Etogliflozin tablet and preparation method thereof

Abstract

The invention provides an Eutogliflozin tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the tablet comprises Eutogliflozin, erythritol, a stabilizer, a diluent, a disintegrating agent and an adhesive; the stabilizer is sodium cholate. According to the Eutogliflozin tablet, the erythritol and the stabilizer sodium cholate are matched, so that the defects of instability and poor solubility of Eutogliflozin can be overcome, and the problems of slow dissolution and poor stability of the prepared Eutogliflozin tablet are avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an etogliflozin tablet and a method for preparing the tablet. Background Art

[0002] Ertugliflozin is a drug developed jointly by Pfizer and Merck. It can reduce renal glucose absorption, increase urinary glucose excretion, and has a non-insulin-dependent blood sugar-lowering effect. Studies have shown that for patients with type 2 diabetes and hypertension, ertugliflozin can not only effectively lower blood sugar levels, but also has a blood pressure-lowering effect comparable to hydrochlorothiazide.

[0003] The chemical name of Etogliflozin is: (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, and the structural formula is as follows:

[0004]

[0005] Etogliflozin is insoluble in water and has a complex structure. Studies have found that the solubility of Etogliflozin tablets is poor, and Etogliflozin is unstable and easily degraded to produce impurities. The related substances in Etogliflozin tablets increase significantly after being stored for more than 6 months.

[0006] Therefore, the research and development focus of the present invention is to select suitable excipients to overcome the defects of instability and poor solubility of etoglipizide and ensure the stable quality of etoglipizide tablets. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the shortcomings of instability and poor solubility of ertogliflozin, thereby solving the technical problems of slow dissolution of ertogliflozin tablets, significant increase of related substances and poor stability.

[0008] The invention provides an etogliflozin tablet, comprising etogliflozin, erythritol, a stabilizer, a diluent, a disintegrant and a binder; the stabilizer is sodium cholate.

[0009] The inventors have found through experimental research that the addition of erythritol to ertogliflozin tablets can overcome the disadvantage of poor solubility of ertogliflozin and solve the problem of slow dissolution of ertogliflozin tablets. The addition of sodium cholate to ertogliflozin tablets can ensure the stability of the preparation quality during drug storage, and effectively solve the problem that ertogliflozin is easily degraded and produces impurities due to its own properties; and the combination of sodium cholate and erythritol can also increase the solubility of ertogliflozin, ensuring the quality and efficacy of the drug preparation.

[0010] In the above-mentioned ertogliflozin tablets, the diluent includes but is not limited to one or more of calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.

[0011] In the above-mentioned ertogliflozin tablets, the disintegrant includes but is not limited to one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

[0012] In the above-mentioned etoglipizide tablets, the binder includes but is not limited to one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, and sodium carboxymethyl cellulose.

[0013] The above-mentioned etoglipizide tablets also include a stabilizer. In order to overcome the stability problem of etoglipizide tablets, the inventors screened the drug excipients and finally found that butylated p-hydroxyanisole was added as a stabilizer. Through the combination of the stabilizer and the stabilizer, the growth of impurities in the etoglipizide tablets can be better controlled, thereby ensuring the stable quality of the etoglipizide tablets.

[0014] Furthermore, the dosage of the stabilizer and the co-stabilizer was screened, and it was determined that the mass dosage ratio of the stabilizer to the co-stabilizer was 1:0.2-0.8.

[0015] In the above-mentioned ertogliflozin tablets, the amount of each component is calculated by mass as follows: ertogliflozin is 5 parts, erythritol is 15-25 parts, stabilizer is 3-10 parts, diluent is 60-140 parts, disintegrant is 1-5 parts, and binder is 1-5 parts.

[0016] In the above-mentioned ertogliflozin tablets, the tablets further contain a lubricant, which includes but is not limited to one or more of micropowdered silica gel, magnesium stearate, stearic acid, calcium stearate, talcum powder, and hard sodium fumarate. The amount of the above-mentioned lubricant can be obtained according to the general cognition level of those skilled in the art.

[0017] The present invention also provides a method for preparing an etogliflozin tablet, comprising the following steps:

[0018] a. Evenly mixing etogliflozin with erythritol, a stabilizer, a diluent, a disintegrant and a binder to prepare a mixed powder;

[0019] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0020] c. tableting the drug granules obtained in step b.

