CN115414347B - Sustained release tablet and preparation method and application thereof - Google Patents

Abstract

The invention discloses dapagliflozin and metformin sustained-release tablets and a preparation method thereof. The sustained release tablet comprises (1) a sustained release layer containing metformin hydrochloride; (2) dapagliflozin layer; (3) a film coating layer; the film coating layer coats the slow-release layer containing metformin hydrochloride and the dapagliflozin layer; wherein, the particle size D of the raw material of the metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ And < 70 μm. The dapagliflozin and metformin sustained release tablet provided by the invention is prepared by adopting a double-layer tabletting process, wherein a metformin hydrochloride sustained release layer adopts a wet granulation process; the dapagliflozin layer adopts a dry granulation process. According to the invention, the dapagliflozin metformin sustained-release tablet with excellent product quality is obtained through screening and optimizing the particle size of the raw materials and optimizing the auxiliary materials and the preparation process of the sustained-release tablet.

Description

Sustained release tablet and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a sustained release tablet and a preparation method and application thereof.

Background

Diabetes is one of the most common endocrine and metabolic diseases, has genetic susceptibility, and is developed under the triggering of environmental factors. With the development of socioeconomic performance, changes in people's lifestyle (increased energy intake and reduced exercise, etc.), and aging population, the incidence of type 2 diabetes tends to increase year by year worldwide, especially in developing countries with a faster rate of increase (it is expected that the increase may be 170% in 2025), presenting a state of popularity. Diabetes now becomes a non-infectious disease that threatens the health and life of people at position 3, following cardiovascular disease and tumors.

Dapagliflozin (Dapagliflozin) is the first approved Sodium-glucose co-transporter 2 (Sodium-glucose cotransporter, SGLT-2) inhibitor to selectively block SGLT-2, reduce reabsorption of glucose by proximal tubules, and increase excretion of glucose in urine, thereby reducing blood glucose. The mechanism of blood glucose reduction is completely different from the existing blood glucose reduction medicines, is independent of the secretion and action of insulin, and is one of the hottest spots for researching the treatment problem of type 2 diabetes in recent years.

XigduoXR combines for the first time the sodium-glucose cotransporter 2 (SGLT 2) inhibitor dapagliflozin (trade name Forxiga) with metformin hydrochloride in slow release form; for adult patients with type 2 diabetes requiring dapagliflozin in combination with metformin, the drug can be used as an auxiliary drug to control blood sugar in combination with diet and exercise. Previously, xigduo (dapagliflozin/immediate release metformin hydrochloride) was approved by the european union in month 1 of 2014, and was the first SGLT2 inhibitor and metformin compound product marketed by the european union. A number of dosage specifications for XigduoXR (dapagliflozin/slow release metformin hydrochloride) have been FDA approved for 29 days 10 months 2014, including 5mg/500mg, 5mg/1000mg, 10mg/500mg and 10mg/1000mg.

The existing preparation has the defect of undefined control of the particle size range of raw materials, so that from the perspective of improving the quality of medicines, the preparation has the advantages of definite particle size of raw materials, stable auxiliary material consumption and reasonable preparation process, and the quality of the final product is equivalent to that of a commercial product.

Disclosure of Invention

The invention aims to provide dapagliflozin and metformin sustained-release tablets and a preparation method thereof.

The dapagliflozin and metformin sustained release tablet provided by the invention comprises (1) a sustained release layer containing metformin hydrochloride; (2) dapagliflozin layer; (3) a film coating layer; the film coating layer coats the slow release containing metformin hydrochlorideA layer and dapagliflozin layer; wherein, the particle size D of the raw material of the metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ ＜70μm；

The dapagliflozin and metformin sustained release tablet has the specification that each tablet contains 500mg of metformin hydrochloride and 5mg of dapagliflozin;

the composition of the metformin hydrochloride-containing sustained-release tablet core is as follows:

wherein the purified water is used as a wetting agent in wet granulation and is removed in the drying process;

the composition of the dapagliflozin layer is as follows:

wherein, 6.15mg of dapagliflozin propylene glycol monohydrate is 5mg calculated as dapagliflozin;

the film coating layer adopts film coating premix (gastric dissolution type), and the coating weight gain range is 2.0% -3.0% (preferably 2.5%) of the total mass of the tablet; the tablet consists of the slow-release layer containing metformin hydrochloride and the dapagliflozin layer.

The dapagliflozin and metformin sustained release tablet provided by the invention is prepared by adopting a double-layer tabletting process, wherein a metformin hydrochloride sustained release layer adopts a wet granulation process; the dapagliflozin layer adopts a dry granulation process.

The specific preparation method of the dapagliflozin and metformin sustained-release tablet provided by the invention comprises the following steps:

1. metformin slow release layer

1) Raw and auxiliary material treatment

Taking metformin hydrochloride and daggerCrushing the gliclazide, and controlling the particle size D of the raw material of the metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ ＜70μm。

2) Premixing

Mixing metformin hydrochloride, magnesium stearate and sodium carboxymethylcellulose in a wet mixing granulator, stirring at 150rpm and shearing at 1500rpm, and mixing for 5min; the magnesium stearate and the sodium carboxymethyl cellulose are added according to the amount of the internal auxiliary materials;

3) Granulating

Setting a wet mixing granulator with a stirring speed of 150rpm, a shearing speed of 1500rpm, an atomization pressure of 0.2Mpa and a peristaltic pump speed of 40rpm, adding the purified water for granulating, continuously granulating for 10min after the liquid adding is finished, passing the wet granules through the crushing granulator, and controlling a proper rotating speed and a screen of 4.0X4.0mm;

4) Drying

Drying wet particles in a fluidized bed with an air inlet temperature of 60 ℃, controlling proper air quantity, and stopping discharging when the water content of the materials is not more than 1.0%;

5) Finishing grain

Granulating the dried material by a crushing and granulating machine, wherein the screen is 1.0mm;

6) General mixing

Adding the granules and hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose E5, microcrystalline cellulose 102 and silicon dioxide required by conversion into a hopper mixer, and mixing for 10min at 8rpm; adding magnesium stearate, mixing for 8min at 8rpm; the magnesium stearate is added according to the amount of the additional auxiliary materials;

2. dapagliflozin layer

1) Pretreatment of raw materials and auxiliary materials

Mechanically crushing dapagliflozin propylene glycol monohydrate, and sieving with a 60-mesh sieve;

