A dapagliflozin metformin extended-release tablet

Abstract

This invention relates to a dapagliflozin-metformin extended-release tablet, which comprises a metformin hydrochloride tablet layer, a dapagliflozin tablet layer, and a gastrointestinal film coating. The metformin hydrochloride tablet layer contains 1000 mg of metformin hydrochloride, magnesium stearate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose 2208, and silicon dioxide. The dapagliflozin tablet layer contains 5-25 mg of amorphous dapagliflozin, 6-15 mg of sodium carboxymethyl starch, anhydrous lactose, microcrystalline cellulose, magnesium stearate, and silicon dioxide. The extended-release tablet of this invention exhibits good stability under high temperature, high humidity, and light exposure. This invention also provides a method for preparing the dapagliflozin-metformin extended-release tablet.

Description

Technical Field

[0001] This invention relates to a dapagliflozin metformin solid dosage form, specifically a dapagliflozin metformin extended-release tablet. Background Technology

[0002] Dapagliflozin is an SGLT-2 inhibitor developed by AstraZeneca for the treatment of diabetes. Its molecular formula is C64-C ... 21 H 25 ClO6, CAS number 461432-26-8, structural formula shown below. Metformin is a classic drug for treating diabetes and is used in combination with various diabetes medications to form compound preparations.

[0003]

[0004] Currently, there are many literature reports on the combination formulation of dapagliflozin and metformin. Based on the mechanism of action and metabolic characteristics of dapagliflozin and metformin, dapagliflozin is required to be rapidly released, with the release basically completed within the first 30 minutes, while metformin hydrochloride is required to be sustained-release. The only sustained-release formulation currently on the market is AstraZeneca's XIGDUO.

[0005] XIGDUO uses dapagliflozin in the hydrated crystalline form of propylene glycol and water, see CN101479287B. Taking the 5mg strength as an example, the tablets consist of a dapagliflozin layer and a metformin extended-release layer. The dapagliflozin layer contains 6.15mg of dapagliflozin propylene glycol monohydrate (5mg dapagliflozin), microcrystalline cellulose, lactose, cropovidone, silica, and magnesium stearate; the metformin extended-release layer contains 1000mg of metformin hydrochloride, magnesium stearate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose 2208, and silica; the film coating uses… II Pink 85F94592 (5mg strength) or II Yellow 85F12372 (10mg specification). This dosage form has a shelf life of 2 years under good storage conditions and performs well in accelerated tests at 40℃±2℃ / 75%RH±5%RH.

[0006] However, in actual drug use, it is difficult to guarantee that drugs will always be stored in an ideal environment that is cool, dry, and protected from light. The existing accelerated testing at 40°C and 75% RH does not reflect the actual storage conditions of drugs. As a chronic disease medication, according to the current "Prescription Management Regulations," each prescription should not exceed 12 weeks' worth of medication, and patients need to take it daily, so it generally will not become ineffective due to exceeding its expiration date. In daily life, drug deterioration is often caused by simply high temperature or high humidity conditions. For example, in summer, the temperature inside a car often reaches above 70°C and remains there for several hours under the sun; during the rainy season, or when the drug packaging becomes damp, drugs can be kept in a high humidity environment above 90% RH for extended periods. The stability of original drug formulations under high temperature or high humidity conditions is not ideal, affecting the shelf life and medication safety.

[0007] Chinese patent CN106924208A describes a dapagliflozin metformin hydrochloride sustained-release tablet, in which the dapagliflozin immediate-release layer uses dapagliflozin·propylene glycol·hydrate and hydroxypropyl cellulose. CN13398097A describes a dapagliflozin immediate-release layer using dapagliflozin·propylene glycol·hydrate, omeprazole, and arginine. Both of these products exhibit poor stability under high temperature or high humidity conditions. Summary of the Invention

[0008] To address the above problems, the present invention provides a dapagliflozin metformin extended-release tablet.

[0009] The tablets consist of a metformin hydrochloride tablet layer, a dapagliflozin tablet layer, and a gastrointestinal film coating. Each tablet contains 5-25 mg of amorphous dapagliflozin and 6-15 mg of sodium carboxymethyl starch in the dapagliflozin tablet layer.

