WO2012159511A1

WO2012159511A1 - Azilsartan solid dispersion, preparation method and pharmaceutical compositions thereof

Info

Publication number: WO2012159511A1
Application number: PCT/CN2012/074162
Authority: WO
Inventors: 徐坚; 师帅; 郭晓峰; 杨闯; 石晓磊
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2011-05-23
Filing date: 2012-04-17
Publication date: 2012-11-29
Also published as: CN103260605B; CN103260605A; TW201247201A

Abstract

An azilsartan solid dispersion, preparation method and pharmaceutical compositions thereof. The azilsartan solid dispersion comprises azilsartan and carrier material, the carrier material being chosen from povidone, poloxamer, polyethylene glycol, hydroxypropyl cellulose, and polyethylene oxide.

Description

Azilsartan solid dispersion, preparation method thereof and pharmaceutical composition

Technical field

The present invention relates to a solid dispersion of azilsartan, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and use thereof in the preparation of an antihypertensive drug. Background technique

Azisartan (English name Azilsartan) is an angiotensin-receptor antagonist drug in the development of hypertension that selectively blocks the binding of angiotensin II to vascular smooth muscle ATI receptors. Blocking the vasoconstrictor of angiotensin II, which is often used to treat hypertension, is also the only angiotensin II receptor antagonist (sartan) drug in the terminal clinical stage.

Azisartan is almost insoluble in water. When it is made into an oral preparation, only azilsartan can be quickly and efficiently dissolved or dispersed in water to absorb well in the gastrointestinal tract. Otherwise, it is absorbed. And there are big obstacles to bio-use. Therefore, it is important and meaningful to improve its water solubility and dissolution without changing the pharmacological properties of its compounds.

CN101528262A discloses a solid composition comprising a pharmaceutically active ingredient, a low melting point oleaginous substance and a low viscosity binder. The technical problem mainly solved by the invention is that when a low melting point oily substance is used to improve the stability of the medicinal ingredient in the solid preparation, the dissolution property of the medicine in the solid preparation is lowered, and the dissolution is ensured by adding a low viscosity adhesive. characteristic. However, this invention does not fundamentally solve the problem that the water solubility of azilsartan is poor and the bioavailability is low.

Solid dispersion (SD) refers to a dispersion system in the form of a solid which is formed by dispersing a drug in a solid carrier. The drug is present in the carrier in a molecular state, a colloidal state, a metastable state, a microcrystalline state, and an amorphous state, and these drugs in an amorphous state (high energy state) have a solubility and a dissolution rate larger than those of other crystal states. Therefore, the present invention is the first attempt to prepare a solid dispersion of azilsartan to achieve a desired dissolution effect of the drug to improve the bioavailability of the drug. Summary of the invention

Since azilsartan is almost insoluble in water, it is essential to improve its solubility in water without changing the pharmacological properties of its compounds.

The inventors discovered through research and practice that the selection of a suitable carrier to prepare azilsartan as a solid dispersion can solve the above problems well.

The present invention provides a solid dispersion of azilsartan containing as an active ingredient azilsartan and a carrier material.

The carrier material is selected from the group consisting of povidone, poloxamer, polyethylene glycol, hydroxypropyl cellulose, polyethylene oxide, and the like. Wherein the povidone is selected from the group consisting of povidone K-17, povidone Κ-25, povidone Κ-30, povidone Κ-90; the poloxamer is selected from the poloxamer 188, Polo Sigma 407; Hydroxypropyl cellulose is selected, for example, from the trade name Klucel® LF Klucel® JF Klucel® -EF Klucel® -EXF, polyoxyethylene selected as polyoxyethylene N80. Povidone K-17, povidone oxime-25, povidone oxime-30, povidone oxime-90 are preferred, and povidone oxime-30 is most preferred.

