WO2021109970A1 - Xanthine derivative pharmaceutical composition and preparation method therefor - Google Patents

Abstract

Disclosed is a xanthine derivative pharmaceutical composition, specifically, a xanthine derivative pharmaceutical composition, a preparation method therefor, and the use thereof as a therapeutic drug, especially as a therapeutic dipeptidyl peptidase (DPP-IV) inhibitor.

Description

Xanthine derivative pharmaceutical composition and preparation method thereof Technical field

The invention belongs to the field of pharmaceutical preparations, and specifically relates to a xanthine derivative pharmaceutical composition and a preparation method thereof and its use as a therapeutic drug, especially as a therapeutic dipeptidyl peptidase (DPP-IV) inhibitor.

Background technique

In the 2013 edition of "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (Draft for Comment)", the newly added DPP-IV inhibitor became one of the highlights. DPP-IV inhibitors reflect the current new direction of diabetes treatment, that is, from simply controlling glycated hemoglobin to improving β-cell function, stably controlling blood sugar and avoiding hypoglycemia. At present, no single-drug therapy can prevent the failure of β-cell function as the disease progresses. According to different clinical individual needs, it is particularly critical to choose the most reasonable drug combination and treatment timing, and the target of DPP-IV inhibitors is the basis. The brand-new mechanism of medicine has become one of the choices and an important choice for the treatment of type 2 diabetes.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are used in the treatment of type 2 diabetes and have a strong selective inhibitory effect on DPP-IV. By inhibiting the activity of DPP-IV to maintain human endogenous levels of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), prolong the action time of GLP-1 and GIP in the human body , GLP-1 and GIP increase the synthesis of insulin and its release from pancreatic β-cells through the intracellular signal channel cyclic adenylate, thereby achieving the effect of lowering blood sugar.

Summary of the invention

The present invention provides a pharmaceutical composition of xanthine derivatives, specifically, a pharmaceutical composition of xanthine derivatives and a preparation method thereof as well as a therapeutic drug, especially as a therapeutic dipeptidyl peptidase ( DPP-IV) Use of inhibitors.

The present invention provides a xanthine derivative pharmaceutical composition, which contains 0.5-600 mg of a compound of formula I, wherein the compound of formula I has the following structure:

Further, the pharmaceutical composition contains 1-400 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1-200 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1-100 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1-50 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1-25 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1-10 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1 to 5 mg of the compound of formula I.

Further, the pharmaceutical composition contains 1 mg of the compound of formula I.

Further, the pharmaceutical composition contains 2.5 mg of the compound of formula I.

Further, the pharmaceutical composition contains 4 mg of the compound of formula I.

Further, the pharmaceutical composition contains 5 mg of the compound of formula I.

Further, the pharmaceutical composition contains 6 mg of the compound of formula I.

Further, the pharmaceutical composition contains 7.5 mg of the compound of formula I.

Further, the pharmaceutical composition contains 10 mg of the compound of formula I.

Further, the pharmaceutical composition contains 25 mg of the compound of formula I.

Further, the pharmaceutical composition contains 30 mg of the compound of formula I.

Further, the pharmaceutical composition contains 50 mg of the compound of formula I.

Further, the pharmaceutical composition contains 100 mg of the compound of formula I.

Further, the pharmaceutical composition contains 200 mg of the compound of formula I.

Further, the pharmaceutical composition contains 400 mg of the compound of formula I.

Further, the pharmaceutical composition contains 600 mg of the compound of formula I.

Further, the pharmaceutical composition contains 0.5-600 mg of the compound of formula I and one or more anti-diabetic drugs other than the compound of formula I, wherein the compound of formula I has the following structure

Further, the pharmaceutical composition contains 1-100 mg of the compound of formula I and one or more anti-diabetic drugs other than the compound of formula I.

Further, the anti-diabetic drug is selected from insulin sensitivity enhancers, compounds that affect abnormal regulation of hepatic glucose production, insulin signal transduction pathway regulators or insulin secretion promoters.

Further, the anti-diabetic drugs are selected from the group consisting of non-sulfonylurea insulin secretagogues, sulfonylurea insulin secretagogues, biguanides, SGLT2 inhibitors, thiazolidinediones, α-glucosidase inhibitors , GPR40 agonist or hydroxymethylglutaryl-CoA reductase inhibitor.

Further, the anti-diabetic drug is selected from repaglinide, nateglinide, mitiglinide, glimepiride, gliclapide, glibenclamide, glibenclamide, acetohexamide , Chlorpropamide, glibenclamide, tolbutamide, tolazamide, glipizide, sulfambutamide, gliquidone, glibenclamide, tolbutamide, tolazamide Urea, gliclazide, metformin, dapagliflozin, canagliflozin, empagliflozin, pioglitazone, rosiglitazone, acarbose, voglibose, miglitol, TAK875, furfur Glipizide, simvastatin, atorvastatin calcium, lovastatin, pravastatin or mevastatin or a pharmaceutically acceptable salt thereof.

Further, the anti-diabetic drug is selected from one of repaglinide, glimepiride, metformin, canagliflozin, pioglitazone, voglibose, simvastatin, or a pharmaceutically acceptable one of repaglinide, glimepiride, metformin, canagliflozin, pioglitazone, voglibose, and simvastatin salt.

Further, the compound of formula I in the pharmaceutical composition exists as a pharmaceutically acceptable salt or as a free base

Further, the compound of formula I in the pharmaceutical composition exists as a free base.

Further, the pharmaceutically acceptable salt is selected from hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.

Further, the pharmaceutically acceptable salt is selected from p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid.

Further, the pharmaceutical composition contains 0.5-600 mg of the compound of formula I, fillers and lubricants, wherein the compound of formula I has the following structure:

Further, the pharmaceutical composition contains 1-400 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 1-200 mg of the compound of formula I, fillers, and lubricants.

Further, the pharmaceutical composition contains 1-100 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 1-50 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 1-25 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 1-10 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 1 to 5 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 600 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 400 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 200 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 100 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 50 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 30 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 25 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 10 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 5 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 2.5 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition contains 1 mg of the compound of formula I, a filler, and a lubricant.

Further, the pharmaceutical composition also contains a binder selected from starch slurry, polyvinylpyrrolidone, polyethylene glycols, copovidone, hydroxypropyl cellulose, hypromellose, One or more of sodium carboxymethyl cellulose, methyl cellulose, and ethyl cellulose.

Further, the adhesive in the pharmaceutical composition is copovidone.

Further, the pharmaceutical composition also contains a disintegrant, and the disintegrant is selected from the group consisting of dry starch, alginic acid, sodium alginate, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose One or more of sodium cellulose, calcium carboxymethyl cellulose and sodium carboxymethyl starch.

Further, the disintegrant in the pharmaceutical composition is low-substituted hydroxypropyl cellulose.

Further, the filler in the pharmaceutical composition is selected from one or more of lactose, sugar alcohols, starch, pregelatinized starch, microcrystalline cellulose, sucrose, inorganic salts and dextrin.

Further, the filler in the pharmaceutical composition is selected from one or two of pregelatinized starch and microcrystalline cellulose.

Further, in the pharmaceutical composition, the lubricant is selected from colloidal silicon dioxide, magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycols, magnesium lauryl sulfate, sodium lauryl sulfate, One or more of sodium stearyl fumarate, stearic acid and calcium hydrogen phosphate.

Further, in the pharmaceutical composition, the lubricant is selected from one or two of colloidal silicon dioxide or magnesium stearate.

