A dapagliflozin tablet and a preparation method thereof

Abstract

The present invention provides a dapagliflozin tablet comprising the following raw materials and excipients in the following weight percentages: 10-20% dapagliflozin, 4-21% disintegrant, 1-15% lubricant, 6-22% glidant, and 40-75% filler. The present invention provides a dapagliflozin tablet that addresses the issue of poor dapagliflozin dissolution rate. The resulting tablets exhibit high stability, high uniformity, rapid dissolution rate, and excellent efficacy. The present invention also provides a method for preparing dapagliflozin tablets. The method is simple and easy to operate and can utilize existing pharmaceutical factory equipment, thereby reducing production costs and facilitating widespread promotion and use.

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] Type 2 diabetes is one of the independent risk factors for heart failure. About 1 / 4 of type 2 diabetes patients have heart failure. The two diseases promote and influence each other, easily forming a comorbid state, increasing the difficulty of treatment. Therefore, the treatment of chronic heart failure combined with type 2 diabetes has also become a hot topic in clinical research. Dapagliflozin has attracted much attention due to its good blood sugar-lowering effect and significant protective effect on the cardiovascular system. Dapagliflozin is a new anti-diabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. It was launched in Europe in 2012 and the FDA also approved it as a treatment for type 2 diabetes in 2014. However, dapagliflozin has poor water solubility, and how to improve the in vitro dissolution of the preparation is the key to its efficacy. CN 106606490 A discloses a dapagliflozin pharmaceutical composition and its preparation process, wherein the dapagliflozin pharmaceutical composition contains dapagliflozin and a carrier material, wherein the carrier material is selected from povidone, poloxamer, polyethylene glycol, hydroxypropyl cellulose, and polyethylene oxide. CN 105853386 B discloses a process for preparing tablets containing dapagliflozin, characterized in that dapagliflozin propylene glycol hydrate is first dissolved in a solvent to form a drug solution, and then the drug solution is wet granulated with a diluent, a binder, a disintegrant, and a lubricant to form tablets containing dapagliflozin. However, existing preparations have unsatisfactory uniformity, stability, and dissolution rate, and have the problem of high production costs. Therefore, a new preparation is needed to improve drug efficacy and reduce production costs. Summary of the Invention

[0003] The present invention aims to provide a dapagliflozin tablet having the advantages of high uniformity, strong stability and fast dissolution rate, and the preparation method is simple and easy.

[0004] In order to achieve the above-mentioned object, the present invention provides the following technical solution: a dapagliflozin tablet, comprising the following raw materials and auxiliary materials in the following weight percentages: 10-20% dapagliflozin, 4%-21% disintegrant, 1-15% lubricant, 6-22% glidant and 40%-75% filler.

[0005] Preferably, the composition comprises the following raw materials and auxiliary materials in the following weight percentages: 12-17% of dapagliflozin, 10%-15% of disintegrant, 5-10% of lubricant, 9-17% of glidant and 45%-65% of filler.

[0006] More preferably, the composition includes the following raw materials and auxiliary materials in the following weight percentages: 14% dapagliflozin, 12% disintegrant, 8% lubricant, 14% glidant and 52% filler.

[0007] In some preferred embodiments, the disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose; the glidant is selected from one or two of colloidal silicon dioxide, mesoporous silicon dioxide, and talc; the lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate; and the filler is selected from one or more of xylitol, mannitol, lactose, microcrystalline cellulose, and pregelatinized starch.

[0008] Preferably, the disintegrant is hydroxypropyl cellulose; in order to improve uniformity and dissolution rate, it is further preferred that the hydroxypropyl cellulose has a weight average molecular weight of 370,000 and a Brookfield viscosity of 150 to 400 mPa.s, and is purchased from Shanghai Linchen Pharmaceutical.

[0009] Preferably, the flow aid is mesoporous silica; more preferably, the mesoporous silica is hollow mesoporous silica, with a surface group of -SiOH and a particle diameter of 350-450 nm, purchased from Pioneer Nano 104014.

[0010] After research, the inventors found that mesoporous silica can improve the uniformity of tablets and significantly increase the dissolution rate. After mesoporous silica is mixed with dapagliflozin and a disintegrant, dapagliflozin exists in the dapagliflozin solid dispersion containing mesoporous silica in molecular form, which improves the physical stability of the dispersion, makes the dapagliflozin solid dispersion insensitive to production conditions, and has higher uniformity. At this time, the intermolecular interaction force of dapagliflozin is small, and no high energy is required to break the lattice energy during the dissolution process. At the same time, mesoporous silica has a high specific surface area, which can make dapagliflozin highly dispersed therein and prevent aggregation. The hydroxyl groups on the surface of mesoporous silica are hydrophilic. When it comes into contact with gastrointestinal fluid, the gastrointestinal fluid penetrates into the solid dispersion, which plays a good wetting role and ensures that dapagliflozin is in full contact with the gastrointestinal fluid, thereby increasing the dissolution rate. In the present invention, hydroxypropyl cellulose not only plays the role of a traditional disintegrant, but also, due to the high surface energy of mesoporous silica, which is easy to agglomerate, the present invention adds hydroxypropyl cellulose to simultaneously increase the surface activity of the dispersion, reduce the surface energy of mesoporous silica, prevent agglomeration, and facilitate the improvement of tablet uniformity and dissolution rate.

