An empagliflozin tablet

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to an empagliflozin tablet. The empagliflozin tablet provided by the application uses corn protein as a binder, and is prepared by a spray drying method with the assistance of a preferred disintegrating agent. The empagliflozin tablet has the advantages of simple preparation process, rapid dissolution, high stability and content uniformity, minimized auxiliary material amount, small tablet weight, saved production cost, and improved patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and specifically relates to an empagliflozin tablet. Background Technology

[0002] Empagliflozin, chemically named (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, molecular formula: C 23 H 27 ClO7, molecular weight: 450.90, structural formula as follows:

[0003]

[0004] Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Combined with exercise and diet, it is used as adjunctive therapy to improve glycemic control in adults with type 2 diabetes. It blocks the reabsorption of glucose in the kidneys, excreting excess glucose from the body, thereby lowering blood glucose levels. This glycemic effect is independent of β-cell function and insulin resistance. Empagliflozin was jointly developed by Boehringer Ingelheim and Eli Lilly. It was first approved for marketing by the European Medicines Agency (EMA) on May 22, 2014, under the brand name Jardiance. It was approved for marketing by the US Food and Drug Administration (FDA) on August 1, 2014, by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on December 26, 2014, and was approved for marketing in China on September 20, 2017, under the brand name Otangjing.

[0005] Empagliflozin is only slightly soluble in water, resulting in low dissolution. Dissolution directly affects drug absorption, leading to low bioavailability and impacting efficacy. Patent ZL201080015987.4 improves empagliflozin dissolution by controlling the particle size distribution of raw materials and the particle size of the drug. However, this preparation method is cumbersome, with significant losses during the micronization process. Micronized materials tend to agglomerate, hindering uniform mixing and reducing production efficiency. The uniformity of the resulting drug formulation needs improvement, and the tablets are relatively heavy, making them difficult for elderly patients to swallow and posing a potential safety hazard. Patent ZL201810965196.6 grinds empagliflozin and sodium hyaluronate to nanoscale and assembles them using mesoporous silica as a carrier, fully exposing the nanoscale interface of empagliflozin. While this increases the dissolution rate, it still suffers from high grinding losses and heavy tablets. Patent ZL202310265826.X improves the solubility of empagliflozin to some extent by controlling the raw materials within a suitable particle size range and selecting appropriate types and amounts of excipients through a wet granulation process. However, the loss during the micronization process is large. The preparation of tablets involves pretreatment of raw materials and excipients, premixing, granulation and drying, granulation, total mixing 1, total mixing 2, and tableting steps, which is a complicated process.

[0006] ZL201510955740.5 describes the preparation of an oral solid dosage form by melt granulation of empagliflozin and polyethylene glycol. The resulting tablets are heavy, dissolve slowly, and polyethylene glycol has a low melting point, posing a risk of tablet sticking during compression. ZL201510071399.7 describes the preparation of tablets by hot melt granulation of empagliflozin and mannitol. The resulting tablets are heavy, dissolve slowly, and require a large amount of mannitol. Mannitol is hygroscopic, which is detrimental to long-term storage, and the high temperature of melt granulation also negatively impacts drug stability. ZL201510932515.X involves grinding and mixing empagliflozin, succinic acid, and avocado oil, then preparing an inclusion complex with hydroxypropyl-β-cyclodextrin and methacrylic acid. This inclusion complex is then combined with other pharmaceutical excipients to form tablets. However, hydroxypropyl-β-cyclodextrin is converted into glucose in the body, and relevant data shows that it has certain nephrotoxicity, making it unsuitable for long-term use by diabetic patients. In addition, the excipient succinic acid in the prescription is a hazardous excipient, which is flammable when exposed to open flames or high heat, and its powder can form an explosive mixture with air. There is a risk of explosion when used in large quantities.