Further, the pharmaceutical composition contains 1-600 mg of the compound of formula I and fillers, lubricants, disintegrants and binders, wherein the compound of formula I has the following structure:

Further, the pharmaceutical composition contains 600 mg of the compound of formula I, a filler, a lubricant, a disintegrant and a binder.

Further, the pharmaceutical composition contains 400 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 200 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 100 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 50 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 25 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 10 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 5 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 2.5 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 1 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.

Further, the pharmaceutical composition contains 1-100 mg of the compound of formula I, 0.5-10.0 mg of colloidal silicon dioxide, 13.65-205.0 mg of microcrystalline cellulose, 11.22-230.0 mg of pregelatinized starch, and 1.2-10.0 of copovidone. mg, low-substituted hydroxypropyl cellulose 1.2-30.0mg, magnesium stearate 0.3-5.0mg.

Further, the pharmaceutical composition contains 1 mg of compound of formula I, 0.5 mg of colloidal silicon dioxide, 13.65 mg of microcrystalline cellulose, 13.72 mg of pregelatinized starch, 1.5 mg of copovidone, and 1.5 mg of low-substituted hydroxypropyl cellulose. mg, magnesium stearate 0.38mg.

Further, the pharmaceutical composition contains 2.5 mg of compound of formula I, 0.5 mg of colloidal silicon dioxide, 54.9 mg of microcrystalline cellulose, 13.72 mg of pregelatinized starch, 1.5 mg of copovidone, and low-substituted hydroxypropyl cellulose 1.5mg, 0.38mg of magnesium stearate.

Further, the pharmaceutical composition contains 5.0 mg of the compound of formula I, 1.0 mg of colloidal silicon dioxide, 109.8 mg of microcrystalline cellulose, 27.45 mg of pregelatinized starch, 3.0 mg of copovidone, and low-substituted hydroxypropyl cellulose 3.0mg, 0.75mg magnesium stearate.

Further, the pharmaceutical composition contains 100 mg of compound of formula I, 0.2 mg of colloidal silicon dioxide, 120 mg of microcrystalline cellulose, 220 mg of pregelatinized starch, 10 mg of copovidone, 35 mg of low-substituted hydroxypropyl cellulose, and stearin Magnesium acid 2.5mg.

Further, the pharmaceutical composition contains 25 mg of compound of formula I, 5 mg of colloidal silicon dioxide, 205 mg of microcrystalline cellulose, 51.3 mg of pregelatinized starch, 6 mg of copovidone, 6 mg of low-substituted hydroxypropyl cellulose, and stearin Magnesium acid 1.5mg.

Further, the pharmaceutical composition contains 1 mg of compound of formula I, 0.2 mg of colloidal silicon dioxide, 44.8 mg of microcrystalline cellulose, 11.22 mg of pregelatinized starch, 1.2 mg of copovidone, and 1.2 mg of low-substituted hydroxypropyl cellulose. mg, magnesium stearate 0.3mg.

Further, the compound of formula I in the pharmaceutical composition is a hydrate thereof, and has the following structure:

Further, the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms. Such as granules, capsules or tablets.

The present invention also provides a preparation method of the xanthine derivative pharmaceutical composition. The preparation process of different dosage forms can be preferably the following preparation methods:

The preparation method of the granules: the compound of formula I and pharmaceutically acceptable auxiliary materials are granulated and dried, then mixed with a lubricant and packaged.

The preparation method of the capsule: mix the compound of formula I, hydrate or its pharmaceutically acceptable salt with pharmaceutically acceptable excipients, and then fill the capsule or mix the compound of formula I with pharmaceutically acceptable excipients, and add the viscous compound. After the mixture is granulated and dried, the lubricant is added, and the capsules are filled after mixing evenly.

Tablet preparation method: mixing the compound of formula I, hydrate or pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients and then directly compressing the tablet, coating with a film coating premix aqueous solution; or applying the compound of formula I , Hydrate or its pharmaceutically acceptable salt is mixed with pharmaceutically acceptable excipients and then dry granulated, mixed with the remaining excipients and compressed into tablets, coated with a film coating premix aqueous solution; or the compound of formula I, hydrated The compound or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable auxiliary material and then added to a binder, granulated and dried, then mixed with a lubricant, and then compressed into a tablet, and then coated with an aqueous solution of a film coating premix.

Another object of the present invention is to disclose the use of the pharmaceutical composition as a medicament for treating dipeptidyl peptidase IV related diseases; specifically, the use is to prepare a drug for treating type II diabetes or impaired glucose tolerance The use of drugs in the treatment of diseases.

The test of the influencing factors of the present invention shows that after being placed under high humidity (RH92.5%) conditions for 10 days, the properties, dissolution, related substances and content of the composition samples prepared in the examples of the present invention have no significant changes; After being placed under the conditions of ℃ and light (4500Lx±500Lx) for 10 days, the properties, dissolution and content of the composition did not change significantly, and the related substances increased slightly. It shows that the pharmaceutical composition prepared by the embodiment of the present invention has good stability and excellent quality.

After formula I compound and other anti-diabetic drugs such as metformin hydrochloride, pioglitazone hydrochloride, voglibose, etc. compose a compound formula, the oral glucose tolerance test (OGTT) test in normal mice shows that under the same conditions, the formula I compound of the present invention and Compared with a compound composed of anti-diabetic drugs and a positive control drug, it has a more significant hypoglycemic effect and is a significant improvement compared with a compound composed of the same anti-diabetic drugs.

Through the tolerability, pharmacokinetics and pharmacodynamic experiments of a single administration in healthy humans, the results show that a single administration of the compound of formula I tablets has good safety and tolerability in Chinese volunteers, and a single oral administration The maximum tolerated dose of the medicine is 600 mg. A single administration of the compound of formula I at a dose of more than 400 mg, one tablet each time, maintains the DPP-4 activity inhibition rate at about 80% 168 hours after administration.

Through the tolerability, pharmacokinetics and pharmacodynamic experiments of multiple administrations in healthy humans, the results show that a single administration of the compound of formula I tablets has good safety and tolerability in Chinese volunteers. The maximum tolerated dose of the medicine is 400 mg. The subject takes the compound of formula I tablets at a dose of more than 200 mg, one tablet per week, and the inhibitory rate of DPP-4 activity is maintained at more than 80% after taking multiple doses of DPP-4. When the compound of formula I tablets are administered once a week, and when the dose is ≥200mg in multiple administrations, the inhibition rate of DDP-4 enzyme activity is maintained at 80% and above, which is expected to maintain a stable therapeutic effect. 200mg-400mg once a week may be administered It is a clinically effective dose.

Description of the drawings

Figure 1 The relationship between DPP-4 enzyme inhibition rate and time after a single oral administration of the compound of formula I in Test Example 1

Detailed ways

The following describes the present invention in further detail with reference to the embodiments, but it is not a limitation of the present invention. Any equivalent replacement in the field made in accordance with the disclosure of the present invention belongs to the protection scope of the present invention.