2) Mixing and sieving

Mixing dapagliflozin propylene glycol monohydrate, anhydrous lactose, microcrystalline cellulose, the crospovidone in the internally added auxiliary materials and the silicon dioxide in the internally added auxiliary materials in a hopper mixer for 10min at the rotating speed of 8rpm; mixing, passing through a 1.0mm crushing and granulating machine, and finally placing the sieved mixture and the magnesium stearate in the internal auxiliary materials into a mixer for mixing for 10min at 8rpm;

3) Granulating

Setting the feeding speed of a dry granulator: 40 rpm-60 rpm; nip: 0.4-0.8 mm; rotation speed of the press roller: 8 rpm-10 rpm; oil pressure: 80-120 bar; crushing rotation speed: 100rpm, screen mesh size: granulating with a round hole 1.0, sampling, and measuring the particle-powder ratio (60 mesh sieve);

4) Mixing

According to the recovery of the particles, mixing the particles with the crospovidone and the silicon dioxide in the additional auxiliary materials in a hopper mixer for 10min at 8rpm; adding the magnesium stearate in the additional auxiliary materials, and mixing for 8min at 8rpm;

3. double-layer sheet pressing

According to the content, carrying out conversion tabletting, controlling the weight range of the tablet to be +/-2% of the metformin layer, controlling the total weight range to be +/-1%, and carrying out tabletting with the hardness of 200-300N (preferably 200-250N);

4. coating layer

1) Preparation of coating liquid

Weighing the purified water with the prescription amount, starting mechanical stirring, slowly dispersing the coating powder with the prescription amount in the water, continuously stirring until the dispersion is uniform (not less than 45 min), and preparing coating liquid with the concentration of 15% (w/w) for standby, wherein stirring is not stopped before and during use;

2) And (3) adjusting parameters of a coating machine, setting the air inlet temperature of the coating machine, and performing coating by proper atomization pressure and spraying rotating speed until the coating is heavier.

Preferred coater parameters are as follows:

compared with the prior art, the invention has the following beneficial technical effects:

the invention defines the particle size of raw materials, wherein the particle size D90 of the raw materials of the metformin is 50-100 mu m, and the particle size D of the raw materials of the dapagliflozin ₉₀ Less than 70 μm; the metformin hydrochloride sustained-release tablet is prepared by adopting a double-layer tabletting process, wherein a wet granulating process is adopted for the metformin hydrochloride sustained-release layer, and the parameters of premixing, wet granulating and total mixing are controlled; the dapagliflozin layer adopts a dry granulation process, and the parameters of premixing, dry granulation and total mixing are controlled. Finally, the content uniformity, the release degree and the like of the double-layer tablet product are ensured to meet the quality requirements.

Drawings

FIG. 1 shows the results of the dissolution profile of a reference formulation LT0087 of metformin hydrochloride layer in various media;

FIG. 2 shows the results of dissolution profiles of the reference formulation LT0087 dapagliflozin layer in different media;

FIG. 3 is the result of the dissolution profile of the metformin layer in each medium in example 1;

FIG. 4 shows the results of dissolution profiles of dapagliflozin layer in the respective media in example 1;

FIG. 5 is the result of pre-experimental investigation of the dissolution profile of the metformin layer in example 2;

FIG. 6 is the result of pre-experimental investigation of the dissolution profile of dapagliflozin layer in example 2;

FIG. 7 is the results of examining the dissolution profile of the metformin layer using the amount of adjuvant in example 2;

FIG. 8 is a graph showing the results of examining the dissolution profile of the metformin layer using the amount of wetting agent in example 2;

FIG. 9 shows the results of the elution profile of dapagliflozin layered microcrystalline cellulose and anhydrous lactose in example 2;

FIG. 10 is the result of the dissolution profile of dapagliflozin layer in example 2, examined with respect to the amount of crospovidone used;

FIG. 11 is the result of examining the dissolution curve of dapagliflozin starting material particle size in example 3;

FIG. 12 is the result of examining the dissolution profile of the metformin granulation parameters in example 3;

fig. 13 is the results of examination of dissolution curves for dapagliflozin layer granulation parameters in example 3.

Detailed Description

The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.

Reference formulation selection: dapagliflozin and metformin sustained release tablets are marketed in multiple countries such as the United states, china and Switzerland, and film coated tablets marketed in the United states by ASTRAZENECA AB, trade names of which are published in the fourth sixteen batches of CDE reference preparation catalogues are selected according to research and development requirementsXR, specification 5mg/500mg as reference formulation for dapagliflozin metformin sustained-release tablet.

According to the invention, through the investigation results of the mixing uniformity and the dissolution curve, the particle size of the metformin is finally determined to be between 70 and 100 mu m. Dapagliflozin particle size is below 70 μm.

Comparative example 1, reference formulation basic investigation information and dissolution curve investigation

1. Basic investigation information of reference preparation

Table 1 summary of basic information investigation results for reference formulations

From the above results, it can be seen that: the reference preparation has a length of about 20mm, a width of about 10.20mm, a thickness of about 7.45mm, a tablet weight of 1.360-1.40 and a hardness of 290-400N.

2. Investigation of dissolution curves of reference formulations

The dissolution curve of the product in different media is examined, and the method and the result are summarized as follows:

table 2 summary of dissolution methods of dapagliflozin and metformin extended release tablets in different media

Note 1: medium preparation method

1.0.1 mol/L hydrochloric acid: 9.0ml of hydrochloric acid was taken, water was added to 1000ml, and the mixture was shaken well.

2. 250mg of 0.2mol/L potassium dihydrogen phosphate solution is taken, 112ml of 0.2mol/L sodium hydroxide solution is added, water is added for dilution to 1000ml, and shaking is carried out.

Acetate buffer saline at ph 4.5: 2.99g of sodium acetate trihydrate is taken, 14ml of acetic acid solution with the concentration of 2mol/L is added, water is added for dilution to 1000ml, and shaking is carried out.

And (2) injection: the number of the rotary basket is 20 meshes by adopting a basket method.