The mass ratio of the active ingredient azilsartan to the carrier material in the present invention is in the range of 1:0.5 to 1:10, preferably 1:1 to 1:6, more preferably 1:2 to 1:6, more preferably 1 : 3 : 5 , most preferably 1: 3 - 1 : 4.

Another object of the present invention is to provide a process for preparing the above solid dispersion of azilsartan, which comprises a solvent method, a melting method and a grinding method, preferably a solvent method.

The solvent method includes the following steps:

(1) Dissolving azilsartan and a carrier in a solvent, stirring uniformly until all the azilsartan and the carrier are dissolved; (2) removing the solvent, drying, and pulverizing to obtain a solid dispersion.

Among them, the solvent used in the step 1 is one or more selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, chloroform and methylene chloride, preferably methanol. The weight ratio of azilsartan and the carrier as an active ingredient to the organic solvent is 1 : 5-1: 50, preferably 1 : 10-1: 30.

The method for removing the organic solvent in the step 2 is selected from the group consisting of reduced pressure distillation, reduced pressure drying, vacuum drying, freeze drying, spray drying, fluidized bed drying, and heat drying, preferably under reduced pressure.

Another object of the present invention is to provide a pharmaceutical composition comprising the solid dispersion of azilsartan and a pharmaceutically acceptable, suitable pharmaceutical excipient. The pharmaceutical composition may be prepared as a tablet, a capsule, a pill, a granule, a pellet, preferably a tablet. The pharmaceutical excipients include, but are not limited to:

(1) The following substances as diluents: lactose, mannitol, sorbitol, microcrystalline cellulose, starch, modified starch, dextrin, cyclodextrin and its derivatives, calcium phosphate, sucrose, pregelatinized starch, Xylitol, fructose, maltitol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate;

(2) The following substances as disintegrants: sodium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, pregelatinized starch, corn starch, and Bipolyvinylpyrrolidone, croscarmellose sodium, microcrystalline cellulose, carboxymethylcellulose calcium, etc.;

(3) The following substances as binder: polyvinylpyrrolidone, starch slurry, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum Wait.

In a preferred embodiment, the pharmaceutical composition of the present invention consists of the solid dispersion of the present invention and mannitol, microcrystalline cellulose, croscarmellose or crospovidone, magnesium stearate.

In a further preferred embodiment, the pharmaceutical composition of the invention consists of azilsartan, povidone, mannitol, microcrystalline cellulose, croscarmellose or crospovidone, magnesium stearate Composition; wherein azilsartan and povidone are made into a solid dispersion of azilsartan. Preferably, the weight ratio of each component is:

(a) azilsartan 5% to 20%, preferably 5 to 15%;

(b) povidone 15% to 60%, preferably 15% to 50%;

(c) mannitol 10% to 30%, preferably 15% to 25%;

(d) microcrystalline cellulose 10% to 30%, preferably 15% to 25%;

(e) croscarmellose or crospovidone 1% to 10%; (f) Magnesium stearate 5% to 15%.

In a preferred embodiment, the pharmaceutical composition further contains a stabilizer selected from the group consisting of maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, and tartaric acid. With sodium hydroxide, monosodium maleate, monosodium fumarate, sodium tartrate, monosodium citrate, propyl gallate, ethylenediaminetetraacetic acid, disodium edetate, butylated hydroxyanisole One or more of sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite and/or ascorbic acid, preferably sodium carbonate, sodium hydrogencarbonate, maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, and citric acid Sodium hydroxide, monosodium maleate, monosodium fumarate and/or monosodium citrate.

Another object of the present invention is to provide a use of the solid dispersion of azilsartan and a pharmaceutical composition containing the solid dispersion for the preparation of an antihypertensive drug.

DRAWINGS

The above and other objects and features of the present invention will become apparent from the accompanying drawings, which

Figure 1 is an X-ray diffraction pattern of azilsartan bulk drug

Figure 2 is an X-ray diffraction diagram of a solid dispersion of azilsartan (Example 1)

Figure 3 is a PVP carrier X-ray diffraction pattern

Figure 4 shows the absorption peak of azilsartan bulk drug

Figure 5 shows the absorption peak of the solid dispersion of azilsartan (Example 1)

Figure 6 shows the absorption peak of the PVP carrier.