[0021] In the above-mentioned method for preparing etoglipizide tablets, the step c further includes the step of adding a lubricant; and / or the step a further includes the step of adding a stabilizer.

[0022] The ertogliflozin tablets provided by the present invention can overcome the poor physicochemical properties of ertogliflozin solubility through the combination of erythritol and sodium cholate, so that the prepared tablets have good dissolution properties. At the same time, the addition of the stabilizer sodium cholate can make the ertogliflozin tablets still have good stability under long-term storage conditions. The present invention can be prepared using conventional preparation processes such as dry granulation, wet granulation, etc., and is more suitable for industrial production. DETAILED DESCRIPTION

[0023] Example 1

[0024]

[0025]

[0026] Preparation method:

[0027] a. mixing etogliflozin with erythritol, sodium cholate, microcrystalline cellulose, lactose, povidone and cross-linked povidone to obtain a mixed powder;

[0028] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0029] c. tableting the drug granules obtained in step b.

[0030] Example 2

[0031] Components Dosage(g) Etorgliflozin 5 Erythritol 21 Sodium Cholate 3 Microcrystalline Cellulose 86 Mannitol 54 Hydroxypropyl Cellulose 1 Croscarmellose Sodium 3

[0032] Preparation method:

[0033] a. mixing etogliflozin with erythritol, sodium cholate, microcrystalline cellulose, mannitol, hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose to obtain a mixed powder;

[0034] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0035] c. tableting the drug granules obtained in step b.

[0036] Example 3

[0037]

[0038]

[0039] Preparation method:

[0040] a. Evenly mix etogliflozin with erythritol, sodium cholate, pregelatinized starch, hydroxypropyl methylcellulose and sodium carboxymethyl starch to prepare a mixed powder;

[0041] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0042] c. tableting the drug granules obtained in step b.

[0043] Example 4

[0044] Components Dosage(g) Etorgliflozin 5 Erythritol 18 Sodium Cholate 6 tert-Butylated 4-Hydroxyanisole 3 Calcium Hydrogen Phosphate 70 lactose 28 Sodium Carboxymethyl Cellulose 3 Sodium carboxymethyl starch 3 Low substituted hydroxypropyl cellulose 1

[0045] Preparation method:

[0046] a. Evenly mix etogliflozin with erythritol, sodium cholate, butylated p-hydroxyanisole, calcium hydrogen phosphate, lactose, sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose to prepare a mixed powder;

[0047] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0048] c. tableting the drug granules obtained in step b.

[0049] Example 5

[0050] Components Dosage(g) Etorgliflozin 5 Erythritol 16 Sodium Cholate 8 tert-Butylated 4-Hydroxyanisole 1.6 Microcrystalline Cellulose 85 lactose 20 Hydroxypropyl Cellulose 2 Povidone 2 Croscarmellose Sodium 3 Micro powder silica gel 2.5

[0051] Preparation method:

[0052] a. mixing etogliflozin with erythritol, sodium cholate, butylated p-hydroxyanisole, microcrystalline cellulose, lactose, hydroxypropyl cellulose, povidone and cross-linked sodium carboxymethyl cellulose to obtain a mixed powder;

[0053] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0054] c. Mix the drug particles prepared in step b and the silica gel powder evenly and compress them into tablets.

[0055] Example 6

[0056]

[0057]

[0058] Preparation method:

[0059] a. Evenly mix etogliflozin with erythritol, sodium cholate, butylated hydroxyanisole, microcrystalline cellulose, starch, povidone and sodium carboxymethyl starch to prepare a mixed powder;

[0060] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0061] c. The drug granules prepared in step b and magnesium stearate are mixed evenly and tableted.

[0062] Example 7

[0063] Components Dosage(g) Etorgliflozin 5 Erythritol 22 Sodium Cholate 7 tert-Butylated 4-Hydroxyanisole 2.8 Microcrystalline Cellulose 76 Povidone 3 Sodium carboxymethyl starch 4 Hard Sodium Fumarate 1 talcum powder 1.2

[0064] Preparation method:

[0065] a. Evenly mix etogliflozin with erythritol, sodium cholate, butylated hydroxyanisole, microcrystalline cellulose, povidone and sodium carboxymethyl starch to prepare a mixed powder;

[0066] b. The mixed powder obtained in step a is dry granulated to obtain drug granules;

[0067] c. The drug particles obtained in step b are mixed evenly with hard sodium fumarate and talcum powder, and tableted.