[0010] The amorphous form of dapagliflozin is the dapagliflozin compound with the molecular formula C. 21 H 25 ClO6, which does not contain lattice water or other lattice solvents, is preferably present in a content of 5-10 mg per tablet, particularly preferably 5 mg or 10 mg.

[0011] Preferably, each tablet contains 12 mg of sodium carboxymethyl starch in its dapagliflozin layer.

[0012] Preferably, the excipients of the dapagliflozin layer also include anhydrous lactose, microcrystalline cellulose, magnesium stearate and silicon dioxide, with the preferred content being 48 mg of anhydrous lactose, 227.5 mg (5 mg specification) or 222.5 mg (10 mg specification) of microcrystalline cellulose per tablet, 3 mg of magnesium stearate and 4.5 mg of silicon dioxide.

[0013] Each of the tablets contains 1000 mg of metformin hydrochloride, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, silicon dioxide, and magnesium stearate.

[0014] The film coating layer is composed of a gastrosoluble film coating material, the components of which are selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, or hydroxypropyl cellulose, preferably commercially available. II (Opadry). Each tablet contains 48-50 mg of film-coating material.

[0015] The present invention also provides a preparation process for the dapagliflozin-metformin sustained-release tablets, including preparing dapagliflozin granules and metformin granules separately, mixing and compressing the dapagliflozin granules and metformin granules into tablets, and coating them.

[0016] The dapagliflozin granules are prepared by dry granulation. The prescribed amounts of raw materials and excipients are weighed. The weighed raw material is mixed with 60-80% of the prescribed amounts of silica, anhydrous lactose, sodium carboxymethyl starch, and microcrystalline cellulose for 1 minute, passed through a 20-mesh sieve, and mixed for another 10 minutes. Finally, magnesium stearate is added and mixed for 5 minutes. The premixed powder is granulated using a dry granulator. The resulting granules are then mixed with 20-40% of the prescribed amounts of silica, anhydrous lactose, sodium carboxymethyl starch, microcrystalline cellulose, and other excipients to obtain dapagliflozin granules.

[0017] The metformin granules are prepared by wet granulation. The active pharmaceutical ingredient (API) is mechanically pulverized for 10 seconds. The prescribed amounts of excipients are weighed, and 50% of the prescribed amounts of sodium carboxymethyl cellulose and 50% of the prescribed amounts of metformin hydrochloride are added to a 4L wet granulation tank. The stirring blade and cutting blade are turned on, and the mixture is stirred for 5-10 minutes. Purified water is sprayed into the mixture within 4 minutes, and the stirring blade and cutting blade speeds are adjusted. Granulation is carried out for 3 minutes. The wet granules are then wet-granulated using a mobile granulator with a 6×6mm aperture screen and dried in a fluidized bed until the moisture content is less than 3%. The dried granules are then dry-granulated using a mobile granulator with a 1.5mm aperture screen. The prepared granules are then mixed with 50% of the prescribed amounts of metformin hydrochloride, 50% of the prescribed amounts of sodium carboxymethyl cellulose, and other excipients to obtain metformin granules.

[0018] In this invention, the terms 5mg and 10mg mean that each tablet contains 5mg or 10mg of dapagliflozin.

[0019] In this invention, dapagliflozin granules and metformin hydrochloride granules are co-compressed into tablets. The resulting tablets will contain areas where dapagliflozin and metformin hydrochloride are respectively enriched. For ease of description, these are referred to as dapagliflozin tablet layers and metformin hydrochloride tablet layers. This description does not imply that there is obvious stratification in the tablets.

[0020] The advantages of this invention are:

[0021] Compared to the original formulation, it improves stability under high temperature and high humidity conditions, thus helping to prevent drug deterioration under extreme conditions.

[0022] While altering the crystal form of the active pharmaceutical ingredient, the overall photostability of the formulation was ensured to meet the standards.

[0023] In a preferred embodiment, the dissolution profile can also be similar to that of the original drug, so changing the medication will not have an adverse effect on the patient. Attached Figure Description

[0024] Other features, objects, and advantages of this application will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0025] Figure 1 The XRD pattern for the amorphous form of dapagliflozin. Detailed Implementation

[0026] The present application will now be described in further detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it. Furthermore, it should be noted that, for ease of description, only the parts relevant to the invention are shown in the accompanying drawings.

