharmaceutical aluminum foil. The sealing pressure is 0.3~0.7MPa, the forming pressure is 0.3~0.7MPa, and the heat sealing temperature is 200~250℃.

[0027] Comparative Example 1: 1. Etoggliflozin tablets formula

[0028] 2. Process The main processing steps for this product include weighing, mixing, granulation, tableting, coating, and packaging. The production process steps are shown below.

[0029] 2.1 Weighing of raw and auxiliary materials Weigh out the following ingredients according to the batch prescription: microcrystalline cellulose, lactose, magnesium stearate, sodium carboxymethyl starch, and L-pyroglutamic acid eletoggliflozin.

[0030] 2.2 Mixing Add microcrystalline cellulose, lactose, magnesium stearate, and sodium carboxymethyl starch to the hopper, set the mixing speed to 10-30 rpm, mix for 5-10 minutes to rinse the inner wall of the hopper, then add L-pyroglutamic acid eletogliflozin to the hopper, set the mixing speed to 10-30 rpm, and mix for 20-30 minutes.

[0031] 2.3 Granulation The mixed materials are granulated and sieved using a granulator with a screen size of 1.0-2.0 mm and a granulation speed of 200-1000 rpm. After granulation, the granulator is rinsed with microcrystalline cellulose (the microcrystalline cellulose is introduced into the raw material bag and rinsed before rinsing). The granulation screen size is 1.0-2.0 mm and the granulation speed is 200-1000 rpm.

[0032] 2.4 Tableting The mixed material is compressed into tablets using a Ф6mm shallow concave circular die. The tableting speed is 60,000-150,000 tablets / hour, the feeder speed is 35-59 rpm, the main pressure is 5KN-25KN, the theoretical tablet weight is 100mg, and the actual tableting hardness range is 20N-150N. The friability is ≤1.0%, and there should be no cracking or fragmentation.

[0033] 2.5 Coating Preparation of coating solution: Add the prepared amount of gastric-soluble film coating premix to the prepared amount of purified water while stirring. After the addition is complete, continue stirring for 30-60 minutes until the mixture is evenly dispersed, and then pass it through an 80-mesh sieve.

[0034] Preheating: Turn on the exhaust, air intake, and air intake heating. Set the main unit speed to 2-10 rpm, air intake temperature to 60-90℃, and air intake volume. Add the wafer cores to the coating pan and preheat to a wafer bed temperature of 40-50℃. Coating: Adjust the atomization pressure to 0.20~0.40MPa, adjust the fan-shaped pressure to 0.20~0.40MPa, and the main unit speed to 2~10rpm. Turn on the peristaltic pump to spray the liquid. During the spraying process, maintain the bed temperature at 30~55℃. When the weight gain is about 3~5%, or when the total amount of sprayed slurry reaches the theoretical slurry usage, the spraying can be stopped. 2.6 Packaging The coated tablets are packaged using solid pharmaceutical composite rigid sheets formed by cold stamping of polyamide / aluminum / polyvinyl chloride and pharmaceutical aluminum foil. The sealing pressure is 0.3~0.7MPa, the forming pressure is 0.3~0.7MPa, and the heat sealing temperature is 200~250℃.

[0035] Comparative Example 2 1. Etoggliflozin tablets formula

[0036] 2. Process The main processing steps for this product include weighing, premixing 1, premixing 2, total mixing, tableting, coating, and packaging. The production process steps are shown below.

[0037] 2.1 Weighing of raw and auxiliary materials Weigh the following ingredients according to the batch prescription: microcrystalline cellulose 1, lactose, magnesium stearate 1, microcrystalline cellulose 2, sodium carboxymethyl starch, magnesium stearate 2, and L-pyroglutamic acid etanerceptin.

[0038] 2.2 Premixed 1 First, add lactose, microcrystalline cellulose 1, and magnesium stearate 1 to the hopper, set the mixing speed to 10-30 rpm, and mix for 5-10 minutes to rinse the inner wall of the hopper. Then, add L-pyroglutamic acid eletogliflozin to the hopper, set the mixing speed to 10-30 rpm, and mix for 5-10 minutes.

[0039] 2.3 Premixed 2 Add the mixture of premix 1 material, microcrystalline cellulose 2 material, and sodium carboxymethyl starch sequentially into the hopper mixer, set the mixing speed to 10-30 rpm, and mix for 10-20 minutes.

[0040] 2.4 Total Mixing Add magnesium stearate 2 to the hopper mixer, set the mixing speed to 10-20 rpm, and mix for 5-10 minutes.

[0041] 2.5 tablets The mixed material is compressed into tablets using a Ф6mm shallow concave circular die. The tableting speed is 60,000-150,000 tablets / hour, the feeder speed is 35-59 rpm, the main pressure is 5KN-25KN, the theoretical tablet weight is 100mg, and the actual tableting hardness range is 20N-150N. The friability is ≤1.0%, and there should be no cracking or fragmentation.