TABLE 3 dissolution profile results of reference formulation LT0087 of metformin hydrochloride layer in various media

Time (h)	Aqueous medium	phosphate buffer at pH6.8	Acetate buffer at pH4.5	0.1M hydrochloric acid
					0.5	18.24	17.24	17.09	18.95
1	28.67	27.53	27.37	29.71
					2	43.33	42.18	42.06	45.04
3	54.04	53.14	53.17	56.63
					4	62.95	61.84	61.98	65.5
6	75.23	74.78	74.91	78.78
					8	83.74	83.80	83.84	87.91
10	88.79	90.00	89.91	93.26
					12	92.19	93.89	93.84	96.96

From the above results, it can be seen that: when the reference preparation metformin hydrochloride layer is dissolved out under the condition of 100rpm of basket method in different media, the dissolution tends to occur, and the cumulative release degree at the dissolution end point is more than 85%.

TABLE 4 dissolution profile results of reference formulation LT0087 of dapagliflozin layer in different media

Time (min)	Aqueous medium	phosphate buffer at pH6.8	Acetate buffer at pH4.5	0.1M hydrochloric acid
					0	0	0	0	0
5	83.86	75.63	71.40	88.11
					10	93.64	94.70	92.63	94.12
15	95.84	97.36	95.18	95.97
					20	96.71	97.84	96.09	96.86
30	97.11	98.67	96.79	97.03
					45	97.60	99.25	97.34	97.79

From the above results, it can be seen that: the reference preparation dapagliflozin layer is dissolved in an aqueous medium, phosphate buffer solution with pH of 6.8 and acetate buffer solution with pH of 4.5, the cumulative dissolution rate of 10min is more than 85%, and the cumulative dissolution rate of 5min is more than 85% in a 0.1M hydrochloric acid medium.

To sum up: combining the FDA dissolution method with reference formulation dissolution data, subsequent studies conducted prescription screening at 100rpm basket.

Example 1 dapagliflozin metformin sustained release tablet and preparation method thereof

1. The prescription composition of the dapagliflozin metformin sustained release tablet is shown in table 5.

Table 5 prescription information

Note [ 1 ]: in actual production, the feeding amount is reduced according to the moisture content. The amount of feed (kg) =500×lot ≡1000 ≡ (1-moisture) ≡content; if the content is more than or equal to 100 percent, the content is calculated as 100 percent.

Note [ 2 ]: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, and the actual prescription is added according to 6.15 mg/tablet conversion. Feed amount (kg) =6.15×lot ≡1000 ≡ (1-moisture) ≡content; if the content is more than or equal to 100 percent, the content is calculated as 100 percent

Note [ 3 ]: as wetting agent in wet granulation, and removed during drying.

Note [ 4 ]: the theoretical tablet weight of the tablet core is 1348.73mg, the coating weight gain range is 2.0-3.0 mg, namely 27-41 mg, and the prescription dosage is designed according to the maximum weight gain of 3.0%. The solvent used in the preparation of the coating liquid is removed after the coated tablet is dried, and the total weight is not taken into account. The concentration of the coating solution is 15%.

2. The preparation method is as follows (according to 10000 tablets of feed preparation):

1. metformin slow release layer

1) And (3) raw material and auxiliary material treatment: pulverizing metformin hydrochloride and dapagliflozin, and controlling particle diameter D of raw material of metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ ＜70μm。

2) Premixing: the metformin, magnesium stearate and sodium carboxymethylcellulose are mixed in a wet mixing granulator, the stirring rotation speed is 150rpm, the shearing rotation speed is 1500rpm, the mixing is carried out for 5min, and 10 samples are taken to detect the mixing uniformity.

3) Granulating: setting a wet mixing granulator with stirring speed of 150rpm, shearing speed of 1500rpm, atomizing pressure of 0.2Mpa, peristaltic pump with speed of 40rpm, adding a proper amount of wetting agent for granulating, continuously granulating for 10min after the liquid adding is finished, passing the wet granules through the crushing granulator, and controlling proper rotating speed and a screen with the speed of 4.0X4.0 mm.

4) And (3) drying: and (3) drying the wet particles in a fluidized bed with the air inlet temperature of 60 ℃, and controlling the proper air quantity to stop discharging when the water content of the materials is not more than 1.0%.

5) Finishing: and (3) granulating the dried material by a crushing and granulating machine, wherein the screen is 1.0mm.

6) Total mixing: adding the granules and hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose E5, microcrystalline cellulose 102 and silicon dioxide required by conversion into a laboratory hopper mixer, and mixing for 10min at 8rpm; adding magnesium stearate, mixing for 8min at 8rpm; 10 samples were taken to detect the uniformity of mixing and two samples were taken to detect the particle content.

2. Dapagliflozin layer

1) Pretreatment of raw materials and auxiliary materials: dapagliflozin propylene glycol monohydrate was mechanically crushed and sieved through a 60 mesh sieve.

2) Mixing and sieving: mixing dapagliflozin propylene glycol monohydrate, anhydrous lactose, microcrystalline cellulose, half of crospovidone and half of silicon dioxide in a laboratory hopper mixer for 10min at 8rpm; mixing, passing through a 1.0mm crushing and granulating machine, and finally placing the mixture after sieving and half of magnesium stearate into a mixer for mixing for 10min at 8rpm; 10 samples were taken to check the mixing uniformity.

3) Granulating: setting the feeding speed of a dry granulator: 40 rpm-60 rpm; nip: 0.4-0.8 mm; rotation speed of the press roller: 8 rpm-10 rpm; oil pressure: 80-120 bar; crushing rotation speed: 100rpm, screen mesh size: 1.0 granulating, sampling, and measuring particle-powder ratio (60 mesh sieve)

4) Mixing: according to the recovery of particles, converting, mixing the particles with the required amount of crospovidone and silicon dioxide in a hopper mixer for 10min at 8rpm; adding magnesium stearate, mixing for 8min at 8rpm, taking 10 samples to detect mixing uniformity, and detecting particle content in 2 samples

3. Double-layer sheet pressing

And (3) carrying out reduced tabletting according to the content, wherein the limit range of tablet weight (metformin layer + -2%, total tablet weight: + -1%), and the hardness is examined to be 200-300N.

4. Coating layer

1) Preparing a coating liquid: weighing purified water with a prescription amount, starting mechanical stirring, slowly dispersing coating powder with the prescription amount in water, continuously stirring until the dispersion is uniform (not less than 45 min), and preparing into coating liquid with a concentration of 15% (w/w), wherein stirring is not stopped before and during use

2) Coating: parameters of a coating machine are regulated, the air inlet temperature of the coating machine is set to be 40-60 ℃, the rotating speed of a main machine is not more than 10 revolutions per minute, and the coating weight gain is 2.0-4.0%.

