An empagliflozin metformin sustained-release tablet and its preparation method

Abstract

The present invention belongs to the technical field of the preparation of empagliflozin metformin tablets, and specifically relates to an empagliflozin metformin sustained-release tablet and a preparation method thereof, which includes a sustained-release tablet core and a rapid-release coating layer; the sustained-release tablet core includes metformin hydrochloride, organic acid, surfactant, sustained-release material, excipient, lubricant, and the rapid-release coating layer includes empagliflozin and film-forming material; compared with the prior art, the beneficial effects of the present invention are as follows: the release of metformin hydrochloride in the empagliflozin metformin sustained-release tablet is more stable and uniform, and the constant-rate release reaches 10 hours, making the side effects caused by metformin hydrochloride smaller; the release stability of metformin hydrochloride in the empagliflozin metformin sustained-release tablet is good after long-term placement, and the shelf life can be up to 24 months; the synergistic viscosity-increasing effect of the surfactant and the organic acid can appropriately reduce the dosage of the sustained-release material, thereby reducing the tablet weight of the empagliflozin metformin sustained-release tablet and improving the compliance of patients taking the medicine.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of empagliflozin metformin tablets, and particularly relates to an empagliflozin metformin sustained-release tablet and a preparation method thereof. Background Art

[0002] When metformin hydrochloride alone cannot effectively control blood glucose, empagliflozin and metformin hydrochloride are used in combination, which can improve the blood glucose control of type 2 diabetes patients on the basis of diet and exercise. However, due to the problem of the half-life of metformin hydrochloride, the ordinary compound preparation of empagliflozin metformin hydrochloride needs to be taken 2 or 3 times a day, while the empagliflozin single preparation only needs to be taken once a day. The inconsistent number of medication times causes great trouble to patients. At the same time, when metformin hydrochloride is a highly soluble drug, it is imperative to control the release to obtain a metformin hydrochloride sustained-release preparation. Moreover, the sustained-release preparation has many advantages compared with the ordinary preparation. The sustained-release preparation can maintain the blood drug concentration required for treatment for a long time, while reducing the peak-valley change of the blood drug concentration, reducing the incidence rate and severity of side effects. The sustained-release preparation can also improve the compliance of patients by reducing the number of medication times. The sustained-release mechanism of the metformin hydrochloride sustained-release preparation is mainly divided into the matrix sustained-release mechanism, the osmotic pump sustained-release mechanism, the membrane-controlled sustained-release mechanism and the pellet sustained-release mechanism. The sustained-release tablets with the matrix sustained-release mechanism have a large tablet weight due to the large amount of sustained-release material used, and the compliance of patients taking them is poor.

[0003] Metformin hydrochloride has very high water solubility, which makes it difficult to control the slow release rate of metformin hydrochloride in the empagliflozin metformin compound preparation. There are phenomena of uneven drug release and incomplete release of metformin hydrochloride in the existing empagliflozin metformin compound preparation. Even during the release process, after the sustained-release matrix collapses, there will be a problem of sudden release of metformin hydrochloride, which causes greater irritation to the gastrointestinal tract of patients and leads to fluctuations in blood drug concentration. In severe cases, there will be a risk of hypoglycemia, endangering the lives of patients. In addition, the strong hydrophilicity of metformin hydrochloride results in strong hygroscopicity of the empagliflozin metformin compound preparation, so that the slow release stability of metformin hydrochloride in the empagliflozin metformin compound preparation gradually decreases with the increase of the storage time, resulting in a short shelf life of the empagliflozin metformin compound preparation. At the same time, since empagliflozin is a poorly soluble drug, the empagliflozin metformin compound preparation also needs to improve the solubility of empagliflozin to ensure that the empagliflozin in the empagliflozin metformin compound preparation can achieve a rapid drug release effect.

