Dapagliflozin tablet and preparation method thereof

Abstract

The invention discloses a dapagliflozin tablet which comprises a tablet core and a coating covering the outer layer of the tablet core, and the tablet core contains dapagliflozin, a filler, a disintegrating agent, a flow aid and a lubricant. The invention also provides a preparation method of the dapagliflozin tablet, and a powder direct compression process is adopted, so that the prepared dapagliflozin tablet product has good in-vitro dissolution, content uniformity and stability, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dapagliflozin tablet and a preparation method thereof. Background Art

[0002] Diabetes is a chronic disease that develops when the pancreas doesn't produce enough insulin or the body can't effectively use the insulin it produces. The number of people with diabetes increased from 108 million in 1980 to 422 million in 2014. Some people with diabetes need medication to help control their blood sugar levels, such as insulin injections, metformin, sulfonylureas, and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors.

[0003] Among them, SGLT-2 inhibitors are a new type of anti-diabetic drugs. SGLT-2 is mainly distributed in the S1 segment of the proximal convoluted tubule of the kidney. It is a low-affinity, high-transport capacity transporter responsible for at least 90% of glucose reabsorption in the kidney. SGLT-2 inhibitors can inhibit the kidney's reabsorption of glucose and promote urinary sugar excretion, thereby playing a role in lowering blood sugar.

[0004] Dapagliflozin is an SGLT-2 inhibitor developed jointly by Bristol-Myers Squibb and AstraZeneca. Dapagliflozin tablets were first approved for marketing in Australia on October 22, 2012, and subsequently approved for marketing in the European Union, the United States, Japan, China and other countries under the trade name Farxiga. Its excipients are: microcrystalline cellulose, lactose, cross-linked polyvinyl alcohol, silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, and iron oxide yellow.

[0005] The solubility of the dapagliflozin compound itself is poor. If used directly as an active ingredient in a formulation, its dissolution and absorption will be significantly restricted, leading to suboptimal efficacy. Therefore, the original research company selected dapagliflozin propylene glycol monohydrate as the active ingredient (API) of the formulation, where the propylene glycol is S-configured, and its structural formula is shown below:

[0006]

[0007] Patent CN106606490A also discloses a dapagliflozin tablet and its preparation method. This patent application attempts to prepare a tablet with improved dissolution by combining dapagliflozin with a carrier material (one of povidone, polyethylene glycol, and hydroxypropyl cellulose) into a solid dispersion, and then combining this dispersion with other excipients to prepare a tablet with improved dissolution. However, the data provided in the patent specification show that the dissolution rate of the dapagliflozin tablets is slow at 5 and 10 minutes, and the dissolution of the formulation is not significantly improved. In addition, the solid dispersion will aggregate and crystallize during storage, resulting in unstable drug properties.

[0008] Patent CN111956622A also discloses a dapagliflozin propylene glycol hydrate pharmaceutical preparation and a preparation method thereof. The preparation includes a drug powder mixture (dapagliflozin propylene glycol hydrate and a first diluent, magnesium aluminum silicate), a second diluent (lactose, microcrystalline cellulose, mannitol, sorbitol, pregelatinized starch, starch) and a disintegrant, and the particle size D90 of the drug powder mixture is ≤18 μm. However, the large amount of diluent components in the preparation will lead to poor compatibility between the excipients and the active ingredients, resulting in poor uniformity. In addition, the patented preparation method adopts a two-step mixing, dry granulation, granulation, and tableting process, and the process steps are complicated.

[0009] Patent CN115869265A discloses a preparation containing a solid dispersion of dapagliflozin and a preparation method. The preparation comprises: a solid dispersion of dapagliflozin (dapagliflozin is amorphous), a diluent, a lubricant, a glidant, and a coating powder. The above ingredients are mixed, dissolved, dried, and mixed and compressed to obtain tablets. However, the amorphous form of dapagliflozin has poor stability when stored for a long time, which will also affect the final pharmacological effect.