5. Packaging arrangement

The product is packed in the same way as the reference preparation, is a high-density polyethylene bottle for oral solid medicine, is provided with a high-density polyethylene bottle cap with an inductive aluminum foil lining, and contains a silica gel drier.

3. Intermediate result summary

TABLE 10 summary of powder detection results

TABLE 11 summary of premix uniformity results

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From the above results: the pre-mixing uniformity of the dapagliflozin layer and the metformin layer meets the requirements.

TABLE 12 summary of results for total mixing uniformity and particle content

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From the above results, it can be seen that: the mixing uniformity of the metformin and dapagliflozin layers meets the requirements; the detection result of the dapagliflozin content is 101.3%, and the dapagliflozin content meets 95.0% -105.0% of the marked amount. The content detection result of the metformin is 100.2 percent, and the content of the metformin satisfies 95.0 to 105.0 percent of the marked quantity.

4. Summarizing dissolution curves

Table 13 metformin layer dissolution summary

Table 14 summary of dapagliflozin layer dissolution

5. Dapagliflozin metformin sustained release tablet detection result

Table 15 detection report

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Conclusion: the quality standard of the dapagliflozin metformin sustained-release tablet is checked, and the check results of the above are in accordance with the regulations. The test result of the small sample intermediate and the finished product meets the requirements, and the prescription process of the small sample intermediate is stable.

EXAMPLE 2 formulation dose investigation of dapagliflozin and metformin extended Release tablet

1. Pre-experiment

The particle size of the raw materials, mixing parameters, tablet hardness and the like are primarily examined.

TABLE 9 preliminary experiment raw and auxiliary material information

Names of raw and auxiliary materials	Lot number	Manufacturer' s
			Metformin hydrochloride	A-12611911019	SHOUGUANG FUKANG PHARMACEUTICAL Co.,Ltd.
Dapagliflozin propylene glycol monohydrate	DP21020001	Xidelong pharmaceutical Co Ltd
			Sodium carboxymethyl cellulose	210403	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Hydroxypropyl methylcellulose E5 (2910)	210101	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
			Hydroxypropyl methylcellulose K100M (2208)	210212	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Microcrystalline cellulose-SH 102	B210503	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
			Microcrystalline cellulose-SH 302	B201203	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
Anhydrous lactose	1068WVW	DFE Pharma GmbH&Co.KG
			Crosslinked povidone	050321010	CHONGQING STAR-TECH & JRS SPECIALTY PRODUCTS Co.,Ltd.
Silica dioxide	210306	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
			Magnesium stearate	210529	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.

Table 10 Pre-experiment prescription design

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Note 1: the wetting agent is used during granulation and is removed during drying.

And (2) injection: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, the actual prescription is fed according to 6.15 mg/tablet, and the tablet weight is increased and decreased above the microcrystalline cellulose 302 in order to ensure that the tablet weight is 300mg unchanged.

Table 11 Pre-experiment prescription Process

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TABLE 12 Pre-experiment particle size detection results

TABLE 13 summary of results of pre-experiment mixing uniformity investigation

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From the above results, it can be seen that: the mixing uniformity and the content of samples of the metformin layer premixed for 3min, 5min and 7min meet the requirements, and no obvious difference exists; the RSD values of the total three time points of mixing are all satisfactory, but the difference is larger, compared with the 10min point, the better. The dapagliflozin layer is poor in premixing 1 (5 min and 10 min), premixing 2 (5 min and 10 min) and total mixing uniformity, and the particle size of the dapagliflozin raw material and the dapagliflozin layer mixing parameters are required to be continuously inspected later.

TABLE 2 result summary of pre-experiment metformin layer dissolution curve investigation

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Note 1: f2 (n=7), sampling points were 0.5, 1, 2, 3, 4, 5, 6, 8h.

And (2) injection: f2 (n=8), sampling points were 0.5, 1, 2, 3, 4, 5, 6, 8, 10h.

Table 15 summary of results of investigation of dissolution curves of dapagliflozin layer in preliminary experiments

Note that: when the dissolution rate is > 85% in 15min, the two curves are considered to be similar.

From the above results, it can be seen that: the metformin layer dissolves out in different media at 100rpm in basket method and is similar to the reference preparation; the dapagliflozin layer dissolves in four media more slowly than the reference formulation and is dissimilar to it.

To sum up: the metformin layer raw material treatment mode is that after mechanical crushing, the raw material is screened by a 80-mesh sieve, the premixing parameter is temporarily set to be the stirring rotation speed of 150rpm, the shearing rotation speed is 1500rpm, and the time is 5min; the total mixing parameters were tentatively set at 8rpm for 10min. The dapagliflozin layer needs to continuously study the particle size and mixing parameters of the raw materials.

2. Sodium carboxymethylcellulose and hypromellose K100M dose investigation

According to the initial prescription YDG-210804-01 of metformin hydrochloride layer prescription composition, the dosage of auxiliary materials of sodium carboxymethyl cellulose and hypromellose K100M is examined. The dosage of sodium carboxymethyl cellulose of the prescription (YDG-210828-01/02 batch) is respectively designed to be 2.5 percent and 10 percent of the dosage; the dosage of the hydroxypropyl methylcellulose K100M in the prescription (YDG-210828-04/05 batch) is 30 percent and 40 percent; and (5) observing the influence of the consumption of different auxiliary materials on the dissolution curve.

Table 16 design of prescription for examining adjuvant dosage (batch: 3000 tablets/g)

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Table 17 adjuvant consumption investigation process

Table 18 powder characteristics investigation results

From the above results, it can be seen that: the YDG-210828-01/02/04/05 batch repose angle, loose density and tap density have no obvious difference; YDG-210828-01 has a particle size distribution in the range of 45-75 μm with fewer particles.

