CN116785268A

CN116785268A - Pharmaceutical composition of SGLT-2 inhibitor

Info

Publication number: CN116785268A
Application number: CN202210245805.7A
Authority: CN
Inventors: 王克艳; 吴世斌; 丁备; 王程程; 王飞
Original assignee: Jiangsu Wanbang Biopharmaceutical Group Co ltd
Current assignee: Jiangsu Wanbang Biopharmaceutical Group Co ltd
Priority date: 2022-03-14
Filing date: 2022-03-14
Publication date: 2023-09-22
Also published as: WO2023173460A1

Abstract

The invention discloses a pharmaceutical composition of an SGLT-2 inhibitor, which comprises the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 50-200 parts of filler, 0.5-5 parts of lubricant, 0-15 parts of disintegrating agent and 0-10 parts of adhesive; the medicine composition has stable quality, does not obviously change related substances, dissolution and content under high temperature, high humidity and strong light irradiation conditions, can meet clinical medication requirements, and provides a new medication option for patients with diabetes and related diseases.

Description

Pharmaceutical composition of SGLT-2 inhibitor

Technical Field

The present invention relates to the field of pharmaceutical formulations. In particular, the invention relates to a pharmaceutical composition of a novel SGLT-2 inhibitor.

Background

Hyperglycemia associated with diabetes is caused by insulin deficiency, i.e., type 1 diabetes (T1 DM), or insulin hyposecretion or insulin resistance (T2 DM). Type 2 diabetes is the most common type of diabetes, with its prevalence rising continuously worldwide. The diabetes accounts for about 90% of the total number of people with diabetes. Type 2 diabetes is characterized by hyperglycemia and can lead to macrovascular and microvascular complications, including retinopathy, nephropathy, neuropathy, and accelerated cardiovascular disease. Excessive hyperglycemia promotes sugar toxicity by increasing insulin resistance and interfering with cellular function. Despite various treatment options, many patients have inadequate glycemic control, with the risk of chronic complications.

(1R, 2R,3S,4S, 6R) -4- (4-chloro-3- (ethoxybenzyl) phenyl) -5, 5-difluoro-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol is a novel oral selective sodium-glucose co-transporter 2 (SGLT 2) inhibitor designed specifically for the treatment of type 2 diabetes, and has the structure shown in formula (I):

(1R, 2R,3S,4S, 6R) -4- (4-chloro-3- (ethoxybenzyl) phenyl) -5, 5-difluoro-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol ameliorates hyperglycemia by SGLT2 inhibiting renal glucose reabsorption. SGLT2 is a sodium-solute co-transporter located in the proximal tubule of the kidney, reabsorbing most of the glomerular filtered glucose. Pharmacological sodium-glucose co-transporter 2 (SGLT 2) inhibition, renal glucose reabsorption may be upregulated in type 2 diabetics, and orally active selective SGLT2 inhibitors may improve glycemic control to a therapeutically useful extent.

Disclosure of Invention

The invention aims to provide a novel pharmaceutical composition of an SGLT-2 inhibitor shown as a formula (I).

The "SGLT2 inhibitor" or "active substance" in the present invention refers to (1R, 2R,3S,4S, 6R) -4- (4-chloro-3- (ethoxybenzyl) phenyl) -5, 5-difluoro-6- (hydroxymethyl) cyclohexane-1, 2, 3-triol having the structure shown in formula (I):

the invention relates to a pharmaceutical composition of an SGLT-2 inhibitor, which comprises the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 50-200 parts of filler, 0.5-5 parts of lubricant, 0-15 parts of disintegrating agent and 0-10 parts of adhesive.

In some specific examples, the pharmaceutical composition of the SGLT-2 inhibitor comprises the following components in parts by weight: 10 parts of SGLT2 inhibitor shown in formula (I), 80-190 parts of filler, 1-2 parts of lubricant, 0-15 parts of disintegrating agent and 0-10 parts of adhesive.

In some more specific examples, the pharmaceutical composition of the SGLT-2 inhibitor provided by the invention comprises the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 50-200 parts of filler, 0.5-5 parts of lubricant, 2-15 parts of disintegrating agent and 2-10 parts of adhesive.

In further more specific examples, the pharmaceutical composition of the SGLT-2 inhibitor of the present invention comprises the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 80-190 parts of filler, 1-2 parts of lubricant, 5-10 parts of disintegrating agent and 3-6 parts of adhesive.