[0004] Therefore, it is particularly important to prepare an empagliflozin metformin compound preparation that simultaneously has the sustained-release effect of metformin hydrochloride and the rapid drug release effect of empagliflozin, and the metformin hydrochloride still maintains good sustained-release stability after being placed, and has a small tablet weight. Summary of the Invention

[0005] The object of the present invention is to solve the problems that the existing empagliflozin metformin compound preparation has uneven drug release and burst release of metformin hydrochloride, and the slow release stability of metformin hydrochloride gradually decreases with the increase of time, and provides an empagliflozin metformin sustained-release tablet and a preparation method thereof.

[0006] The present invention relates to an empagliflozin metformin sustained-release tablet, and the sustained-release tablet comprises a sustained-release tablet core and a rapid-release coating layer; the sustained-release tablet core comprises metformin hydrochloride, an organic acid, a surfactant, a sustained-release material, an excipient, and a lubricant, and the rapid-release coating layer comprises empagliflozin and a film-forming material.

[0007] Preferably, the organic acid includes one or more of citric acid, malic acid, dinitrobenzoic acid, ethylenediaminetetraacetic acid, sulfurous acid, metabisulfurous acid, boric acid, tannic acid, periodic acid, malonic acid, terephthalic acid, adipic acid, and oxalic acid.

[0008] Preferably, the surfactant includes one or more of sodium dodecyl sulfate, polysorbate, polyethylene glycol ether, polyethylene glycol sulfate, polyoxyethylene ethyl ether, lauryl chloride, chlorosulfonamide, chlorodiphenylsulfonate, and chlorothioamide.

[0009] Preferably, the weight ratio of the organic acid to the surfactant in the sustained-release tablet core is 3:1 to 3.

[0010] Preferably, the weight ratio of metformin hydrochloride to empagliflozin is 100:1 to 15.

[0011] Preferably, the particle size D 90 value of metformin hydrochloride is 40 to 100 μm.

[0012] Preferably, the particle size D 90 value of empagliflozin does not exceed 50 μm.

[0013] Preferably, the sustained-release material includes one of hydroxypropyl methylcellulose, high-substituted hydroxypropyl cellulose, polyoxyethylene, sodium alginate, methylcellulose, and sodium carboxymethylcellulose; the excipient includes one of starch, lactose, microcrystalline cellulose, mannitol, and xylitol; the lubricant includes one of magnesium stearate, talc powder, and silicon dioxide; and the film-forming material is a coating premix.

[0014] A preparation method of an empagliflozin metformin sustained-release tablet, and the steps of preparing the empagliflozin metformin sustained-release tablet are as follows:

[0015] Step 1: Add the organic acid and the surfactant to an air jet mill. The feeding air pressure is 0.3 - 0.5 mPa, and the crushing air pressure is 0.5 - 1.0 mPa. After crushing the organic acid and the surfactant, a mixture of the organic acid and the surfactant is obtained.

[0016] Step 2: Prepare the metformin hydrochloride, the sustained-release material, and the mixture of the organic acid and the surfactant into granules by fluidized bed granulation. After drying the granules, use a rapid granule sizing machine to size the granules.

[0017] Step 3: Add the granules, the excipient, and the lubricant into a total mixing tank. After mixing evenly, perform tabletting to obtain the sustained-release tablet core.

[0018] Step 4: Dissolve the empagliflozin and the coating premix in purified water, and use a high-efficiency coating machine to coat the sustained-release tablet core to obtain the empagliflozin metformin sustained-release tablets.

[0019] A preparation method of empagliflozin metformin sustained-release tablets, and the steps for preparing the empagliflozin metformin sustained-release tablets are as follows:

[0020] Step 1: Dissolve the organic acid and the surfactant in purified water respectively to prepare a wetting solution.

[0021] Step 2: Add the metformin hydrochloride and the sustained-release material into a mixer and mix evenly to prepare a substrate. Use the melt extrusion technology to prepare the wetting solution and the substrate into granules, and control the granulation temperature at 40 - 70 °C and the granulation screen aperture at 10 - 60 mesh.