[0007] Therefore, based on existing excipients and production conditions, and under the premise of ensuring low production costs and a simple and easy-to-implement preparation process, it is necessary to study a technical solution that, through appropriate formulation and preparation process, enables empagliflozin tablets to have a smaller tablet weight while also possessing good content uniformity, in vitro dissolution effect, and stability. Summary of the Invention

[0008] In view of the shortcomings of the prior art, the purpose of the present invention is to provide an empagliflozin tablet with small tablet weight, good content uniformity and stability, and rapid drug dissolution.

[0009] To minimize tablet weight, the inventors initially considered eliminating fillers from the formulation and selecting only binders, disintegrants, and lubricants to prepare tablets, attempting to reduce the tablet weight to below 30mg. However, due to the loose and poor flowability of the raw materials, direct tableting was not feasible; tablets prepared using conventional wet or dry granulation processes exhibited poor dissolution. After repeated screening, it was discovered that spray-dried granules had good flowability, were easy to compress, and were porous, which facilitated drug dissolution. However, different binders and disintegrants significantly affected drug dissolution and content uniformity. After repeated screening, the inventors finally determined the optimal formulation.

[0010] Specifically, the objective of this invention is achieved through the following technical solution:

[0011] An empagliflozin tablet comprising empagliflozin, zein, and other pharmaceutically acceptable excipients.

[0012] The empagliflozin tablets are prepared by spray drying using zein as a binder.

[0013] Other pharmaceutically acceptable excipients include disintegrants and lubricants.

[0014] The tablets weigh no more than 27 mg, preferably no more than 20 mg.

[0015] Preferably, the disintegrant is selected from one or a combination of polacrine potassium, sodium carboxymethyl starch, hydroxypropyl cellulose, and croscarmellose sodium, and more preferably one or a combination of polacrine potassium and sodium carboxymethyl starch.

[0016] Preferably, the lubricant is selected from one or a combination of magnesium stearate, calcium stearate, talc, sodium stearoyl fumarate, and other similar materials.

[0017] The weight ratio of empagliflozin to zein is 1:0.02-0.06.

[0018] Preferably, the weight ratio of empagliflozin to zein is 1:0.04.

[0019] Preferably, the weight ratio of empagliflozin to disintegrant is 1:0.4-1.4.

[0020] More preferably, the weight ratio of empagliflozin to disintegrant is 1:0.9.

[0021] Preferably, the tablet contains the following components in parts by weight:

[0022]

[0023] In a preferred embodiment, the tablet contains the following components in parts by weight:

[0024]

[0025] Meanwhile, the present invention provides a preparation process for empagliflozin tablets, comprising the following steps: adding empagliflozin and zein to a 75% ethanol solution and stirring until completely dissolved; adding a disintegrant under stirring conditions and continuing to stir until the disintegrant is evenly dispersed; spray drying to obtain empagliflozin granules; adding a lubricant and mixing evenly, and compressing into tablets to obtain the final product.

[0026] There are no particular restrictions on the amount of 75% ethanol solution used, as long as it can dissolve the prescribed amount of empagliflozin and zeaxanthin.

[0027] Compared with existing technologies, the empagliflozin tablets of this invention have a simple preparation process, rapid dissolution, high stability and content uniformity, minimize the amount of excipients used, have a small tablet weight, save production costs, and help improve patient compliance. Detailed Implementation

[0028] The present invention will be further described below through specific embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0029] All raw materials and reagents used in this invention are commercially available.

[0030] Example 1

[0031] prescription:

[0032]

[0033]

[0034] Preparation process:

[0035] Add the prescribed amount of empagliflozin and zein to 10 ml of 75% ethanol solution and stir until completely dissolved; add sodium carboxymethyl starch under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into tablets with a diameter of Ф3.0 mm to obtain the final product.