Table 19 results of the dissolution profile of the metformin layer (ph 6.8 phosphate medium) were examined with respect to the amount of auxiliary material

From the above results, it can be seen that: the dissolution results of YDG-210903-01/02/03 are similar to those of a reference preparation, and the three batches of results have no obvious difference, so that the influence of the dosage of sodium carboxymethyl cellulose on dissolution is small; similarly, the results of the YDG-210903-01/04/05 batch of dissolution are similar to those of the reference preparation, which shows that the dosage of the hypromellose K100M in the range has less influence on dissolution. Through evaluation, the dosage of sodium carboxymethyl cellulose and the dosage of hydroxypropyl methylcellulose K100M in the subsequent prescription process research are still unchanged, namely the dosage of the carboxymethyl cellulose is 4.84 percent, and the dosage of the hydroxypropyl methylcellulose K100M is 34.63 percent.

3. Inspection of wetting agent dosage

The amount of wetting agent can have an effect on granulating effect, how much particles are dissolved out, etc. Therefore, the use amount of the wetting agent needs to be further examined; meanwhile, the added auxiliary materials are added with 1% anhydrous lactose, and the influence of the anhydrous lactose on dissolution is examined. The dosage of the wetting agent is designed to be 12 percent and 15 percent (namely, the dosage of the wetting agent in the prescription YDG-210919-01 is 12 percent and the dosage of the wetting agent in the prescription YDG-210919-02 is 15 percent), and the influence of the dosages of different wetting agents on the material fluidity granulation effect and the dissolution curve is examined.

TABLE 3 wetting agent dosage investigation prescription design (batch: 3000 tablets/g)

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Note 1: after the metformin hydrochloride is folded into water and purified, the metformin hydrochloride is fed, the content is 99.8 percent, and the water content is 0.1 percent

Table 21 wetting agent dosage investigation Process

TABLE 22 summary of powder detection results for wetting agent dosage investigation

From the above results, it can be seen that: the repose angles and apparent tap densities of YDG-210804-01 and YDG-210919-01/02 are not obviously different, but the particle size distribution of YDG-210919-01/02 is mainly 0-45 mu m, the particle size distribution of YDG-210804-01 is mainly 45-75 mu m, and the particle size distribution of YDG-210919-01/02 is mainly 0-45 mu m.

Table 23 summary of the wetting agent dosage investigation dissolution results (pH 6.8 phosphate Medium)

Time (h)	Reference LT0087	YDG-210919-01	YDG-210919-02	YDG-210804-01
					0.5	17.24	18.95	16.84	19.59
1	27.53	28.53	26.08	29.52
					2	42.18	42.59	39.66	43.71
3	53.14	53.31	50.38	53.81
					4	61.84	61.98	59.18	61.95
6	74.78	75.04	73.13	74.39
					8	83.80	83.48	82.19	82.61
10	90.00	89.24	88.67	88.66
					f2(n＝8)	/	95	83	88

From the above results, it can be seen that: the YDG-210919-01/02 batch dissolved in phosphate buffer pH6.8 at 100rpm in basket method was similar to the reference formulation, and YDG-210919-01 batch and reference formulation f2 were as high as 95, so that the subsequent formulation process study was performed according to the formulation process of the batch.

4. Dapagliflozin layer microcrystalline cellulose and anhydrous lactose consumption investigation

According to the process composition of the reference preparation patent dapagliflozin layer prescription, the dosage of auxiliary materials microcrystalline cellulose and anhydrous lactose is inspected, namely, 15g of anhydrous lactose and microcrystalline cellulose are added on the basis of an original grinding prescription, meanwhile, the tablet weight of dapagliflozin is added, the influence of the dosage on a dissolution curve is inspected, and the specific prescription design is shown in the following table:

table 24 dapagliflozin layer microcrystalline cellulose and anhydrous lactose dose investigation prescription design (batch: 3000 tablets/g)

Note 1: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, the actual prescription is 6.15 mg/tablet, the content is 99.2%, the water content is 3.5% (the feeding amount after water folding and purity reducing=19.27)

Table 25 dapagliflozin layered microcrystalline cellulose and anhydrous lactose usage investigation process

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Table 26 inspection summary of the powder for inspection of the amount of microcrystalline cellulose and anhydrous lactose in dapagliflozin layer

From the above results, it can be seen that: the YDG-211015-01/02 batch repose angle, bulk density, tap density and particle size distribution have no obvious difference.

Table 27 examination and summary of microcrystalline cellulose and anhydrous lactose consumption of dapagliflozin layer

From the above results, it can be seen that: YDG-211015-01/02/03 of the batch content is free of abnormality.

Table 28 examination of the amount of microcrystalline cellulose and anhydrous lactose used in the dapagliflozin layer and the elution were summarized (pH 6.8 phosphate medium)

Time (min)	Reference LT0087	YDG-211025-01	YDG-211025-02	YDG-211025-03
					5	75.63	80.26	75.83	75.38
10	94.7	90.69	88.75	91.72
					15	97.36	94.33	93.27	95.17
20	97.84	96.29	95.26	97.23
					30	98.67	98.45	97.68	98.88
45	99.25	99.16	98.13	100.45
					f2	/	Similar to	Similar to	Similar to

From the above results, it can be seen that: the dissolution trend of YDG-211025-01/02/03 batch of dapagliflozin layer in the phosphate medium with the pH of 6.8 is consistent with that of a reference preparation under the condition of 100 revolutions of basket method; since the reference formulation patent is about to expire, in order to avoid patent conflict, the subsequent prescription study examined the tablet weight of the reference formulation patent increased to 315mg with 20% anhydrous lactose and 71.86% microcrystalline cellulose.

6. Examination of the amount of crospovidone

Since crospovidone is used as a disintegrant in dapagliflozin, the amount of crospovidone may affect dissolution, and thus the amount of crospovidone is examined. According to the composition of YDG-211025-02 batches, the dosage of YDG-211029-01 batches of crospovidone is designed to be 2%, the dosage of YDG-211029-02 batches of crospovidone is designed to be 6%, and the influence of the dosage of the crospovidone on dissolution is examined, wherein the specific prescription is as follows:

table 29 formulation for examination of the amount of crospovidone (batch: 3000 tablets/g)

Note 1: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, the actual prescription is 6.15 mg/tablet, the content is 99.2%, the water content is 3.5% (the feeding amount after water folding and purity reducing=19.27)

Table 30 Process for investigating the amount of crospovidone used

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Table 31 summary of powder characteristics detection results examined by amount of crospovidone