[0042] 2.6 Coating Preparation of coating solution: Add the prepared amount of gastric-soluble film coating premix to the prepared amount of purified water while stirring. After the addition is complete, continue stirring for 30-60 minutes until the mixture is evenly dispersed, and then pass it through an 80-mesh sieve.

[0043] Preheating: Turn on the exhaust, air intake, and air intake heating. Set the main unit speed to 2-10 rpm, air intake temperature to 60-90℃, and air intake volume. Add the wafer cores to the coating pan and preheat to a wafer bed temperature of 40-50℃. Coating: Adjust the atomization pressure to 0.20~0.40MPa, adjust the fan-shaped pressure to 0.20~0.40MPa, and the main unit speed to 2~10rpm. Turn on the peristaltic pump to spray the liquid. During the spraying process, maintain the bed temperature at 30~55℃. When the weight gain is about 3~5%, or when the total amount of sprayed slurry reaches the theoretical slurry usage, the spraying can be stopped. 2.7 Packaging The coated tablets are packaged using solid pharmaceutical composite rigid sheets formed by cold stamping of polyamide / aluminum / polyvinyl chloride and pharmaceutical aluminum foil. The sealing pressure is 0.3~0.7MPa, the forming pressure is 0.3~0.7MPa, and the heat sealing temperature is 200~250℃.

[0044] Comparative Example 3 1. Etoggliflozin tablets formula

[0045] 2. Process The main processing steps for this product include weighing, premixing 1, granulation, premixing 2, total mixing, tableting, coating, and packaging. The production process steps are shown below.

[0046] 2.1 Weighing of raw and auxiliary materials Weigh the following ingredients according to the batch prescription: microcrystalline cellulose 1, lactose, magnesium stearate 1, microcrystalline cellulose 2, sodium carboxymethyl starch, magnesium stearate 2, and L-pyroglutamic acid etanerceptin.

[0047] 2.2 Premixed 1 Add lactose, microcrystalline cellulose 1, magnesium stearate 1, and L-pyroglutamic acid etanerceptin to the hopper, set the mixing speed to 10-30 rpm, and mix for 10-20 minutes.

[0048] 2.3 Granulation Premix 1 material is granulated and sieved using a granulator with a sieve size of 1.0-2.0 mm and a granulation speed of 200-1000 rpm. After granulation, the granulator is rinsed with microcrystalline cellulose 2 (microcrystalline cellulose 2 is introduced into the raw material bag to rinse the bag before rinsing) with a sieve size of 1.0-2.0 mm and a granulation speed of 200-1000 rpm.

[0049] 2.4 Premixed 2 Add the granulated premix 1 material, the mixture of microcrystalline cellulose 2 and sodium carboxymethyl starch to the hopper mixer in sequence, set the mixing speed to 10-30 rpm, and mix for 10-20 minutes.

[0050] 2.5 Total Mixture Add magnesium stearate 2 to the hopper mixer, set the mixing speed to 10-20 rpm, and mix for 5-10 minutes.

[0051] 2.6 Tableting The mixed material is compressed into tablets using a Ф6mm shallow concave circular die. The tableting speed is 60,000-150,000 tablets / hour, the feeder speed is 35-59 rpm, the main pressure is 5KN-25KN, the theoretical tablet weight is 100mg, and the actual tableting hardness range is 20N-150N. The friability is ≤1.0%, and there should be no cracking or fragmentation.

[0052] 2.7 Coating Preparation of coating solution: Add the prepared amount of gastric-soluble film coating premix to the prepared amount of purified water while stirring. After the addition is complete, continue stirring for 30-60 minutes until the mixture is evenly dispersed, and then pass it through an 80-mesh sieve.

[0053] Preheating: Turn on the exhaust, air intake, and air intake heating. Set the main unit speed to 2-10 rpm, air intake temperature to 60-90℃, and air intake volume. Add the wafer cores to the coating pan and preheat to a wafer bed temperature of 40-50℃. Coating: Adjust the atomization pressure to 0.20~0.40MPa, adjust the fan-shaped pressure to 0.20~0.40MPa, and the main unit speed to 2~10rpm. Turn on the peristaltic pump to spray the liquid. During the spraying process, maintain the bed temperature at 30~55℃. When the weight gain is about 3~5%, or when the total amount of sprayed slurry reaches the theoretical slurry usage, the spraying can be stopped. 2.8 Packaging The coated tablets are packaged using solid pharmaceutical composite rigid sheets formed by cold stamping of polyamide / aluminum / polyvinyl chloride and pharmaceutical aluminum foil. The sealing pressure is 0.3~0.7MPa, the forming pressure is 0.3~0.7MPa, and the heat sealing temperature is 200~250℃.

[0054] Weight difference determination Take 20 tablets each of the etoggliflozin tablets from Examples 1 and 3, accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet separately to calculate the weight difference. The results are as follows:

[0055] As can be seen from the above data, the weight difference of the eltogliflozin tablets prepared in the embodiments of the present invention is within ±1.0%, and the weight difference stability is good; the weight difference of the eltogliflozin tablets prepared in Comparative Examples 1 and 3 is within ±1.5%, and the weight difference stability is good. Comparative Example 2, due to the elimination of the granulation step, is not conducive to the subsequent direct powder compression process, which affects the stability of the weight difference, and the weight difference is greater than ±4.0%.