Compatibility test of raw materials

In order to screen the excipients suitable for the preparation of the present invention, the filler mannitol 200SD, microcrystalline cellulose PH102, pregelatinized starch and the dihydrate of the compound of formula I were mixed in a certain proportion, and they were set to accelerate (40℃, RH75%±5). %) closed and accelerated (40°C, RH75%±5%) open conditions for 10 days and 30 days to investigate the properties and related substances. The test results are shown in the following table. The related substance detection adopts the related substance chromatographic conditions explored in the early stage of the API. The specific chromatographic conditions are as follows:

Mobile phase: mobile phase A: 0.02mol/L sodium dihydrogen phosphate (0.1% triethylamine, adjust the pH to 3.0 with phosphoric acid);

Mobile phase B: acetonitrile;

Chromatographic column: octadecylsilane bonded silica gel as filler (4.6mm×25cm, 5μm);

Flow rate: 1.0ml/min;

Column temperature: 30℃;

Detection wavelength: 220nm;

Gradient program:

Table 1 Compatibility test results of raw and auxiliary materials

The above test results show that:

(1) The dihydrate of the compound of formula I and mannitol 200SD under accelerated (40℃±2℃, RH75%±5%) open and airtight storage conditions are compared with the dihydrate of the compound of formula I in a single place. Compared with, the number and total amount of impurities increased significantly, indicating that the compatibility of the dihydrate of the compound of formula I and mannitol 200SD is not good;

(2) The mixture of the dihydrate of the compound of formula I, microcrystalline cellulose, and pregelatinized starch under accelerated (40℃±2℃, RH75%±5%) open and airtight storage conditions, and a single place Compared with the dihydrate of the compound of formula I, the impurities have no obvious changes, indicating that the dihydrate of the compound of formula I has better compatibility with microcrystalline cellulose and pregelatinized starch.

Example 1 Each 1000 tablets contains the following ingredients (0.5mg)

Component To Compound of formula I 0.5g Colloidal silica 0.2g Microcrystalline cellulose 37.2g starch 9.3g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、胶态二氧化硅、微晶纤维素、淀粉加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 1.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and starch in a prescription amount into a mixing hopper to mix; press tablets; use Film coating premix aqueous solution coating, ready-to-have.

Example 2 Each 1000 tablets contains the following ingredients (1.5mg)

Component To Formula I compound 1.5g Colloidal silica 0.2g Microcrystalline cellulose 37.2g starch 9.3g

Preparation method: the same as in Example 1.

Example 3 Each 1000 tablets contains the following ingredients (4.0mg)

Component To Compound of formula I 4.0g Colloidal silica 1.0g Microcrystalline cellulose 109.8g starch 27.5g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、胶态二氧化硅、微晶纤维素、淀粉加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and starch in a prescription amount into a mixing hopper to mix; press tablets; use Film coating premix aqueous solution coating, ready-to-have.

Example 4 Each 1000 tablets contains the following ingredients (6.0mg)

Component To

Compound of formula I 6.0g Colloidal silica 1.2g Microcrystalline cellulose 108.8g starch 27.2g

Preparation method: the same as in Example 3.

Example 5 Each 1000 tablets contains the following ingredients (1.0mg)

Component To Compound of formula I 1.0g Colloidal silica 0.2g Microcrystalline cellulose 37.2g Pregelatinized starch 9.3g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、胶态二氧化硅、微晶纤维素、预胶化淀粉加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 1.5g of film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and pregelatinized starch in a prescribed amount into a mixing hopper to mix; Tablets; coated with a film-coating premix aqueous solution, ready to be obtained.

Example 6 Each 1000 tablets contains the following ingredients (2.0mg)

Component To Compound of formula I 2.0g Colloidal silica 0.5g Microcrystalline cellulose 54.9g Pregelatinized starch 13.72g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、胶态二氧化硅、微晶纤维素、预胶化淀粉加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 2.25g of film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and pregelatinized starch in a prescribed amount into a mixing hopper to mix; Tablets; coated with a film-coating premix aqueous solution, ready to be obtained.

Example 7 Each 1000 tablets contains the following ingredients (2.5mg)

Component To Dihydrate of compound of formula I 2.5g Colloidal silica 0.5g Microcrystalline cellulose 54.9g Pregelatinized starch 13.72g Copovidone 1.5g Low-substituted hydroxypropyl cellulose 1.5g Magnesium stearate 0.38g

配成浓度约为14％(w/w)的水混悬液， 备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 2.25g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; combine the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

Example 8 Each 1000 tablets contains the following ingredients (5.0mg)

Component To Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 109.8g Pregelatinized starch 27.45g Copovidone 3.0g Low-substituted hydroxypropyl cellulose 3.0g Magnesium stearate 0.75g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

Example 9 Each 1000 tablets contains the following ingredients (10.0mg)

Component To Dihydrate of compound of formula I 10.0g Colloidal silica 2.0g Microcrystalline cellulose 105.0g Pregelatinized starch 26.25g

Preparation method: the same as in Example 8.

Examples 10-14: Each 1000 capsules in each example contains the following components

Component Example 10 Example 11 Example 12 Example 13 Example 14 Compound of formula I 6.5g 7.5g 12.5g 15.0g 20.0g Microcrystalline cellulose 108.4g 108.2g 102.6g 100.2g 118.3g Pregelatinized starch 27.09g 27.1g 25.7g 25.1g 29.6g Magnesium stearate 0.8g 0.8g 0.8g 0.8g 0.8g

Example 10 Preparation method:

Add the prescription amount of the compound of formula I and the prescription amount of microcrystalline cellulose, pregelatinized starch, and magnesium stearate into a mixing hopper and mix; fill the capsules to get it.

The preparation method of Example 11 is the same as that of Example 10.

The preparation method of Example 12 is the same as that of Example 10.

The preparation method of Example 13 is the same as that of Example 10.

The preparation method of Example 14 is the same as that of Example 10.

Examples 15-16: Each example contains the following components per 1000 tablets

Component Example 15 Example 16 Compound of formula I 25.0g 30.0g Colloidal silica 5.0g 6.0g Microcrystalline cellulose 113.5g 108.7g starch 28.4g 27.2g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物与处方量的微晶纤维素、淀粉、胶态二氧化硅加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Example 15 Preparation method: 5.2g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound in the prescription amount and the microcrystalline cellulose, starch, and colloidal silicon dioxide in the prescription amount into the mixing hopper to mix; Tablets; coated with a film-coating premix aqueous solution, ready to be obtained.

The preparation method of Example 16 is the same as that of Example 15.

Examples 17-19: Each 1000 capsules in each example contains the following components

Component Example 17 Example 18 Example 19 Compound of formula I 40.0g 50.0g 60.0g Colloidal silica 8.0g 10.0g 12.0g Microcrystalline cellulose 99.1g 120.1g 110.5g starch 24.8g 30.1g 27.7g

Example 17 Preparation method:

Add the prescription amount of the compound of formula I and the prescription amount of microcrystalline cellulose, starch, and colloidal silicon dioxide into a mixing hopper and mix; fill the capsules to get it.

The preparation method of Example 18 is the same as that of Example 17.

The preparation method of Example 19 is the same as that of Example 17.