[0027] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. This application will now be described in detail with reference to the accompanying drawings and embodiments.

[0028] Example 1

[0029] Preparation of the amorphous form of dapagliflozin.

[0030] Dapagliflozin was dissolved in isopropyl acetate, the solvent was removed by rotary evaporation, and the solution was dried under vacuum at room temperature for two days to obtain an amorphous solid of dapagliflozin. The X-ray diffraction pattern is shown in the attached figure of this application specification. Figure 1 The absence of obvious characteristic peaks indicates that the product is a typical amorphous form. Elemental analysis results are shown in Table 1, and proton NMR data are shown in Table 2.

[0031] Table 1. Elemental analysis results (C and H only)

[0032] element C H Theoretical value 61.69 6.16 Measured value 61.77 6.19

[0033] Table 2. Proton NMR Spectrum Data

[0034]

[0035]

[0036] Note: The molecular formula of dapagliflozin is C21 H 25 ClO6 has four active protons on its sugar ring, which do not produce peaks in the proton spectrum.

[0037] The test was conducted according to the guidelines for hygroscopicity testing of drugs in Part IV, 9103 of the 2020 edition of the Chinese Pharmacopoeia. An appropriate amount of dapagliflozin raw material was placed under a relative humidity of 80% ± 2% for 24 hours and weighed. The weight gain due to moisture absorption is shown in Table 3.

[0038] Table 3. Hygroscopic test of active pharmaceutical ingredients

[0039]

[0040] The results showed that the average moisture absorption weight gain of dapagliflozin raw material was 7.8%, indicating that amorphous dapagliflozin has strong hygroscopicity.

[0041] According to the import registration standard for dapagliflozin tablets (JX20140204), the total impurities in the formulation must be ≤0.9%, and further stability testing must be conducted on the amorphous active pharmaceutical ingredient.

[0042] Using amorphous dapagliflozin raw material for testing, after storage at 60°C for 30 days, the total impurities were 0.86%, indicating good stability at high temperatures. After storage at 92.5% RH for 30 days, it became a viscous semi-liquid after 5 days, losing its solid form, and the impurities exceeded 3%, at which point the test was terminated, showing that it has excessive water absorption and is extremely unstable in high humidity environments. After storage under 4500lx±500lx light for 30 days, the total impurities were 0.55%, which is worse than the original tablets.

[0043] Example 2

[0044] Preparation of dapagliflozin granules and metformin hydrochloride granules.

[0045] In this embodiment, the amount of raw materials and excipients is calculated based on the production scale of 1000 tablets each of 5mg and 10mg specifications.

[0046] Table 4 Prescription Information

[0047]

[0048] The preparation method of dapagliflozin granules is as follows: Weigh the prescribed amount of raw and excipient materials, mix the weighed raw drug, 50% of the prescribed amount of silica, anhydrous lactose, 50% of sodium carboxymethyl starch, and microcrystalline cellulose for 1 min, pass through a 20-mesh sieve, mix for another 10 min, and finally add 50% of magnesium stearate and mix for 5 min. Granulate the premixed powder using a dry granulation machine. Final mixing: Add the granulated material to a mixing tank, weigh 50% of the prescribed amount of sodium carboxymethyl starch and add it to the mixing tank, mix for 10 min, and finally add 50% of colloidal silica and 50% of magnesium stearate to the mixing tank, mix for 5 min.

[0049] The preparation method of the metformin granules is as follows: the raw material is mechanically pulverized and passed through an 80-mesh sieve; the prescribed amount of raw and excipient materials are weighed, and 50% of the prescribed amount of metformin hydrochloride, 6.5g of the prescribed amount of magnesium stearate, and 50% of the prescribed amount of metformin hydrochloride are added to a 4L wet granulation pot and premixed for 3 minutes. Then, the prescribed amount of sodium carboxymethyl cellulose is added and premixed for 5 minutes. The stirring blade and cutting blade are turned on, and the spray gun is turned on to spray purified water into the above-mentioned powder mixture within 4 minutes. The speed of the stirring blade and cutting blade is adjusted, and granulation is carried out for 3 minutes. The wet granules after the above granulation are wet granulated using a mobile granulator with a 6×6mm aperture screen and dried in a fluidized bed until the moisture content is less than 3%. The dried granules are dry granulated using a mobile granulator with a 1.5mm aperture screen. Total mixing: Add the granulated material to the mixing tank, weigh the prescribed amount of hydroxypropyl methylcellulose and add it to the mixing tank, mix for 20 minutes; finally, add the prescribed amount of colloidal silica and the prescribed amount of 50% magnesium stearate to the mixing tank, mix for 5 minutes.