[0036] Example 2

[0037] prescription:

[0038]

[0039] Preparation process:

[0040] Add the prescribed amount of empagliflozin and zein to 8 ml of 75% ethanol solution and stir until completely dissolved; add sodium carboxymethyl starch under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add magnesium stearate and mix evenly, then press into tablets with a diameter of Ф2.5 mm to obtain the final product.

[0041] Example 3

[0042] prescription:

[0043]

[0044] Preparation process:

[0045] Add the prescribed amount of empagliflozin and zein to 12 ml of 75% ethanol solution and stir until completely dissolved; add sodium carboxymethyl starch under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into tablets with a diameter of Ф3.5 mm to obtain the final product.

[0046] Example 4

[0047] prescription:

[0048]

[0049]

[0050] Preparation process:

[0051] Add the prescribed amount of empagliflozin and zein to 8 ml of 75% ethanol solution and stir until completely dissolved; add polacrine potassium under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into 3.0 mm tablets to obtain the final product.

[0052] Example 5

[0053] prescription:

[0054]

[0055] Preparation process:

[0056] Add the prescribed amount of empagliflozin and zein to 8 ml of 75% ethanol solution and stir until completely dissolved; add sodium carboxymethyl starch under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into tablets with a diameter of Ф3.0 mm to obtain the final product.

[0057] Example 6

[0058] prescription:

[0059]

[0060] Preparation process:

[0061] Add the prescribed amount of empagliflozin and zein to 15 ml of 75% ethanol solution and stir until completely dissolved; add sodium carboxymethyl starch under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into 3.5 mm tablets to obtain the final product.

[0062] Example 7

[0063] prescription:

[0064]

[0065]

[0066] Preparation process:

[0067] Add the prescribed amount of empagliflozin and zein to 10 ml of 75% ethanol solution and stir until completely dissolved; add croscarmellose sodium under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into tablets with a diameter of Ф3.0 mm to obtain the final product.

[0068] Example 8

[0069] prescription:

[0070] Empagliflozin 10mg

[0071]

[0072] Preparation process:

[0073] Mix the prescribed amounts of empagliflozin, zein, and sodium carboxymethyl starch evenly, add 10 ml of 75% ethanol solution to granulate, pass through a 20-mesh sieve, dry at 50°C, add magnesium stearate and mix evenly, and press into tablets with a diameter of 3.0 mm.

[0074] Comparative Example 1

[0075] prescription:

[0076]

[0077] Preparation process:

[0078] Add the prescribed amount of empagliflozin and copovidone to 10 ml of 75% ethanol solution and stir until completely dissolved; add sodium carboxymethyl starch under stirring and continue stirring until evenly mixed; spray dry to obtain empagliflozin granules; add talc powder and mix evenly, then press into tablets with a diameter of Ф3.0 mm to obtain the final product.

[0079] Comparative Example 2

[0080] prescription:

[0081]

[0082]

[0083] Preparation process:

[0084] Weigh out the prescribed amounts of empagliflozin and mannitol 1, mix them, and add them to a hot melt extruder. Set the temperature to 200℃. After extrusion, remove and cool the material, then pulverize it using a mechanical pulverizer. Pass the pulverized material through a 40-mesh sieve. Mix mannitol 2, croscarmellose sodium, and magnesium stearate evenly, compress the mixture into tablets, and the product is ready.

[0085] Comparative Example 3

[0086] prescription:

[0087]

[0088] Preparation process:

[0089] The prescribed amounts of empagliflozin and povidone K30 were dissolved in an acetone:methanol (1:1) solvent and spray-dried at an inlet air temperature of 85°C, an air volume of 25 kg / hr, an nebulization pressure of 0.5 bar, a nebulizing gas flow rate of 1.5 kg / hr, and a liquid supply flow rate of 4.5 ml / min. The resulting spray-dried powder was then vacuum-dried at 45°C for 24 hours to obtain a solid dispersion. The obtained solid dispersion was then added to the prescribed amounts of lactose, sodium carboxymethyl starch, sodium dodecyl sulfate, and silicon dioxide, mixed, and directly compressed into tablets.