[0010] Therefore, in view of the problems existing in the existing dapagliflozin compositions, there is still a need to provide a dapagliflozin tablet that has fast dissolution, good content uniformity, good stability, is suitable for long-term storage, and has an efficient and quick preparation process. Summary of the Invention

[0011] In order to solve the problems existing in the prior art, the present invention provides a dapagliflozin tablet and a preparation method thereof. The obtained tablets have good in vitro dissolution, uniformity and stability. The preparation method is efficient and fast and is suitable for industrial production.

[0012] Therefore, on one hand, the present invention provides a dapagliflozin tablet, comprising a tablet core and a coating covering the outer layer of the tablet core, wherein the tablet core contains dapagliflozin, a filler, a disintegrant, a glidant, and a lubricant.

[0013] Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, microcrystalline cellulose colloidal silicon dioxide co-processed product, and sorbitol.

[0014] More preferably, the filler is selected from a co-processed microcrystalline cellulose colloidal silica, wherein the co-processed product is a composite of microcrystalline cellulose and micropowdered silica gel, and the composite is selected from one or more of PROSOLV SMCC50, PROSOLV SMCC90, and PROSOLVSMCCHD90; more preferably, the composite is selected from PROSOLV SMCC50, or PROSOLV SMCC90, or PROSOLV SMCCHD90.

[0015] Preferably, dapagliflozin is added in the form of dapagliflozin propylene glycol monohydrate (i.e., the API is dapagliflozin propylene glycol monohydrate).

[0016] Preferably, the disintegrant is selected from one or more of hydroxypropyl cellulose, carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, and cross-linked polyvinylpyrrolidone; more preferably, the disintegrant is selected from cross-linked polyvinylpyrrolidone.

[0017] Preferably, the glidant is selected from one or more of micro-powdered silica gel, silicon dioxide, and talc; more preferably, the glidant is selected from silicon dioxide.

[0018] Preferably, the lubricant is selected from one or more of magnesium stearate and sodium stearyl fumarate; more preferably, the lubricant is selected from magnesium stearate.

[0019] Preferably, the coating is a gastric soluble film coating premix.

[0020] Preferably, the dosage of key components in the dapagliflozin tablets provided by the present invention is as follows: the disintegrant accounts for 2% to 7% of the total weight of the tablet core, the glidant accounts for 0.66% to 1.66% of the total weight of the tablet core, and the lubricant accounts for 0.3 to 1.3% of the total weight of the tablet core; the coating weight gain accounts for 2 to 4% of the total weight of the tablet core; preferably, the coating weight gain accounts for 3 to 3.5% of the total weight of the tablet core.

[0021] Preferably, the dapagliflozin tablets provided by the present invention have a dosage form of 1 mg, 2.5 mg, 5 mg, 10 mg or 50 mg; more preferably, the dosage form is 5 mg or 10 mg.

[0022] Most preferably, the preferred formulation of the dapagliflozin tablets of the present invention consists of a tablet core and a coating covering the outer layer of the tablet core, and the coating material is selected from a gastric-soluble film coating premix; the components in the tablet core and their amounts are: dapagliflozin propylene glycol monohydrate accounts for 4.92% of the total weight of the tablet core, PROSOLV SMCC90 accounts for 88.12% of the total weight of the tablet core, cross-linked polyvinylpyrrolidone accounts for 5.00% of the total weight of the tablet core, silicon dioxide accounts for 1.16% of the total weight of the tablet core, and magnesium stearate accounts for 0.80% of the total weight of the tablet core.

[0023] On the other hand, the present invention also provides a method for preparing the above-mentioned dapagliflozin tablets, comprising the following steps:

[0024] 1) Weigh the prescribed amount of the active ingredient (dapagliflozin propylene glycol monohydrate), filler, and disintegrant, sieve, and premix to obtain a premix;

[0025] 2) adding a prescribed amount of a glidant and a lubricant to the premix obtained in step 1), and mixing the mixture to obtain a mixture;

[0026] 3) directly compressing and coating the mixture obtained in step 2), controlling the coating weight gain to be 2% to 4% of the total weight of the tablet core, to obtain dapagliflozin tablets.

[0027] Preferably, the premixing time in step 1) is 25 to 35 minutes, and the rotation speed is 10 rpm; more preferably, the premixing time in step 1) is 30 minutes.