[0050] Example 3

[0051] Preparation of 5mg tablets

[0052] Tableting was performed using dapagliflozin granules (5mg specification) and metformin hydrochloride granules prepared in Example 2. The tablet weight was calculated based on the actual content of dapagliflozin granules and metformin hydrochloride granules, and tableting was performed using a high-speed rotary tablet press with a 20.3×10.8mm die.

[0053] Coating: Prepare the Opadry film coating solution with a solid content of 15%, control the tablet bed temperature at 40-45℃, and achieve a coating weight gain of 3%.

[0054] Example 4

[0055] Preparation of 10mg tablets.

[0056] Tableting was performed using dapagliflozin granules (10mg specification) and metformin hydrochloride granules prepared in Example 2. The tablet weight was calculated based on the actual content of dapagliflozin granules and metformin hydrochloride granules, and tableting was performed using a high-speed rotary tablet press with a 20.3*10.8mm die.

[0057] Coating: Prepare the Opadry film coating solution with a solid content of 15%, control the tablet bed temperature at 40-45℃, and achieve a coating weight gain of 3%.

[0058] Examples 5-9

[0059] 5mg tablets were prepared according to the methods of Examples 2 and 3, but the content of sodium carboxymethyl starch was changed to 3mg, 6mg, 9mg, 15mg and 18mg respectively.

[0060] Examples 10-14

[0061] 10mg tablets were prepared according to the methods in Examples 2 and 4, but the content of sodium carboxymethyl starch was changed to 3mg, 6mg, 9mg, 15mg and 18mg, respectively.

[0062] Comparative Example 1

[0063] 5mg tablets were prepared using dapagliflozin in its amorphous form as the active pharmaceutical ingredient, prepared in Example 1. The excipients and processes were the same as in Examples 2 and 3, but 12mg of cropovidone was used as the disintegrant instead of sodium carboxymethyl starch.

[0064] Comparative Example 2

[0065] To prepare 10mg tablets, the active pharmaceutical ingredient was dapagliflozin in amorphous form prepared in Example 1. The excipients and processes were the same as in Examples 2 and 4, but the disintegrant was 12mg cropovidone instead of sodium carboxymethyl starch.

[0066] The following tests, 1-4, demonstrate the properties of the tablets prepared in Examples 3-14 and Comparative Examples 1 and 2. Unless otherwise specified, the reference formulation used is AstraZeneca XIGDUO (5mg).

[0067] Experiment Example 1: High Temperature Stability Experiment

[0068] The samples were placed at 60℃ for 30 days, and single impurities and total impurities were detected. The results are shown in Table 5.

[0069] Table 5 shows the results of the stability test at 60℃. In the table, / represents not detected.

[0070]

[0071]

[0072]

[0073] As can be seen from the table, the compounds of Examples 3-14 and Comparative Example 1 exhibited better high-temperature stability than XIGDUO. The reason for this result may be that under higher temperature conditions, the XIGDUO crystal form loses its water of crystallization and undergoes crystal transformation, and the water of crystallization forms a solution environment in some locations, leading to accelerated degradation of dapagliflozin.

[0074] Experiment Example 2: High Humidity Stability Experiment

[0075] The samples were placed at 25℃ and 92.5% RH for 30 days, and the total impurity content was determined. The results are shown in Table 6.

[0076] Table 6: Stability test results at 25℃ and 92.5%RH.

[0077]

[0078]

[0079]

[0080] As can be seen from the table, the high moisture stability of tablets is not related to the dapagliflozin content.

[0081] Tests on Examples 3-14 showed that when the sodium carboxymethyl starch content was 18 mg, the tablets had strong water absorption. By using a lower dose of sodium carboxymethyl starch, the stability of the tablets under high humidity could be effectively improved.