Example 20 contains the following ingredients per 1000 tablets (1.0mg)

Component To Dihydrate of compound of formula I 1.0g Colloidal silica 0.2g Microcrystalline cellulose 44.8g Pregelatinized starch 11.22g Copovidone 1.2g Low-substituted hydroxypropyl cellulose 1.2g Magnesium stearate 0.3g

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用； 将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 2.0g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

Example 21 Each 1000 tablets contains the following ingredients (25.0mg)

Component To Dihydrate of compound of formula I 25.0g Colloidal silica 5.0g Microcrystalline cellulose 205.2g Pregelatinized starch 51.3g Copovidone 6.0g Low-substituted hydroxypropyl cellulose 6.0g Magnesium stearate 1.5g

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 9.0g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

Example 22 Each 1000 tablets contains the following ingredients (100.0mg)

Component To Dihydrate of compound of formula I 100.0g Colloidal silica 10.0g Microcrystalline cellulose 115.0g Pregelatinized starch 230.0g Copovidone 10.0g Low-substituted hydroxypropyl cellulose 30.0g Magnesium stearate 5.0g

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、预胶化淀粉、共聚维酮、胶态二氧化硅、内加部分低取代羟丙基纤维素、内加部分硬脂酸镁加入混合料斗中混合，制备预混粉末，然后将预混粉末置于干法制粒机中，制成干颗粒；干颗粒中加入处方量的微晶纤维素、外加部分低取代羟丙基纤维素、外加部分硬脂酸镁总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 15.0g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; combine the formula I compound dihydrate, pregelatinized starch, copovidone, colloidal silicon dioxide, and internal addition in the prescribed amount Low-substituted hydroxypropyl cellulose and part of magnesium stearate are added to the mixing hopper and mixed to prepare a pre-mixed powder. Then the pre-mixed powder is placed in a dry granulator to make dry granules; the dry granules are added in the prescribed amount The microcrystalline cellulose, a part of low-substituted hydroxypropyl cellulose, and a part of magnesium stearate are added together; tableted; coated with an aqueous solution of film-coating premix agent to obtain.

Example 23 Each 1000 tablets contains the following ingredients (5.0mg)

Component To

Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 106.8g Pregelatinized starch 26.7g Copovidone 6.0g Low-substituted hydroxypropyl cellulose 3.0g Magnesium stearate 1.5g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

Example 24 Each 1000 tablets contains the following ingredients (10mg)

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量式I化合物的对甲苯磺酸盐、微晶纤维素、预胶化淀粉、硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; add the p-toluenesulfonate, microcrystalline cellulose, pregelatinized starch, and magnesium stearate of the compound of formula I in the prescribed amount into the mixing hopper Medium mixing; tablet compression; coating with aqueous solution of film coating premix, ready to be obtained.

Example 25 Each 1000 tablets contains the following ingredients (10mg)

Component To Hydrochloride of compound of formula I 10.76g Microcrystalline cellulose 105.0g Pregelatinized starch 26.25g Sodium Stearyl Fumarate 0.75g

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的盐酸盐、甘露醇、微晶纤维素、硬脂富马酸钠加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound hydrochloride, mannitol, microcrystalline cellulose, and sodium stearyl fumarate into the mixing hopper Mixing; tableting; coating with a film-coating premix aqueous solution, ready to be obtained.

Example 26 Each 1000 tablets contains the following ingredients (10mg)

Component To Tartrate salt of compound of formula I 13.12g Microcrystalline cellulose 105.0g Pregelatinized starch 26.25g Magnesium Lauryl Sulfate 0.75g

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的酒石酸盐、微晶纤维素、预胶化淀粉、月桂醇硫酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; add the formula I compound tartrate, microcrystalline cellulose, pregelatinized starch, and magnesium lauryl sulfate into a mixing hopper to mix ; Compressing tablets; Coating with a film-coating premix aqueous solution, ready to be obtained.

Example 27 Each 1000 tablets contains the following ingredients (10mg)

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的三氟乙酸盐与微晶纤维素、预胶化淀粉、十二烷基硫酸钠加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; combine the formula I compound trifluoroacetate with microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate Add it to the mixing hopper to mix; compress tablets; use the film coating premix aqueous solution to coat, and it is ready.

Examples 28 to 33: Each example contains the following ingredients per 1000 tablets

Component Example 28 Example 29 Example 30 Example 31 Example 32 Example 33 Compound of formula I 0.5g 2.5g 5.0g 10.0g 25.0g 100.0g Metformin Hydrochloride 1000.0g 1000.0g 1000.0g 1000.0g 1000.0g 1000.0g Microcrystalline cellulose 139.3g 137g 134.0g 128.0g 110.0g 20.0g Polyvinylpyrrolidone 24.0g 24.0g 24.0g 24.0g 24.0g 24.0g Sodium Stearyl Fumarate 12.0g 12.0g 12.0g 12.0g 12.0g 12.0g

Preparation method of Example 28:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、微晶纤维素、盐酸二甲双胍加入混合料斗中混合，得到预混粉末；将预混粉末置于制粒机中，加入聚乙烯吡咯烷酮水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的硬脂富马酸钠，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Prepare the prescription amount of polyvinylpyrrolidone into a 5% (w/w) aqueous solution for use; 36.0g of film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; add the formula I compound, microcrystalline cellulose, and metformin hydrochloride in a prescription amount into a mixing hopper and mix to obtain a pre-mixed powder; the pre-mixed powder Place it in a granulator, add an aqueous solution of polyvinylpyrrolidone to make wet granules; dry the wet granules; add a prescription amount of sodium stearyl fumarate and mix together; press tablets; use a film coating premix aqueous solution to coat, Immediately.

The preparation method of Example 29 is the same as that of Example 28.

The preparation method of Example 30 is the same as that of Example 28.

The preparation method of Example 31 is the same as that of Example 28.

The preparation method of Example 32 is the same as that of Example 28.

The preparation method of Example 33 is the same as that of Example 28.

Example 34: Each 1000 bags contains the following components

Component To Hydrochloride of compound of formula I 5.38g Metformin Hydrochloride 1000.0g talcum powder 0.2g Microcrystalline cellulose 139.3g Copovidone 24.0g

Preparation method of Example 34:

Prepare the prescription amount of copovidone into a 5% (w/w) aqueous solution for later use; add the prescription amount of formula I compound hydrochloride, microcrystalline cellulose, and metformin hydrochloride into a mixing hopper and mix to obtain a premixed powder ; Place the pre-mixed powder in a granulator, add an aqueous solution of copovidone to make wet granules; dry the wet granules; add a prescription amount of talcum powder, mix together; package, and get ready.

Examples 35-40: Each 1000 capsules in each example contains the following components

Component Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 Compound of formula I 0.5g 2.5g 5.0g 10.0g 25.0g 100.0g Pioglitazone hydrochloride 30.0g 30.0g 30.0g 30.0g 30.0g 30.0g Colloidal silica 2.0g 3.0g 4.0g 5.0g 6.0g 10.0g Microcrystalline cellulose 157.84g 156.0g 153.6g 148.8g 134.4g 108.0g starch 39.46g 39.0g 38.4g 37.2g 33.6g 27.0g Hydroxypropyl cellulose 4.8g 4.8g 4.8g 4.8g 4.8g 6.0g

Example 35 Preparation method:

Prepare the prescription amount of hydroxypropyl cellulose into a 6% (w/w) aqueous solution for use; add the prescription amount of formula I compound, microcrystalline cellulose, starch, and pioglitazone hydrochloride into a mixing hopper and mix to obtain a premixed powder ; Place the pre-mixed powder in a granulator, add a prescription amount of hydroxypropyl cellulose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of colloidal silica, mix together; fill the capsules to get .

The preparation method of Example 36 is the same as that of Example 35.

The preparation method of Example 37 is the same as that of Example 35.

The preparation method of Example 38 is the same as that of Example 35.

The preparation method of Example 39 is the same as that of Example 35.

The preparation method of Example 40 is the same as that of Example 35.

Example 41: Each 1000 tablets contains the following components

Component To Hydrochloride of compound of formula I 5.38g Pioglitazone hydrochloride 30.0g Microcrystalline cellulose 122.8g lactose 30.7g Hypromellose 4.0g Polyethylene glycol 6000 2.0g

Example 41 Preparation method:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的盐酸盐、微晶纤维素、乳糖、盐酸吡格列酮加入混合料斗中混合，得到预混粉末；将预混粉末置于制粒机中，加入处方量的羟丙甲纤维素水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的聚乙二醇6000，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Prepare the prescription amount of hypromellose into a 5% (w/w) aqueous solution for use; 6.0g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound hydrochloride, microcrystalline cellulose, lactose, and pioglitazone hydrochloride into a mixing hopper and mix to obtain a premix Powder; put the pre-mixed powder in a granulator, add a prescription amount of hypromellose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of polyethylene glycol 6000, mix together; press tablets; use Film coating premix aqueous solution coating, ready-to-have.