In some embodiments, the filler of the present invention is selected from the group consisting of lactose, sucrose, fructose, starch, pregelatinized starch, corn starch, glucose, mannitol, xylitol, sorbitol, microcrystalline cellulose, wood cellulose, calcium carbonate, and mixtures of one or more of calcium hydrogen phosphate; preferred fillers are lactose and microcrystalline cellulose combinations. The inventors found that good material flow can be achieved with a combination of lactose and microcrystalline cellulose as filler, preferably in a weight ratio of lactose to microcrystalline cellulose of about 1:2 to about 2:1; more preferably 1: 1-2:1, most preferably 1:1.

In some embodiments, the microcrystalline cellulose described herein is selected from one of pH101, pH102, pH301, or pH302, more preferably pH102.

In some embodiments, the lubricant described herein is selected from magnesium stearate, sodium hard fumarate, carnauba wax, palm wax, stearic acid, hydrogenated vegetable oil, preferably the lubricant is magnesium stearate.

In some embodiments, the disintegrants of the invention are selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, starch, low substituted hydroxypropyl cellulose, preferably sodium carboxymethyl starch.

In some embodiments, the binder of the present invention is selected from one or more of hypromellose, cornstarch, pregelatinized starch, polyvinylpyrrolidone, ethylcellulose, preferably the binder is hypromellose. In some embodiments, wherein the viscosity of the hypromellose is from 4 mPa-s to 60 mPa-s, further preferably from 4 mPa-s to 6 mPa-s, for example the hypromellose may be hypromellose E5, hypromellose E30 or hypromellose 50, preferably hypromellose E5 or hypromellose E30; the inventor finds that the hydroxypropyl methylcellulose with the viscosity or the model is selected to have better dissolution.

The pharmaceutical compositions of the present invention may further comprise an outer coating. Preferably, the outer protective coating may comprise the following: one or more coating polymers, one or more plasticizers, one or more anti-adhesion agents, one or more glidants, or one or more colorants. In one embodiment, the outer coating is opadry, and in some embodiments, the weight of the opadry is 1wt% to 5wt% of the weight of the uncoated tablet.

The SGLT-2 inhibitor pharmaceutical composition is an oral preparation, and can be in the form of tablets, granules or capsules.

The SGLT-2 inhibitor pharmaceutical composition is an oral preparation, wherein the compound I is present in a daily dosage which is provided within the range of 5-25 mg/day, and the daily dosage is single dosage or divided dosage or multiple dosage. In some embodiments, the invention relates to a pharmaceutical composition wherein the amount of compound (I) is 5mg per dose. In some embodiments, the invention relates to a pharmaceutical composition wherein the amount of compound (I) is 10mg per dose. In some embodiments, the invention relates to a pharmaceutical composition wherein the amount of compound (I) is 25mg per dose. The SGLT2 inhibitor is present in a daily dosage ranging from 5 to 25 mg/day, is convenient to administer, has high patient compliance, and can provide excellent therapeutic effects within a safety window.

The invention also provides a preparation method of the SGLT2 inhibitor pharmaceutical composition, which comprises the following steps:

(1) Pretreating an SGLT2 inhibitor of formula (I); mixing with filler, lubricant, binder and disintegrating agent after pretreatment;

(2) Tabletting or encapsulating.

In some embodiments, the pretreatment in step (1) means that the particle size of the SGLT2 inhibitor of formula (I) is controlled to be D90.ltoreq.60. Mu.m, and even more preferably D90.ltoreq.30. Mu.m, and the inventors have found that controlling the particle size within this range provides better dissolution. The pretreatment method may be selected from methods conventional in the art, such as sieving, pulverizing, grinding, etc.

The pharmaceutical composition of the present invention may be further coated and protected on tablets using coating materials using methods conventional in the art after tabletting.

The novel SGLT2 inhibitor pharmaceutical composition prepared by the invention can be used for treating II diabetes and related diseases.

The pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents. Such other therapeutic agents include, but are not limited to, antidiabetic agents, antihypertensive agents, and hypolipidemic agents.

Advantages of the invention over other prior art:

the medicine composition disclosed by the invention has good material flowability, is favorable for material transfer and ensures filling uniformity, and the prepared finished product has small weight difference and meets the relevant regulations of quality control.

The medicine composition of the invention can be dissolved out rapidly, more than 59% in 5 minutes, more than 85% in 10 minutes and more than 90% in 15 minutes, and can play a role rapidly after entering the body.