[0028] Preferably, the total mixing time in step 2) is 3 to 10 minutes, and the rotation speed is 10 rpm; more preferably, the total mixing time in step 2) is 5 minutes.

[0029] Preferably, the coating solution in step 3) has a 12% solids content and is prepared by weighing the prescribed amount of purified water and a gastric-soluble film coating premix, first adding the purified water, then stirring the gastric-soluble film coating premix, sieving, and stirring. Preferably, during the coating process in step 3), the coating weight gain is controlled to 3% to 3.5% of the total weight of the tablet core.

[0030] Compared with the prior art, the dapagliflozin tablets and preparation method provided by the present invention have the following beneficial effects:

[0031] 1. Reduce the types of excipients in the preparation and reduce the production cost of the preparation;

[0032] 2. The filler uses only a co-processed product of microcrystalline cellulose and colloidal silicon dioxide, which improves the fluidity and compressibility of the material during tablet preparation and the uniformity of the active ingredients, providing a dapagliflozin tablet with faster dissolution and better stability;

[0033] 3. The preparation process of tablets is simplified, with only mixing and direct compression steps. The operation is simple and fast, and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the dissolution curve of the 5 mg specification preparation in Example 7.

[0035] Figure 2 This is the dissolution curve of the 10 mg specification preparation in Example 7. DETAILED DESCRIPTION

[0036] The following are specific embodiments of the present invention to further describe the technical solution of the present invention, but the scope of protection of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

[0037] Products marketed in Argentina based on the original research of AstraZeneca Based on the prescription disclosed in the review report, the specific prescription of the reference preparation is as follows:

[0038]

[0039] Example 1 Preparation of Dapagliflozin Tablets of the Present Invention

[0040] The dapagliflozin tablets provided by the present invention are composed of a tablet core and a coating covering the outer layer of the tablet core. The specific formulations and dosages of the tablet core are as follows, with the mass percentage being 100%:

[0041]

[0042]

[0043] Furthermore, the coating material of the dapagliflozin tablets in Example 1 is a gastric-soluble film coating premix, and the coating weight gain is 2% to 4% of the total mass of the tablet core, preferably 3% to 3.5%.

[0044] The preparation process of the above prescription is as follows:

[0045] 1) Weigh the prescribed amount of the main drug, filler, and disintegrant, sieve them, and add them to the mixer hopper for premixing. Set the premixing speed to 10 rpm and the premixing time to 25-35 minutes to obtain a premix;

[0046] 2) adding the prescribed amount of glidant and lubricant to the premix obtained in step 1), and mixing the mixture in a mixer hopper at a mixing speed of 10 rpm and a mixing time of 3-10 min to obtain a mixture;

[0047] 3) The mixture obtained in step 2) is directly compressed into tablets, and then a pre-prepared coating solution is taken and coated in a high-efficiency coating machine, with the coating weight gain controlled to be 2% to 4% (preferably 3% to 3.5%), to obtain dapagliflozin tablets.

[0048] Furthermore, the coating solution described in step 3) of the above preparation process can be pre-prepared as follows: weigh the prescribed amount of purified water and gastric-soluble film coating premix, add them to the liquid preparation bucket while stirring; after stirring is completed, pass through a 60-mesh sieve, continue stirring evenly, and set aside.

[0049] It should be noted that in the preparation method described in Example 1, in step 3), those skilled in the art can select a suitable punch according to tablets of different specifications. The punch may include but is not limited to a diamond punch, a circular punch, a curved punch, etc., as long as the tableting requirements are met.

[0050] It should be noted that in the formulation described in Example 1, the filler is a microcrystalline cellulose colloidal silica co-processed product. In addition to PROSOLV SMCC90, the filler can also be selected from any of the models such as PROSOLV SMCC50 and PROSOLV SMCCHD90. As long as the microcrystalline cellulose colloidal silica co-processed product meets the same effect as PROSOLV SMCC90, it should be regarded as equivalent to the technical solution of the present invention.