Figure 7 shows the effect of different carrier species on the dissolution rate of azartan solid dispersion.

Figure 8 shows the effect of different carrier ratios on the dissolution rate of azartan solid dispersion.

Figure 9 is a comparison of dissolution rates of Example 19 and Comparative Example 1 of the present invention.

Figure 10 Example 19 Changes in dissolution behavior within 1 month at 25 ° C / 60% RH

detailed description

The invention is further illustrated by the following examples, which are merely illustrative and are not intended to limit the scope of the invention in any way. Among them, Examples 1-14 are preparations of solid dispersions; Examples 15-20 are preparations of solid dispersion pharmaceutical compositions.

Example 1

Weigh 5 g of azilsartan and 2.5 g of povidone PVP-K30, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, then pulverize. A 60 mesh sieve gave a solid dispersion of azilsartan.

Example 2

Weigh 5 g of azilsartan and 5 g of povidone PVP-K30, add 400 mL of methanol to stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, pulverize, pass 60 Mesh screening A solid dispersion of valsartan.

Example 3

Weigh 5 g of azilsartan and 10 g of povidone PVP-K30, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, then pulverize. A 60 mesh sieve gave a solid dispersion of azilsartan.

Example 4

Weigh 5 g of azilsartan and 15 g of povidone PVP-K30, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, then pulverize. A 60 mesh sieve gave a solid dispersion of azilsartan.

Example 5

Weigh 5 g of azilsartan and 20 g of povidone PVP-K30, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, then pulverize. A 60 mesh sieve gave a solid dispersion of azilsartan.

Example 6

Weigh 5 g of azilsartan and 25 g of povidone PVP-K30, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, then pulverize. A 60 mesh sieve gave a solid dispersion of azilsartan.

Example 7

Weigh 5 g of azilsartan and 30 g of povidone PVP-K30, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, then pulverize. A 60 mesh sieve gave a solid dispersion of azilsartan.

Example 8

Weigh 5 g of azilsartan and 25 g of PVP-K25, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, crush, pass 60 mesh sieve , that is, a solid dispersion of azilsartan is obtained.

Example 9

Weigh 5 g of azilsartan and 25 g of PVP-K90, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, crush, pass 60 mesh sieve , that is, a solid dispersion of azilsartan is obtained.

Example 10

Weigh 5 g of azilsartan and 25 g of HPC-EF, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, crush, pass 60 mesh sieve , that is, a solid dispersion of azilsartan is obtained.

Example 11

Weigh 5 g of azilsartan and 25 g of poloxamer 188, add 400 mL of methanol to stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, pulverize, pass 60 mesh Sieve, that is, get Valsartan solid dispersion

Example 12

Weigh 5 g of azilsartan and 25 g of polyethylene glycol PEG4000, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, crush, pass 60 mesh By sieving, a solid dispersion of azilsartan is obtained.

Example 13

Weigh 5 g of azilsartan and 25 g of polyethylene glycol PEG6000, add 400 mL of methanol, stir until dissolved, transfer it to a vacuum drying oven, keep at 40 ° C, dry under reduced pressure for 24 h, crush, pass 60 mesh By sieving, a solid dispersion of azilsartan is obtained.

Example 14

5 g of azilsartan and 20 g of povidone PVP-K30 were weighed and stirred by adding 400 mL of methanol until dissolved. This solution was spray dried. The inlet and outlet temperatures of spray drying are maintained at 90 ° C and 50, respectively.

At °C, samples were collected to obtain a solid dispersion of azilsartan.