[0056] Content determination The eletoggliflozin tablets from Examples 1-3 were analyzed by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512) to determine the content. The results are as follows:

[0057] As can be seen from the above data, the content of the eletogliflozin tablets prepared in the embodiments of the present invention is above 99.0%; the content of comparative examples 1-2 is above 99.0%, slightly lower than that of the embodiments; in comparative example 3, the hopper wall was not washed during premixing, and the main component was adsorbed on the hopper wall due to the static electricity of the hopper wall during mixing, resulting in the loss of the main component, and thus the content was significantly lower than that of the embodiments.

[0058] Content uniformity determination Ten tablets each of the eletoggliflozin tablets from Examples 1 and 3 and Comparative Examples 1-3 were dissolved and their content uniformity was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512). The results are as follows:

[0059] As can be seen from the above data, the eletogliflozin tablets prepared in the embodiments of the present invention have a good content uniformity with A+2.2S < 2.0; Comparative Example 1, due to the omission of the premixing step, resulted in poor mixing uniformity, which affected the content uniformity, with A+2.2S > 10.0, indicating poor content uniformity; Comparative Example 2, due to the omission of the granulation step, affected the tableting, which in turn affected the content uniformity, resulting in a worse content uniformity than the embodiments; Comparative Example 3, due to the omission of the washing step, resulted in the raw material being adsorbed by the hopper wall, which reduced the content and affected the content uniformity, resulting in a worse content uniformity than the embodiments.

[0060] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An eratogliptin tablet, characterized in that, It includes the following components: L-pyroglutamic acid eletoggliflozin, lactose, microcrystalline cellulose, magnesium stearate, and sodium carboxymethyl starch.

2. The atorpagliflozin tablet as described in claim 1, characterized in that, The components are as follows by mass: 5-7 parts L-pyroglutamic acid etoragliptin, 25-35 parts lactose, 50-70 parts microcrystalline cellulose, 0.5-2 parts magnesium stearate, and 2-4 parts sodium carboxymethyl starch.

3. A method for preparing eletogliflozin tablets as described in claim 1, characterized in that, The specific steps are as follows: (1) Premix 1: First, add lactose, part of microcrystalline cellulose and part of magnesium stearate into the hopper and mix. Then add L-pyroglutamic acid eletoggliflozin into the hopper. (2) Granulation: The premixed material 1 is granulated and sieved using a granulator; after granulation, the granulator is rinsed with a portion of microcrystalline cellulose. (3) Premix 2: The premix 1 material after granulation, the mixture of part of microcrystalline cellulose, and sodium carboxymethyl starch are added to the hopper mixer in sequence; (4) Final mixing: Continue to add some magnesium stearate to the hopper mixer; (5) Tableting: The total mixture is compressed into tablets; (6) Coating: Add the prepared amount of purified water to the prepared amount of gastric-soluble film coating premix while stirring. After adding, continue stirring until the mixture is evenly dispersed. (7) Preheating: Turn on the exhaust, air intake, and air intake heating, add the tablet cores to the coating pan and preheat to the tablet bed temperature of 40~50℃. (8) Coating: Turn on the peristaltic pump to spray the liquid, and maintain the temperature of the tablet bed at 30~55℃ during the spraying process; when the weight gain is about 3~5%, or when the total amount of sprayed slurry reaches the theoretical amount of slurry, stop spraying. (9) Packaging: The coated tablets are packaged using solid pharmaceutical composite hard sheets made of polyamide / aluminum / polyvinyl chloride cold stamping and pharmaceutical aluminum foil.

4. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: In step (2), the granulation screen is 1.0-2.0 mm and the granulation speed is 200-1000 rpm.

5. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: In step (5), the tableting speed is 60,000-150,000 tablets / h, the feeder speed is 35-59 rpm, the main pressure is 5KN-25KN, the theoretical tablet weight is 100mg, and the actual tableting hardness range is 20N-150N.

6. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: In step (7), the main unit speed is 2~10 rpm and the air inlet temperature is 60~90℃.

7. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: In step (8), the temperature of the tablet bed is maintained at 30~55℃ during the liquid spraying process.

8. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: In step (8), the atomization pressure is adjusted to 0.20~0.40MPa, the fan pressure is adjusted to 0.20~0.40MPa, and the main unit speed is 2~10rpm.

9. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: In step (9), the sealing pressure is 0.3~0.7MPa, the forming pressure is 0.3~0.7MPa, and the heat sealing temperature is 200~250℃.

10. The method for preparing eletogliflozin tablets as described in claim 3, characterized in that: The addition ratio of microcrystalline cellulose in steps (1) and (2) is 1:1; the addition ratio of magnesium stearate in steps (1) and (4) is 1:1.

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