Detection item	YDG-211029-01	YDG-211029-02
			Angle of repose (°)	36.51	40.07
Bulk density g/cm 3	0.67	0.63
			Tap density g/cm 3	0.84	0.8
Compression degree%	20.0	21.0
			Particle-powder ratio%	34.2	39.9

Table 32 examination of the amount of dapagliflozin layer crosslinked povidone the results of the dissolution of the same were summarized (pH 6.8 phosphate medium)

Time (min)	Reference LT0087	YDG-211025-02	YDG-211102-01	YDG-211102-02
					5	75.63	75.83	66.54	79.18
10	94.7	88.75	82.55	88.67
					15	97.36	93.27	86.8	92.29
20	97.84	95.26	89.23	93.72
					30	98.67	97.68	90.82	95.41
45	99.25	98.13	92.25	96.24
					f2	/	Similar to	Similar to	Similar to

From the above results, it can be seen that: the dissolution trend of YDG-211002-01/02 in phosphate buffer with pH of 6.8 is consistent with that of the reference preparation, but no YDG-211025-02 is obvious, so that the later prescription process investigation is still carried out on the basis of YDG-211025-02 (namely, the dosage of the crospovidone is 4%).

EXAMPLE 3 formulation study of dapagliflozin and metformin sustained release tablet

1. Inspection of the particle size of dapagliflozin raw material

According to the YDG-210804-01 batch dissolution results, dapagliflozin is slowly dissolved and the dissolution end point is low, so that dapagliflozin raw materials are crushed, and the influence of the particle size of the crushed raw materials on dissolution curves, mixing uniformity and the like is examined.

Table 33 design of the investigation prescription of the particle size of the raw material for dapagliflozin layer (batch: 3000 tablets/g)

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Note 1: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, and the actual prescription is 6.15 mg/tablet.

Table 34 raw material particle size investigation process for dapagliflozin layer

Table 35 raw material particle size investigation of gliflozin layer particle size detection results

From the above results, it can be seen that: raw material untreated D ₉₀ (μm) is greater than 130, D after mechanical crushing ₉₀ The (mu m) is between 55 and 65.

Table 36 raw material particle size inspection and mixing uniformity test results for dapagliflozin layer

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From the above results, it can be seen that: the content uniformity of samples of the dapagliflozin layer in premixing 1 and premixing 2-5min is good, and the content uniformity of samples of 10min is not good; the mixing uniformity of the samples for 5min and 10min is not greatly different, so that the temporary mixing time of the premixing 1 is 10min, the temporary mixing time of the premixing 2 is 10min, and the total mixing time is also 10min.

Table 37 summary of the results of the particle size investigation of the dapagliflozin starting material (pH 6.8 phosphate Medium)

Time (min)	Reference LT0087	YDG-210804-01	YDG-210818-01
				0	0	0	0
5	75.63	51.81	77.04
				10	94.70	70.60	87.01
15	97.36	77.58	90.43
				20	97.84	81.77	91.83
30	98.67	86.86	93.29
				45	99.25	91.15	94.58
f2	/	Dissimilar and dissimilar	Similar to

From the above, it can be seen that: the mixing uniformity of the mechanically crushed raw materials meets the requirement, and the dissolution trend is consistent with that of the reference preparation, so that the prescription mode of researching the prescription process of the subsequent dapagliflozin layer prescription is that the mechanically crushed raw materials are screened by a 60-mesh sieve, and the particle size D ₉₀ The control is less than 70 mu m.

2 wet granulation parameter investigation

Since the granulating parameters have an influence on the dissolution curve and the like, the granulating parameters need to be examined. The stirring speed of the prescription YDG-210919-01 batch wet mixing granulator is 150rpm, the shearing speed is 1500rpm, the liquid is added for granulating for 7min, the stirring speed of the prescription YDG-210927-01 batch wet mixing granulator during liquid adding and granulating is 100rpm, and the shearing speed is 1000rpm; the stirring rotation speed is 200rpm and the shearing rotation speed is 2000rpm when the prescription YDG-210927-02 batches of wet mixing granulator are added with liquid and granulated; and (5) observing the influence of different granulating parameters on granulating states and dissolution curves.

Table 38 metformin layer granulation parameters investigate recipe design (batch: 3000 tablets/g)

Note 1: after the metformin hydrochloride is folded into water and purified, the metformin hydrochloride is fed, the content is 99.8 percent, and the water content is 0.1 percent

Table 39 technological process for investigating granulation parameters of metformin layer

Table 40 metformin layer granulation parameters investigation powder detection results summary

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From the above results, it can be seen that: the YDG-210927-01/02 batch repose angle, apparent density, tap density and particle size distribution have no obvious difference; friability and tablet weight differences are within the criteria.

Table 41 summary of the dissolution results for the granulation parameters of the metformin layer

Time (h)	Reference LT0087	YDG-210919-01	YDG-210927-01	YDG-210927-02
					0.5	17.24	18.95	19.86	20.16
1	27.53	28.53	30.11	30.67
					2	42.18	42.59	44.84	45.42
3	53.14	53.31	55.79	56.48
					4	61.84	61.98	64.6	65.26
6	74.78	75.04	77.28	77.71
					8	83.8	83.48	85.83	86.26
10	90	89.24	91.42	91.85
					f2	/	95	79	75

From the above results, it can be seen that: the dissolution of YDG-210927-01/02 batch was similar to that of the reference formulation at 100 revolutions per basket in phosphate medium pH6.8, and there was no obvious difference between the three batches, but it was more advantageous when the stirring speed was 150rpm and the shearing speed was 1500rpm, in comparison to the granulation parameters of batch YDG-210919-01.

3 investigation of drying temperature and Total mixing parameters

Different drying temperatures may affect related substances, and meanwhile, the total mixing parameters may affect the mixing uniformity, so that the drying temperatures and the total mixing parameters need to be studied, and the drying temperatures and the total mixing parameters are examined according to the YDG-210919-01 batch metformin layer prescription process, and the specific process design is as follows:

table 42 drying temperature and Total mixing parameters investigate recipe design (batch: 5000 tablets/g)

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Table 43 drying temperature and total mixing parameters investigation process

Table 44 examination summary of drying temperature and total mixing parameters

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Table 45 summary of results of drying temperature and mixing uniformity measurements for total mixing parameters

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From the above results, it can be seen that: mixing 1 was better in mixing uniformity at 10min, mixing 2 had no significant difference in mixing uniformity at three time points, and mixing 2 (i.e., total mixing time was tentatively 5 min) to prevent production scale-up batch and equipment-to-equipment variation.