Example 15

Azilsartan-Povidone PVP-K30 Solid Dispersion (1:3.5) 2.88 g Mannitol 200SD 0.91 g Microcrystalline Cellulose PH102 0.91 g Croscarmellose Sodium 0.25 g Magnesium Stearate 0.05 g Preparation Method: The prescribed amount of the solid dispersion and the auxiliary material other than magnesium stearate are mixed uniformly, passed through a 30 mesh sieve, and mixed again, and then a prescribed amount of magnesium stearate is added. After mixing evenly, 8.5

250 mg, pressure 7 to 9 kg, and the mixture was tableted.

Example 16

Azisartan-hydroxypropylcellulose HPC-EF solid dispersion (1:3) 2.56 g Mannitol 200SD 1.07 g Microcrystalline cellulose PH102 1.07 g Crosslinked PVP 0.25 g Magnesium stearate 0.05 g Preparation method: The prescribed amount of the solid dispersion is mixed with the excipients other than magnesium stearate. After mixing uniformly, pass through a 30 mesh sieve, mix again and add the prescribed amount of magnesium stearate. After mixing, use a 8.5 mm die to weigh 250 mg. 7 to 9 kg, the mixture was tableted.

Example 17

Azilsartan-povidone PVP-K30 solid dispersion (1: 4) 8.0 g

Mannitol 200SD 1.875 g

Microcrystalline cellulose PH102 1.875 g Crosslinked PVP 0.625 g

Magnesium stearate 0.125 g

Preparation method: a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing well, pass through the mesh and mix again and add the prescribed amount of magnesium stearate (using a 60 mesh sieve). After mixing, the mixture was compressed using an 8.5 L die at a weight of 250 mg and a pressure of 7 to 9 kg.

Example 18

Azilsartan-povidone PVP-K30 solid dispersion (1: 4) 8.0 g

Mannitol 200SD 1.875 g

Microcrystalline cellulose PH102 1.875 g

Crosslinked PVP 0.625 g

Magnesium stearate 0.125 g

Preparation method: a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing well, pass through a 30 mesh sieve, mix again and add the prescribed amount of magnesium stearate. After mixing evenly, use 10.5 mm die to weight

500 mg, pressure 7 to 9 kg, and the mixture was tableted.

Example 19

Azilsartan-Povidone PVP-K30 Solid Dispersion (1 : 4) 3.2 g

Mannitol 200SD 1.69 g

Microcrystalline cellulose PH102 1.69 g

Crosslinked PVP 0.35 g

Magnesium stearate 0.07 g

Preparation method: a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, pass through a 30 mesh sieve, mix again, add the prescribed amount of magnesium stearate, mix well and use 9.5 mm die to weight

350 mg, pressure 7 to 9 kg, the mixture was compressed.

Example 20

Azilsartan-Povidone PVP-K30 Solid Dispersion (1 : 3 ) 2.56 g

Mannitol 200SD 2.01 g

Microcrystalline cellulose PH102 2.01 g

Crosslinked PVP 0.35 g

Magnesium stearate 0.07 g

Preparation method: a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, a 30-mesh sieve was added, and after mixing, a prescribed amount of magnesium stearate was added, and after mixing, a 9.5 mm die was used, and the mixture was tableted at a weight of 350 mg and a pressure of 7 to 9 kg. Example 21

Azilsartan-Povidone PVP-K30 Solid Dispersion (1 : 5 ) 3.84 g Mannitol 200SD 1.37 g

Microcrystalline cellulose PH102 1.37 g

Crosslinked PVP 0.35 g

Magnesium stearate 0.07 g

Preparation method: a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, pass through a 30 mesh sieve, mix again, add the prescribed amount of magnesium stearate, mix well and use a 9.5 mm die to weigh the mixture with a weight of 350 mg and a pressure of 7 to 9 kg. Example 22