Examples 42-47: Each of the examples contains the following components per 1000 tablets

Component Example 42 Example 43 Example 44 Implementation 45 Example 46 Example 47 Compound of formula I 0.5g 2.5g 5.0g 10.0g 25.0g 100.0g Voglibose 0.3g 0.3g 0.3g 0.3g 0.3g 0.3g Microcrystalline cellulose 48.6g 111.4g 109.0g 104.2g 112.6g 283.8g sucrose 12.2g 27.8g 27.2g 26.0g 28.1g 70.9g Hypromellose 1.3g 3.0g 3.0g 3.0g 3.6g 10.0g Magnesium stearate 0.7g 1.5g 1.5g 1.5g 1.8g 5.0g

Example 42 Preparation method:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、微晶纤维素、蔗糖、伏格列波糖得到预混粉末；将预混粉末置于制粒机中，加入处方量的羟丙甲纤维素水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的硬脂酸镁，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Prepare the prescription amount of hypromellose into a 5% (w/w) aqueous solution for use; 1.95g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; prepare the formula I compound, microcrystalline cellulose, sucrose, and voglibose in the prescribed amount to obtain a pre-mixed powder; place the pre-mixed powder In the granulator, add a prescription amount of hypromellose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of magnesium stearate and mix together; press tablets; use a film coating premix aqueous solution package Clothes, get it.

Preparation methods of Examples 43-45:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、微晶纤维素、蔗糖、伏格列波糖得到预混粉末；将预混粉末置于制粒机中，加入处方量的羟丙甲纤维素水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的硬脂酸镁，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 The prescription amount of hypromellose is made into a 5% (w/w) aqueous solution for use; 4.5g of film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; prepare the formula I compound, microcrystalline cellulose, sucrose, and voglibose in the prescribed amount to obtain a pre-mixed powder; place the pre-mixed powder In the granulator, add a prescription amount of hypromellose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of magnesium stearate and mix together; press tablets; use a film coating premix aqueous solution package Clothes, get it.

Preparation method of Example 46:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、微晶纤维素、蔗糖、伏格列波糖得到预混粉末；将预混粉末置于制粒机中，加入处方量的羟丙甲纤维素水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的硬脂酸镁，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Prepare the prescription amount of hypromellose into a 5% (w/w) aqueous solution for use; 5.4g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; prepare the formula I compound, microcrystalline cellulose, sucrose, and voglibose in the prescribed amount to obtain a pre-mixed powder; place the pre-mixed powder In the granulator, add a prescription amount of hypromellose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of magnesium stearate and mix together; press tablets; use a film coating premix aqueous solution package Clothes, get it.

Preparation method of Example 47:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物、微晶纤维素、蔗糖、伏格列波糖得到预混粉末；将预混粉末置于制粒机中，加入处方量的羟丙甲纤维素水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的硬脂酸镁，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Prepare the prescription amount of hypromellose into a 5% (w/w) aqueous solution for use; 15.0g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; prepare the formula I compound, microcrystalline cellulose, sucrose, and voglibose in the prescribed amount to obtain a pre-mixed powder; place the pre-mixed powder In the granulator, add a prescription amount of hypromellose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of magnesium stearate and mix together; press tablets; use a film coating premix aqueous solution package Clothes, get it.

Example 48: Each 1000 tablets contains the following components

Component To Trifluoroacetate of compound of formula I 6.18g Voglibose 0.3g Microcrystalline cellulose 43.2g dextrin 10.8g Ethyl cellulose 1.3g Stearic acid 0.7g

Example 48 Preparation method:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量式I化合物的三氟乙酸盐、微晶纤维素、糊精、伏格列波糖加入混合料斗中混合，得到预混粉末；将预混粉末置于制粒机中，加入处方量的乙基纤维素水溶液制成湿颗粒；湿颗粒进行干燥；加入处方量的硬脂酸，总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 The prescription amount of ethyl cellulose is made into a 6% (w/w) aqueous solution for use; 1.95g of film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the trifluoroacetate, microcrystalline cellulose, dextrin, and voglibose of the compound of formula I in the prescribed amount into the mixing hopper Mix to obtain a pre-mixed powder; place the pre-mixed powder in a granulator, add a prescription amount of ethyl cellulose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of stearic acid, and mix together; tableting ; Use film coating premix aqueous solution to coat, ready.

Examples 49-50: Each 1000 capsules in each example contains the following components

Component Example 49 Example 50 Compound of formula I 25.0g 30.0g Colloidal silica 5.0g 6.0g Microcrystalline cellulose 113.5g 108.7g starch 28.4g 27.2g

Example 49 Preparation method:

Add the prescription amount of the compound of formula I and the prescription amount of microcrystalline cellulose, starch, and colloidal silicon dioxide into a mixing hopper and mix; fill the capsules to get it.

The preparation method of Example 50 is the same as that of Example 49.

Example 51 contains the following ingredients per 1000 tablets (5.0mg)

Component To Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 68.2g Pregelatinized starch 68.2g Copovidone 3.0g Low-substituted hydroxypropyl cellulose 3.0g Magnesium stearate 1.5g

Preparation:

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉、式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose, pregelatinized starch, the sieving material of the compound of formula I and magnesium stearate are added into a mixing hopper and mixed; compressed tablets; coated with an aqueous solution of a film-coating premix agent to obtain the product.

Example 52 Each 1000 tablets contains the following ingredients (5.0mg)

Component To Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 109.2g Pregelatinized starch 27.3g Copovidone 3.0g Low-substituted hydroxypropyl cellulose 3.0g Magnesium stearate 1.5g

The preparation method of Example 52 is the same as that of Example 51.

Examples 53 to 54 contain the following ingredients per 1000 tablets (2.5mg)

Component Example 53 Example 54 Dihydrate of compound of formula I 2.5g 2.5g Colloidal silica 0.5g 0.5g Microcrystalline cellulose 34.1g 13.65 Pregelatinized starch 34.1g 54.6g Copovidone 1.5g 1.5g Low-substituted hydroxypropyl cellulose 1.5g 1.5g Magnesium stearate 0.75g 0.75g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Example 53 Preparation method: 2.25g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

The preparation method of Example 54 is the same as that of Example 53.

Examples 55-58 Contain the following ingredients per 1000 tablets (2.5mg)

Component Example 55 Example 56 Example 57 Example 58 Dihydrate of compound of formula I 2.5g 2.5g 2.5g 2.5g Colloidal silica 0.5g 0.5g 0.5g 0.5g Microcrystalline cellulose 54.6g 53.4g 52.2g 55.2g Pregelatinized starch 13.65g 13.35g 13.05g 13.8g Copovidone 1.5g 3g 4.5g 1.5g Low-substituted hydroxypropyl cellulose 1.5g 1.5g 1.5g 0.75g Magnesium stearate 0.75g 0.75g 0.75g 0.75g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的式I化合物的二水合物、胶态二氧化硅、微晶纤维素、共聚维酮、低取代羟丙基纤维素、预胶化淀粉加入混合料斗中混合后过筛，再将上述式I化合物过筛物料和硬脂酸镁加入混合料斗中混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Example 55 Preparation method: 2.25g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.