[0011] In order to reduce the friction between the particles and improve the uniformity of the tablet, the lubricant is selected from magnesium stearate and calcium stearate. Further preferably, the weight ratio of the magnesium stearate and calcium stearate is 1:1 to 5. Further preferably, the weight ratio of the magnesium stearate and calcium stearate is 1:3. Through the reasonable ratio of magnesium stearate and calcium stearate, a stable synergistic effect is achieved, which can provide a more suitable viscosity for the tablet and enhance the stability of the tablet. The magnesium stearate was purchased from Merck PHR1316, and the calcium stearate was purchased from Merck 26411.

[0012] Preferably, the filler is selected from xylitol, mannitol, and lactose. Further preferably, the weight percentage of xylitol, mannitol, and lactose in the filler is 1:1:2 to 10. Further preferably, the weight percentage of xylitol, mannitol, and lactose in the filler is 1:1:5.

[0013] The inventors found that fillers affect the uniformity of tablets. Xylitol, mannitol and lactose are more suitable fillers for use with dapagliflozin after mixing in the present invention. During the mixing process of drugs and excipients, the most critical influencing factor is the unreasonable control of the mixed drugs of the drugs, which makes the uniformity effect of the drug content control work not obvious. Fillers have a certain effect on the drug release of skeleton tablets. The filler of the present invention has a pore-forming effect, so it can increase the porosity of the tablets, reduce the resistance to drug diffusion, and thus accelerate the release of the drug. The type and ratio of fillers selected by the present invention are more suitable for the drug system of dapagliflozin, and synergize with the other excipients to improve uniformity.

[0014] The second aspect of the present invention provides a method for preparing the dapagliflozin tablets, comprising the following steps:

[0015] (1) Dissolve dapagliflozin in methanol, add a glidant and a disintegrant, stir until completely dissolved, dry at 60-70°C to remove the solvent, obtain a dapagliflozin solid dispersion, and sieve; (2) Mix the dapagliflozin solid dispersion, a lubricant, and a filler, and obtain dapagliflozin tablets by direct powder compression.

[0016] In order to improve the uniformity of the tablets, preferably, the particle size after sieving in step (1) is 50-80 μm; and in step (2), a high-speed mixing granulator is used for mixing, the speed of the stirring paddle is 12-15 r / min, and the speed of the shear knife is 8-15 r / min.

[0017] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0018] (1) The present invention provides a dapagliflozin tablet, which solves the problem of poor dissolution rate of dapagliflozin. The prepared tablets have high stability, high uniformity, fast dissolution rate and good efficacy.

[0019] (2) The present invention provides a method for preparing dapagliflozin tablets. The preparation method is simple and easy to operate, and can use existing equipment in pharmaceutical factories, thereby saving production costs and facilitating large-scale promotion and use. DETAILED DESCRIPTION

[0020] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0021] Example 1

[0022] This embodiment provides a dapagliflozin tablet comprising the following raw materials and excipients in the following weight percentages: 14% dapagliflozin, 12% disintegrant, 8% lubricant, 14% glidant, and 52% filler. The disintegrant is hydroxypropyl cellulose; the glidant is mesoporous silica; the lubricant is selected from magnesium stearate and calcium stearate; and the filler is selected from xylitol, mannitol, and lactose. The weight ratio of xylitol, mannitol, and lactose in the filler is 1:1:5; and the weight ratio of magnesium stearate to calcium stearate is 1:3.

[0023] The preparation method of the dapagliflozin tablets comprises the following steps: (1) dissolving dapagliflozin in methanol (0.1 g of raw materials corresponds to 1 mL of methanol), adding a glidant and a disintegrant, stirring until completely dissolved, and drying at 65° C. to remove the solvent to obtain a dapagliflozin solid dispersion with a sieved particle size of 50 to 80 μm; (2) mixing the dapagliflozin solid dispersion, a lubricant, and a filler in a high-speed mixing granulator for 40 minutes, with the stirring blade rotating at a speed of 20 r / min and the shear blade rotating at a speed of 10 r / min; and obtaining dapagliflozin tablets after direct pressing of the powder.

[0024] Example 2

[0025] The difference between this embodiment and embodiment 1 is that the disintegrant is sodium carboxymethyl starch, purchased from Aladdin, C105665.

[0026] Example 3

[0027] The difference between this embodiment and embodiment 1 is: a dapagliflozin tablet, comprising the following raw materials and auxiliary materials in the following weight percentages: 14% dapagliflozin, 1% disintegrant, 25% lubricant, 4% glidant and 56% filler.

[0028] Example 4

[0029] The difference between this embodiment and Example 1 is that this embodiment provides a dapagliflozin tablet, comprising the following raw materials and auxiliary materials in the following weight percentages: 14% dapagliflozin, 15% disintegrant, 19% glidant and 52% filler.