[0022] Step 3: After drying the granules, add the excipient and the lubricant, mix evenly, and then perform tabletting to obtain the sustained-release tablet core.

[0023] Step 4: Dissolve the empagliflozin and the coating premix in the purified water, and use a high-efficiency coating machine to coat the sustained-release tablet core to obtain the empagliflozin metformin sustained-release tablets.

[0024] Compared with the prior art, the advantages and positive effects of the present invention are as follows:

[0025] Compared with the prior art, by using the empagliflozin metformin sustained-release tablets and the preparation method of the present invention,

[0026] (1) Organic acids have a stronger hydrophilic ability than metformin hydrochloride. During storage, water will be preferentially taken by the organic acids, preventing water from destroying the activity of metformin hydrochloride in the tablets during storage. This improves the release stability of metformin hydrochloride after long-term storage. The shelf life of this sustained-release tablet can be up to 24 months, and the release curves of the tablets at 0 months and after 24 months of storage are comparable.

[0027] (2) Surfactants and organic acids can wrap and complex with each other. A specific ratio of surfactants and organic acids has a synergistic viscosity-increasing effect. The combination of surfactants and organic acids can increase the strength of the sustained-release matrix formed by the sustained-release materials in the tablets, thereby better controlling the release of metformin hydrochloride, ensuring a more stable, uniform, and constant release of metformin hydrochloride for up to 10 hours, reducing the side effects caused by metformin hydrochloride, and preventing the sudden release or slow release of metformin hydrochloride in the empagliflozin metformin sustained-release tablets, improving the release stability of metformin hydrochloride in the empagliflozin metformin sustained-release tablets.

[0028] (3) The synergistic viscosity-increasing effect of surfactants and organic acids can appropriately reduce the amount of sustained-release materials in the empagliflozin metformin sustained-release tablets, thereby reducing the tablet weight of the empagliflozin metformin sustained-release tablets and improving the compliance of patients taking the tablets.

[0029] (4) The particle size D 90 value of empagliflozin in the coating layer does not exceed 50 μm, ensuring that empagliflozin in the empagliflozin metformin sustained-release tablets can achieve a rapid drug release effect.

[0030] (5) Empagliflozin is combined with the sustained-release part of metformin hydrochloride in a coated form, avoiding the problem of difficult control of content uniformity due to the large difference in the amounts of empagliflozin and metformin hydrochloride in the empagliflozin metformin sustained-release tablets.

[0031] (6) Surfactants can increase cell permeability by dissolving the lipids of the biological membrane, thereby improving the absorption of metformin hydrochloride and enhancing the blood drug concentration stability of the empagliflozin metformin sustained-release tablets. Description of the Drawings

[0032] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments.

[0033] Figure 1 is the metformin hydrochloride release curve of the stability retention product of Example 1 in Test Example 1.

[0034] Figure 2 is the metformin hydrochloride release curve of the stability retention product of Comparative Example 1 in Test Example 1. Detailed Embodiments

[0035] In order to more clearly understand the above objects, features and advantages of the present invention, the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0036] In the following description, many specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention may be practiced in other ways than those described herein. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0037] Example 1

[0038] Formulation:

[0039]

[0040] Preparation steps:

[0041] Add citric acid and sodium lauryl sulfate to a jet mill, with a feeding air pressure of 0.3 mPa and a grinding air pressure of 0.5 mPa. After grinding citric acid and sodium lauryl sulfate, a mixture of citric acid and sodium lauryl sulfate is obtained; a mixture of metformin hydrochloride, hypromellose K4M, citric acid and sodium lauryl sulfate is prepared into granules by fluidized bed granulation. After the granules are dried, they are sized using a high-speed sieving machine; the granules, starch, and magnesium stearate are added to a total mixing tank, mixed evenly, and then compressed into tablets to obtain sustained-release tablet cores; empagliflozin and coating premix - Opadry are dissolved in purified water, and the sustained-release tablet cores are coated using a high-efficiency coating machine to obtain empagliflozin metformin sustained-release tablets.