The preparation method of Example 56 is the same as that of Example 55.

The preparation method of Example 57 was the same as that of Example 55.

The preparation method of Example 58 is the same as that of Example 55.

Example 59 Each 1000 tablets contains the following ingredients (5.0mg)

Component To Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 104.4g Pregelatinized starch 26.1g Copovidone 9.0g Low-substituted hydroxypropyl cellulose 3.0g Magnesium stearate 1.5g

The preparation method of Example 59 is the same as that of Example 51.

Example 60 Each 1000 tablets contains the following ingredients (5.0mg)

Component To Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 110.4g Pregelatinized starch 27.6g Copovidone 3.0g Low-substituted hydroxypropyl cellulose 1.5g Magnesium stearate 1.5g

The preparation method of Example 60 was the same as that of Example 51.

Example 61 Each 1000 tablets contains the following ingredients (2.5mg)

Component To Dihydrate of compound of formula I 2.5g Colloidal silica 0.5g Microcrystalline cellulose 54.9g Pregelatinized starch 13.7g Copovidone 1.5g Low-substituted hydroxypropyl cellulose 1.5g Magnesium stearate 0.375g

The preparation method of Example 61 was the same as that of Example 55.

Example 62 A blank sample of 2.5 mg specification, every 1000 tablets contains the following ingredients.

Component To Colloidal silica 0.50g Microcrystalline cellulose 56.90g Pregelatinized starch 14.22g Copovidone 1.50g Low-substituted hydroxypropyl cellulose 1.50g Magnesium stearate 0.38g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的胶态二氧化硅、微晶纤维素、预胶化淀粉、共聚维酮、低取代羟丙基纤维素、硬脂酸镁混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 2.25g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, copovidone, and low-substituted hydroxypropyl fiber Mixing vegetarian and magnesium stearate; compressing tablets; coating with aqueous solution of film coating premix, ready to be obtained.

Example 63 A blank sample of 5 mg specification contains the following ingredients per 1000 tablets.

Component To

Colloidal silica 1.00g Microcrystalline cellulose 113.80g Pregelatinized starch 28.45g Copovidone 3.00g Low-substituted hydroxypropyl cellulose 3.00g Magnesium stearate 0.75g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的胶态二氧化硅、微晶纤维素、预胶化淀粉、共聚维酮、低取代羟丙基纤维素、硬脂酸镁混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 4.5g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, copovidone, and low-substituted hydroxypropyl fiber Mixing vegetarian and magnesium stearate; compressing tablets; coating with aqueous solution of film coating premix, ready to be obtained.

Example 64 A blank sample of 25 mg specifications contains the following ingredients per 1000 tablets.

Component To Colloidal silica 5.00g Microcrystalline cellulose 225.20g Pregelatinized starch 56.30g Copovidone 6.00g Low-substituted hydroxypropyl cellulose 6.00g Magnesium stearate 1.50g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的胶态二氧化硅、微晶纤维素、预胶化淀粉、共聚维酮、低取代羟丙基纤维素、硬脂酸镁混合；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 9g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, copovidone, and low-substituted hydroxypropyl fiber Mixing vegetarian and magnesium stearate; compressing tablets; coating with aqueous solution of film coating premix, ready to be obtained.

Example 65 A blank sample of 100 mg specification contains the following ingredients per 1000 tablets.

Component To Precrossed starch 230g Low-substituted hydroxypropyl cellulose 30g Copovidone 10g Colloidal silica 10g Microcrystalline cellulose 215g Magnesium stearate 5g

配成浓度约为14％(w/w)的水混悬液，备用；将处方量的预胶化淀粉、共聚维酮、胶态二氧化硅、内加部分低取代羟丙基纤维素、内加部分硬脂酸镁加入混合料斗中混合，制备预混粉末，然后将预混粉末置于干法制粒机中，制成干颗粒；干颗粒中加入处方量的微晶纤维素、外加部分低取代羟丙基纤维素、外加部分硬脂酸镁总混；压片；采用薄膜包衣预混剂水溶液包衣，即得。 Preparation method: 15.0g film coating premix

Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of pregelatinized starch, copovidone, colloidal silicon dioxide, internally added part of low-substituted hydroxypropyl cellulose, Add part of magnesium stearate into the mixing hopper and mix to prepare pre-mixed powder, then put the pre-mixed powder in a dry granulator to make dry granules; add prescription amount of microcrystalline cellulose and additional part to the dry granules Low-substituted hydroxypropyl cellulose and a part of magnesium stearate are mixed; tableting; coated with aqueous solution of film coating premix, ready to be obtained.

Influence factor test

Take the embodiments of the present invention 1, 2, 3, 4, 5, 6, 7, 8, 9, 15, 16, 18, 23, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 , 61 samples were placed under the conditions of high temperature 60℃, high humidity (RH90%±5%) and light (4500lx±500lx) for 10 days, and samples were taken after 10 days for the detection of properties, dissolution, related substances and content.

Dissolution testing method: refer to the second method of appendix ⅹC of the 2015 edition of the Chinese Pharmacopoeia.

Content and related substance detection method: refer to Appendix VD of Part Two of Chinese Pharmacopoeia 2015 Edition.

The test results are shown in Table 2 to Table 4.

Table 2 High temperature 60℃ test results

Table 3 High humidity (RH90%±5%) test results

Table 4 Light (4500lx±500lx) test results

It can be seen from the above results that, after being placed under high humidity (RH92.5%) conditions for 10 days, the properties, dissolution, related substances and content of the samples of the present invention have no obvious changes; After being placed under the condition of ±500Lx) for 10 days, there was no significant change in properties, dissolution and content, and related substances increased slightly but all met the product quality requirements, indicating that the samples of the examples of the present invention have good stability and excellent quality.

Test Example 1 Study on tolerance, pharmacokinetics, and pharmacodynamics of a single dose in healthy humans

1 Test materials and research objects

1.1 Medicines

Control sample:

Formula I compound simulation tablets, specifications: 2.5mg/tablet (prepared in reference example 62, no active ingredient), 5mg/tablet (prepared in reference example 63, no active ingredient), 25mg/tablet (prepared in reference example 64 Obtained, no active ingredient), 100mg/tablet (prepared in Example 65, no active ingredient)

Samples of the test drug group:

Example 7 Sample: 2.5mg/tablet

Example 8 Sample: 5mg/tablet

Example 21 Sample: 25mg/tablet

Example 22 Sample: 100mg/tablet

1.2 Test equipment

Triple Quad 5500 mass spectrometer (Analyst software 1.6.3), provided by AB Sciex;

LC30AD high performance liquid chromatography system, provided by Shimadzu;

METTLER TOLEDO XS205DU electronic balance, provided by METTLER TOLEDO;

Sartorius MCM36 electronic balance, provided by Sartorius;

Thermo Scientific ^TM Forma 88700V ultra-low temperature refrigerator, provided by Thermo Company;

Thermo Scientific ^TM 232F-AEC-TSC freezer refrigerator, provided by Thermo Company;

Haier 2～8℃ refrigerator, provided by Haier Company;

Eppendorf 5920R centrifuge, provided by Eppendorf;

BF2006 Nitrogen Dryer, provided by Beijing Bafang Century Technology Co., Ltd.

1.3 Research objects

Healthy subjects, aged 18-45 years old, BMI 19-28.