[0068] Comparative Example

[0069]

[0070] The preparation method is the same as Example 1.

[0071] Dissolution assay

[0072] Take the ertogliflozin tablets of Examples 1-7 and Comparative Examples 1-6, use pH 6.8 phosphate buffer as the dissolution medium, and follow the dissolution method (Chinese Pharmacopoeia 2020 Edition Part IV 0931 Dissolution and Dissolution Assay (Method 2)), the speed is 75 revolutions per minute, and the dissolution solution is taken at 5min, 15min, 30min, 45min, and 60min. HPLC determination is used to measure the solubility (%), and the results are as follows:

[0073]

[0074]

[0075] From the above data, it can be seen that the ertogliflozin tablets prepared in Examples 1-7 of the present invention have an initial dissolution of more than 45% in 5 minutes and are completely dissolved in 60 minutes, with good dissolution. However, in Comparative Examples 1-6, erythritol and the stabilizer sodium cholate were not added at the same time, and the dissolution data of the ertogliflozin tablets obtained were less than 40% in the initial dissolution of 5 minutes and less than 85% in the cumulative dissolution data of 60 minutes, which showed problems of slow dissolution and incomplete dissolution.

[0076] Stability test

[0077] The samples of ertogliflozin prepared in Examples 1-7 and Comparative Examples 1-6 were placed continuously for 12 months at 60° C. and RH 75%. The content (%) of total impurities of ertogliflozin at 0 day and 12 months was detected by high performance liquid chromatography. The results were as follows:

[0078]

[0079]

[0080] The tablets obtained in the above examples and comparative examples were subjected to accelerated tests and found that in Examples 1-7 of the present invention, the obtained tablets of ertogliflozin have good stability through the combination of erythritol and the stabilizer sodium cholate, and the increase of total impurities can be well controlled after the accelerated test to ensure the safety of the patient's medication. Among them, the increase of the co-stabilizer can better control the stability of ertogliflozin, while the stabilizer sodium cholate was not added in Comparative Examples 1, 5, and 6. After 12 months of accelerated experiments, the related substances of the obtained tablets of ertogliflozin increased significantly.

Claims

1. An etoglipizide tablet, characterized in that: The invention comprises etoglipizide, erythritol, a stabilizer, a diluent, a disintegrant and a binder; the stabilizer is sodium cholate.

2. The ertogliflozin tablet according to claim 1, characterized in that The diluent is one or more of calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.

3. The ertogliflozin tablet according to claim 1, characterized in that The disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

4. The ertogliflozin tablet according to claim 1, characterized in that The binder is one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and sodium carboxymethyl cellulose.

5. The ertogliflozin tablet according to claim 1, characterized in that: The tablet further contains a stabilizer; the stabilizer is tert-butyl-p-hydroxyanisole.

6. The ertogliflozin tablet according to claim 5, characterized in that: The mass dosage ratio of the stabilizer to the auxiliary stabilizer is 1:0.2-0.

8.

7. The ertogliflozin tablet according to claim 1, characterized in that: The dosage of each component is calculated by weight: 5 parts of etogliflozin, 15-25 parts of erythritol, 3-10 parts of stabilizer, 60-140 parts of diluent, 1-5 parts of disintegrant, and 1-5 parts of binder.

8. The ertogliflozin tablet according to claim 1, characterized in that: The tablet further contains a lubricant, which is one or more of micro powder silica gel, magnesium stearate, stearic acid, calcium stearate, talcum powder, and hard sodium fumarate.

9. A method for preparing the etogliflozin tablets according to claim 1, characterized in that: The following steps are involved: a. Evenly mixing etogliflozin with erythritol, a stabilizer, a diluent, a disintegrant and a binder to prepare a mixed powder; b. The mixed powder obtained in step a is dry granulated to obtain drug granules; c. tableting the drug granules obtained in step b.

10. The method for preparing the ertogliflozin tablet according to claim 9, characterized in that: The step c further includes the step of adding a lubricant; and / or the step a further includes the step of adding a stabilizer.

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