The medicine composition has stable quality, does not obviously change related substances, dissolution and content under high temperature, high humidity and strong light irradiation conditions, can meet clinical medication requirements, and provides a new medication option for patients with diabetes and related diseases.

Drawings

FIG. 1 example 7 effect of different microcrystalline cellulose types on dissolution;

FIG. 2 dissolution graphs for examples 8-10;

FIG. 3 shows the comparison of different lactose/microcrystalline cellulose ratios versus dissolution;

FIG. 4 shows the effect of different hypromellose types on dissolution.

Detailed Description

The following examples facilitate a better understanding of the present invention, but are not intended to limit the same. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores.

The "active substances" described in the following examples all refer to compounds having the structure shown in formula (I):

EXAMPLE 1 hard Capsule (25 mg) product

Granules for filling were prepared, with a raw material ratio of 10%, a filler microcrystalline cellulose ratio of 48.48%, a lactose ratio of 40.52% and magnesium stearate of 1% (table 1).

TABLE 1

Composition of the components	Amount/mg	Parts by weight
			Active substances	25	10
Microcrystalline cellulose	121.2	48.48
			Lactose and lactose	101.3	40.52
Magnesium stearate	2.5	1
			Total weight of	250	100

1) Weighing active substances, and grinding in a grinding process until the particle size of the raw materials meets the requirement (D90 is less than or equal to 30 mu m).

2) Mixing the active ingredients, microcrystalline cellulose, and lactose.

3) Then adding magnesium stearate for mixing.

4) The mixed pellets were filled into 2# opaque capsules at 250 mg/pellet to provide 25mg capsules.

EXAMPLE 2 hard Capsule (10 mg) product

Example 1 granules for capsule filling were filled into 4# opaque capsule shells at 100 mg/granule to provide 10mg capsules.

EXAMPLE 3 hard Capsule (5 mg) product

Hard gelatin capsule 5mg product was prepared according to the recipe in Table 2.

TABLE 2

Composition of the components	Amount/mg	Parts by weight
			Active substances	5	10
Microcrystalline cellulose	50	4100
			Lactose and lactose	44	88
Magnesium stearate	1	2
			Total weight of	100	100

2) Mixing the active ingredients, microcrystalline cellulose, and lactose.

3) Mixing was performed with magnesium stearate added.

4) The mixed pellets were filled into opaque 4# capsules at 100 mg/pellet to provide 5mg capsules.

Example 4 granule (25 mg)

Granules containing 25mg (example 4), 10mg (example 5) of the SGLT2 inhibitor were prepared as prescribed in table 3 below.

Table 3 single dose prescription:

composition of the components	mg/bag	Parts by weight
			Active substances	25	10
Microcrystalline cellulose	150	60
			Lactose and lactose	52.5	21
Croscarmellose sodium	12.5	5
			Hydroxypropyl cellulose E5	7.5	3
Magnesium stearate	2.5	1
			Total weight of	250	100

1) Weighing active substances, and crushing by using an airflow crusher until the particle size of the raw materials meets the requirement (D90 is less than or equal to 30 mu m).

2) Granulating: premixing active substances, microcrystalline cellulose, lactose and croscarmellose sodium, adding prescribed amount of binder solution to obtain soft material, sieving, and granulating.

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

5) The mixed granules were bagged at 250 mg/bag.

Example 5 granule (10 mg)

Example 4 granules for preparing 25mg of granules were packed in bags at 100 mg/bag to provide 10mg of granules.

Example 6 granule (5 mg)

The 5mg formulation of the granule is shown in Table 4:

TABLE 4 Table 4

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

5) The mixed granules were bagged at 100 mg/bag.

EXAMPLE 7 Effect of different microcrystalline cellulose types on Material flowability

1. The prescription information is shown in table 5:

TABLE 5

Composition of the components	Amount/mg	Parts by weight
			Active substances	25	10
Microcrystalline cellulose	100	40
			Lactose and lactose	102.5	41
Croscarmellose sodium	12.5	5
			Hydroxypropyl methylcellulose E5	7.5	3
Magnesium stearate	2.5	1
			Sheet weight	250	100
Opadry coating powder (yellow)	7.5	3 (calculated as plain film)

2. The process comprises the following steps:

2) Granulating: premixing active substances, microcrystalline cellulose, lactose and croscarmellose sodium, adding prescribed amount of binder solution to obtain soft material, sieving, and granulating. Wherein, the microcrystalline cellulose type is respectively selected from pH101, pH102 and pH302 for three-batch granulation, and the flowability of the materials is examined.