Azilsartan-povidone PVP-K30 solid dispersion (1: 4) 8.0 g

Mannitol 2.500 g

Hydroxypropyl cellulose HPC-SSL 1 000 g

Microcrystalline cellulose PH101 0.250 g

Crosslinked PVP 0.625 g

Magnesium stearate 0.125 g

Preparation Method 1 : According to the above formula, the first four solid powders were mixed through a 30 mesh sieve. Granulation was carried out using a 5% aqueous solution of hydroxypropylcellulose as a binder. After the wet granules passed through a 20 mesh sieve, they were placed in an oven at 40 ° C for drying. After drying, the granules were taken out and passed through a 20 mesh sieve. Then add the prescribed amount of cross-linked PVP and magnesium stearate and mix well. The mixture was compressed using a 8.5 mm die at a weight of 250 mg and a pressure of 7 to 9 kg.

Preparation Method 2: Azilsartan-Povidone PVP-K30 solid dispersion, mannitol, and microcrystalline cellulose in the above formulation were uniformly mixed and passed through a 30 mesh sieve to carry out dry granulation. The formulation was cross-linked with PVP and magnesium stearate. After mixing evenly, the mixture was compressed using a 8.5 mm die at a weight of 250 mg and a pressure of 7 to 9 kg. Comparative example 1

Preparation according to Example 1 of CN101528262A Experimental Example 1 : Powder X-ray Diffraction (XRPD) Analysis of Azilsartan Solid Dispersion

Figure 1 is an X-ray diffraction pattern of azilsartan bulk drug

Figure 3 is a PVP carrier X-ray diffraction pattern

It can be seen that the ratio of azilsartan to PVPK30 is only 1:0.5, and the solid dispersion of azilsartan is formed. The crystal diffraction peak of azilsartan disappears, and the solid dispersion exists in an amorphous or molecular state. Experimental Example 2: Differential Scanning Scanning (DSC) Analysis of Azilsartan Solid Dispersion

Figure 4. Absorption peak of azilsartan drug substance Figure 5. Absorption peak of azartan solid dispersion (Example 1)

Figure 6. Absorption peak of PVP carrier

As seen from Figures 4 to 6, the drug has a distinct endothermic peak at 211.88 ° C, indicating that the drug substance is present in a crystalline state, and when the azisartan and the carrier form a solid dispersion, the crystallization peak of the drug disappears. It is indicated that the solid dispersion of azilsartan exists in an amorphous or molecular state. Experimental Example 3: Effect of different carrier species on dissolution of solid dispersion of azilsartan

Example 6, Example 8, Example 9, Example 10, Example 11, Example 12, Example

The solid dispersion and the drug substance described in 13 were placed in a capsule, and the dissolution behavior was evaluated. The dissolution conditions are as follows: Dissolution medium: pH 4.5 acetate buffer 900 mL

Dissolution method: According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.

The dissolution profile was determined by UV spectrophotometry as shown in Figure 7.

Figure 7 Effect of different carrier species on the dissolution rate of solid dispersion of azilsartan.

The results showed that PVP promoted the dissolution of azilsartan much better than other carrier materials. Experimental Example 4: Effect of ratio of azilsartan to carrier PVPK30 on dissolution of solid dispersion The solid dispersions described in Example 3, Example 4, Example 5, Example 6 and Example 7 were filled into capsules. In the middle, the dissolution behavior was evaluated, and the dissolution conditions were the same as in Experimental Example 4.

The dissolution profile was determined by UV spectrophotometry as shown in Fig. 8.

The results showed that in the range of lower carrier drug ratios, as the proportion of PVPK30 in the solid dispersion of azilsartan increased, the dissolution of the solid dispersion of azilsartan also increased, but when PVPK30 and Aceh When the ratio of sartan is more than 4:1, the ratio of carrier drug continues to increase, and the increase of dissolution is not obvious. When the ratio is as large as 5:1, the proportion of the carrier continues to increase and the dissolution decreases. Experimental Example 5: Comparison of solubility of azilsartan bulk drug and azilsartan solid dispersion in water Refer to Chinese Pharmacopoeia 2010 version for approximate solubility determination method: Add excess amount of azilsartan and azilsartan solid dispersion in quantitative water Body, vigorously shaken for 30 seconds every 5 minutes at 25 °C. After 30 minutes, it was filtered through a 0.45 μηι microporous membrane, and the concentration of azilsartan in the filtrate was determined by HPLC. The experimental results are shown in Table 1.