[0030] Example 5

[0031] The difference between this embodiment and embodiment 1 is that the weight ratio of the magnesium stearate to calcium stearate is 1:10.

[0032] Example 6

[0033] The difference between this embodiment and embodiment 1 is that the weight ratio of xylitol, mannitol and lactose is 1:1:1.

[0034] Example 7

[0035] The preparation method of the dapagliflozin tablets comprises the following steps: (1) dissolving dapagliflozin in methanol (0.1 g of raw materials corresponds to 1 mL of methanol), adding a glidant and a disintegrant, stirring until completely dissolved, and drying at 65° C. to remove the solvent to obtain a dapagliflozin solid dispersion; (2) mixing the dapagliflozin solid dispersion, a lubricant, and a filler in a high-speed mixing granulator for 25 minutes, with the stirring blade rotating at a speed of 10 r / min and the shear blade rotating at a speed of 10 r / min; and obtaining dapagliflozin tablets after direct pressing of the powder.

[0036] Performance Testing

[0037] (1) Take 10 tablets of each of the dapagliflozin tablets prepared in Examples 1 to 7 and 10 tablets of commercially available dapagliflozin tablets (Andatang) in the control group, place each tablet in a 50 mL (5 mg specification) volumetric flask, add an appropriate amount of mobile phase, sonicate to dissolve the drug, add mobile phase to dilute to the scale, shake well, centrifuge, take the supernatant and filter, accurately measure 4 mL of the filtrate, place it in a 20 mL volumetric flask, add mobile phase to dilute to the scale, shake well, and use it as the test solution. The content was determined by HPLC, and A+2.2S was calculated according to Part IV of the 2015 edition of the Chinese Pharmacopoeia, and the uniformity was determined.

[0038] (2) The dapagliflozin tablets prepared in Examples 1 to 7 and the commercially available dapagliflozin tablets (Andatang) in the control group were taken respectively, and 900 mL of hydrochloric acid solution with a pH of 1.2 was used as the dissolution medium. The dissolution was carried out by the paddle method at 50 revolutions per minute. 5 mL of the solution was taken every 5 minutes, filtered, and the filtrate was taken as the test solution. The dissolution rate was determined by HPLC.

[0039] Table 1 Performance test results

[0040]

[0041]

[0042] The above results indicate that the dapagliflozin tablets prepared by the present invention have high uniformity, with a dissolution rate reaching 90% in just 5 minutes, indicating a rapid dissolution rate. Compared with existing dapagliflozin tablets on the market, they offer significantly improved stability and overall performance, demonstrating positive implications for the treatment of type 2 diabetes.

[0043] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing dapagliflozin tablets, characterized in that: The method comprises the following steps: (1) dissolving dapagliflozin in methanol, adding a glidant and a disintegrant, stirring until completely dissolved, drying at 60-70° C. to remove the solvent, obtaining a dapagliflozin solid dispersion, and sieving the solid dispersion; (2) sieving and mixing the dapagliflozin solid dispersion, a lubricant, and a filler, and directly compressing the powder to obtain dapagliflozin tablets; The dapagliflozin tablets are composed of the following raw materials and auxiliary materials in the following weight percentages: 10-20% dapagliflozin, 4%-21% disintegrant, 1-15% lubricant, 6-22% glidant and 40%-75% filler; The disintegrant is hydroxypropyl cellulose; the glidant is mesoporous silica; the lubricant is selected from magnesium stearate and calcium stearate, and the weight ratio of magnesium stearate to calcium stearate is 1:1 to 5; the filler is selected from xylitol, mannitol and lactose, and the weight ratio of xylitol, mannitol and lactose is 1:1:2 to 10.

2. The preparation method according to claim 1, characterized in that The particle size after sieving in step (1) is 50-80 μm; in step (2), a high-speed mixing granulator is used for mixing, the rotation speed of the stirring paddle is 15-25 r / min, and the rotation speed of the shear knife is 8-15 r / min.

3. The preparation method according to claim 1, characterized in that The invention comprises the following raw and auxiliary materials in the following weight percentages: 12-17% of dapagliflozin, 10-15% of disintegrant, 5-10% of lubricant, 9-17% of glidant and 45-65% of filler.

4. The preparation method according to claim 1, characterized in that The invention comprises the following raw materials and auxiliary materials in the following weight percentages: 14% of dapagliflozin, 12% of disintegrant, 8% of lubricant, 14% of glidant and 52% of filler.

5. The preparation method according to claim 1, characterized in that The hydroxypropyl cellulose has a weight average molecular weight of 370,000 and a Brookfield viscosity of 150 to 400 mPa.s.

6. The preparation method according to claim 1, characterized in that The mesoporous silica is hollow mesoporous silica, the surface group is -SiOH, and the particle diameter is 350-450nm.

7. A dapagliflozin tablet, characterized in that: The compound is prepared by the preparation method according to any one of claims 1 to 6.

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