Table 46 summary of drying temperature and Total mixing parameters

From the above results, it can be seen that: the different drying temperatures have no influence on related substances, so that the control range of the drying temperature in the subsequent prescription process research is 50-70 ℃.

4. Dry granulation parameter investigation

The dapagliflozin layer adopts dry granulation, and different granulation parameters can influence dissolution, so that the granulation parameters are examined according to YDG-211025-01 batch (feeding speed: 40rpm; press roll gap: 0.4-0.8 mm; press roll rotation speed: 8rpm; oil pressure: 100-120 bar; crushing rotation speed: 100rpm, screen aperture: 1.0). The specific design parameters are as follows:

table 47 dapagliflozin layer granulation parameters investigation prescription design

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Table 48 dapagliflozin layer granulation parameters investigation recipe composition (batch: 1000 tablets/g)

Note 1: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, the actual prescription is 6.15 mg/tablet, the content is 99.2%, the water content is 3.5% (the feeding amount after water folding and purity reducing=19.27)

Table 49 dapagliflozin layer granulation parameter investigation process

Table 50 inspection of the granulation parameters of dapagliflozin layer powder test results summary

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From the above results, it can be seen that: the particle-powder ratio is between 30% and 65% in the range of the investigation parameters; and the faster the rotation speed of the compression roller is, the lower the oil pressure is, the less particles are; the larger the screen pore size the more particles.

Table 51 summary of examination results of the granulation parameters of dapagliflozin layer

From the above results, it can be seen that: YDG-211104-05/6/07 dissolved out faster than the reference formulation. The crushing speed and the pore diameter of the screen mesh have a certain influence on dissolution, and the pore diameter of the screen mesh is not required to be too large, and the crushing speed is not required to be too high.

In summary, the dry granulation parameters of the subsequent dapagliflozin layer prescription process study are tentatively set as follows: the feeding speed is 40-60 rpm, the oil pressure is 60-120 bar, the rotation speed of the press roller is 8-12 rpm, the crushing speed is about 100rpm, and the aperture of the screen is 1.0mm.

5. Inspection of total mixing parameters of dapagliflozin layer

Carrying out total mixing parameters according to YDG-211025-01 batch prescription process; the design total mixing parameters are as follows: mixing for 5min and 10min by total mixing 1, and rotating at 8rpm; the total mixture 2 is mixed for 5min, 8min and 10min, and the rotating speed is 8rpm. And (5) examining the influence of different mixing parameters on the mixing uniformity.

Table 52 dapagliflozin layer total blending parameter investigation prescription design

Note 1: the specification of the product is 5mg according to dapagliflozin, which is equivalent to 6.15mg of dapagliflozin propylene glycol monohydrate, the actual prescription is 6.15 mg/tablet, the content is 99.2%, the water content is 3.5% (the feeding amount after water folding and purity reducing=64.24)

Table 53 shows the total mixed parameter investigation technological process of gliflozin layer

Table 4 summary of results of inspection for mixing uniformity of dapagliflozin layer total mixing parameters

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From the above results, it can be seen that: the uniformity and the content of the total mixture 1 are not greatly influenced after 5min and 10min of mixing; however, in order to ensure that the difference of batch amplifying equipment affects the mixing uniformity, the mixing parameter of the total mixture 1 is tentatively set to be 10min, and the rotating speed is 8rpm; the RSD value is larger when the total mixing is carried out for 5min and 8min, and the RSD value is within 3 percent after the mixing is carried out for 10min, so that the mixing is better. The total mixing time was thus tentatively 10min, at 8rpm.

Claims (2)

1. A dapagliflozin and metformin sustained release tablet comprises (1) a sustained release layer containing metformin hydrochlorideThe method comprises the steps of carrying out a first treatment on the surface of the (2) dapagliflozin layer; (3) a film coating layer; the film coating layer coats the slow-release layer containing metformin hydrochloride and the dapagliflozin layer; wherein, the particle size D of the raw material of the metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ 55-65 μm;

the dapagliflozin and metformin sustained release tablet has the specification that each tablet contains 500mg of metformin hydrochloride and 5mg of dapagliflozin;

the composition of the metformin hydrochloride-containing sustained-release tablet core is as follows:

wherein the purified water is used as a wetting agent in wet granulation and is removed in the drying process;

the composition of the dapagliflozin layer is as follows:

wherein, 6.15mg of dapagliflozin propylene glycol monohydrate is 5mg calculated as dapagliflozin;

the film coating layer adopts gastric-soluble film coating premix, and the coating weight gain range is 2.0% -3.0% of the total mass of the tablet; the tablet consists of the slow-release layer containing metformin hydrochloride and the dapagliflozin layer;

the metformin hydrochloride sustained-release tablet is prepared by adopting a double-layer tabletting process, wherein a metformin hydrochloride sustained-release layer adopts a wet granulating process; the dapagliflozin layer adopts a dry granulation process; the preparation method of the dapagliflozin and metformin sustained-release tablet comprises the following steps:

1. metformin slow release layer

1) Raw and auxiliary material treatment

Pulverizing metformin hydrochloride and dapagliflozin, and controlling particle diameter D of raw material of metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ In the range of 55 to 65 mu m,

2) Premixing

Mixing metformin hydrochloride, magnesium stearate and sodium carboxymethylcellulose in a wet mixing granulator, stirring at 150rpm and shearing at 1500rpm, and mixing for 5min; the magnesium stearate and the sodium carboxymethyl cellulose are added according to the amount of the internal auxiliary materials;

3) Granulating

Setting a wet mixing granulator with a stirring speed of 150rpm, a shearing speed of 1500rpm, an atomization pressure of 0.2Mpa and a peristaltic pump speed of 40rpm, adding the purified water for granulating, continuously granulating for 10min after the liquid adding is finished, passing the wet granules through the crushing granulator, and controlling a proper rotating speed and a screen of 4.0X4.0mm;

4) Drying

Drying wet particles in a fluidized bed with an air inlet temperature of 60 ℃, controlling proper air quantity, and stopping discharging when the water content of the materials is not more than 1.0%;

5) Finishing grain

Granulating the dried material by a crushing and granulating machine, wherein the screen is 1.0mm;