[0042] Example 2

[0043] Formulation:

[0044]

[0045] Preparation steps:

[0046] Dissolve malic acid and polysorbate in purified water respectively to prepare a wetting solution; add metformin hydrochloride and methylcellulose to a mixer and mix evenly to prepare a substrate; the wetting solution and the substrate are prepared into granules using melt extrusion technology, controlling the granulation temperature at 40 °C and the granulation screen aperture at 40 mesh; after the granules are dried, microcrystalline cellulose and silicon dioxide are added and mixed evenly, and then compressed into tablets to obtain sustained-release tablet cores; empagliflozin and coating premix - Opadry are dissolved in purified water, and the sustained-release tablet cores are coated using a high-efficiency coating machine to obtain empagliflozin metformin sustained-release tablets.

[0047] Comparative Example 1

[0048] The difference between this comparative example and Example 1 is that the sustained-release tablet core does not contain citric acid and sodium lauryl sulfate.

[0049] Test Example 1

[0050] The samples in Example 1 and Comparative Example 1 were placed in a drug stability retention chamber at a temperature of 25°C ± 2 and a humidity of RH65% ± 5 for investigation. Samples were taken at 0 months, 6 months, 12 months, 18 months, and 24 months respectively for a comparative experiment on the stability of the metformin hydrochloride release rate. Determination of the release curve: According to the standard operating procedure of the first method for the examination of release rate, using 900 ml of pH 6.8 phosphate buffer solution as the release medium, with a rotation speed of 50 revolutions per minute, and operating according to the law. At 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, 5 ml of the solution was taken respectively, filtered, and immediately 5 ml of pH 6.8 phosphate buffer solution at the same temperature was added to the dissolution cup; 1 ml of each successive filtrate was accurately measured and placed in a 100 ml volumetric flask, diluted to the mark with pH 6.8 potassium dihydrogen phosphate buffer solution, and shaken well to obtain the test sample. The f2 value method was used to measure the similarity of the metformin hydrochloride release curve. The test results are shown in Figure 1 、 Figure 2 、Table 1 and Table 2, where RSD is the relative standard deviation.

[0051] Table 1 Comparison of the similarity of the metformin hydrochloride release curve in Example 1 (f2 value method)

[0052]

[0053] Table 2 Comparison of the similarity of the metformin hydrochloride release curve in Comparative Example 1 (f2 value method)

[0054]

[0055] From Figure 1 、 Figure 2 、Table 1 and Table 2, it can be concluded that: the metformin hydrochloride release curve in the empagliflozin metformin sustained-release tablets of Example 1 is more stable and uniform compared with that of Comparative Example 1; the metformin hydrochloride release curves of the empagliflozin metformin sustained-release tablets in Example 1 at 6 months, 12 months, 18 months, and 24 months are similar to that at 0 months, while the metformin hydrochloride release curves of the empagliflozin metformin sustained-release tablets in Comparative Example 1 at 6 months, 12 months, 18 months, and 24 months are quite different from that at 0 months; the f2 values of the empagliflozin metformin sustained-release tablets in Example 1 at 6 months, 12 months, 18 months, and 24 months are all larger than those in Comparative Example 1, reaching more than 70; the above experimental results show that adding organic acids and surfactants to the empagliflozin metformin sustained-release tablets can make the release of metformin hydrochloride more stable and uniform, and at the same time, the empagliflozin metformin sustained-release tablets added with organic acids and surfactants have good release stability of metformin hydrochloride after long-term placement, and the shelf life of the empagliflozin metformin sustained-release tablets can be up to 24 months.