[0051] It should be noted that the formulation described in Example 1 can be applied to dapagliflozin tablets of different strengths, including but not limited to 1 mg, 2.5 mg, 5 mg, 10 mg, 50 mg, etc. The following are examples of specific dapagliflozin tablet formulations of various strengths developed based on clinical needs. The total weight of the tablet cores in actual development may be adjusted without limitation. As long as the following formulation ratios are met, different strengths shall be considered equivalent to the technical solution of the present invention.

[0052] Prescription A: 5mg, based on a core tablet weight of 125mg per tablet, the core tablet and coating formulations are as follows:

[0053]

[0054]

[0055] Prescription B: 10 mg, based on a core tablet weight of 250 mg per tablet, the core tablet and coating formulations are as follows:

[0056]

[0057] Example 2 Investigation of factors affecting the dosage of disintegrant

[0058] Based on the tablet core formulation of Example 1, only the amount of the disintegrant crospovidone was changed (set to 2%, 5%, and 7%), and the types and amounts of the other components in the formulation remained unchanged. The dissolution behavior differences of the different formulations in a pH = 4.5 acetate buffer medium were investigated. The dissolution results are shown in Table 1.

[0059] Table 1. Effect of different disintegrant dosages on dissolution behavior

[0060]

[0061] As shown in Table 1, when the disintegrant dosage is 2% to 7%, it has no significant effect on the dissolution of the preparation, and only slightly affects the dissolution at 5 minutes. However, the cumulative dissolution amount at 15 minutes is greater than 85%, which is similar to the dissolution of the reference preparation.

[0062] In summary, the optimal dosage of disintegrant crospovidone was determined to be 5%.

[0063] Example 3 Investigation of factors affecting the amount of glidant

[0064] Based on the core tablet formulation of Example 1, only the amount of the glidant silicon dioxide was changed (set to 0.66%, 1.16%, and 1.66%), and the types and amounts of the other components in the formulation remained unchanged. The dissolution behavior of the different formulations in a pH = 4.5 acetate buffer medium was investigated. The results are shown in Table 2.

[0065] Table 2. Effect of different glidant dosages on dissolution behavior

[0066]

[0067] As shown in Table 2, the glidant dosage of 0.66% to 1.66% had no significant effect on the dissolution of the preparation, and the cumulative dissolution amount at 15 min was greater than 85%, which was similar to the dissolution of the reference preparation.

[0068] In summary, the optimal dosage of the flow aid silicon dioxide is determined to be 1.16%.

[0069] Example 4 Investigation of factors affecting the amount of lubricant

[0070] Based on the tablet core formulation of Example 1, only the amount of lubricant magnesium stearate was changed (set to 0.30%, 0.80%, and 1.30%), and the types and amounts of the other components in the formulation remained unchanged. The dissolution behavior differences of different formulations in a pH = 4.5 acetate buffer medium were investigated. The results are shown in Table 3.

[0071] Table 3. Effect of different lubricant dosages on dissolution behavior

[0072]

[0073]

[0074] As shown in Table 3, when the lubricant dosage is 0.30% to 1.30%, there is no significant effect on the dissolution of the preparation. The cumulative dissolution amount at 15 min is greater than 85%, which is similar to the dissolution of the reference preparation.

[0075] In summary, the optimal dosage of lubricant magnesium stearate is determined to be 0.80%.

[0076] Example 5 Investigation of factors affecting coating weight gain

[0077] Based on the core tablet formulation of Example 1, different coating weight gains (set to 0%, 3.9%, and 6.4%) were performed to investigate the differences in dissolution behavior of different formulations in a pH = 4.5 acetate buffer medium. The results are shown in Table 4.

[0078] Table 4. Effect of different coating weight gain on dissolution behavior

[0079]

[0080] As shown in Table 4, the coating weight gain within the range of 0-6.4% had little effect on dissolution, and the cumulative dissolution amount at 15 min was greater than 85%, which was similar to the dissolution of the reference preparation.

[0081] Example 6 Investigation of factors affecting premixing time

[0082] Based on the preparation process of Example 1, only the premixing time in step 1) was changed (set to 25 min, 30 min, and 35 min), and the difference in mixing uniformity of the premix was investigated.