2 Test method

2.1 Test grouping and dosing schedule

The test groups and dosing schedule are shown in Table 5 below:

Table 5 Test grouping and dosing schedule

Group Dosage (mg) Route of administration Number of test group Number of control group test 1 2.5 oral 10 2 Tolerance, PK 2 5 oral 10 2 Tolerance, PK 3 10 oral 10 2 Tolerance, PK 4 25 oral 10 2 Tolerance, PK/PD 5 50 oral 10 2 Tolerance, PK/PD 6 100 oral 10 2 Tolerance, PK/PD 7 200 oral 10 2 Tolerance, PK/PD 8 400 oral 10 2 Tolerance, PK/PD 9 600 oral 6 2 Tolerance

2.2 Observation of tolerance

Observe the subjects' vital signs, clinical symptoms and signs, laboratory examinations, 12-lead electrocardiogram, upper abdominal B-ultrasound, chest radiographs, and whether there are any adverse events after medication.

2.3 Pharmacokinetic test/pharmacodynamic test

Pharmacokinetic test:

Tests were performed at 2.5, 5, 10, 25, 50, 100, 200, 400 mg doses. Venous blood samples were collected before and after administration to detect the plasma concentration of eutagliptin.

Blood sample collection: 2.5～10mg dose group before administration (-30min～0min) and after administration 0.25h±1min, 0.5h±2min, 0.75h±2min, 1h±3min, 1.5h±3min, 2h±3min, 2.5h±3min, 3h±3min, 3.5h±3min, 4h±3min, 5h±3min, 6h±3min, 8h±10min, 12h±10min, 24h±30min, 48h±30min, 72h±30min, 96h±30min, Venous blood samples were collected 3.0mL at 120h±30min; 5.0mL venous blood samples were collected before administration (-30min～0min) in the 25mg dose group, and the other blood sampling time points and blood volume were the same as those in the 2.5～10mg group; the 50～400mg dose group was in the administration Collect 5.0mL venous blood sample before (-30min～0min), 0.25h±1min, 0.5h±2min, 0.75h±2min, 1h±3min, 1.5h±3min, 2h±3min, 2.5h±3min, 3h after administration ±3min, 3.5h±3min, 4h±3min, 5h±3min, 6h±3min, 8h±10min, 12h±10min, 24h±30min, 48h±30min, 72h±30min, 96h±30min, 120h±30min, 144h± 3.0 mL of venous blood samples were collected at 30min, 168h±30min, and 192h±30min.

Pharmacodynamic test:

The 25, 50, 100, 200, and 400 mg dose groups were in the pharmacokinetic test at the same time, the pharmacodynamic study was carried out to detect the DPP-4 activity in the plasma of the subjects, and calculate the DPP-4 inhibition rate (DPP-4 inhibition Rate = 1-measured value/baseline value). Investigate the inhibitory effect of eutagliptin tablets on DPP-4 and its pharmacodynamic characteristics, as well as the relationship between pharmacokinetics and pharmacodynamics. The specific blood collection time point was the same as the pharmacokinetic blood collection time point, and 2.0 mL of venous blood samples were collected for testing.

3 Statistical methods

3.1 Tolerance analysis

Describe the selection, selection, withdrawal, and rejection of subjects. The safety analysis set was used to statistically describe and analyze the demographic data, physical examination and laboratory examination results, adverse events or/and adverse reactions. The test group of each dose group and the placebo group were compared and analyzed.

3.2 Pharmacokinetic analysis

The pharmacokinetic parameters were calculated using WinNonlin 8.1 software. The non-compartmental model was used to calculate the pharmacokinetic parameters of each subject, and the WPS 2019 was used to calculate the mean and standard deviation of each parameter to evaluate the pharmacokinetic characteristics of the drug in the body. The proportional relationship between pharmacokinetic parameters and dose will be analyzed by regression analysis and the 95% two-sided confidence interval (95% CI) of the slope will be calculated. .

Analyze using a set of conforming schemes.

3.3 Pharmacodynamic analysis

According to the quantitative changes of pharmacodynamic indicators over time, the drug effects and kinetic characteristics are analyzed, and the quantitative relationship between pharmacokinetics and pharmacodynamics is preliminarily evaluated. The pharmacodynamic index is DPP-4 inhibition rate (DPP-4 inhibition rate = 1-measured value/baseline value), and preliminary evaluation of the inhibitory effect of eutagliptin tablets on DPP-4 and its effect kinetic characteristics. The pharmacodynamic parameters were calculated with NONMEM software, and the E _max model formula was adopted: E=E _max *C/(EC ₅₀ +C).

4 test results

4.1 Results of tolerance analysis

A total of 104 subjects were enrolled in the tolerance test, and one subject withdrew from the test with a positive blood pregnancy test on day -1, and the rest did not fall off or were eliminated. A total of 103 healthy volunteers completed 9 dose group trials with a single dose. The dose was increased from 2.5 mg to 600 mg in the dose group. None of the subjects could not tolerate it, and none of the subjects reached the criteria for stopping the trial.

After the medication, the subjects' vital signs were stable; there were no discomforts and abnormal signs; no clinically significant abnormalities appeared in the electrocardiogram; no serious adverse events occurred, and no trial suspension, dose reduction, or medication suspension occurred due to adverse events.

A single administration of the compound of formula I tablets has good safety and tolerability in Chinese volunteers, and the maximum tolerated dose in a single oral administration is 600 mg.

4.2 Results of pharmacokinetic analysis

The pharmacokinetic concentration analysis was performed on the subjects in the test group in the protocol set (PPS set). The PPS set included 88 subjects, of which 73 were in the test group and 15 were in the placebo group, so 73 subjects were used Perform pharmacokinetic parameter analysis. The main pharmacokinetic parameters of the compounds of formula I are summarized in Table 6 below.

Table 6 Means (standard deviations) of the main pharmacokinetic parameters of the compounds of formula I in the plasma of each dose group

*Tmax is expressed as the median (minimum-maximum)

4.3 Results of pharmacodynamic analysis

The relationship between DPP-4 enzyme inhibition rate and time after a single oral administration of the compound of formula I is shown in Figure 1.

The inhibition rate of DPP-4 enzyme in each dose group of 25-400 mg was over 97% 24h after treatment, and the inhibition rate of DPP-4 enzyme was over 75.7% in the 200-400 mg dose group 168h after treatment.

Subjects taking the compound of formula I at a dose of more than 400 mg, one tablet each time, the inhibitory rate of DPP-4 activity is maintained at about 80% within a 168-hour dosing interval.

5 Conclusion

A single administration of the compound of formula I at a dose of more than 400 mg, one tablet each time, maintains the DPP-4 activity inhibition rate at about 80% 168 hours after administration.