[0090] Comparative Example 4

[0091] prescription:

[0092]

[0093]

[0094] Preparation process:

[0095] Weigh the prescribed amounts of empagliflozin and polyethylene glycol and add them to a solid dispersion mixer. Melt the mixture at 170°C, then remove it and quickly place it in a refrigerator to solidify. Vacuum dry the mixture and pulverize it through an 80-mesh sieve. Mix the prescribed amounts of microcrystalline cellulose, pregelatinized starch, crospovidone, and magnesium stearate evenly, and compress the mixture into tablets to obtain the final product.

[0096] Verification of dissolution in Example 1

[0097] 1. Test materials: Empagliflozin tablets prepared in Examples 1-8 and Comparative Examples 1-4.

[0098] 2. Test methods:

[0099] Take this product and perform the dissolution and release assay according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 900 ml of pH 6.8 phosphate buffer solution as the dissolution medium and a rotation speed of 50 rpm. Take samples at 5, 10, 15, 20, and 30 min, discard 5 ml of the initial filtrate, and use the subsequent filtrate as the test solution; accurately weigh an appropriate amount of empagliflozin reference standard, dissolve and dilute it with acetonitrile-water (50:50) to prepare a solution containing approximately 0.55 mg per ml, accurately measure an appropriate amount, and dilute it with the dissolution medium to prepare a solution containing approximately 11 μg per ml.

[0100] Octylsilane-bonded silica gel was used as the stationary phase; the mobile phase consisted of 0.01 mol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid) and acetonitrile (65:35); the flow rate was 1.2 mL / min; the column temperature was 40 °C; the detection wavelength was 224 nm; and the injection volume was 40 μL. Accurately measure the reference solution and the test solution, inject them separately into the liquid chromatograph, and record the chromatograms. The dissolution amount per tablet was calculated based on peak area using the external standard method, and the limit was 85% of the labeled amount, which should comply with regulations.

[0101] 3. Experimental results: The experimental results are shown in Table 1.

[0102] Table 1. Results of dissolution test for empagliflozin tablets

[0103]

[0104] As shown in Table 1, the tablets in the embodiments of the present invention dissolve rapidly; Example 8 uses wet granulation, resulting in slightly slower dissolution; and Comparative Example 1 uses copovidone as a binder, resulting in poor dissolution rate.

[0105] Verification of Accelerated Stability in Example 2

[0106] 1. Test materials: Empagliflozin tablets prepared in Examples 1-8 and Comparative Examples 1-4.

[0107] 2. Test methods:

[0108] Take this product and place it in a constant temperature and humidity chamber at high temperature (40℃) and high humidity (75±5% relative humidity) for accelerated testing. Take samples on day 0 and at month 6 for determination of related substances.

[0109] Related substances test method: Take 5 tablets of this product, place them in a 50ml volumetric flask, add about 40ml of acetonitrile-water (30:70), sonicate to dissolve empagliflozin, cool to room temperature, dilute to the mark with acetonitrile-water (30:70), shake well, centrifuge, and take the supernatant as the test solution. Use octylsilane-bonded silica gel as the packing material; use 0.05% trifluoroacetic acid solution (take 0.5ml of trifluoroacetic acid and add 1000ml of water) as mobile phase A, and 0.05% trifluoroacetic acid acetonitrile solution (take 0.5ml of trifluoroacetic acid and add 1000ml of acetonitrile) as mobile phase B, and perform linear gradient elution according to the table below; the detection wavelength is 275nm; the column temperature is 40℃; the injection volume is 80μl.

[0110]

[0111] If there are impurity peaks in the chromatogram of the test solution, after deducting the solvent peak and excipient peak, the peak area of ​​impurity A shall not be greater than the main peak area of ​​the control solution (0.20%), the peak area of ​​impurity B shall not be greater than 0.75 times (0.15%) the main peak area of ​​the control solution, the peak area of ​​any other single impurity peak shall not be greater than the main peak area of ​​the control solution (0.20%), and the sum of the peak areas of all impurities shall not be greater than 2.5 times (0.5%) the main peak area of ​​the control solution.