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

5) Tabletting: according to theoretical weight useTabletting is carried out by a die.

6) Coating: the coating solution was prepared to 10% using the opadry coating powder, and the coating was performed using a coating machine.

3. Powder properties:

the total mixed material was taken and the material fluidity was measured, and the results were as shown in Table 6 below:

TABLE 6 preparation of Total Mixed Material powder Properties from microcrystalline cellulose of different types

Microcrystalline cellulose model	Bulk density of	Tap density	Calf index%
				pH101	0.355	0.608	41.6
pH102	0.383	0.527	27.3
				pH302	0.375	0.533	29.6

Karl index= (tap density-bulk density)/tap density x 100%.

Therefore, the three materials are tableted by using a tablet press, and the three materials all meet the tabletting requirements under the action of a forced feeder of the tablet press, but in order to meet the large-scale production and amplification requirements, the microcrystalline cellulose with the pH of 102 has obvious advantages as a filler.

4. Dissolution profile

Taking 6 tablets of the above example 7, and measuring by adopting a second method of the four-part rule 0931 of the Chinese pharmacopoeia 2020 edition, and a dissolution device: a paddle method; rotational speed: 75rpm; temperature: 37 plus or minus 0.5 ℃; dissolution medium: a solution containing 0.2%Tween80 0.1mol/L hydrochloric acid; volume of medium: 900ml; sampling time: sampling at 5, 10, 15, 30 and 45min respectively;

the measuring method comprises the following steps: according to high performance liquid chromatography (China Pharmacopeia 2020 edition, four division rule 0512), adopting Waters Symmetry shield RP18 (50 mm×4.6mm,3.5 μm) or other chromatographic columns with equivalent performance, and isocratically eluting with acetonitrile-water (35:65) as mobile phase for 10 min; the column temperature is 30 ℃; the flow rate is 1ml per minute; the detection wavelength is 224nm; the sample volume was 20. Mu.l.

TABLE 7 comparison of microcrystalline cellulose to dissolution for different models

As shown in Table 7 and figure 1, the dissolution of microcrystalline cellulose pH101, pH102 and pH302 can achieve the rapid dissolution effect of more than 85% in 15min, but the dissolution of pH102 serving as a filler is more than 85% in 10min, so that the oral administration can take effect rapidly, and compared with pH302, the oral administration has low price and better fluidity.

Example 8 tablet (25 mg)

Tablets containing 25mg (example 8), 10mg (example 9) of the SGLT2 inhibitor were prepared as described in table 8 below.

TABLE 8

Composition of the components	Amount/mg	Parts by weight
			Active substances	25	10
Microcrystalline cellulose pH102	100	40
			Lactose and lactose	102.5	41
Croscarmellose sodium	12.5	5
			Hydroxypropyl methylcellulose	7.5	3
Magnesium stearate	2.5	1
			Sheet weight	250	100
Opadry coating powder (yellow)	7.5	3 (calculated as plain film)

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

Example 9 tablet (10 mg)

Example 8 granules for the preparation of tablets 25mg, per tablet weight 100mg, were usedThe tabletting mold was subjected to tabletting to obtain 100mg tablets. The same coating powder is used for coating.

Example 10 tablet (5 mg)

Tablet 5mg formulation is as in table 9:

TABLE 9

Composition of the components	Amount/mg	Parts by weight
			Active substances	5	10
Microcrystalline cellulose pH102	40	80
			Lactose and lactose	46	92
Croscarmellose sodium	5	10
			Hydroxypropyl methylcellulose	3	6
Magnesium stearate	1	2
			Sheet weight	100	100
Opadry coating powder (Red)	3	3 (calculated as plain film)

1) Weighing active substances, and crushing by using an airflow crusher until the particle size of the raw materials meets the requirement (D90 is less than or equal to 60 mu m).