[0083] Inspection method: Stop the machine and take 11 samples (5 points on the upper layer, 5 points at the corner edge, and 1 point at the discharge port), take 3 samples at each point, and the single sampling volume is about 0.50-0.75g. The mixing uniformity data of each point is measured, and the average value and RSD value are calculated by statistical methods.

[0084] According to the investigation results, the single-point mixing uniformity at the three time points of 25 min, 30 min, and 35 min was within ±10% of the average value, and the RSD was ≤5.0%. The results are shown in Table 5.

[0085] Table 5. Effect of different premixing times on mixing uniformity (%)

[0086] 25min 30min 35min average value(%) 4.1 4.0 4.1 RSD (%) 1.0 0.5 0.8

[0087] As shown in Table 5, during premixing, at the three time points of 25 min, 30 min, and 35 min, the content and RSD of mixing uniformity all met the internal control requirements, indicating that the mixing uniformity was good.

[0088] Example 7 Comparison of dissolution effects between the dapagliflozin tablets of the present invention and the original tablets

[0089] (1) Comparison of technical effects of 5mg tablets

[0090] As can be seen from Example 1 above, the application example of the prescription provided by the present invention at a 5 mg specification is prescription A; the original commercially available dapagliflozin tablets (trade name: ) The application example at the 5mg specification is prescription a.

[0091] Take prescription A and prescription a, adopt the paddle method ("Chinese Pharmacopoeia" 2020 edition General Chapter 0931 Second Method), use pH 4.5 acetate buffer as the dissolution medium, the volume is 1000 ml, the speed is 50 revolutions per minute, operate according to the law, sample at 5min, 10min, 15min, 20min, 30min, 45min, and the cumulative dissolution amount of each tablet of dapagliflozin is determined by HPLC. The results are shown in Table 6 and the dissolution curve is shown in Table 6. Figure 1 .

[0092] Table 6. Comparison of cumulative dissolution amounts between prescription A and prescription a

[0093] 5min 10min 15min 20min 30min 45min Prescription A 58.4±8.6 82.4±5.0 89.0±3.0 92.3±2.5 95.3±2.0 97.4±1.9 Prescription a 77.0±5.4 89.6±2.6 93.7±2.4 96.3±2.5 98.6±2.0 99.1±1.9

[0094] From Table 6 and Figure 1 It can be seen that in pH 4.5 acetate buffer, the cumulative dissolution amount of the present invention is ≥85% compared with the original research in 15 minutes, and the dissolution of the two is similar.

[0095] (2) Comparison of technical effects of 10mg tablets

[0096] As can be seen from Example 1 above, the application example of the prescription provided by the present invention at a 10 mg specification is prescription B; the original commercially available dapagliflozin tablets (trade name: ) The application example at the 10 mg specification is prescription b.

[0097] Take prescription B and prescription b, adopt the paddle method ("Chinese Pharmacopoeia" 2020 edition General Chapter 0931 Second Method), use pH 4.5 acetate buffer as the dissolution medium, the volume is 1000 ml, the speed is 50 revolutions per minute, operate according to the law, sample at 5min, 10min, 15min, 20min, 30min, 45min, and the cumulative dissolution amount of each tablet of dapagliflozin is determined by HPLC. The results are shown in Table 7 and the dissolution curve is shown in Table 7. Figure 2 .

[0098] Table 7. Comparison of the cumulative dissolution amount of prescription B and prescription b

[0099] 5min 10min 15min 20min 30min 45min Prescription B 80.9±4.3 90.4±2.4 94.7±1.8 96.2±1.9 97.9±2.1 99.0±2.3 Prescription b 60.3±11.3 87.6±4.2 91.0±3.6 93.1±2.3 94.8±2.1 96.1±1.9

[0100] From Table 7 and Figure 2 As can be seen, in pH 4.5 acetate buffer, the cumulative dissolution rate of the present invention and the original drug at 15 minutes was ≥85%, indicating similar dissolution. Furthermore, the dissolution rate of the present invention was significantly higher than that of the original drug, especially at 5 minutes, indicating that the initial drug release rate of the present invention was superior to that of the original drug.