[0112] 3. Experimental results: The experimental results are shown in Table 2.

[0113] Table 2. Stability test results

[0114]

[0115]

[0116] As shown in Table 2, the tablets of the present invention have excellent stability.

[0117] Verification of content uniformity in Example 3

[0118] 1. Test materials: Empagliflozin tablets prepared in Examples 1-8 and Comparative Examples 1-4.

[0119] 2. Test methods:

[0120] Take one tablet of this product and place it in a 20ml volumetric flask. Add about 15ml of acetonitrile-water (20:80) and sonicate for 25 minutes to dissolve empagliflozin. Let it cool to room temperature and dilute to the mark with acetonitrile-water (20:80). Shake well and centrifuge at 13,000 rpm for 10 minutes. Take the supernatant as the test solution. Separately, accurately weigh empagliflozin reference standard, dissolve and dilute it with acetonitrile-water (20:80) to prepare a solution containing about 0.5mg per ml as the reference solution.

[0121] The column was packed with octylsilane-bonded silica gel; the mobile phase was 0.01 mol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile (65:35); the flow rate was 1.2 mL / min; the column temperature was 40 °C; the detection wavelength was 224 nm; and the injection volume was 40 μL. Accurately measure the reference solution and the test solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the content per tablet by peak area using the external standard method; it should meet the requirements (A + 2.2S ≤ 15.0).

[0122] 3. Experimental results: The experimental results are shown in Table 3.

[0123] Table 3 Results of the test on the uniformity of empagliflozin tablet content

[0124]

[0125] As shown in Table 3, the present invention uses corn gluten as a binder, which is beneficial to improving the roundness of spray-dried granules, improving granule flowability, reducing tablet weight differences, and ensuring tablet content uniformity.

Claims

1. An empagliflozin tablet, characterized in that, This includes empagliflozin, zein, and other pharmaceutically acceptable excipients.

2. The empagliflozin tablets as described in claim 1, characterized in that, The empagliflozin tablets are prepared by spray drying using zein as a binder.

3. The empagliflozin tablets as described in claim 1, characterized in that, Other pharmaceutically acceptable excipients include disintegrants and lubricants.

4. The empagliflozin tablets as described in claim 1, characterized in that, The tablets weigh no more than 27 mg, preferably no more than 20 mg.

5. The empagliflozin tablets as described in claim 3, characterized in that, The disintegrant is selected from one or a combination of polacrine potassium, sodium carboxymethyl starch, hydroxypropyl cellulose, and croscarmellose sodium, preferably one or a combination of polacrine potassium and sodium carboxymethyl starch.

6. The empagliflozin tablets as described in claim 3, characterized in that, The lubricant is selected from one or a combination of magnesium stearate, calcium stearate, talc, sodium stearoyl fumarate, and other similar materials.

7. The empagliflozin tablets as described in claim 1, characterized in that, The weight ratio of empagliflozin to zein is 1:0.02-0.06, preferably 1:0.

04.

8. The empagliflozin tablets as described in claim 3, characterized in that, The weight ratio of empagliflozin to disintegrant is 1:0.4-1.

4.

9. The empagliflozin tablets as described in claim 3, characterized in that, The tablets contain the following components in parts by weight:

10. The preparation process of empagliflozin tablets according to any one of claims 1-9, characterized in that, The process includes the following steps: adding empagliflozin and zein to a 75% ethanol solution and stirring until completely dissolved; adding a disintegrant while stirring and continuing to stir until the disintegrant is evenly dispersed; spray drying to obtain empagliflozin granules; adding a lubricant and mixing evenly; and compressing into tablets to obtain the final product.

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