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

Dissolution Curve determination

The tablets of examples 8, 9 and 10 were measured by the second method of the fourth rule 0931 of the chinese pharmacopoeia 2020 edition, 6 tablets each, and the elution device: a paddle method; rotational speed: 75rpm; temperature: 37 plus or minus 0.5 ℃; dissolution medium: a solution containing 0.2%Tween80 0.1mol/L hydrochloric acid; volume of medium: 900ml; sampling time: sampling at 5, 10, 15, 30 and 45min respectively;

Table 10 results of elution profiles of examples 8 to 10

Time (min)	Example 8	Example 9	Example 10
				5	61.1％	59.8％	62.4％
10	85.8％	85.0％	89.4％
				15	91.5％	90.7％	93.3％
30	96.2％	95.3％	95.6％
				45	97.5％	97.0％	96.5％

As shown in Table 10 and FIG. 2, the dissolution results were substantially identical for the 25mg, 10mg, and 5mg samples of the present invention. When the D90 of the active ingredient is less than or equal to 60 mu m, more than 59% of the active ingredient can be dissolved in 5 minutes, more than 85% of the active ingredient can be dissolved in 10 minutes, and more than 90% of the active ingredient can be dissolved in 15 minutes, so that the pharmaceutical composition provided by the invention can be quickly dissolved out, and can quickly play a therapeutic role after oral administration.

EXAMPLE 10 investigation of different lactose/microcrystalline cellulose ratios

1. Prescription process information

The different lactose/microcrystalline cellulose ratio recipe information is shown in Table 10 below

TABLE 10 influence of different lactose/microcrystalline cellulose ratios on granulating flowability and dissolution

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

2. Powder properties

The total mixed material was taken and the material fluidity was measured, and the results were as shown in Table 11 below:

TABLE 11 powder Properties of different materials

Lactose/microcrystalline cellulose approximately	Bulk density of	Tap density	Calf index%
				1:2	0.383	0.625	38.7
1:1	0.383	0.527	27.3
				2:1	0.375	0.560	33.0

3. Dissolution profile

Taking 6 tablets of the above example 10, and measuring by adopting a second method of the four-part rule 0931 of Chinese pharmacopoeia 2020 edition, and a dissolution device: a paddle method; rotational speed: 75rpm; temperature: 37 plus or minus 0.5 ℃; dissolution medium: a solution containing 0.2%Tween80 0.1mol/L hydrochloric acid; volume of medium: 900ml; sampling time: sampling at 5, 10, 15, 30 and 45min respectively;

Table 12 comparison of different lactose/microcrystalline cellulose ratios versus dissolution

As shown in Table 12 and FIG. 3, the total blend material had a Carr index of 38.7% with a lactose/microcrystalline cellulose ratio of about 1:2, and was acceptably fluid but eluted more slowly. The dissolution difference is smaller when the ratio of lactose to microcrystalline cellulose is about 1:1 and 2:1, and the ratio of lactose to microcrystalline cellulose is about 1:1, so that the subsequent production and the amplification requirements are more favorable.

EXAMPLE 11 investigation of the proportions of different hypromellose types

1. Prescription process information

TABLE 13 prescription composition for different adhesive types

3) Drying and granulating: drying and granulating the wet granules.

4) Mixing the magnesium stearate with the granule.

2. Powder properties

TABLE 14 influence of different adhesive types on intermediate flowability

Prescription of prescription	Prescription 23	Prescription 24	Prescription 25
				Bulk density (g/ml)	0.383	0.394	0.400
Tap Density (g/ml)	0.527	0.618	0.611
				Calf index%	27.3	36.2	34.5

3. The dissolution profile test was performed on the sample in example 11 described above using the dissolution profile test method in example 10, and the results are shown in table 15.

TABLE 15 influence of different adhesive types on dissolution curves

Prescription of prescription	Hydroxypropyl methylcellulose E5	Hydroxypropyl methylcellulose E30	Hydroxypropyl methylcellulose E50
				5min	76.8％	70.8％	67.2％
10min	87.2％	85.1％	80.5％
				15min	91.2％	88.2％	82.6％
30min	93.6％	90.6％	87.0％
				45min	96.5％	92.5％	89.9％

As shown in Table 15 and FIG. 4, when hypromellose E5 and E30 were used, the dissolution rate reached 85% or more in 10 minutes, whereas when hypromellose E50 was used, the dissolution rate was slow. When the hypromellose E5 is used, the material fluidity is better, the dissolution rate can reach more than 90% at 15min, the effect can be quickly achieved, and the treatment effect can be quickly exerted after oral administration.

Example 12 influence factor test

For the highest specification sample of example 8, influence factor investigation was performed, influence factor test conditions: high temperature: 60 ℃; high humidity: 90% ± 5%; illumination: 4500 lx.+ -. 500lx, UV 90 μ w.h/cm ² 。

The sample is placed for 30 days, and is sampled respectively for 10 days and 30 days, and the key quality attribute of the small sample is detected according to the finished product quality standard draft.