Table 1 Comparison of solubility of azilsartan bulk drug and azilsartan solid dispersion in water

The results showed that the formation of a solid dispersion of azilsartan significantly improved the water solubility of azilsartan. Experimental Example 6:

The dissolution ratios of Example 19 of the present invention and Comparative Example 1 were respectively compared. The dissolution conditions were the same as in Experimental Example 4.

The dissolution profile was determined by ultraviolet spectrophotometry as shown in Fig. 9. Fig. 9. Comparison of dissolution rates of Example 19 of the present invention and Comparative Example 1.

The experimental results show that the solid dispersion of azilsartan significantly increased the dissolution of azilsartan in pH 4.5 acetate buffered saline compared to Comparative Example 1. It shows the excellent performance of the present invention in the dissolution of the preparation, which is of great significance for the improvement of the bioavailability of azilsartan. Experimental Example 7: Changes in related substances after a month of acceleration of azilsartan solid dispersion tablets at 30 ° C / 60% RH

The change of the related substances in the storage of the 19th, 30th, and 60% RH conditions of Example 19, Example 20, and Example 21 of the present invention was examined to evaluate the chemical stability of the solid dispersion of azilsartan. . The experimental results are shown in Table 2. Table 2 Example 19, Example 20, Example 21 and comparison of the related substances in the drug substance at 30 ° C / 60% RH for 1 month

It can be seen from the experimental results of Table 2 that after storage of Example 19, Example 20 and Example 21 at 30 ° C / 60% RH for 1 month, the related substances hardly increased, and it was related at each time point. The results of the substance determination are similar to those of the drug substance. This fully demonstrates that the stability of the drug substance is successfully maintained during the production process of the solid dispersion of azilsartan, and the solid dispersion of azilsartan solids maintains good chemical stability during storage under accelerated conditions. Sex. Experimental Example 8: Changes in dissolution behavior of azilsartan solid dispersion tablets after one month accelerated at 30 ° C / 60% RH

The change of dissolution behavior in Example 19 of the present invention under storage at 30 ° C / 60% RH for one month was examined. The experimental results are shown in Figure 10. From the experimental results of Fig. 10, it was found that the dissolution behavior of Example 19 was almost unchanged after storage for one month at 30 ° C / 60% RH. It is indicated that the azilsartan solid dispersion tablets have no dissolution reduction during storage under accelerated conditions, which shows the good stability of the azilstan solid dispersion tablets.

Claims

Claim

1. A solid dispersion of azilsartan comprising azilsartan and a carrier material selected from the group consisting of povidone, poloxamer, polyethylene glycol, hydroxypropyl cellulose, polyoxygenation One or more of ethylene.

2. The solid dispersion according to claim 1, wherein the carrier material is selected from the group consisting of povidone K-17, povidone-25, povidone-30, povidone-90 One of Polosham 188, Poloxamer 407, Polyethylene Glycol 4000, Polyethylene Glycol 6000, Klucel® LF, Klucel® JF, Klucel® EF, Klucel® EXF, Polyethylene Oxide N80 or Preferably, the carrier material is selected from one or more of povidone K-17, povidone Κ-25, povidone oxime 30, povidone oxime-90, more preferably povidone oxime-30 .

The solid dispersion according to claim 1 or 2, wherein the mass ratio of the azilsartan to the carrier material is 1:0.5-1:10, preferably 1:1:1:6 More preferably, it is 1: 2 - 1: 6 , more preferably 1: 3- 1: 5, and most preferably 1: 3- 1: 4.