[0082] Experiment Example 3: Light Stability Test

[0083] The samples were placed at 4500 lx ± 500 lx for 30 days, and the results are shown in Table 7. The photostability of the example formulation was not as good as the reference formulation, but it was still within the acceptable range. Furthermore, the photostability of the example formulation was better than that of Comparative Examples 1 and 2.

[0084] Table 7 Results of the light stability test

[0085]

[0086]

[0087] Experiment Example 4: Dissolution Experiment

[0088] Since dapagliflozin requires immediate release, and bioequivalence studies require a release of more than 85% at 15 minutes, this embodiment focuses on examining the dissolution profiles of the embodiments, comparative examples, and references under acidic conditions simulating the gastric environment.

[0089] Table 8. Dissolution test results, 5mg specification

[0090]

[0091] Table 9. Dissolution test results, 10mg specification

[0092]

[0093] Comparative Examples 1 and 2 dissolved too quickly. Although they passed the BE test, their dissolution curves differed significantly from the reference, which may affect registration.

[0094] Further testing of Examples 5-14 revealed that when the sodium carboxymethyl starch content was 3 mg, the dissolution rate was below 80% within 15 minutes, failing the bioequivalence test. To ensure dissolution rate, the sodium carboxymethyl starch content should be above 6 mg / tablet.

Claims

1. A sustained release tablet of dapagliflozin metformin, characterized in that: the tablet is composed of a metformin hydrochloride layer, a dapagliflozin layer and a gastro-soluble film coating, the dapagliflozin layer is composed of dapagliflozin in amorphous form, sodium carboxymethyl starch, lactose anhydrous, microcrystalline cellulose, magnesium stearate and silicon dioxide, the dapagliflozin layer of the tablet contains 5-25 mg of dapagliflozin in amorphous form and 6-15 mg of sodium carboxymethyl starch per tablet, the method for preparing the tablet comprises preparing dapagliflozin granules and metformin hydrochloride granules respectively, mixing the dapagliflozin granules and the metformin hydrochloride granules to press into tablets and coating, and the dapagliflozin granules are prepared by dry granulation.

2. The sustained release tablet according to claim 1, characterized in that:

3. The sustained release tablet according to claim 1, characterized in that: the content of dapagliflozin in amorphous form in each tablet is 5 mg or 10 mg. the dapagliflozin layer of the tablet contains 12 mg of sodium carboxymethyl starch per tablet. the silicon dioxide is colloidal silicon dioxide. The said Dapagliflozin amorphous form is Dapagliflozin compound, molecular formula is C 21 H 25 ClO6, without lattice water or other lattice solvent components. the dapagliflozin layer of the tablet contains 48 mg of lactose anhydrous, 3 mg of magnesium stearate and 4.5 mg of silicon dioxide per tablet; provided that the 5 mg specification contains 227.5 mg of microcrystalline cellulose per tablet and the 10 mg specification contains 222.5 mg of microcrystalline cellulose per tablet.

4. The sustained release tablet according to claim 1, wherein:

7. The sustained release tablet according to claim 1, characterized in that:

5. The sustained release tablet according to claim 1, wherein: the metformin hydrochloride layer of the tablet contains 1000 mg of metformin hydrochloride per tablet, and the excipients are sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide and magnesium stearate.

6. The sustained release tablet according to claim 1, wherein: the film coating is composed of gastro-soluble film coating materials, and the components are selected from one or more of hydroxypropyl methyl cellulose, polyvinyl alcohol or hydroxypropyl cellulose, and the content of the film coating materials in each tablet is 48-50 mg. the film coating is Opadray® II. the method comprises preparing dapagliflozin granules and metformin hydrochloride granules respectively, mixing the dapagliflozin granules and the metformin hydrochloride granules to press into tablets and coating. the dapagliflozin granules are prepared by dry granulation, and the metformin hydrochloride granules are prepared by wet granulation.

8. The sustained release tablet according to claim 1, wherein: ​ 9. The sustained release tablet according to claim 8, wherein: ​ 10. The process for the preparation of sustained release Dapagliflozin Metformin tablets as claimed in claim 1 wherein: ​ 11. The production method according to claim 10, characterized by: ​

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