6) General mixing

Adding the granules and hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose E5, microcrystalline cellulose-PH 102, anhydrous lactose 21AN and silicon dioxide required by conversion into a hopper mixer, mixing for 10min, and stirring at 8rpm; adding magnesium stearate, mixing for 8min at 8rpm; the magnesium stearate is added according to the amount of the additional auxiliary materials;

2. dapagliflozin layer

1) Pretreatment of raw materials and auxiliary materials

Mechanically crushing dapagliflozin propylene glycol monohydrate, and sieving with a 60-mesh sieve;

2) Mixing and sieving

Mixing dapagliflozin propylene glycol monohydrate, anhydrous lactose 21AN, microcrystalline cellulose-SH 302 and silicon dioxide in the internal auxiliary materials in a hopper mixer for 10min at the rotating speed of 8rpm; mixing, passing through a 1.0mm crushing and granulating machine, and finally placing the sieved mixture and the magnesium stearate in the internal auxiliary materials into a mixer for mixing for 10min at 8rpm;

3) Granulating

Setting the feeding speed of a dry granulator: 40rpm to 60rpm; nip: 0.4-0.8 mm; rotation speed of the press roller: 8-10 rpm; oil pressure: 80-120 bar; crushing rotation speed: 100rpm, screen mesh size: granulating with a round hole 1.0, and sieving with a 60-mesh sieve to sample and measure the particle-powder ratio;

4) Mixing

According to the recovery of the particles, mixing the particles with the crospovidone and the silicon dioxide in the additional auxiliary materials in a hopper mixer for 10min at 8rpm; adding the magnesium stearate in the additional auxiliary materials, and mixing for 8min at 8rpm;

3. double-layer sheet pressing

Performing reduced tabletting according to the content, controlling the weight range of the tablet to be +/-2% of the metformin layer, controlling the total weight range to be +/-1%, and performing tabletting with the hardness of 200-300N;

4. coating layer

1) Preparation of coating liquid

Weighing the purified water with the prescription amount, starting mechanical stirring, slowly dispersing the coating powder with the prescription amount in the water, continuously stirring for not less than 45min until the coating powder is uniformly dispersed, and preparing the coating liquid with the concentration of 15% (w/w) for later use, wherein the stirring is not stopped before and during use;

2) And (3) adjusting parameters of a coating machine, setting the air inlet temperature of the coating machine, and performing coating by proper atomization pressure and spraying rotating speed until the coating is heavier.

2. The preparation method of dapagliflozin and metformin sustained-release tablet of claim 1, comprising the following steps:

1. metformin slow release layer

1) Raw and auxiliary material treatment

Pulverizing metformin hydrochloride and dapagliflozin, and controlling particle diameter D of raw material of metformin ₉₀ The grain diameter D of dapagliflozin raw material is 50-100 mu m ₉₀ In the range of 55 to 65 mu m,

2) Premixing

Mixing metformin hydrochloride, magnesium stearate and sodium carboxymethylcellulose in a wet mixing granulator, stirring at 150rpm and shearing at 1500rpm, and mixing for 5min; the magnesium stearate and the sodium carboxymethyl cellulose are added according to the amount of the internal auxiliary materials;

3) Granulating

Setting a wet mixing granulator with a stirring speed of 150rpm, a shearing speed of 1500rpm, an atomization pressure of 0.2Mpa and a peristaltic pump speed of 40rpm, adding the purified water for granulating, continuously granulating for 10min after the liquid adding is finished, passing the wet granules through the crushing granulator, and controlling a proper rotating speed and a screen of 4.0X4.0mm;

4) Drying

Drying wet particles in a fluidized bed with an air inlet temperature of 60 ℃, controlling proper air quantity, and stopping discharging when the water content of the materials is not more than 1.0%;

5) Finishing grain

Granulating the dried material by a crushing and granulating machine, wherein the screen is 1.0mm;

6) General mixing

Adding the granules and hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose E5, microcrystalline cellulose-PH 102, anhydrous lactose 21AN and silicon dioxide required by conversion into a hopper mixer, mixing for 10min, and stirring at 8rpm; adding magnesium stearate, mixing for 8min at 8rpm; the magnesium stearate is added according to the amount of the additional auxiliary materials;

2. dapagliflozin layer

1) Pretreatment of raw materials and auxiliary materials

Mechanically crushing dapagliflozin propylene glycol monohydrate, and sieving with a 60-mesh sieve;

2) Mixing and sieving

Mixing dapagliflozin propylene glycol monohydrate, anhydrous lactose 21AN, microcrystalline cellulose-SH 302 and silicon dioxide in the internal auxiliary materials in a hopper mixer for 10min at the rotating speed of 8rpm; mixing, passing through a 1.0mm crushing and granulating machine, and finally placing the sieved mixture and the magnesium stearate in the internal auxiliary materials into a mixer for mixing for 10min at 8rpm;

3) Granulating

Setting the feeding speed of a dry granulator: 40rpm to 60rpm; nip: 0.4-0.8 mm; rotation speed of the press roller: 8-10 rpm; oil pressure: 80-120 bar; crushing rotation speed: 100rpm, screen mesh size: granulating with a round hole 1.0, and sieving with a 60-mesh sieve to sample and measure the particle-powder ratio;

4) Mixing

According to the recovery of the particles, mixing the particles with the crospovidone and the silicon dioxide in the additional auxiliary materials in a hopper mixer for 10min at 8rpm; adding the magnesium stearate in the additional auxiliary materials, and mixing for 8min at 8rpm;

3. double-layer sheet pressing

Performing reduced tabletting according to the content, controlling the weight range of the tablet to be +/-2% of the metformin layer, controlling the total weight range to be +/-1%, and performing tabletting with the hardness of 200-300N;

4. coating layer

1) Preparation of coating liquid

Weighing the purified water with the prescription amount, starting mechanical stirring, slowly dispersing the coating powder with the prescription amount in the water, continuously stirring for not less than 45min until the coating powder is uniformly dispersed, and preparing the coating liquid with the concentration of 15% (w/w) for later use, wherein the stirring is not stopped before and during use;

2) And (3) adjusting parameters of a coating machine, setting the air inlet temperature of the coating machine, and performing coating by proper atomization pressure and spraying rotating speed until the coating is heavier.