A method for producing a solid dispersion of azilsartan according to any one of claims 1 to 3, which is selected from the group consisting of a solvent method, a melting method, a grinding method, and preferably a solvent method.

5. A method of preparing a solid dispersion of azilsartan according to claim 4, wherein the method comprises the steps of:

(1) Dissolving azilsartan and a carrier in a solvent, and stirring until the azilsartan and the carrier are all dissolved;

(2) The solvent is removed, dried, and pulverized to obtain a solid dispersion.

The method for preparing a solid dispersion of azilsartan according to claim 5, wherein the solvent is one or more selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, chloroform and dichloromethane, preferably Methanol.

The method for preparing a solid dispersion of azilsartan according to claim 5 or 6, wherein the weight ratio of azilsartan to the carrier and the solvent is 1: 5-1: 50, preferably It is 1: 10-1: 30.

The method for preparing a solid dispersion of azilsartan according to any one of claims 5 to 7, wherein the method for removing the solvent is selected from the group consisting of reduced-pressure distillation, reduced-pressure drying, vacuum drying, and freeze-drying. One or more of spray drying, fluidized bed drying, and heat drying, preferably drying under reduced pressure.

A pharmaceutical composition comprising the solid dispersion of azilsartan according to any one of claims 1 to 3 and a pharmaceutically acceptable pharmaceutical excipient.

The pharmaceutical composition according to claim 9, wherein the composition is in the form of a tablet or a capsule. It is in the form of a dose, a pill, a granule or a pellet, preferably a tablet.

The pharmaceutical composition according to claim 9 or 10, which further comprises one or more of a pharmaceutically acceptable diluent, a disintegrating agent, and a binder, the diluent being selected from the group consisting of lactose , mannitol, sorbitol, microcrystalline cellulose, starch, modified starch, dextrin, cyclodextrin and its derivatives, calcium phosphate, sucrose, pregelatinized starch, xylitol, fructose, maltitol, dextran, One or more of glucose, calcium sulfate, and calcium hydrogen phosphate; the disintegrant is selected from the group consisting of sodium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, and a low-substituted hydroxypropyl group. One or more of cellulose, pregelatinized starch, corn starch, crosslinked polyvinylpyrrolidone, croscarmellose sodium, microcrystalline cellulose, carboxymethylcellulose calcium; One or more of polyvinylpyrrolidone, starch syrup, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum.

The pharmaceutical composition according to any one of claims 9 to 11, which comprises azilsartan, povidone, mannitol, microcrystalline cellulose, croscarmellose or crospovidone And magnesium stearate composition.

13. The pharmaceutical composition according to claim 12, wherein the weight ratio of each component is:

(a) azilsartan 5% to 20%, preferably 5 to 15%;

(b) povidone 15% to 60%, preferably 15% to 50%;

(c) mannitol 10% to 30%, preferably 15% to 25%;

(d) microcrystalline cellulose 10% to 30%, preferably 15% to 25%;

(e) croscarmellose or crospovidone 1% to 10%;

(f) Magnesium stearate 5%~15%.

The pharmaceutical composition according to any one of claims 9 to 13, which further comprises a stabilizer selected from the group consisting of maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, and hydrazine. Acid and sodium hydroxide, tartaric acid and sodium hydroxide, monosodium maleate, monosodium fumarate, sodium tartrate, monosodium citrate, propyl gallate, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid One or more of sodium, butyl hydroxyanisole, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite and/or ascorbic acid, preferably sodium carbonate, sodium hydrogencarbonate, maleic acid and sodium hydroxide, fumaric acid and hydrogen Sodium oxide, citric acid and sodium hydroxide, monosodium maleate, monosodium fumarate and/or monosodium citrate.

Use of the solid dispersion according to any one of claims 1 to 3 or the pharmaceutical composition according to any one of claims 9 to 14 for the preparation of an antihypertensive drug.