[0101] Example 8 Comparison of the stability of the dapagliflozin tablets of the present invention and the original tablets

[0102] A comparative experiment was carried out using a 10 mg preparation. Prescription B and prescription b were used for impurity spectrum analysis in accordance with the requirements of drug registration review, and the single impurity content was determined. The results are shown in Table 8.

[0103] Table 8. Comparison of impurity profiles of formulation B and formulation b

[0104] Impurity I Impurity V-1 Impurity II Other single miscellaneous Impurity limits ≤0.4％ ≤0.2％ ≤0.2％ ≤0.2％ Prescription B ND 0.01 ND 0.12 Prescription b ND ND ND 0.15

[0105] Note: “ND” means not detected.

[0106] As can be seen from Table 8, both the present invention and the original research meet the impurity limit requirements, and the unknown single impurity content of the present invention is even lower than that of the original research, indicating that the quality control level of the present invention is better than that of the original research.

Claims

1. A dapagliflozin tablet comprising a tablet core and a coating covering the outer layer of the tablet core, characterized in that: The tablet core contains dapagliflozin, a filler, a disintegrant, a glidant and a lubricant.

2. The dapagliflozin tablet according to claim 1, characterized in that The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, microcrystalline cellulose colloidal silicon dioxide co-processed product, and sorbitol.

3. The dapagliflozin tablets according to claim 2, characterized in that The filler is selected from microcrystalline cellulose colloidal silicon dioxide co-processed product, wherein the co-processed product is a composite of microcrystalline cellulose and micropowder silica gel, and the composite is selected from one or more of PROSOLV SMCC50, PROSOLV SMCC90, and PROSOLV SMCCHD90.

4. The dapagliflozin tablet according to any one of claims 1 to 3, characterized in that The dapagliflozin is dapagliflozin propylene glycol monohydrate, the disintegrant is selected from one or more of hydroxypropyl cellulose, carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone, the glidant is selected from one or more of micropowdered silica gel, silicon dioxide, and talc, the lubricant is selected from one or more of magnesium stearate and sodium stearyl fumarate, and the coating is a gastric-soluble film coating premix; preferably, the disintegrant is cross-linked polyvinylpyrrolidone, the glidant is silicon dioxide, and the lubricant is magnesium stearate.

5. The dapagliflozin tablet according to any one of claims 1 to 4, characterized in that The disintegrant accounts for 2% to 7% of the total weight of the tablet core; the glidant accounts for 0.66% to 1.66% of the total weight of the tablet core; the lubricant accounts for 0.3% to 1.3% of the total weight of the tablet core; and the coating weight gain accounts for 2% to 4% of the total weight of the tablet core.

6. The dapagliflozin tablet according to claim 5, characterized in that The specifications of the dapagliflozin tablets are 1 mg, 2.5 mg, 5 mg, 10 mg or 50 mg.

7. A method for preparing the dapagliflozin tablets according to any one of claims 1 to 6, characterized in that: The steps include: 1) Weighing the prescribed amount of dapagliflozin, filler, and disintegrant, sieving, and premixing to obtain a premix; 2) adding a prescribed amount of a glidant and a lubricant to the premix obtained in step 1), and mixing the mixture to obtain a mixture; 3) directly compressing the mixture obtained in step 2) and coating the tablets, controlling the coating weight gain to be 2% to 4% of the total weight of the tablet core, to obtain dapagliflozin tablets.

8. The preparation method according to claim 7, characterized in that The premixing time in step 1) is 25 to 35 minutes, and the rotation speed is 10 rpm; preferably, the premixing time in step 1) is 30 minutes.

9. The preparation method according to claim 7, characterized in that The total mixing time in step 2) is 3 to 10 minutes, and the rotation speed is 10 rpm; preferably, the total mixing time in step 2) is 5 minutes.

10. The preparation method according to claim 7, characterized in that The coating solution in step 3) is a coating solution with a solid content of 12%, and the preparation method is: weigh the prescribed amount of purified water and gastric-soluble film coating premix, first add purified water, then stir and add the gastric-soluble film coating premix, sieve and stir to obtain; preferably, during the coating process of step 3), the coating weight gain is controlled to 3% to 3.5% of the total weight of the tablet core.

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