TABLE 16 example 8 quality measurement results

Conclusion: as shown in the test results of Table 16, the tablet samples prepared by the invention are placed for 30 days at the high temperature of 60 ℃ under high humidity of 90% +/-5% and under strong light irradiation, and the related substances, dissolution and content are not obviously changed, which proves that the novel SGLT2 inhibitor pharmaceutical composition prepared by the invention has stable properties.

Many modifications and variations of the pharmaceutical compositions and methods of the present invention can be made by those of ordinary skill in the art to achieve the same technical result without departing from the principles and spirit of the invention, which are within the same or equivalent scope as that of the invention.

Claims

1. The pharmaceutical composition of the SGLT-2 inhibitor is characterized by comprising the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 50-200 parts of filler, 0.5-5 parts of lubricant, 0-15 parts of disintegrating agent and 0-10 parts of adhesive.

2. The pharmaceutical composition of the SGLT-2 inhibitor according to claim 1, characterized by comprising the following components in parts by weight: 10 parts of SGLT2 inhibitor shown in formula (I), 80-190 parts of filler, 1-2 parts of lubricant, 0-15 parts of disintegrating agent and 0-10 parts of adhesive.

3. The pharmaceutical composition of the SGLT-2 inhibitor according to claim 1, characterized by comprising the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 50-200 parts of filler, 0.5-5 parts of lubricant, 2-15 parts of disintegrating agent and 2-10 parts of adhesive; preferably, the composition comprises the following components in parts by weight: 9-11 parts of SGLT2 inhibitor shown in formula (I), 80-190 parts of filler, 1-2 parts of lubricant, 5-10 parts of disintegrating agent and 3-6 parts of adhesive.

4. A pharmaceutical composition of SGLT-2 inhibitors according to any of claims 1 to 3, characterized in that the filler is selected from the group consisting of lactose, sucrose, fructose, starch, pregelatinized starch, corn starch, glucose, mannitol, xylitol, sorbitol, microcrystalline cellulose, wood cellulose, calcium carbonate, calcium hydrogen phosphate, or a mixture of one or more thereof; preferred fillers are lactose and microcrystalline cellulose combinations; preferably, the weight ratio of lactose to microcrystalline cellulose is 1:2-2:1; more preferably 1:1 to 2:1, most preferably 1:1.

5. A pharmaceutical composition of an SGLT-2 inhibitor according to any one of claims 1 to 3, characterized in that the microcrystalline cellulose is selected from one of PH101, PH102, PH301 or PH302, more preferably PH102; the lubricant is selected from magnesium stearate, sodium hard fumarate, carnauba wax, palm wax, stearic acid, hydrogenated vegetable oil, preferably magnesium stearate; the disintegrating agent is selected from cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, starch, low-substituted hydroxypropyl cellulose, preferably sodium carboxymethyl starch; the adhesive is selected from one or more of hypromellose, hydroxypropyl cellulose, corn starch, pregelatinized starch, polyvinylpyrrolidone and ethyl cellulose, and is preferably hypromellose; preferably, the viscosity of the hypromellose is 4 mPas to 60 mPas, more preferably 4 mPas to 6 mPas.

6. A pharmaceutical composition of an SGLT-2 inhibitor according to any one of claims 1 to 3, characterized in that the pharmaceutical composition comprises an outer coating; preferably, the outer coating is opadry, more preferably, the weight of opadry is 1 to 5% by weight of the uncoated tablet.

7. The pharmaceutical composition of an SGLT-2 inhibitor according to claim 1, characterized in that the pharmaceutical composition is an oral formulation, preferably a tablet, granule or capsule.

8. The pharmaceutical composition of SGLT-2 inhibitors according to claim 1, characterized in that it is present in a daily dose of compound I providing a daily dose in the range of 5-25 mg/day.

9. A method of preparing a pharmaceutical composition of an SGLT-2 inhibitor according to claim 1, characterized by comprising the steps of:

(2) And tabletting or encapsulating.

Preferably, the pretreatment in the step (1) means that the particle size of the SGLT2 inhibitor of the formula (I) is controlled to be D90.ltoreq.60. Mu.m, more preferably D90.ltoreq.30. Mu.m.

10. Use of a pharmaceutical composition of an SGLT-2 inhibitor according to claim 1 for the preparation of a medicament for the treatment of diabetes II and related diseases.