[0056] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention in any other form. Any person skilled in the relevant art may use the technical content disclosed above to make changes or modifications into equivalent embodiments with equivalent changes and apply them to other fields. However, as long as they do not depart from the technical solution content of the present invention, any simple modifications and equivalent changes made to the above embodiments based on the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. An empagliflozin metformin sustained-release tablet, characterized in that, The sustained-release tablet comprises a sustained-release tablet core and a rapid-release coating layer; the sustained-release tablet core comprises metformin hydrochloride, an organic acid, a surfactant, a sustained-release material, an excipient, and a lubricant, and the rapid-release coating layer comprises empagliflozin and a film-forming material; The organic acid comprises one or more of citric acid, malic acid, ethylenediaminetetraacetic acid, tannic acid, periodic acid, malonic acid, adipic acid, and oxalic acid; The surfactant comprises one or more of sodium dodecyl sulfate, polysorbate, polyethylene glycol ether, polyethylene glycol sulfate, polyoxyethylene ethyl ether, lauryl alcohol chloride, sulfamide chloride, diphenylsulfonic acid chloride, and thioamide chloride; In the sustained-release tablet core, the weight ratio of the organic acid to the surfactant is 3:1 to 3.

2. The empagliflozin metformin sustained-release tablet according to claim 1, characterized in that The weight ratio of the metformin hydrochloride to the empagliflozin is 100:1 to 15.

3. The empagliflozin metformin sustained-release tablet according to claim 2, characterized in that, The particle size D of metformin hydrochloride 90 is 40 to 100 μm.

4. The empagliflozin metformin sustained-release tablet according to claim 3, characterized in that, The particle size D of empagliflozin 90 is not more than 50 μm.

5. The empagliflozin metformin sustained-release tablet according to claim 4, wherein The sustained-release material comprises one of hydroxypropyl methylcellulose, highly substituted hydroxypropyl cellulose, polyoxyethylene, sodium alginate, methylcellulose, and sodium carboxymethylcellulose; the excipient comprises one of starch, lactose, microcrystalline cellulose, mannitol, and xylitol; the lubricant comprises one of magnesium stearate, talc powder, and silicon dioxide; and the film-forming material is a coating premix.

6. A preparation method of empagliflozin metformin sustained-release tablets, characterized in that, The steps for preparing the empagliflozin metformin sustained-release tablet according to claim 5 are as follows: Step 1: Add the organic acid and the surfactant to a jet mill, with a feeding air pressure of 0.3 to 0.5 mPa and a pulverizing air pressure of 0.5 to 1.0 mPa. After the organic acid and the surfactant are pulverized, a mixture of the organic acid and the surfactant is obtained; Step 2: Prepare the metformin hydrochloride, the sustained-release material, and the mixture of the organic acid and the surfactant into granules by fluidized bed granulation. After the granules are dried, they are sized using a high-speed granule sizing machine; Step 3: Add the granules, the excipient, and the lubricant to a total mixing tank, mix evenly, and then press tablets to obtain the sustained-release tablet core; Step 4: Dissolve the empagliflozin and the coating premix in purified water, and use a high-efficiency coating machine to coat the sustained-release tablet core to obtain the empagliflozin metformin sustained-release tablet.

7. A preparation method of empagliflozin metformin sustained-release tablets, characterized in that, The steps for preparing the empagliflozin metformin sustained-release tablet according to claim 5 are as follows: Step 1: Dissolve the organic acid and the surfactant in purified water respectively to prepare a wetting solution; Step 2: Add the metformin hydrochloride and the sustained-release material to a mixer and mix evenly to prepare a substrate; the wetting solution and the substrate are prepared into granules using a melt extrusion technique, controlling the granulation temperature at 40 to 70 °C and the granulation screen aperture at 10 to 60 meshes; Step 3: After the granules are dried, add the excipient and the lubricant, mix evenly, and then press tablets to obtain the sustained-release tablet core; Step 4: Dissolve the empagliflozin and the coating premix in the purified water, and use a high-efficiency coating machine to coat the sustained-release tablet core to obtain the empagliflozin metformin sustained-release tablet.

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