Claims (21)

A xanthine derivative pharmaceutical composition, characterized in that the pharmaceutical composition contains 0.5-600 mg of a compound of formula I, wherein the compound of formula I, a hydrate, or a pharmaceutically acceptable salt, and the structure of formula I is as follows:

The xanthine derivative pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 1 to 400 mg of the compound of formula I, 1 to 200 mg of the compound of formula I, 1 to 100 mg of the compound of formula I, and 1 to 50 mg of the compound of formula I Compound, 1-25 mg of formula I compound, 1-10 mg of formula I compound, or 1 to 5 mg of formula I compound. The xanthine derivative pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 1 mg, 2.5 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 100 mg, 200 mg, 400 mg or 600 mg of the compound of formula I. A xanthine derivative pharmaceutical composition, characterized in that the pharmaceutical composition contains 0.5-600 mg of a compound of formula I and one or more anti-diabetic drugs other than the compound of formula I, wherein the compound of formula I has the following structure

The xanthine derivative pharmaceutical composition according to claim 4, wherein the pharmaceutical composition contains 1-100 mg of the compound of formula I and one or more anti-diabetic drugs other than the compound of formula I. The xanthine derivative pharmaceutical composition according to claim 5, wherein the anti-diabetic drug is selected from the group consisting of insulin sensitivity enhancers, compounds that affect the abnormal regulation of hepatic glucose production, insulin signal transduction pathway regulators, or insulin Secretion promoters; preferably non-sulfonylurea insulin secretagogues, sulfonylurea insulin secretagogues, biguanides, SGLT2 inhibitors, thiazolidinediones, α-glucosidase inhibitors, GPR40 agonists or Hydroxymethylglutaryl-CoA reductase inhibitor, more preferably repaglinide, nateglinide, mitiglinide, glimepiride, gliclapide, glibenclamide, and glibenclamide , Acetohexamide, chlorpropamide, glibenclamide, tolbutamide, tolazamide, glipizide, sulfambutamide, gliquidone, glibenclamide, tolbutamide , Sulfacyclohexamide, gliclazide, metformin, dapagliflozin, canagliflozin, empagliflozin, pioglitazone, rosiglitazone, acarbose, voglibose, miglita Alcohol, TAK875, Furagliptin, Simvastatin, Avastatin Calcium, Lovastatin, Pravastatin or Mevastatin or a pharmaceutically acceptable salt thereof; more preferably Repaglinide, Glimebe One of urea, metformin, canagliflozin, pioglitazone, voglibose, simvastatin or a pharmaceutically acceptable salt thereof. The xanthine derivative pharmaceutical composition according to claim 1, wherein the compound of formula I in the pharmaceutical composition is in the form of a pharmaceutically acceptable salt or in the form of a free base, preferably in the form of a free base,

The xanthine derivative pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable salt is selected from hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, Citric acid, acetic acid or trifluoroacetic acid, preferably p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid. The xanthine derivative pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains 0.5-600 mg of the compound of formula I, fillers and lubricants, wherein the compound of formula I has the following structure:

The xanthine derivative pharmaceutical composition according to claim 9, wherein the pharmaceutical composition contains 1-400 mg of the compound of formula I and fillers, lubricants; and contains 1-200 mg of the compound of formula I and fillers, Lubricant; containing 1-100mg of formula I compound and fillers and lubricants; containing 1-50mg of formula I compound and fillers and lubricants; containing 1-25mg of formula I compounds and fillers and lubricants; containing 1 ~10mg of the compound of formula I and fillers and lubricants; or 1-5 mg of the compound of formula I and fillers and lubricants. The xanthine derivative pharmaceutical composition according to claim 9, wherein the pharmaceutical composition contains 600 mg, 400 mg, 200 mg, 100 mg, 50 mg, 30 mg, 25 mg, 10 mg, 5 mg, 2.5 mg or 1 mg of the compound of formula I And fillers, lubricants. The xanthine derivative pharmaceutical composition according to claim 1 or 9, characterized in that the pharmaceutical composition further contains a binder, and the binder is selected from starch slurry, polyvinylpyrrolidone, polyethylene glycol One or more of copovidone, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, methyl cellulose, and ethyl cellulose, preferably copovidone. The xanthine derivative pharmaceutical composition according to claim 1 or 9, wherein the pharmaceutical composition further contains a disintegrant, and the disintegrant is selected from the group consisting of dry starch, alginic acid, sodium alginate, and sodium alginate. One or more of bispovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl cellulose calcium and sodium carboxymethyl starch, preferably low-substituted hydroxypropyl cellulose Vegetarian. The xanthine derivative pharmaceutical composition according to claim 1, wherein the filler in the pharmaceutical composition is selected from lactose, sugar alcohols, starch, pregelatinized starch, microcrystalline cellulose, sucrose, One or more of inorganic salts and dextrin, preferably one or two of pregelatinized starch and microcrystalline cellulose. The xanthine derivative pharmaceutical composition according to claim 9, characterized in that, in the pharmaceutical composition, the lubricant is selected from colloidal silica, magnesium stearate, talc, hydrogenated vegetable oil, polyethylene One or more of glycols, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid and calcium hydrogen phosphate, preferably colloidal silicon dioxide or magnesium stearate One or two of them. The xanthine derivative pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 1-600 mg of the compound of formula I and fillers, lubricants, disintegrants and binders, wherein the compound of formula I Has the following structure:

The xanthine derivative pharmaceutical composition according to claim 16, wherein the pharmaceutical composition contains 600mg, 400mg, 200mg, 100mg, 50mg, 25mg, 10mg, 5mg, 2.5mg or 1mg of the compound of formula I and filler Agents, lubricants, disintegrants and adhesives. The xanthine derivative pharmaceutical composition according to claim 1 or 4, wherein the pharmaceutical composition contains 1-100 mg of the compound of formula I, 0.5-10.0 mg of colloidal silicon dioxide, and 13.65 mg of microcrystalline cellulose. 205.0mg, pregelatinized starch 11.22-230.0mg, copovidone 1.2-10.0mg, low-substituted hydroxypropyl cellulose 1.2-30.0mg, magnesium stearate 0.3-5.0mg; the pharmaceutical composition contains the compound of formula I 1mg, colloidal silicon dioxide 0.5mg, microcrystalline cellulose 13.65mg, pregelatinized starch 13.72mg, copovidone 1.5mg, low-substituted hydroxypropyl cellulose 1.5mg, magnesium stearate 0.38mg; the drug combination It contains 2.5 mg of compound of formula I, 0.5 mg of colloidal silicon dioxide, 54.9 mg of microcrystalline cellulose, 13.72 mg of pregelatinized starch, 1.5 mg of copovidone, 1.5 mg of low-substituted hydroxypropyl cellulose, and stearic acid Magnesium 0.38mg; the pharmaceutical composition contains 5.0mg of compound of formula I, 1.0mg of colloidal silicon dioxide, 109.8mg of microcrystalline cellulose, 27.45mg of pregelatinized starch, 3.0mg of copovidone, and low-substituted hydroxypropyl fiber The pharmaceutical composition contains 100 mg of compound of formula I, 0.2 mg of colloidal silicon dioxide, 120 mg of microcrystalline cellulose, 220 mg of pregelatinized starch, 10 mg of copovidone, and low-substituted hydroxy Propyl cellulose 35mg, magnesium stearate 2.5mg; the pharmaceutical composition contains 25mg of formula I compound, colloidal silicon dioxide 5mg, microcrystalline cellulose 205mg, pregelatinized starch 51.3mg, copovidone 6mg, low Substitute 6 mg of hydroxypropyl cellulose, 1.5 mg of magnesium stearate; or the pharmaceutical composition contains 1 mg of compound of formula I, 0.2 mg of colloidal silicon dioxide, 44.8 mg of microcrystalline cellulose, 11.22 mg of pregelatinized starch, and copolymer Vividone 1.2mg, low-substituted hydroxypropyl cellulose 1.2mg, magnesium stearate 0.3mg. The pharmaceutical composition of xanthine derivatives according to claim 1, wherein the hydrate in the pharmaceutical composition has the following structure:

The xanthine derivative pharmaceutical composition according to claim 1 or 4, wherein the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, preferably granules, capsules or tablets. A use of the xanthine derivative pharmaceutical composition according to claim 1 or 4, characterized in that the pharmaceutical composition is used as a medicine for the treatment of dipeptidyl peptidase IV related diseases, preferably in Use in preparing medicine for treating type II diabetes or impaired glucose tolerance disease.

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